MR properties of excised neural tissue following experimentally induced demyelination

Changes in the magnetic resonance (MR) parameters of demyelinated neural tissue were measured in vitro using an experimental animal model. A tellurium (Te) diet was applied to weanling rats to induce the demyelination process in the sciatic nerve. The quantitative MR parameters, such as T(1), T(2) relaxation time constants and magnetization transfer (MT) were measured each day after applying the Te diet (up to 7 days) and were found to be substantially different from those of normal nerves. An increase in the average T(1) and T(2) was observed along with a decrease in the MT ratio (MTR) and the quantitative MT parameter M(0B), which describes the semisolid pool of protons. Most of the MR parameters correlated very well with the myelin fraction of neural tissue evaluated by quantitative histopathology. The T(2) relaxation spectrum provided the most efficient quantitative assessment of changes in neural tissue microstructure and its analysis resulted in a powerful tool to distinguish the processes of demyelination and inflammation. In comparison, the MT measurements were less successful.     

Methylenetetrahydrofolate reductase C677T and methionine synthase A2756G gene polymorphisms and associated risk of cardiovascular diseases: A study from Jammu region

AimPotent risk factors at both genetic and non-genetic levels are accountable for susceptibility and instigation of different cardiovascular phenotypes. Recently, homocysteine is being identified as an important predictor for cardiovascular diseases. Homocysteine remethylation plays a key role in the synthesis of methionine and S-adenosine methionine. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) genes are known to regulate the homocysteine remethylation reaction and higher homocysteine level is significantly associated with diverse cardiovascular phenotypes. In this context, we aimed to carry out a study on the association of MTHFR (C677T) and MTR (A2756G) gene polymorphism with CVD in population of Jammu region of J&K state.Materials and methodsA total of 435 individuals were enrolled (195 CVD patients and 240 controls) for the case–control study. Genotyping of MTHFR C677T and MTR A2756G gene polymorphism was done by PCR-RFLP technique. Biochemical parameters were estimated by biochemical analyser.ResultsMetabolic variables such as serum LDL-C, TC and TG were significantly higher in patients (p < 0.0001), whereas serum HDL-C was higher in controls. Majority of the patients were having history of hypertension (57.44%; p < 0.0001) as a concomitant condition. The evaluation of genetic association showed that, MTHFR C6877T (OR: 8.89, 95% CI: 2.01–39.40) and MTR A2756G (OR: 1.48, 95% CI: 1.09–2.00) polymorphisms associated with higher risk of CVD.ConclusionThe present study reveals significant differences in nongenetic variables among patients and control as well as association of gene polymorphisms with CVD risk.     

Comparison of MRI signatures in pattern I and II multiple sclerosis models

The majority of individuals with multiple sclerosis (MS) exhibit T‐cell‐ and macrophage‐dominated lesions (patterns I and II; as opposed to III and IV). These lesions, in turn, may be distinguished on the basis of whether or not there are immunoglobulin and complement depositions at the sites of active myelin destruction; such depositions are found exclusively in pattern II lesions. The main aim of this study was to determine whether pattern I and pattern II MS lesions exhibit distinct MRI signatures. We have used a recently described focal MOG‐induced EAE model of the rat brain, which recapitulates many of the hallmarks of pattern II MS; we compared this with our previous work in a delayed type hypersensitivity model of a pattern I type lesion in the rat brain. Demyelinating lesions with extensive inflammation were generated, in which the T2‐weighted signal was increased. Magnetisation transfer ratio (MTR) maps revealed loss and subsequent incomplete recovery of the structure of the corpus callosum, together with changes in tissue water diffusion and an associated increase in ventricle size. Notably, the MTR changes preceeded histological demyelination and may report on the processes leading to demyelination, rather than demyelination per se. Immunohistochemically, these MRI‐detectable signal changes correlated with both inflammatory cell infiltration and later loss of myelin. Breakdown of the blood–brain barrier and an increase in the regional cerebral blood volume were also evident in and around the lesion site at the early stage of the disease. Interestingly, however, the MRI signal changes in this pattern II type MS lesion were remarkably consistent with those previously observed in a pattern I lesion. These findings suggest that the observed signal changes reflect the convergent histopathology of the two models rather than the underlying mechanisms of the disease. Copyright © 2009 John Wiley & Sons, Ltd.     

