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L Abel

Publications and source records attributed to L Abel.

At least 37 records · Page 2Linked to original sources
PubMed2000

Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population.

BACKGROUND: Transmission of human herpesvirus 8 (HHV-8), the aetiological agent of Kaposi's sarcoma, is known to occur during sex among homosexual men. However, other modes of HHV-8 transmission remain to be elucidated in endemic populations. METHODS: We did a population-based seroepidemiological survey in a village in French Guiana among 1337 individuals of African origin (age 2-91 years) who had reliable genealogical data. Plasma samples were taken and tested for HHV-specific IgG by immunofluorescence assay. Risk factors and familial correlations for HHV-8 seropositivity were modelled by logistic regression analysis by use of the estimating equations approach, which expresses familial dependences in terms of odds ratios. Familial odds ratios were also acquired by use of the distribution of all possible pairs of a given familial dependence. FINDINGS: The overall HHV-8 seroprevalence was 13.2% with no difference according to sex. HHV-8 seropositivity was strongly age dependent: at 1.2% under 5 years, HHV-8 seroprevalence rose up to a plateau around 15% between 15 and 40 years, and showed a seroprevalence of more than 27% in individuals older than 40 years. Strong familial aggregation in HHV-8 seroprevalence was found with high mother-child (odd ratio 2.8 [95% CI 1.6-5.0]) and sib-sib (3.8 [1.6-9.5]) correlations. By contrast, no significant correlation between spouses (0.6 [0.2-1.9]) was seen. INTERPRETATION: This pattern of familial aggregation, together with the variation of HHV-8 seroprevalence with age, indicate that, in endemic populations, HHV-8 transmission mainly occurs from mother to child and between siblings during childhood and adolescence.

Adolescent↗
PubMed2000

The survival motor neuron protein of Schizosacharomyces pombe. Conservation of survival motor neuron interaction domains in divergent organisms.

Spinal muscular atrophy is a common often lethal neurodegenerative disease resulting from deletions or mutations in the survival motor neuron gene (SMN). SMN is ubiquitously expressed in metazoan cells and plays a role in small nuclear ribonucleoprotein assembly and pre-mRNA splicing. Here we characterize the Schizosacharomyces pombe orthologue of SMN (yeast SMN (ySMN)). We report that the ySMN protein is essential for viability and localizes in both the cytoplasm and the nucleus. Like human SMN, we show that ySMN can oligomerize. Remarkably, ySMN interacts directly with human SMN and Sm proteins. The highly conserved carboxyl-terminal domain of ySMN is necessary for the evolutionarily conserved interactions of SMN and required for cell viability. We also demonstrate that the conserved amino-terminal region of ySMN is not required for SMN and Sm binding but is critical for the housekeeping function of SMN.

Amino Acid Sequence↗
PubMed2000

Detection of a major gene predisposing to human T lymphotropic virus type I infection in children among an endemic population of African origin.

Human T lymphotropic virus type I (HTLV-I) is a human oncoretrovirus that causes an adult T cell leukemia/lymphoma and a chronic neuromyelopathy. To investigate whether familial aggregation of HTLV-I infection (as determined by specific seropositive status) could be explained in part by genetic factors, we conducted a large genetic epidemiological survey in an HTLV-I-endemic population of African origin from French Guiana. All of the families in 2 villages were included, representing 83 pedigrees with 1638 subjects, of whom 165 (10.1%) were HTLV-I seropositive. The results of segregation analysis are consistent with the presence of a dominant major gene predisposing to HTLV-I infection, in addition to the expected familial correlations (mother-offspring, spouse-spouse) due to the virus transmission routes. Under this genetic model, approximately 1. 5% of the population is predicted to be highly predisposed to HTLV-I infection, and almost all seropositive children <10 years of age are genetic cases, whereas most HTLV-I seropositive adults are sporadic cases.

Adolescent↗
PubMed2000

Human interferon-gamma-mediated immunity is a genetically controlled continuous trait that determines the outcome of mycobacterial invasion.

