Elevated plasma total homocysteine and C677T mutation of the methylenetetrahydrofolate reductase gene in patients with spina bifida

Total plasma homocysteine (tHcy) was significantly higher in 28 children with spina bifida (median 6.05 mumol/l) as compared with 76 controls (median 4.94 mumol/l). This difference was confined to a subgroup of patients (16/28) with one or two C677T-mutated alleles in the methylenetetrahydrofolate reductase gene. Since we found no significant difference between patients and controls in serum folate, erythrocyte folate, serum cobalamin or serum methylmalonic acid, which were within the normal range for both patients and controls, the elevated tHcy could not be attributed to vitamin deficiencies. Our findings point to an additional genetic defect involving folate- dependent enzymes in a subgroup of patients with neural-tube defects.      

A new T677C mutation of the aspartoacylase gene encodes for a protein with no enzymatic activity

ObjectiveTo verify the effect of and to date the unknown T677C mutation of the human N-acetylaspartoacylase (hASPA) gene on the function of the mutated enzyme.Design and methodsWild type and I226T-mutated proteins were expressed and purified from a transformed Escherichia coli colony. Enzymatic activities were measured in the presence of varying substrate concentrations.ResultsWhilst kinetic parameters of wild type hASPA were in line with data in literature, I226T-mutated hASPA showed no enzymatic activity.ConclusionData indicated that this new mutation might be responsible in homozygosis for the phenotype corresponding to Canavan disease.     

Methylenetetrahydrofolate reductase gene C677T mutation is related to the defects in the internal elastic lamina of the artery wall

BACKGROUND: The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene leads to C/C, C/T and T/T genotypes, which affect the plasma homocysteine concentration in humans. In mini-pigs, high serum homocysteine levels are associated with defects in the internal elastic lamina (IEL) of the artery wall, which are apparently related to the migration of smooth muscle cells into the intima during atherogenesis. We studied the association between the MTHFR genotypes and the number of gaps in the IEL in the wall of the five major abdominal arteries. MATERIALS AND METHODS: The autopsy study included 123 subjects (90 males and 33 females) aged 18-93. For the light microscopy, a 0.5 cm circular segment of the coeliac, the superior mesenteric, the inferior mesenteric and the renal arteries were cut and embedded in paraffin blocks. The circumference of the IEL, the thickness of the intima and the number of the gaps per millimetre in the IEL were measured by MOP 3 image analysis. RESULTS: The T-allele carriers (C/T and T/T) of the MTHFR gene had significantly less gaps in the IEL than the subjects with the C/C genotype in the superior mesenteric and in the left renal arteries (2.02 +/- 2.25 vs. 2.53 +/- 1.89, P < 0.04 and 0.56 +/- 1.09 vs. 1.82 +/- 2.66, P < 0.02, respectively). The trend was similar for the coeliac and the right renal arteries. CONCLUSIONS: Our result suggests that MTHFR polymorphism may be involved in the fragmentation of the IEL.     

The risk of venous thromboembolism associated with peripherally inserted central catheters in ambulant cancer patients

Background

Deep vein thrombosis (DVT) is a common complication of peripherally inserted central catheters (PICCs). PICCs are increasingly utilised in the management of cancer patients, a group which carries both additional risks for vascular thromboembolism as well as for complex morbidity. We analysed a cohort of cancer patients subjected to PICC insertion in a single cancer centre for the incidence of all-type vascular thromboembolism (VTE) and investigated relative risk factors.

Methods

In this clinical audit, the records of patients referred for PICC insertion in our centre in the period between 1/1/2011 and 1/4/2014 were retrospectively reviewed. The primary outcomes investigated were a) PICC-related deep vein thrombosis (PRDVT) and b) distant VTE (lower limb DVT and pulmonary embolism). 4Fr single lumen PICCs were placed in all patients. The Kaplan Meier method was used to study time from PICC insertion to PRDVT/VTE. Survival curves were compared using the log rank method. Logistic and Cox regression analyses were used to assess local, distant and combined endpoints.

Results

Four hundred ninety patients were included in the analysis of which 27 (5.5%) developed a PRDVT. Statistically significant risk factors for developing PRDVT in multivariate analysis included more than one attempt for insertion (OR 2.61, 95%CI: 1.12–6.05) and the use of fluoropyrimidine containing chemotherapy (OR 4.27, 95%CI 1.3–14.07). Twenty-six patients developed a distant VTE. Male gender was the only significant risk factor for distant VTE. When all-type VTE were considered together fluoropyrimidine containing chemotherapy (OR 4.54, 95% CI 1.63–12.61), male gender (OR 2.03, 95% CI 1.04–3.93) and white cell count (OR 1.12, 95% CI 1.00–1.26) were statistically significant as risk factors in this analysis.

