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Folate and vitamin B12 are needed for the proper embryo-fetal development possibly through their interacting role in the 1-carbon metabolism. Folate fortification reduces the prevalence of complex birth defects, and more specifically neural tube defects (NTDs). GIF and FUT2 are 2 genes associated with the uptake and blood level of vitamin B12. We evaluated GIF and FUT2 as predictors of severe birth defects, in 183 aborted fetuses compared with 375 healthy newborns. The GIF290C allele frequency was estimated to 0.4% in healthy newborns and to 8.1% in NTD fetuses (odds ratio 17.8 [95% confidence interval CI: 4.0-77.6]). The frequency of FUT2 rs601338 secretor variant was not different among groups. The GIF 290C heterozygous/ FUT2 rs601338 secretor variant combined genotype was reported in 6 of the 37 NTD fetuses, but not in other fetuses and healthy newborns ( P < .0001). This GIF/ FUT2 combined genotype has been previously reported in children with congenital gastric intrinsic factor (GIF) deficiency, with respective consequences on B12 binding activity and GIF secretion. In conclusion, a genotype reported in congenital GIF deficiency produces also severe forms of NTD. This suggests that vitamin B12 delivery to neural tissue by the CUBN/GIF pathway could play a role in the neural tube closure mechanisms. [ABSTRACT FROM AUTHOR]

Background Allergic IgE-mediated reactions to neuromuscular blocking agents ( NMBAs) are the main cause of immediate hypersensitivity reactions in anaesthesia; their predominant occurrence in the absence of previous exposure to NMBAs suggests a risk related to environmental exposure. Objective To investigate the prevalence of specific IgE to quaternary ammonium ions in two populations professionally exposed to quaternary ammonium compounds, in the north-eastern France. Methods The study had a retrospective follow-up design whereby apprentices were assessed after their 2-year training period as apprentices. The professionally exposed hairdresser populations ( n = 128) were compared with baker/pastry makers ( n = 108) and 'non-exposed' matched control subjects ( n = 379). Results We observed a 4.6-fold higher frequency of positive IgE against quaternary ammonium ions in hairdressers (HD), compared with baker/pastry makers (BP) and control (C) groups. The competitive inhibition of quaternary ammonium Sepharose radioimmunoassay (QAS-IgE RIA) with succinylcholine was significantly higher in HD, compared with BP and C groups, with inhibition percentage of 66.2 ± 7.4, 39.7 ± 6.0 and 43.8 ± 9.9, respectively ( P < 0.001). The specific IgE against quaternary ammonium ions recognized also two compounds widely used by hairdressers, benzalkonium chloride and polyquaternium-10, in competitive inhibition of IgE RIA. When considering the whole study population, hairdresser professional exposure and total IgE > 100 kU/L were the two significant predictors of IgE-sensitization against quaternary ammonium ions in the multivariate analysis of a model that included age, sex, professional exposure, increased concentration of total IgE (IgE > 100 kU/L) and positive IgE against prevalent allergens (Phadiatop®; P = 0.019 and P = 0.001, respectively). Conclusion and Clinical Relevance The exposure to hairdressing professional occupational factors increases Ig E-sensitization to NMBAs and quaternary ammonium ion compounds used in hairdressing. Besides the pholcodine hypothesis, our study suggests that repetitive exposure to quaternary ammonium compounds used in hairdressing is a risk factor for NMBAs sensitization. [ABSTRACT FROM AUTHOR]

Background: Genetic polymorphisms of APO-E, homocysteine, and the IL-1 gene cluster (IL-1A, IL-1B, receptor antagonist IL-1RN) are associated with sporadic Alzheimer's disease and may involve interdependent pathways of neuronal toxicity.Objective: To determine whether these polymorphisms and the genetic determinants of homocysteine (methylenetetrahydrofolate reductase, MTHFR; methionine synthase, MTR; transcobalamin, TC) are associated with an increased risk of severe dementia in Alzheimer's disease.Methods: 152 patients with Alzheimer's disease and 136 controls were studied. The association of occurrence and dementia severity (Reisberg score <6 and >or=6) of Alzheimer's disease with APO-E, IL-1A, IL-1B, IL-1RN, MTHFR677 C-->T and 1298A-->C, MTR 2756 A-->G, and TC 776 C-->G polymorphisms was evaluated by multivariate logistic regression analysis after adjustment for age, sex, and age of onset of Alzheimer's disease.Results: IL-1A TT and IL-1B CT/TT associated genotypes were at risk of Alzheimer's disease (odds ratio 4.80 (95% confidence interval, 1.32 to 17.40), p = 0.017); the MTR 2756 AA genotype was at risk of severe dementia (OR 2.97 (1.23 to 7.21), p = 0.016); IL-1 RN*2 was protective (OR 0.28, (0.11 to 0.69), p = 0.006). Allele epsilon4 of the APO-E and IL-1B CC genotypes increased the risk of severe Alzheimer's disease associated with the MTR 2756 AA genotype by 3.3-fold and 1.5-fold, respectively.Conclusions: Distinct determinants of the IL-1 gene cluster are related to the generation and progression of Alzheimer's disease. MTR only influences progression of the disease, which may be enhanced by carriage of allele epsilon4 of APO-E. [ABSTRACT FROM AUTHOR]

