PubMed Health⌕ Search

Biomedical subjects

Jean-Louis Guéant

Publications and source records attributed to Jean-Louis Guéant.

At least 19 recordsLinked to original sources
PubMed2007

Environmental influence on the worldwide prevalence of a 776C->G variant in the transcobalamin gene (TCN2).

BACKGROUND: A 776C-->G variant (dbSNP ID: rs1801198) in the transcobalamin gene (TCN2; MIM# 275350) decreases the cellular and plasma concentration of transcobalamin and thereby influences the cellular availability of vitamin B(12). OBJECTIVE: To evaluate the worldwide prevalence of this variant and its association with homocysteine plasma level. METHODS: The study was performed in 1433 apparently healthy subjects, including Afro-Americans and Afro-Africans and in 251 Afro-Africans participants with severe malaria. RESULTS: The frequencies of the 776G allele were the highest in China (0.607; 95% CI 0.554 to 0.659), low in West Africa (Bénin and Togo, 0.178; 0.154 to 0.206), and intermediate in France (0.445; 0.408 to 0.481), Italy (0.352; 0.299 to 0.409), Morocco (0.370; 0.300 to 0.447) and Mexico (0.374; 0.392 to 0.419). The 776G genotype was more frequent in Afro-Americans from New York (16.7; 8.4 to 30.7) and in Afro-African patients with severe malaria (6.0%; 95% CI 3.7 to 9.6) than in healthy Afro-African volunteers (p = 0.0004 and p = 0.033, respectively), while no difference was observed for MTHFR 677TT and 677T alleles. A disequilibrium of TCN2 genotype distribution was recorded in patients with severe malaria, with a twofold higher GG genotype than expected (p = 0.010). An association between the TCN2 polymorphism and homocysteine was observed only in Mexico and France, the two countries with the highest rate of low plasma concentration of vitamin B(12) (<100 pmol/l). CONCLUSION: Given the dramatic heterogeneity of the 776G allele frequency worldwide, this polymorphism may be prone to a selective pressure or confers an evolutionary advantage in confronting environmental factors, one of which is malaria.

Adult↗
PubMed2007

Plasma vitamin values and antiepileptic therapy: case reports of pregnancy outcomes affected by a neural tube defect.

BACKGROUND: Folic acid supplementation reduces the occurrence of neural tube defects (NTDs); however, it is not clear whether it protects against teratogenic effects of antiepileptic drugs. METHODS: We report the cases of four pregnant women receiving valproic acid therapy, who all had NTD-affected offspring, despite periconceptional 5 mg/day of folic acid supplementation (cases), and investigated homocysteine metabolism, linked with folate metabolism. Their plasma homocysteine, folates, and vitamin B6 and B12 results were compared with values of two other women, who were also receiving valproic acid and folic acid complement, but who had normal pregnancies (valproic acid controls), and values of 40 pregnant women who had normal pregnancies and were not receiving any therapy (controls without therapy). Because of the possible existence of a genetic susceptibility, polymorphisms in homocysteine metabolism were sought. RESULTS: Two cases showed a decreased phosphopyridoxal level, compared with levels in the controls not receiving therapy. The genotype TT (C677T) is an NTD genetic susceptibility, but it was observed in only one valproic acid control. Various polymorphisms were observed in the cases, but were also common in the controls. Several studies have reported that valproic acid therapy lowers vitamin B6 levels. Our case with the greatest decrease in plasma phosphopyridoxal, who was taking periconceptional folic acid plus pyridoxine therapy, had a normal second pregnancy outcome. CONCLUSIONS: In addition to folates, other vitamins, such as vitamin B6, may have played a role in NTDs in our patients taking an antiepileptic drug.

Adult↗
PubMed2006

Quantitative methylation-sensitive arbitrarily primed PCR method to determine differential genomic DNA methylation in Down Syndrome.