Conclusions

This is a large study of VTE following PICC insertion in cancer patients which also looks at the rate of distant VTE. The observed PRDVT incidence is comparable with available literature. Fluoropyrimidine containing chemotherapy and more than one attempt for PICC insertion were independent predictors of PICC-associated VTE whilst the former remained an independent predictor of all-type VTE. Anticoagulation did not prevent thrombotic events in this cohort.

     

The risk of recurrent venous thromboembolism among patients with high factor IX levels

Summary.  High factor IX (FIX) is a risk factor of deep vein thrombosis. The impact of high FIX on the risk of recurrent venous thrombosis is unknown. We prospectively followed 546 patients after anticoagulation for a first spontaneous venous thromboembolism. Patients with a natural coagulation inhibitor deficiency, lupus anticoagulant or cancer were excluded. At 3 years, the likelihood of recurrence was 23% among patients with high FIX (exceeding the 75th percentile) compared with 11% among patients with lower levels. Among patients with high FIX, the relative risk of recurrence was 2.2 (95% CI: 1.3–3.6) before and was 1.6 (95% CI: 1.0–2.8) after adjustment for age, gender, duration of anticoagulation, FV Leiden, FII G20210A, high FVIII and hyperhomocysteinemia. Compared with patients with low factor IX (< 138 IU dL⁻¹) and low FVIII (≤ 234 IU dL⁻¹), the relative risk of recurrence was 1.5 among patients with high FIX and low FVIII, 2.7 among patients with low FIX and high FVIII and 6.6 among patients with high FIX and high FVIII. High levels of FIX confer an increased risk of recurrent venous thromboembolism and enhance the risk of recurrence among patients with high FVIII.     

Prophylaxis of venous thromboembolism in patients with chronic obstructive pulmonary disease

At present, almost 25% of the world population suffer from venous thromboembolism (VTE). This condition is currently regarded as a continuum of thromboembolism of pulmonary artery (TEPA) and venous thromboses including superficial venous thromboses. These diseases are not infrequently concomitant and asymptomatic. Up to 75% of the cases of venous thrombosis in the lower extremities are associated with latent TEPA and 80% of the cases of pulmonory embolism with asymptomatic venous thrombosis. The mortality rate from TEPA is estimated to be one person per 1,000. The data of autopsies indicate that 50-80% of the TEPA cases are not diagnosed at all. As many as 300 subjects of 100,000 suffer trophic ulcers in the lower extremities as a result of previous venous thrombosis. Prophylaxis is supposed to be the principal means of VTE control. Chronic lung diseases are the leading risk factors of VTE. Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality throughout the world. It is expected to become the third major cause of death by 2020. Hospitalization of COPD patients in therapeutic clinics increases the risk of VTE by 7.98 times. Prophylaxis of VTE in COPD patients may reduce the frequency of exacerbation and hospitalization and increase life expectancy.     

静脉血栓患者炎性因子和凝血指标的关系

目的探讨重症监护病房高危静脉血栓患者炎性指标和纤维蛋白原、D-二聚体关系及防治措施。方法对128例重症监护病房高危静脉血栓患者(实验组)和65例正常对照者(对照组)分别进行高敏-C反应蛋白和纤维蛋白原、D-二聚体检测;应用肝素(5000U,每天3次,静脉注射)或低分子量肝素(100U/kg,皮下注射),华发林(2～3mg,口服),5d前后检测上述指标变化。结果实验组的高敏C-反应蛋白、纤维蛋白原、D-二聚体高于对照组,差异具有统计学意义(P<0.05～0.01);应用肝素、低分子量肝素或华发林后,上述指标显著性降低(P<0.05或<0.01)。结论重症监护病房高危静脉血栓患者存在明显的高凝状态,采用抗凝尤其是低分子肝素可改善血液流变学、降低血液黏度,高敏C反应蛋白、纤维蛋白原和D-二聚体可作为抗凝的有效指标。     

Association of the C677T polymorphism in the MTHFR gene with migraine: a meta-analysis