Genotypes of the C677T and A1298C polymorphisms of the MTHFR gene as a cause of human spontaneous embryo loss

BACKGROUND Polymorphisms C677T and A1298C of the MTHFR gene have been implicated in fetal viability. In this study, we determined the allele and genotype frequencies of these polymorphisms in different populations, including spontaneous abortion (SA) fetal tissues, with the objective of evaluating their impact on fetal viability. METHODS 342 samples of fetal tissues, selected from SA occurring during the 1980s, 230 samples from subjects born in the 1980s and a third set of samples from 204 subjects born in the 1950s, were genotyped by using TaqMan probes. RESULTS The wild CC genotype of the C677T polymorphism showed a strong protective effect against abortion (0.03 in SA versus 0.47 in 1950s and 0.43 in 1980s) (P < 0.0001). Genotypes of three mutations in the combinations of polymorphisms for C677T and A1298C showed a very low frequency in the living population; however, the three mutations genotypes were over expressed in the SA group (0.02 in 1950s; 0.03 in 1980s and 0.17 in SA) (P < 0.0001). Samples with four mutations (n = 2) were found only in the SA group. CONCLUSIONS There is no linkage disequilibrium between C667T and A1298C polymorphisms. Fetal viability is directly related to the CC genotype as a protector while the three and four mutation MTHFR genotypes appear to be a determinant on fetal non-viability and SA.     

Influence of combined methionine synthase (MTR 2756A > G) and methylenetetrahydrofolate reductase (MTHFR 677C > T) polymorphisms to plasma homocysteine levels in Korean patients with ischemic stroke

PURPOSE: Methionine synthase (MTR) and 5,10-methylenetetrahydrofolate reductase (MTHFR) are the main regulatory enzymes for homocysteine metabolism. The present case- control study was conducted to determine whether there is an association between the MTR 2756A > G or MTHFR 677C > T polymorphism and plasma homocysteine concentration in Korean subjects with ischemic stroke. MATERIALS AND METHODS: DNA samples of 237 patients who had an ischemic stroke and 223 age and sex-matched controls were studied. MTR 2756A > G and MTHFR 677C > T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Frequencies of mutant alleles for MTR and MTHFR polymorphisms were not significantly different between the controls and cases. The patient group, however, had significantly higher homocysteine concentrations of the MTR 2756AA and MTHFR 677TT genotypes than the control group (p=0.04 for MTR, p=0.01 for MTHFR). The combined MTR 2756AA and MTHFR 677TT genotype (p= 0.04) and the homocysteine concentrations of the patient group were also higher than those of the controls. In addition, the genotype distribution was significant in the MTHFR 677TT genotype (p=0.008) and combined MTR 2756AA and MTHFR 677TT genotype (p=0.03), which divided the groups into the top 20% and bottom 20% based on their homocysteine levels. CONCLUSION: The results of the present study demonstrate that the MTR 2756A > G and MTHFR 677C > T polymorphisms interact with elevated total homocysteine (tHcy) levels, leading to an increased risk of ischemic stroke.     

Monitoring of the effect of intervertebral disc nucleus pulposus ablation by MRI

In order to investigate intervertebral disc (IVD) degeneration and repair, a quantitative non‐invasive tool is needed. Various MRI methods including qCPMG, which yields dipolar echo relaxation time (T_DE), magnetization transfer contrast (MTC), and ¹H and ²H double quantum filtered (DQF) MRI were used in the present work to monitor changes in rat IVD after ablation of the nucleus pulposus (NP), serving as a model of severe IVD degeneration. In the intact IVD, a clear distinction between the annulus fibrosus (AF) and the NP is obtained on T₂ and T_DE weighted images as well as on MTC maps, reflecting the high concentration of ordered collagen fibers in the AF. After ablation of the NP, the distinction between the compartments is lost. T₂ and T_DE relaxation times are short throughout the disc and MTC is high. ¹H and ²H DQF signal, which in intact discs is obtained only for the AF, is now observable throughout the tissue. These results indicate that after ablation, there is an ingression of collagen fibers from the AF into the area that was previously occupied by the NP, as was confirmed by histology. Copyright © 2010 John Wiley & Sons, Ltd.     