Relative levels of DNA hypermethylation were quantified in DS individuals using a new method based on a combination of methylation-sensitive arbitrarily primed polymerase chain reaction (MS-AP-PCR) and quantification of DNA fragments with the Agilent 2100 bioanalyzer. Four of the DS individuals had low plasma total homocysteine (tHcy) level (4.3 +/- 0.3 micromol/l) and 4 other had high-tHcy level (14.1 +/- 0.9 micromol/l). Eight healthy control individuals were matched to the DS cases for age, sex, and tHcy levels. We have identified and quantified six hypermethylated fragments. Their sizes ranged from 230-bp to 700-bp. In cases and controls, low-tHcy did not affect methylation level of identified fragments, mean methylation values were 68.0 +/- 39.7% and 52.1 +/- 40.3%, respectively. DNA methylation in DS individuals did not change significantly (59.7+/-34.5%) in response to high-tHcy level in contrast to controls (23.4 +/- 17.7%, P = 0.02). Further, the quantitative MS-AP-PCR using this microfludic system is a useful method for determining differential genomic DNA methylation.

Adolescent↗
PubMed2006

Evidence for a functional genetic polymorphism of the human retinoic acid-metabolizing enzyme CYP26A1, an enzyme that may be involved in spina bifida.

BACKGROUND: CYP26A1, together with CYP26B1 and CYP26C1, are key enzymes of all-trans retinoic acid (RA) inactivation and their specific and restricted expression in developing embryos participate in the fine tuning RA levels. As RA is a critical regulator of gene expression during embryonic development, the imbalance between the synthesis and degradation of RA during embryogenesis could contribute to malformations and developmental defects. METHODS: A PCR-single strand conformation polymorphism (PCR-SSCP) strategy was developed to screen for CYP26A1 sequence variations that could affect the enzyme expression and/or activity and applied to DNA samples from 80 unrelated Caucasians, comprising 40 French healthy volunteers and 40 Italian patients with spina bifida. The consequence of the 1-bp deletion identified in the coding sequence was investigated by an in vitro functional assay using COS-7 cells. RESULTS: A total of 7 polymorphisms were identified, comprising 1 nucleotide deletion in the coding sequence (g.3116delT) that results in a frameshift and consequently in the creation of a premature stop codon. The g.3116delT mutation is of particular interest because it was identified in a patient with spina bifida and likely encodes a truncated protein with no enzymatic activity, as demonstrated by our preliminary in vitro data. CONCLUSIONS: Despite the fact that our findings could not show any evidence that the CYP26A1 genetic polymorphism has implications in the pathogenesis of spina bifida, this work represents the first description of a functional genetic polymorphism affecting the coding sequence of the human CYP26A1 gene.

Animals↗
PubMed2006

Lack of association between microsatellite instability and benign adrenal tumors.

BACKGROUND: The adrenal gland may give rise to pheochromocytomas, which are catecholamine-producing tumors originating from the adrenal medulla, or to adrenocortical tumors, which derive from the adrenocortical cortex and may be secreting or not. The genetic mechanisms underlying the formation of these tumors include somatic mutations in susceptibility genes, especially in the familial forms, and allelic loss, especially in chromosome 1. AIM: The aim of this study was to investigate a third genetic mechanism by evaluating microsatellite instability using the reference markers (Bat25, Bat26, D2S123, D5S346, D17S250) validated by the National Cancer Institute. Microsatellite loci were analyzed in 32 benign tumors, including 11 pheochromocytomas and 21 adrenocortical tumors, in patients with and without familial syndrome. RESULTS: The different alleles of microsatellite loci were reliably detected by DNA fragments analysis, whereas data obtained after melting-point analysis on the Lightcycler were inconsistent. No microsatellite instability was detected in any tumor. One patient with a unilateral pheochromocytoma showed a loss of heterozygosity for D17S250. A second patient with a MEN-2A syndrome and a two-sided pheochromocytoma exhibited a loss of heterozygosity for D2S123 in the right tumor only and a retention of heterozygosity for all markers in the left tumor. CONCLUSIONS: These results suggest that microsatellite instability, evaluated by the five reference markers of the National Cancer Institute, is not a feature of benign adrenal tumors.

