Helen Burke

Maternal Vitamin B12 Status and Risk of Neural Tube Defects in a Population With High Neural Tube Defect Prevalence and No Folic Acid Fortification

OBJECTIVE. Folic acid fortification has reduced neural tube defect prevalence by 50% to 70%. It is unlikely that fortification levels will be increased to reduce neural tube defect prevalence further. Therefore, it is important to identify other modifiable risk factors. Vitamin B12 is metabolically related to folate; moreover, previous studies have found low B12 status in mothers of children affected by neural tube defect. Our objective was to quantify the effect of low B12 status on neural tube defect risk in a high-prevalence, unfortified population. METHODS. We assessed pregnancy vitamin B12 status concentrations in blood samples taken at an average of 15 weeks’ gestation from 3 independent nested case-control groups of Irish women within population-based cohorts, at a time when vitamin supplementation or food fortification was rare. Group 1 blood samples were from 95 women during a neural tube defect–affected pregnancy and 265 control subjects. Group 2 included blood samples from 107 women who had a previous neural tube defect birth but whose current pregnancy was not affected and 414 control subjects. Group 3 samples were from 76 women during an affected pregnancy and 222 control subjects. RESULTS. Mothers of children affected by neural tube defect had significantly lower B12 status. In all 3 groups those in the lowest B12 quartiles, compared with the highest, had between two and threefold higher adjusted odds ratios for being the mother of a child affected by neural tube defect. Pregnancy blood B12 concentrations of <250 ng/L were associated with the highest risks. CONCLUSIONS. Deficient or inadequate maternal vitamin B12 status is associated with a significantly increased risk for neural tube defects. We suggest that women have vitamin B12 levels of >300 ng/L (221 pmol/L) before becoming pregnant. Improving B12 status beyond this level may afford a further reduction in risk, but this is uncertain.

Methylenetetrahydrofolate reductase thermolabile variant and oral clefts

Folic acid can prevent neural tube defects; in some cases the mechanism is probably a correction of a metabolic defect caused by thermolabile methylenetetrahydrofolate reductase (MTHFR) found in increased frequency in cases. It is less clear whether folic acid can prevent oral clefts, in part because it is not known whether thermolabile MTHFR is more common in those with oral clefts. This study examined the prevalence of the mutation (677 C-->T) that causes thermolabile MTHFR in subjects with oral clefts from a national Irish support group, and an anonymous control group randomly selected from a neonatal screening program covering all births in Ireland. Eighty-three of 848 control subjects were homozygous (TT) thermolabile MTHFR (9.8%). This defect was almost three times as common in the 27 subjects (25.9%) with isolated cleft palate (odds ratio 3.23, 95% confidence interval 1.32 -7.86, P = 0. 02) and somewhat more common in the 66 subjects with cleft lip with or without cleft palate (15.2%, odds ratio 1.65, 95% confidence interval 0.81-3.35, P = 0.20). When the two groups with different etiologies were combined, the overall odds ratio was 2.06 (95% confidence interval 1.16-3.66, P = 0.02). In the Irish population homozygosity for the common folate-related polymorphism associated with thermolabile MTHFR is significantly more frequent in those with isolated cleft palate, and could be etiologically important. Am. J. Med. Genet. 86:71-74, 1999. Published 1999 Wiley-Liss, Inc.

Low blood folates in NTD pregnancies are only partly explained by thermolabile 5,10-methylenetetrahydrofolate reductase: low folate status alone may be the critical factor.

