Analysis of the MTHFR 1298A-->C and 677C-->T polymorphisms as risk factors for neural tube defects

The thermolabile variant (677TT) of methylenetetrahydrofolate reductase (MTHFR) is a known risk factor for neural tube defects (NTDs). The relationship between a second MTHFR polymorphism (1298A→C) and NTD risk has been inconsistent between studies. We genotyped 276 complete NTD triads (mother, father and child affected with an NTD) and 256 controls for MTHFR 1298A→C. Our findings do not support a role for the 1298A→C polymorphism in NTDs (OR 0.85 (95% CI 0.49–1.47), p= 0.55), nor do we observe a combined effect with the 677C→T polymorphism. Electronic Publication     

Analysis of pressure waves as a mean of diagnosing vascular obstructions

A feasibility study was made to examine whether pressure measurements can be used to diagnose vascular obstructions in blood vessels. Distortion of a pressure wave due to an obstruction in an elastic tube was investigated theoretically and experimentally. Linear theory and the method of characteristics were employed in developing mathematical expressions for the distortion of the pressure wave. The quality of the models developed was examined by performing experiments on a latex tube with rigid obstructions. A nonlinear model using the method of characteristics was in good agreement with the experiment data for obstructions with any severity, while a linear model was applicable to small obstructions. The nonlinear model is proposed as a mathematical model for the detection of vascular obstructions by analysing pressure waves.     

Physiological and pharmacological aspects of local transfer of substances in the ovarian adnexa in women

An intimate arrangement between the utero-ovarian vein and the ovarian artery has been found in many species. The anatomical structure suggests the existence of a counter-current system of exchange, and many animal experiments point to a physiological importance of this transfer system. In man, the utero-ovarian vein forms a plexus around the ovarian artery. In-vitro experiments have demonstrated a local transfer of progesterone; in-vivo experiments have proved that krypton and progesterone can be transferred from the utero-ovarian vein to the ovarian artery. The physiological and pharmacological importance of the counter-current system is still under evaluation, and further investigations are needed. It has been suggested that counter-current transfer facilitates local communication between the ovary, Fallopian tube, and uterus. This may be important in a context of luteolysis, follicular selection and maturation, fertilization, and the recognition and maintenance of pregnancy. The pharmacological and therapeutic potential may be limited, as the ovarian adnexa are relatively difficult to access. Instillation of hormones into the uterine lumen will probably induce a higher plasma concentration in the ovarian arterial blood than in peripheral arterial plasma. A culdoscopic or endoscopic approach might permit introduction of long-acting depots in the uterine fundus near the Fallopian tubes and/or ovaries.     

Evaluation of endocrine disrupting activity of plasticizers in polyvinyl chloride tubes by estrogen receptor alpha binding assay

Polyvinyl chloride (PVC) tubing is an indispensable medical material for extracorporeal circulation therapy. However, di(2-ethylhexyl)phthalate (DEHP), a suspected endocrine disruptor, can be eluted from PVC, suggesting that an alternative material that does not contain DEHP is needed for clinical applications. First, we evaluated the endocrine disrupting risks of the plasticizers contained in PVC tubes by investigating their binding affinities for the human estrogen receptor alpha (ERα). Our results revealed that, while DEHP has some binding affinity for ERα, neither epoxidized soybean oil nor tris(2-ethylhexyl)trimellitate (an alternative to DEHP) has any affinity for ERα. Second, we evaluated the endocrine disrupting risks of a tube made of newly developed plasticizer-free (PF) materials. We confirmed the presence of DEHP and detected several unidentified substances in plasma stored within the PVC tube. This plasma's competitive binding affinity for ERα was significantly higher than that of control plasma (P < 0.01). In contrast, the profile of plasma stored in the PF tube was similar to that of the control, both in terms of high-performance liquid chromatography chromatograms and competitive binding capacity for ERα, suggesting that the PF tube is biocompatible and is useful for reducing the elution of substances capable of binding to ERα. Presented in part at the 42nd Congress of the Japanese Society for Artificial Organs, October 5–7, 2004, Tokyo, Japan     

Bilateral salpingectomy does not compromise ovarian stimulation in an in-vitro fertilization/embryo transfer programme

The question whether salpingectomy has a negative influenceon ovarian function and the outcome of pregnancy in an in-vitrofertilization (IVF) and embryo transfer treatment programmeis not yet answered. We performed a retrospective case-controlstudy to investigate the possible negative effect of salpingectomyon ovarian response to human menopausal gonadotrophins (HMG)during IVF and embryo transfer. The study group was composedof 26 patients with bilateral salpingectomy. In 67 cycles weanalysed different parameters of ovulation such as the numberof days of ovarian stimulation, numbers of ampoules of HMG,pre-ovulatory oestradiol concentrations and the numbers of oocytesretrieved. These parameters were compared to a control groupof 134 cycles in 134 women with healthy Fallopian tubes. Nodifferences were found. Implantation ratio, pregnancy rate andoutcome were the same in both groups. We conclude that bilateralsalpingectomy had no detrimental effect on ovarian performanceduring IVF and embryo transfer treatment nor on the outcome.     