Adrenal Gland Neoplasms↗
PubMed2006

Antiepileptic drugs: a case report in a pregnancy with a neural tube defect.

While receiving lamotrigine, a patient pregnant with triplets suffered a double fetal neural tube defect. Plasma homocysteine, folate, vitamins B12 and B6 (pyridoxal phosphate), and red cell folate levels were measured in samples while she was receiving folic acid therapy for 1 month during the second trimester of pregnancy. Some mutations were sought, involved in homocysteine metabolism and linked with the folate metabolism. Her results were compared with those of a pregnant woman with normal triplets and with those of 58 pregnant women, with a normal pregnancy. Results indicated a decrease in vitamin B12 and B6 values in plasma in the patient, and a genotype AG (polymorphism A66G) was observed, but was not found in the pregnant woman with normal triplets. Even if lamotrigine therapy is not known to be associated with significant changes in red cells or in serum folate, periconceptional folic acid supplementation is counseled for women, along with periconceptional B12 and B6 vitamin supplementation when their plasma values are decreased.

Adult↗
PubMed2006

Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: a comparative study in Mexican, West African, and European populations.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism is heterogeneously distributed worldwide, with the highest and lowest frequencies of the T allele in Mexico and Africa, respectively, and a south-to-north gradient in Europe. Distribution of MTHFR 1298A-->C is less well known. It has been hypothesized that 677T frequency could result in part from gene-nutrient interactions. OBJECTIVE: The objective was to compare the association of 677T and 1298C alleles with plasma concentrations of homocysteine, folate, and vitamin B-12 in geographical areas with contrasting 677T allele frequencies. DESIGN: Healthy young adults (n = 1277) were recruited in Mexico City, the West African countries of Bénin and Togo, France, and Sicily (Italy). Homocysteine, folate, and vitamin B-12 were measured in plasma, and MTHFR polymorphisms were measured in genomic DNA. RESULTS: Mexico City and Sicily reported the highest and Bénin and Togo reported the lowest plasma concentrations of folate. Mexico City had the highest 677T allele prevalence and the lowest influence of 677TT genotype on homocysteine, whereas the opposite was observed in Africa. The prevalence of the 1298C allele was lowest in the Mexicans and Africans and highest in the French. The percentage of the 677T genotype was significantly associated with the folate concentrations in 677CC carriers in a univariate analysis (R = 0.976; 95% CI: 0.797, 0.996; P < 0.0002) and in a multiple regression model that included homocysteine, vitamin B-12, and age (P = 0.0002). CONCLUSION: Our data agree with the hypothesis of a gene-nutrient interaction between MTHFR 677C-->T polymorphism and folate status that may confer a selective advantage of TT-homozygous genotype when dietary intake of folate is adequate, at least in the areas studied.

Adolescent↗
PubMed2006

Gene-gene interactions of IL13 and IL4RA variants in immediate allergic reactions to betalactam antibiotics.

OBJECTIVES: Immediate reactions - particularly anaphylactic ones - to betalactams are the most common adverse reactions to antibiotics mediated by a specific immunologic mechanism. The genetic risk factors influencing these mechanisms are poorly known. We aimed to evaluate the association between immediate allergic reactions to betalactams and the polymorphisms of IL13 (R130Q and -1055C>T variants) and IL4RA (I50V, S478P, and Q551R variants). METHODS: We determined these gene variants in 210 patients and 265 age-paired and gender-paired control subjects from Italy. RESULTS: The combination of the less frequent allele of the IL13 R130Q polymorphism with any of the predominant homozygous genotypes of the three polymorphisms of IL4RA was more significantly associated with the risk of betalactam allergy (P=0.0006, 0.0077, and 0.0041, respectively) than any polymorphism considered alone (P=0.1745, 0.0268, 0.1812, 0.0152, respectively). The same associations were observed with serum IgE levels (IL13/IL4RA variant combinations: P=0.0009, 0.0007, 0.0020, respectively and each variant: P=0.0201, 0.0021, 0.0531, and 0.0417, respectively). The combination of IL4RA variants with -1055 C>T polymorphism produced similar associations. CONCLUSION: Our data suggest that these combinations of IL13 and IL4RA variants are predictors of immediate allergic reactions to betalactams through a mechanism related to IgE production.