The article discusses the study concerning the frequency of meroporem allergy in patients with penicillin allergy. The study, which involved 104 patients with a previous allergic to penicillin and positive results on skin tests for penicillin allergy, found out that the remaining 103 patients tolerated the morepenem challenges without an allergic reaction.

Background: The deficiency in methyl donors, folate and vitamin B12, increases homocysteine and produces myocardium hypertrophy with impaired mitochondrial fatty acid oxidation and increased BNP, through hypomethylation of peroxisome-proliferator-activated-receptor gamma co-activator-1α, in rat. This may help to understand better the elusive link previously reported between hyperhomocysteinemia and BNP, in human. We investigated therefore the influence of methyl donors on heart mitochondrial fatty acid oxidation and brain natriuretic peptide, in two contrasted populations., Methods: Biomarkers of heart disease, of one carbon metabolism and of mitochondrial fatty acid oxidation were assessed in 1020 subjects, including patients undergoing coronarography and ambulatory elderly subjects from OASI cohort., Results: Folate deficit was more frequent in the coronarography population than in the elderly ambulatory volunteers and produced a higher concentration of homocysteine (19.3 ± 6.8 vs. 15.3 ± 5.6, P<0.001). Subjects with homocysteine in the upper quartile (≥ 18 μmol/L) had higher concentrations of NT-pro-BNP (or BNP in ambulatory subjects) and of short chain-, medium chain-, and long chain-acylcarnitines, compared to those in the lower quartile (≤ 12 μmol/L), in both populations (P<0.001). Homocysteine and NT-pro-BNP were positively correlated with short chain-, medium chain-, long chain-acylcarnitines and with acylcarnitine ratios indicative of decreased mitochondrial acyldehydrogenase activities (P<0.001). In multivariate analysis, homocysteine and long chain acylcarnitines were two interacting determinants of NT-pro-BNP, in addition to left ventricular ejection fraction, body mass index, creatinine and folate., Conclusions: This study showed that homocysteine predicts increased NT-pro-BNP (or BNP) through a link with impaired mitochondrial fatty oxidation, in two contrasted populations., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The incidence of immune-mediated anaphylaxis during anesthesia ranges from 1 in 10,000 to 1 in 20,000. Neuromuscular blocking agents are most frequently incriminated, followed by latex and antibiotics, although any drug or substance used may be a culprit. Diagnosis relies on tryptase measurements at the time of the reaction and skin tests, specific immunoglobulin E, or basophil activation assays. Treatment consists of rapid volume expansion and epinephrine administration titrated to symptom severity., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

The incidence of immune-mediated anaphylaxis during anesthesia ranges from 1 in 10,000 to 1 in 20,000. Neuromuscular blocking agents represent the most frequently involved substances, followed by latex and antibiotics, but every drug or substance used may be involved. Diagnosis relies on tryptase measurements at the time of the reaction and skin tests and specific IgE or basophil activation assays.

Neuromuscular blocking agents are the leading drugs responsible for immediate hypersensitivity reactions during anaesthesia. Most hypersensitivity reactions represent IgE-mediated allergic reactions. Their incidence is estimated to be between 1 in 3,000 to 1 in 110,000 general anaesthetics. However striking variations have been reported among countries. The mechanism of sensitisation seems to implicate the presence of a substituted ammonium ion in the molecule. Due to lack of exposure prior to the reaction in a large number of reactors, it has been hypothesised that sensitisation may involve other, as yet undefined, substituted (quaternary and tertiary) ammonium ion containing compounds such as pholcodine, present in the environment of the patient. This hypothesis is still under investigation. The mechanism of non-IgE mediated hypersensitivity reactions is less well known. Identified mechanisms correspond to direct histamine release or interactions with muscarinic and nicotinic receptors. Allergic reactions cannot be clinically distinguished from non-IgE-mediated reactions. Therefore, any suspected hypersensitivity reaction must be investigated using combined pre and postoperative testing. Because of the frequent but not systematic cross-reactivity observed with muscle relaxants, every available neuromuscular blocking agent should be tested, using intradermal tests to confirm the responsibility of the suspected drug which should be definitely excluded. Cross-sensitivity investigation will also try to identify the safety of drugs that can be potentially used in future anaesthesia. The determination of basophil activation investigations using direct leukocyte histamine release test or flow cytometry would be of particular interest to investigate cross sensitisation in complement to skin tests. There is no demonstrated evidence supporting systematic pre-operative screening in the general population at this time. However, since no specific treatment has been shown to reliably prevent anaphylaxis, allergy assessment must be performed in all high-risk patients. In view of the relative complexity of allergy investigation, and of the differences between countries, an active policy to identify patients at risk and to provide any necessary support from expert advice to anaesthetists and allergologists through the constitution of allergo-anaesthesia centres in every country should be promoted.