Interaction of folate and homocysteine pathway genotypes evaluated in susceptibility to neural tube defects (NTD) in a German population

Neural tube defects (NTD) are likely to result from an interaction of several genes and environmental factors. Because periconceptional folate intake reduces the NTD risk in the fetus, and because mothers of children with NTD showed elevated plasma homocysteine levels, gene polymorphisms of the folate and homocysteine pathway, such as 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T, MTHFR 1298A→C and cystathionine β-synthase (CBS) 844ins68, have been implicated in the etiology of NTD. Several studies have demonstrated that these polymorphisms may indeed be associated with NTD in some populations. In order to evaluate the role of these polymorphisms and their interaction in NTD, we genotyped 417 individuals for case-control studies and 129 families for transmission disequilibrium tests. We are the first to present detailed data on MTHFR haploid genotypes in combination with CBS 844ins68. The MTHFR risk genotype 677CT/1298AC, known to be associated with decreased enzyme activity and increased homocysteine, was found significantly more often in patients than in controls (P = 0.02). A CBS insertion allele in addition to MTHFR 677CT/1298AC heterozygosity or MTHFR 677TT/1298AA homozygosity did not result in an increased risk for NTD. This is in agreement with the recently reported homocysteine-lowering effect of the CBS 844ins68 allele in carriers of MTHFR variants. Received: August 28, 2000 / Accepted: December 4, 2000     

神经管畸形患儿还原叶酸载体基因和叶酸之间交互作用

目的 探讨神经管畸形(neural tube defects,NTDs)患儿还原叶酸载体基因(reduced folate carrier gene,RFCI）A80G多态性与母亲孕早期未增补叶酸之间的关联性,为寻找NTDs危险因素的遗传易感标志物提供流行病学依据。方法采用限制性片段长度多态性-聚合酶链反应方法,对104个NTDs患儿及其母亲和100名正常儿童及其母亲的外周血DNA进行RFCI第80位单核苷酸多态性检测,通过病例对照研究,调查了后代RFCI A80G基因型与母亲孕期前后增补叶酸之间的基因环境交互作用。结果 RFCI GG基因型的子代发生NTDs危险高于AA基因型子代(OR=2．56,95％CI=1．04～6．36);母亲孕早期不增补叶酸,生育NTDs的危险高于增补叶酸的母亲(OR=7．69,95％CI=2．86～21．75);母亲孕期未增补叶酸,其子代GG基因型,发生NTDs的危险是AA基因型的3．30倍(95％CI=1．15～9．65);在叶酸和RFCI基因交互作用研究中,母亲未增补叶酸和子代GG基因型同时存在,发生NTDs的危险是8．80(95％CI=2．86～29．82),交互作用系数为1．45,,结论 在中国人群中,RFCI GG基因型可能是NTDs发生的遗传易感基因之一,子代RFCI GG基因型与母亲孕期叶酸缺乏之间存在交互作用,可能增加NTDs的发病危险。     

Velo-cardio-facial syndrome and DiGeorge sequence with meningomyelocele and deletions of the 22q11 region

Approximately 5% of children with neural tube defects (NTDs) have a congenital heart defect and/or cleft lip and palate. The cause of isolated meningomyelocele, congenital heart defects, or cleft lip and palate has been largely thought to be multifactorial. However, chromosomal, teratogenic, and single gene causes of combinations of NTDs with congenital heart defects and/or cleft lip and palate have been reported. We report on 3 patients with meningomyelocele, congenital heart defects, and 22q11 deletions. Two of the children had the clinical diagnosis of velo-cardio-facial syndrome (VCFS); both also have bifid uvula. The third child had DiGeorge sequence (DGS). The association of NTDs with 22q11 deletions has not been reported previously. An accurate diagnosis of the 22q11 deletions is critical as this micro-deletion and its associated clinical problems is transmitted as an autosomal dominant trait due to the inheritance of the deletion-bearing chromosome. We recommend that all children with NTDs and congenital heart defects, with or without cleft palate, have cytogenetic and molecular studies performed to detect 22q11 deletions. © 1994 Wiley-Liss, Inc.     

Screening for coeliac disease as a possible maternal risk factor for neural tube defect

Coeliac disease is an important cause of malabsorption, particularly of folic acid, in adults. We investigated the possibility that it might be a maternal risk factor for neural tube defect (NTD)-associated pregnancy by screening affected mothers using serum endomysial antibody (EmA) which has high sensitivity and specificity for coeliac disease. One (1.6%) of 60 patients was EmA positive and had a diagnosis of coeliac disease confirmed by the finding of villous atrophy on jejunal biopsy. In conclusion, the majority of NTD-associated pregnancies are not associated with maternal coeliac disease and our study is additional evidence that abnormalities of folic acid metabolism rather than absorption are the most important risk factors for NTD. Further studies are needed to determine whether the coeliac disease prevalence among women with NTD-affected pregnancy is higher than that of the general population.