Thermolabile 5,10-methylenetetrahydrofolate reductase (MTHFR) is the first folate-related variant to be associated with an increased risk of neural tube defects (NTDs). The variant causes high plasma homocysteine levels and reduced red cell folate (RCF) levels, both of which have also been linked to an increased risk of NTDs. We examined the relationship between folate status and presence of the common mutation MTHFR C677T in 82 NTD-affected and 260 control mothers. Homozygosity for the TT genotype was associated with very low folate status among both the cases (n = 13) and the controls (n = 21). However, after exclusion of TT homozygotes, only 10% of the remaining 240 controls had RCF levels less than 200 microg/L compared with 29% of the 69 cases (odds ratio, 3.67; 95% confidence interval, 1.88-7.18; P < 0.001), and those with RCF less than 150 microg/L had eight times higher risk of NTD than subjects with levels over 400 microg/L. Plasma homocysteine levels of non-TT cases were also higher than those of controls (P = 0.047). This study shows that homozygosity for the C677T MTHFR variant cannot account for reduced blood folate levels in many NTD-affected mothers. Thus, a strategy of genetic screening of all childbearing women for this variant would be ineffective as a method of primary prevention of NTDs. The data suggest that low maternal folate status is itself the major determinant of NTD risk, or else that other folate-dependent genetic variants confer risk through the reduction of folate levels. These results emphasize the importance of a food-fortification program as a population strategy for reducing the occurrence of NTDs.

Outcome of hip fracture in older Irish women: a 2-year follow-up of subjects in a case-control study

To assess outcome after hip fracture in older Irish women, 106 consecutive females aged over 50 years admitted to a general hospital with a hip fracture were compared to 89 age- and gender-matched controls from the same catchment area. Interview-based data were collected on socio-demographic factors, mobility and activities of daily living before recruitment and 2 years later. Information was also collected on residence, further falls and fractures and use of health and community support services during the 2-year period. Mortality at 2 years was higher in cases (23.6%) compared to controls (10.1%; P = 0.01). Cases were significantly less mobile and more dependent in the activities of daily living. Of the cases who were community dwellers at baseline, 26.6% were institutionalised at 2 years compared with 9.2% of controls (P = 0.01). During the 2 years cases were significantly more likely to have multiple falls and a further hip or pelvic fracture. Hospital and nursing home admissions and use of physiotherapy, day centre and home help services were also significantly greater among cases. The marked adverse impact of hip fracture reported in this study underlines the importance of public health strategies to prevent these injuries in older people.

Predictors of first hip fracture and mortality post fracture in older women

BackgroundHip fracture causes significant morbidity and mortality in older women.AimTo document factors contributing to the risk of hip fracture in older women and to assess the effect of hip fracture on subsequent mortality.MethodsCase-control study of 89 women with hip fracture and 89 controls, with two-year follow-up. Singh index and bone mineral density were calculated.ResultsOsteoporotic indices did not differ significantly between cases and controls. Significant predictors of risk were sleeping tablets, perception of health as fair/poor and a lower mental status score. Patients were 3.57 times more likely to die in the first year after fracture, with no difference between the groups in year two. After adjustment, hip fracture did not remain significantly associated with mortality. Inability to walk 100 yards alone prior to fracture and lower social class were significantly associated with mortality at 12 months. Age alone was significantly associated at 12–24 months.ConclusionsFactors related to falls and fracture may be more discriminatory predictors of hip fracture risk than osteoporosis in older females. Medications for sleep should be prescribed with caution. Hip fracture may have an independent effect on one year mortality, this effect is not seen in the second year.

Glycosylated lanthanide cyclen complexes as luminescent probes for monitoring glycosidase enzyme activity

The development of synthetic chemical probes for the detection of enzymes is extremely important for biological, medicinal, and industrial applications. Here we report the synthesis of an array of novel glycosylated Tb(iii) complexes, their photophysical properties in solution, and their ability to function as luminescent probes for observing glycosidase enzyme activity in real time. Our initial studies into the application of these complexes for the detection of the Concanavalin A (ConA) lectin is also reported, highlighting the broad scope of these novel chemical probes.

Exploring chemoselective S -to- N acyl transfer reactions in synthesis and chemical biology

S-to-N acyl transfer is a high-yielding chemoselective process for amide bond formation. It is widely utilized by chemists for synthetic applications, including peptide and protein synthesis, chemical modification of proteins, protein-protein ligation and the development of probes and molecular machines. Recent advances in our understanding of S-to-N acyl transfer processes in biology and innovations in methodology for thioester formation and desulfurization, together with an extension of the size of cyclic transition states, have expanded the boundaries of this process well beyond peptide ligation. As the field develops, this chemistry will play a central role in our molecular understanding of Biology.