Adult↗
PubMed2006

Hypersensitivity to aromatic anticonvulsants: in vivo and in vitro cross-reactivity studies.

Aromatic antiepileptic drugs (phenytoin, carbamazepine, oxcarbazepine, and phenobarbital) are frequently associated with cutaneous eruptions. A cell-mediated pathogenic mechanism has been demonstrated in most of such reactions on the basis of positive responses to patch tests and/or lymphocyte transformation tests. Therefore, such tests are useful tools for evaluating anticonvulsant hypersensitivity reactions. Moreover, an in vitro lymphocyte toxicity assay, which exposes the patient's lymphocytes to arene oxides, has detected lymphocyte susceptibility to toxic metabolites in a large percentage of patients with hypersensitivity reactions to aromatic anticonvulsants. Although several hypersensitivity reactions to sequential exposure to more than one aromatic anticonvulsant (i.e., clinical cross-reactivity) have been reported, there are few studies performed with patch tests and/or lymphocyte transformation tests assessing immunologic cross-reactivity, and their data are contradictory. In any case, considering studies performed in samples of at least 10 patients, the immunologic cross-reactivity rate among aromatic anticonvulsants appears to be low. On the other hand, the reported rate of the toxic cross-reactivity (i.e., assessed by lymphocyte toxicity assays) is high. Further in vivo and in vitro studies in large samples of subjects are needed to evaluate cross-reactivity among aromatic anticonvulsants.

Anticonvulsants↗
PubMed2006

Hypersensitivity reactions to iodinated contrast media.

Adverse reactions after iodinate contrast media (ICM) administration have been observed, which can be classified as immediate (i.e., occurring within one hour after administration) and delayed or non-immediate (i.e., occurring more than one hour after administration). Even though the incidence of ICM adverse reactions has been significantly reduced by the introduction of non-ionic compounds, immediate reactions still occur in about 3% of administrations. Different pathogenic mechanisms have been suggested for ICM reactions, including immunologic ones. Basophils and mast cells participate in immediate reactions through the release of mediators like histamine and tryptase, whereas a T-cell-mediated pathogenic mechanism is involved in most non-immediate reactions, particularly maculopapular rashes. Skin tests and specific IgE assays are carried out to diagnose immediate hypersensitivity reactions, while both delayed-reading intradermal tests and patch tests are usually performed to evaluate non-immediate reactions. However, in vitro specific IgE assays are not commercially available. As far as in vitro tests are concerned, a response involving ICM-related T-cell activity may be assessed by the lymphocyte transformation test. Allergologic evaluation appears to be indicated in hypersensitivity reactions to ICM, although the sensitivity, specificity, and predictive values of allergologic tests have not yet been established. This paper summarizes the current state of the art and addresses the research that is still needed on the pathogenic mechanisms, diagnosis, and prevention of ICM-induced hypersensitivity reactions.

Contrast Media↗
PubMed2006

IgE-mediated hypersensitivity to cephalosporins.