There are conflicting data concerning the association between migraine and C677T polymorphism of the MTHFR gene. The C677T polymorphism reduces enzymatic capability by 50% and causes hyperhomocysteinaemia. We performed a meta-analysis of all published studies investigating the association between the MTHFR gene and migraine. Pooled odds ratios (OR) were estimated using random (RE) and fixed effects (FE) models. Among the overall 2961 migraineurs there was no significant difference compared with controls. Only in migraine with aura was the TT genotype associated with a higher risk of disease compared with the CC genotype [FE OR 1.30, 95% confidence interval (CI) 1.06, 1.58; RE OR 1.66, 95% CI 1.06, 2.59]. In the same subgroup a significant difference was observed in the comparison between TT and CT + CC genotypes (FE OR 1.32, 95% CI 1.10, 1.59; RE OR 1.63, 95% CI 1.10, 2.43). This study provides evidence for an association of the MTHFR gene only in migraine with aura.     

The long-term risk of cancer in patients with a first episode of venous thromboembolism

Summary.  Background: In patients with venous thromboembolism (VTE), 15–20% will have prevalent cancer when VTE is diagnosed but little is known about such patients' long-term risk, time course and predictors of new cancer. Patients and methods: We studied an inception cohort of patients with a first VTE who were not diagnosed with cancer within 3 months after VTE and who had follow-up for up to 120 months. We determined the annual risk for a new cancer [number of events and 95% confidence interval (CI)] per 100 person-years in all patients and in those with unprovoked VTE and identified predictors for new cancer. Results: We studied 1852 patients with VTE who received anticoagulant therapy for 12 months (mean) and were followed for 4.2 years (mean). During follow-up, there were 105 (5.7%) patients diagnosed with new cancer during the period after the initial 3 months from diagnosis, for an annual risk of 1.32 (CI, 1.09–1.60) per 100 person-years. The risk for new cancer appeared uniform over time. The annual risk for new cancer was more than 2-fold higher in patients presenting with unprovoked compared with those with provoked VTE [1.76 (CI, 1.39–2.20) vs. 0.83 (CI, 0.58–1.16) per 100 person-years; P  < 0.001]. Clinical predictors for new cancer were increasing age [hazard ratio (HR), 1.23; CI, 1.05–1.44] and unprovoked VTE (HR, 1.86; CI, 1.21–2.87). Conclusion: In patients with a first VTE and without prevalent cancer, the risk for new cancer is about 1–2% per year, appears to be uniform over time, and is higher in patients with unprovoked VTE and those with advanced age.     

Evaluation of the risk of venous thromboembolism in the medical patients

The venous thromboembolic risk seems to be demonstrated in medical patients since the incidence of symptomatic and asymptomatic deep vein thrombosis (DVT) without any prophylactic methods is respectively about 50 per cent in stroke, 25 per cent in acute myocardial infarction (AMI) and 15 per cent in internal medicine. A synthesis of clinical trials performed in medical patients shows that prophylactic doses of heparins (unfractionated heparin or low molecular weight heparins) reduce the incidence of DVT by 40 to 60 per cent compared with the lack of any antithrombotic agents but without any significant effect on total mortality. Other antithrombotic agents such as antiplatelet agents seem to reduce the incidence of DVT by about 40 per cent associated with a significant decrease in total mortality of stroke or AMI. But the recommendations made on the basis of these results have to be extremely cautious since the number of medical patients included in clinical trials is quite limited compared with the surgical area. Moreover, each of these recommendations is not sufficiently proven. Thus more clinical trials have to be carried out with a placebo control group in internal medicine and an aspirin control group for stroke and AMI.     

先天性心脏病术后患儿中心静脉导管相关深静脉血栓风险预测模型的构建及验证

目的 构建先天性心脏病术后患儿中心静脉导管相关深静脉血栓(central venous catheter-associated deep venous thromboses,CADVT)风险预测模型,并验证该模型的预测效果。方法 便利选取2021年1月—11月在浙江省某三级甲等儿童专科医院心脏外科监护室住院的234例患儿作为建模组,根据是否发生CADVT,将其分为CADVT组(53例)和非CADVT组(181例)。采用Logistic回归分析建立风险预测模型,采用Hosmer-Lemeshow检验判断模型的拟合优度,采用受试者操作特征曲线(receiver operator characteristic curve,ROC)检测模型的预测效果,并绘制列线图。选取2021年12月—2022年2月同一所医院收治的60例先天性心脏病术后患儿作为验证组,采用Hosmer-Lemeshow检验和ROC曲线对模型进行外部验证。结果 先天性心脏病术后患儿CADVT发生率为22.65%。CVC留置时长(OR=1.172)、D-二聚体浓度(OR=1.169)、纤维蛋白原浓度(OR=3.888)、镇静天数...     