Individuals with inherited disorders of interferon gamma (IFN-gamma)-mediated immunity appear to be specifically vulnerable to mycobacterial infections. The severity of clinical features of affected individuals differs between cases. Some patients die of mycobacterial infection in early childhood, whereas others have long asymptomatic periods in childhood and as adults. This rare syndrome also shows high allelic and non-allelic genetic heterogeneity. Mutations in IL12B, encoding the interleukin (IL)-12 p40 subunit, and in IL12RB1, encoding the beta1 chain of the IL-12 receptor, result in impaired IFN-gamma production. Mutations in IFNGR1 and IFNGR2, encoding the two IFN-gamma receptor chains, and mutations in STAT1, encoding an essential signaling component, result in impaired cellular responses to IFN gamma. Different types of mutation define two types of complete and two types of partial IFNgammaR1 deficiency. Complete and partial IFNgammaR2 deficiency have also been described. We herein compare the genotypes, cellular phenotypes, and clinical phenotypes of healthy individuals and patients with the seven known genetic disorders impairing cellular responses to IFN-gamma. Patients with defective IFN-gamma production were not considered in this study. The mutations and clinical features of patients with IFNgammaR1, IFNgammaR2, and STAT-1 deficiency are reviewed. Selected cell lines from each of the eight groups were tested for their response to IFN-gamma. We find that individuals may be classified into four broad groups based on genotype, cellular phenotype, and clinical phenotype (normal individuals and patients with mild, intermediate, or severe disease). This correlation suggests that IFN-gamma-mediated cell activation is a genetically controlled quantitative trait and that it determines the outcome of mycobacterial invasion in man.

Adult↗
PubMed2000

Granulomatous reaction to intradermal injection of lepromin (Mitsuda reaction) is linked to the human NRAMP1 gene in Vietnamese leprosy sibships.

The Mitsuda test, which measures the specific immune response against intradermally injected lepromin, has a high prognostic value for susceptibility or resistance to the lepromatous form of leprosy. A sib-pair linkage analysis between the Mitsuda response and the NRAMP1 gene was done among 20 nuclear families with leprosy (totaling 118 sibs) from Ho Chi Minh City, Vietnam. All family subjects were genotyped for several intragenic and flanking NRAMP1 markers, leading to the definition of a fully informative NRAMP1 haplotype. Significant linkage was observed between NRAMP1 and Mitsuda reaction when considered either as a quantitative (P<.002) or as a categorical (P=.001) trait. Separate analyses among healthy and affected sibs showed evidence for linkage in both subsamples, indicating that linkage between the Mitsuda reaction and NRAMP1 is independent of leprosy status. These results support the view that NRAMP1 plays a regulatory role for the development of acquired antimycobacterial immune responses as determined by in vivo Mitsuda test reaction.

Carrier Proteins↗
PubMed2000

Vertical fixation disparity curve and the effects of vergence training in a normal young adult population.

BACKGROUND: The vertical forced vergence fixation disparity (VFD) curve represents the amount of vertical fixation disparity, the steady-state vertical bifixation error of the eyes, at various levels of vertical vergence demand. The main aim of the present study was to examine the effects of vertical vergence training on the slope of the VFD curve in a normal, young adult population. METHODS: Forty-five subjects with normal vision and binocular function underwent vertical vergence training for 1 week. The training was done using a vertical prism bar, and the vertical fixation disparity was measured using the Disparometer. RESULTS: The mean slope of the VFD curve in a normal, young adult population was 1.103 min arc/delta. The slope of the VFD curve decreased significantly after the training and remained flattened for at least 3 months. There was no evidence to support the idea that the decrease in the VFD slope was related to the increase of vertical fusional amplitude. CONCLUSIONS: Vertical prism bar training provided a long-term effect, both increasing the vertical fusional amplitude and flattening the slope of the VFD curve. The decrease in the slope of the VFD curve was thought to be independent of the increase of vertical fusional amplitude.

Adolescent↗
PubMed2000

[Genetic predisposition to bilharziasis in humans: research methods and application to the study of Schistosoma mansoni infection].