Like penicillins, cephalosporins may cause IgE-mediated reactions such as urticaria, angioedema, and anaphylactic shock, which occur because of sensitization to determinants shared with penicillins or to unique cephalosporin haptens. In particular, side-chain structures may be responsible for selective sensitization or cross-reactivity. For this reason, individual free cephalosporins are usually employed in skin testing, in addition to the classic penicillin reagents. Cephalosporin skin tests are sensitive in diagnosing immediate hypersensitivity to these betalactams. As far as in vitro tests are concerned, IgE assays for cephalosporins, specifically sepharose-radioimmunoassays, are a potentially useful tool in evaluating immediate reactions and could be used as complementary tests. In selected cases displaying negative results in both skin tests and IgE assays, a graded challenge with the implicated cephalosporin can be performed. Cephalosporin IgE-mediated hypersensitivity may be a transient condition; therefore, allergologic exams should be repeated in patients with negative initial allergologic work-ups, including challenges. Performing allergologic tests with cephalosporins other than the culprit, as well as with penicillin reagents, allows the identification of cross-reactivity with penicillins, selective responses, or cross-reactivity among cephalosporins. In the latter group, cross-reactivity is more frequently related to R1 than to R2 side-chain recognition. In assessing the selectivity of the response, negative results in skin testing with cephalosporins other than the responsible one appear to be a reliable indicator of tolerability.

Cephalosporins↗
PubMed2006

Association of homocysteine (but not of MTHFR 677 C>T, MTR 2756 A>G, MTRR 66 A>G and TCN2 776 C>G) with ischaemic cerebrovascular disease in Sicily.

Association between methylenetetrahydrofolate reductase polymorphism (MTHFR 677 C>T ), a determinant of homocysteine plasma level (t-Hcys), with ischaemc cerebrovascular disease (iCVD) seems to be neutral in North Europe and North America. The association of 2756 A>G of methionine synthase (MTR), 66 A>G of methionine synthase reductase (MTRR) and 776 C>G of transcobalamin ( TCN2 ) needs to be evaluated further. It was the objective of this study to evaluate the association of these polymorphisms, t-Hcys, vitamin B12 and folate levels with iCVD, in an Italian population from Sicily. We investigated the association of these polymorphisms, t-Hcys, vitamin B12 and folate with iCVD in 252 subjects, including 131 cases and 121 sex- and age-matched healthy controls. t-Hcys was higher in the iCVD group than in controls [15.3 (11.5 - 17.9) vs. 11.6 (9.4 - 14.5) microM; P = 0.0007] and also in subjects with TCN2 776CG genotype, compared to homozygous genotypes [13.5 (9.9 +/- 16.9) vs. 11.7 (9.6 +/- 14.4) microM; P = 0.0327]. The folate level in cases and controls was consistent with an adequate dietary intake [12.7 (9.0 - 15.3) vs. 12.5 (9.6 - 16.9) nM; P = 0.7203]. In multivariate analysis, t-Hcys was a significant independent predictor of iCVD with an odds ratio of 1.14 (95 % C.I.: 1.06 - 1.24; P = 0.0006). No association was found between MTHFR, MTR, MTRR and TCN2 polymorphisms and iCVD risk. We have found an influence of t-Hcys and a neutral effect of MTHFR, MTR, MTRR and TCN2 on iCVD risk in Sicily. The neutral influence of these polymorphisms may be explained by adequate status in folate and vitamin B12. Other factors underlying the increased t-Hcys need further investigations.

Aged↗
PubMed2005

Allele epsilon 4 of APOE is a stronger predictor of Alzheimer risk in Sicily than in continental South Italy.

The genotype of apolipoprotein E was examined in 173 sporadic Alzheimer's disease (AD) patients, 132 with late onset (LOAD) and 41 with early onset (EOAD), and in 174 healthy matched controls from Sicily. Despite a low frequency of the epsilon 4 allele (6.3%, 95% CI: 4.2--9.4) in controls, epsilon 4 allele was a stronger predictor of AD risk (odds ratio: 5.8, 95% CI: 3.5--9.4; p<0.0001) than in most of the studies performed in other regions of Italy, and it has no influence on age at onset. epsilon 4/epsilon 4 and epsilon 4/epsilon 3 genotypes were similar predictors of AD risk. Conversely, a decreased risk was found in epsilon 3 allele carriers (odds ratio: 0.3, 95% CI: 0.2--0.4; p<0.0001), which remained significant when considering EOAD cases only (odds ratio: 0.2, 95% CI: 0.1--0.4, p<0.0001). In conclusion, differences in association strength of epsilon 4 allele with AD between Sicily and other regions of Italy suggest an influence of complex gene-gene and gene-environment interactions.