Methylenetetrahydrofolate reductase C677T gene polymorphism and the association with dyslipidemia in type 2 diabetic Palestinian patients

BackgroundDyslipidemia in diabetes is common and characterized by hypertriglyceridemia with decreased levels of high‐density lipoprotein. The objective of this study was to assess the prevalence of MTHFR C677T polymorphism in Palestinian T2DM patients and to investigate the association between this polymorphism and lipid profile in diabetic patients with and without dyslipidemia.MethodsA total of 208 T2DM patients including 98 with dyslipidemia and 110 without dyslipidemia were enrolled in this study. The MTHFR C677T genotyping was conducted by PCR‐RFLP followed by agarose gel electrophoresis.ResultsThere were no significant differences in either the genotype distribution or allele frequency in T2DM patients with or without dyslipidemia (37.8% CC, 54% CT, 8.2% TT vs. 48.2% CC, 41.8% CT, 11% TT; p = 0.209). However, among the dyslipidemic group, the TT carriers have a higher HDL level (46.8 ± 17.8) compared to (CC+CT) carriers (34.68 + 11.9) (p = 0.01). In the group without dyslipidemia, there was a significant elevation in diastolic blood pressure (DBP) among the CC carriers (83.6 ± 10.6) compared to those who carried at least one mutant allele (CT+TT) (78.1 ± 11.1) (p = 0.009).ConclusionsThe study shows that in our Palestinian population the MTHFR 677TT genotype lowers DBP significantly in patients without dyslipidemia and is related to increased level of HDL in diabetic dyslipidemia patients.     

Genotyping of the MTHFR gene polymorphism, C677T in patients with leukemia by melting curve analysis.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) plays a critical role in folate metabolism and displays common genetic polymorphisms affecting the enzyme activity. The MTHFR genetic polymorphisms have been associated with a decrease in the risk of developing the lymphoid but not myeloid form of pediatric and adult leukemias. AIM: In this study we describe the genotyping of the MTHFR C677T polymorphism by melting curve analysis with the LightCycler in a case-controlled study of patients with acute lymphocytic leukemia (ALL), myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), and assess the effect of this common polymorphism on the leukemia risk in adult patients in Turkey. METHODS: DNA from peripheral blood lymphocytes was used for genotyping in the LightCycler PCR by melting curve analysis. The risk of leukemia associated with the MTHFR polymorphism was evaluated by comparing the genotype frequencies between the control and patient groups. RESULTS: The frequency of the homozygote variant genotype (677TT) was lower than that in healthy individuals in all three leukemia groups. The 677TT genotype did not appear to have a protective effect in patients with ALL (Odds ratio [OR] = 0.78 with a 95% confidence interval [CI] = 0.24-2.59), compared with healthy controls. The difference was higher (4.3-fold) in patients with AML, but still non-significant (OR = 0.23 with a 95% CI = 0.03-1.83). In patients with CML, the frequencies of both heterozygous (677CT) and homozygote variant genotypes were lower (OR = 0.72 and 0.66, respectively). CONCLUSIONS: Our results suggest that the MTHFR C677T polymorphism displays a similar distribution pattern in lymphoid and myeloid leukemias and that the frequency of the homozygote variant genotype (677TT) is lower in all leukemia types.     

慢性阻塞性肺疾病患者并发静脉血栓栓塞症危险因素的Meta分析

目的通过Meta分析明确住院COPD患者发生静脉血栓栓塞症(venous thromboembolism,VTE)的危险因素。方法计算机检索PubMed、Web of Science、Cochrane Library、Embase、MEDLINE、中国生物医学文献数据库、中国知网、维普数据库及万方数据库,收集关于COPD患者并发VTE危险因素的研究,检索时限为从建库至2018年5月。由2名评价人员按照标准独立进行文献筛选、资料提取和质量评价后,采用RevMan 5.3软件进行Meta分析。结果共纳入14篇文献,包括316 297例研究对象,共14项危险因素。Meta分析显示,高龄、吸烟史、卧床史、合并糖尿病及肿瘤是COPD患者并发VTE的重要危险因素。结论高龄患者、有吸烟史和卧床史、合并糖尿病或肿瘤的COPD患者发生VTE的可能性较大。目前关于COPD患者并发VTE危险因素的研究证据尚不充足,且各研究样本量差异较大。肥胖、深静脉置管、PaO2异常的预测价值,证据尚不充分,后期尚需进行更多高质量研究进行验证。