Drug allergy refers to a hypersensitivity reaction for which either an IgE or T-cell-mediated mechanism is demonstrated. The recognition of the drug by B and T cells is influenced by variants of HLA genes. The genetic factors involved in IgE-mediated mechanisms have been studied mainly in beta-lactam reactions, and they appear to be related to human leukocyte antigen presentation (HLA A2 and DRw52), TNFA -308G>A, class switching to IgE by B cells (variants of IL-13 and of IL-4RA), and expression of IgE receptors on target cells (variant of the FcepsilonRIbeta gene). Delayed T-cell-mediated reactions are also associated with HLA alleles. Studies have reported an association of HLA-B*1502 and HLA-B*5801 in patients with the Stevens-Johnson syndrome or toxic epidermal necrolysis provoked by carbamazepine, as well as of HLA-B*5701 with abacavir hypersensitivity. HLA-B*5701 seems to be a strong predictor in whites, but not in Hispanics or Africans. Carbamazepine hypersensitivity is also influenced by gene variants of cytochrome P450 enzymes on the generation of reactive metabolites, while CYP2C9*2 and CYP2C9*3 polymorphisms influence the bioactivation of sulfamethoxazole in prohapten. Pharmacogenetic studies on aspirin hypersensitivity have identified distinct types of predictors, such as HLA genotypes, a polymorphism in the promoter of the FcepsilonRIalpha gene, and variants in genes of enzymes from the arachidonic acid pathway. In the future, identification of genetic predictors will benefit from genomewide association studies that also take ethnic differences into account. Ideally, predictors will help to prevent adverse reactions, as suggested by a recent study on the effectiveness of prospective HLA-B*5701 screening to prevent hypersensitivity reactions to abacavir in HIV patients.

Folates belong to the vitamin B group and are involved in a large number of biochemical processes, particularly in the metabolism of homocysteine. Dietary or genetically determined folate deficiency leads to mild hyperhomocysteinemia, which has been associated with various pathologies. Molecular mechanisms of homocysteine-induced cellular dysfunction include increased inflammatory cytokine expression, altered nitric oxide bioavailability, induction of oxidative stress, activation of apoptosis and defective methylation. Whereas the involvement of folate metabolism and homocysteine in ageing-related diseases, in several developmental abnormalities and in pregnancy complications has given rise to a large amount of scientific work, the role of these biochemical factors in the earlier stages of mammalian reproduction and the possible preventive effects of folate supplementation on fertility have, until recently, been much less investigated. In the present article, the possible roles of folates and homocysteine in male and female subfertility and related diseases are systematically reviewed, with regard to the epidemiological, pathological, pharmacological and experimental data of the literature from the last 25 years.

The pathogenic mechanism of neural tube defects may involve genetic polymorphisms and nutritional factors related to homocysteine metabolism. We evaluated the association of polymorphisms of three genes affecting vitamin B12-dependent remethylation of homocysteine, transcobalamin (TC), methionine synthase (MTR) and MTR reductase (MTRR), combined or not with methylenetetrahydrofolate reductase (MTHFR), with the risk of having neural tube defect in 40 children with spina bifida and 58 matched controls from South Italy. MTR 2756 AG/GG, TC 777 CG/GG /MTHFR 677 CC and MTRR 66 GG /MTHFR 677 CC genotypes increased the risk with odds ratios of 2.6 (P=0.046), 2.4 (P=0.028) and 4.5 (P=0.023), respectively. In contrast, MTHFR 677 TT was protective (odds ratio=0.11, P=0.009). In conclusion, genetic determinants affecting the cellular availability or MTRR-dependent reduction of B12 may increase the risk of spina bifida.