Age Factors↗
PubMed2005

Mild neonatal hypoxia exacerbates the effects of vitamin-deficient diet on homocysteine metabolism in rats.

Elevated plasma homocysteine has been linked to pregnancy complications and developmental diseases. Whereas hyperhomocysteinemia is frequently observed in populations at risk of malnutrition, hypoxia may alter the remethylation of homocysteine in hepatocytes. We aimed to investigate the combined influences of early deficiency in nutritional determinants of hyperhomocysteinemia and of neonatal hypoxia on homocysteine metabolic pathways in developing rats. Dams were fed a standard diet or a diet deficient in vitamins B12, B2, folate, month, and choline from 1 mo before pregnancy until weaning of the offspring. The pups were divided into four treatment groups corresponding to "no hypoxia/standard diet," "hypoxia (100% N2 for 5 min at postnatal d 1)/standard diet," "no hypoxia/deficiency," and "hypoxia/deficiency," and homocysteine metabolism was analyzed in their liver at postnatal d 21. Hypoxia increased plasma homocysteine in deficient pups (21.2 +/- 1.6 versus 13.3 +/- 1.2 microM, p < 0.05). Whereas mRNA levels of cystathionine beta-synthase remained unaltered, deficiency reduced the enzyme activity (48.7 +/- 2.9 versus 83.6 +/- 6.3 nmol/h/mg, p < 0.01), an effect potentiated by hypoxia (29.4 +/- 4.7 nmol/h/mg, p < 0.05). The decrease in methylene-tetrahydrofolate reductase activity measured in deficient pups was attenuated by hypoxia (p < 0.05), and methionine-adenosyltransferase activity was slightly reduced only in the "hypoxia/deficiency" group (p < 0.05). Finally, hypoxia enhanced the deficiency-induced drop of the S-adenosylmethionine/S-adenosylhomocysteine ratio, which is known to influence DNA methylation and gene expression. In conclusion, neonatal hypoxia may increase homocysteinemia mainly by decreasing homocysteine transsulfuration in developing rats under methyl-deficient regimen. It could therefore potentiate the well-known adverse effects of hyperhomocysteinemia.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2005

Cross-reactivity among drugs: clinical problems.

Cross-reactivity among drugs is either mediated by immunologic mechanisms or not. The former kind is usually explained by the presence of common antigenic determinants in the cross-reacting drugs. In the case of compounds provoking non-allergic hypersensitivity reactions, cross-reactivity is explained by a common pharmacological characteristic, such as the inhibitory effect of non-steroidal anti-inflammatory drugs on cyclooxygenase-1 and the capability of muscle relaxants or contrast media to release histamine through a non-immunologic mechanism. The main clinical problem deriving from cross-reactivity among drugs is the compelling need to choose a potentially cross-reactive compound and, therefore, to assess cross-reactivity by diagnostic tests. In choosing alternative compounds, skin testing has been used in evaluating IgE-mediated cross-reactivity between penicillins and cephalosporins, as well as among muscle relaxants. In assessing T cell-mediated cross-reactivity among contrast media, corticosteroids, anticonvulsants and heparins, delayed-reading intradermal tests and patch tests, together with lymphocyte transformation tests, can be performed. Because of the limited sensitivity of in vivo and in vitro testing, the most prudent way of establishing the tolerability of a compound of the same group in patients who especially require one is a graded challenge when other allergologic tests are negative.

Animals↗