李氏5号方对半乳糖老化小鼠海马神经元褪黑素受体和Nogo受体表达的影响

为了观察李氏5号方对半乳糖老化小鼠海马神经元褪黑素受体(MTR)和Nogo受体(NogoR)表达的影响。我们将昆明小鼠随机分为五组:正常对照组(C组)、D半乳糖模型组(D组)、李氏5号方大剂量药物治疗组(L组)、中剂量药物治疗组(M组)和小剂量药物治疗组(S组);D、L、M、S四组每日皮下注射半乳糖65mg/kg体重,持续三个月。应用免疫组织化学染色方法检测小鼠海马神经元MTR和NogoR的表达水平。NogoR免疫组化染色结果:D组海马阳性反应细胞着色浅,少有突起,细胞数目少,仅为正常小鼠的20%,三个剂量李氏5号方治疗组染色结果与C组相似。结果提示:半乳糖老化小鼠海马神经元MTR免疫反应阳性神经元数的上调可能是老化小鼠的一种代偿性反应;NogoR表达下调提示老化小鼠可能存在脑白质的损害,出于机体自我保护的需要,NogoR表达下调以避免神经元修复机制对大脑的进一步损害;不同剂量的李氏5号方水提取液对两种受体的调节作用极为明显,说明这两种受体的表达可受到外源性药物的干预。     

Long T2 water in multiple sclerosis: What else can we learn from multi-echo T2 relaxation?

Multi-echo T₂ measurements are invaluable in studying brain pathology in multiple sclerosis (MS). In addition to information about myelin water and total water content, the T₂ distribution has the potential to detect additional water reservoirs arising from other sources such as inflammation or edema. The purpose of this study was to better define the T₂ distribution in MS lesions and normal appearing white matter (NAWM) with particular emphasis on the characterisation of longer T₂ components.Magnetisation transfer (MT), T₁ and 48-echo T₂ relaxation data were acquired in 20 MS subjects and regions of interest were drawn in lesions and NAWM. Twenty-seven out of 107 lesions exhibited signal with a markedly prolonged T₂ (200–800 ms). Lesions with a Long-T₂ signal also exhibited a longer geometric mean T₂ (GMT₂), increased water content (WC), higher T₁, reduced magnetisation transfer ratio (MTR) and decreased myelin water fraction (MWF) than lesions without a Long-T₂ signal. Those subjects with Long-T₂ lesions had a significantly longer disease duration than subjects without this lesion subtype. A strong correlation was observed between T₁ and Long-T₂ fraction, while a slightly weaker relationship was found for GMT₂, MTR and MWF with Long-T₂ fraction. A potential source of the Long-T₂ signal is an increase in extracellular water. This study supports the usefulness of increasing the data acquisition window of the multi-echo T₂ relaxation sequence to better characterise the T₂ decay in MS.     

MTHFR和MTR的基因多态性对马来酸依那普利叶酸片药动学影响的研究

目的:考察亚甲基四氢叶酸还原酶(MTHFR)和蛋氨酸合成酶(MTR)的基因多态性对中国健康成年人口服马来酸依那普利叶酸片后依那普利药动学的影响。方法:36名健康志愿者单剂量口服10mg/0.8mg马来酸依那普利叶酸片后,于不同时间点取血,采用液-质联用法测定血药浓度,并进行血样基因型分析及同型半胱氨酸水平测定。结果:MTHFR存在CC、CT和TT3种基因型,其多态性对依那普利的主要药动学参数未见显著影响;而MTR存在AA、AG2种类型,与AA型相比,AG型对依那普利吸收很好,但排泄较慢。结论:MTHFR基因多态性不影响所研究人群的依那普利药动学,而MTR的AA和AG基因型引起依那普利药动学的差异。