The development of genetic epidemiology methods using recent human genetic mapping information together with the growing availability of candidate genes has led to major advances in the identification of host genes in human schistosomiasis. Two phenotypes have been studied so far in the infection by Schistosoma mansoni: infection levels by the parasite as measured by the faecal egg counts, and the severe hepatic fibrosis caused by S. mansoni assessed by ultrasound examination. The first study was performed on Brazilian pedigrees and provided strong evidence for a major gene controlling infection levels by S. mansoni denoted as SM1 which was mapped to chromosome 5q31-q33. This region contains several candidate genes involved in the regulation of the Th1/Th2 response, and the direct role of polymorphisms located within these genes is under investigation. The second study conducted in Sudan also showed the presence of a major gene influencing the development of severe hepatic fibrosis due to S. mansoni infection denoted as SM2. This gene is not located in the 5q31-q33 region, but maps to chromosome 6q22-q23 and is closely linked to the IFN-gamma R1 gene encoding the receptor of the strongly anti-fibrogenic cytokine Interferon-gamma. These findings indicate that two distinct genetic loci control human predisposition to schistosomiasis, SM1 located in the 5q31-q33 region which is likely to play a role in the Th1/Th2 differentiation, and SM2 in 6q22-q23 influencing disease progression with a possible involvement in the regulation of IFN-gamma.

Animals↗
PubMed1999

Introduction of the IBD information into the weighted pairwise correlation method for linkage analysis.

The Weighted Pairwise Correlation (WPC) approach is a non-parametric method of linkage analysis that allows analysis of any kind of phenotypes (quantitative, binary, binary with age of onset) and to consider all pairs of relatives in a pedigree. The principle of this method is to test whether two relatives having close phenotypes also resemble at the marker locus more than expected under the null hypothesis of no linkage. So far, this marker resemblance was estimated by the proportion of alleles shared Identical By State (IBS) by the two relatives. Here, we propose a method to incorporate the Identical By Descent (IBD) information into the WPC approach. For any kind of relative pairs, the computation of the proportion of alleles shared IBD is based on the identification of the closest couple of ancestors, denoted as the reference couple. The IBD information is obtained for pairs of relatives having the same reference couple using individual genotypic vectors derived from this couple. This reconstruction of the IBD information is performed rapidly even in large pedigrees. Simulation studies conducted under various genetic models demonstrate that the use of IBD instead of IBS information leads to a large increase of power, especially in the situation of poorly informative markers.

Genetic Linkage↗
PubMed1999

Maximum-Likelihood-Binomial method for genetic model-free linkage analysis of quantitative traits in sibships.

Sib-pair linkage studies are widely used to investigate the genetic factors implicated in complex quantitative traits. To analyze these data, we propose a Maximum-Likelihood-Binomial (MLB) approach, which considers the sibship as a whole and relies on the idea of binomial distributions of parental alleles among offsprings. The method is based on the introduction of a latent binary variable capturing the linkage information between the observed quantitative trait and the marker, and the final likelihood can be expressed assuming a parametric distribution for the studied trait but also without any assumption on this distribution. The test for linkage is a simple likelihood ratio test involving a single parameter. The performances of the MLB method are assessed by a simulation study in different kinds of family samples. In the case of families with various sibship sizes, both MLB approaches (assuming or not a parametric distribution for the quantitative trait) provide very consistent results in terms of type I errors and yield power levels generally higher than those of the classical Haseman-Elston method. In the case of extremely discordant sib pairs, we analytically show that, for a common asymptotic type I error, the distribution-free MLB statistic is expected to be more powerful than the test proposed by Risch and Zhang [(1995) Science 268:1584-1589]. In samples including both extremely concordant and discordant sib-pairs, simulation studies show that the MLB approach is at least as powerful as the EDAC method [Gu et al. (1996) Genet Epidemiol 13:513-533]. This MLB method, which can be easily extended to perform multipoint analysis and to account for genetic heterogeneity, appears to be quite an interesting alternative for mapping quantitative trait loci in humans.

Alleles↗
PubMed1999

Genome search for alcohol dependence using the weighted pairwise correlation linkage method: interesting findings on chromosome 4.

The nonparametric (model-free) method of linkage analysis Weighted Pairwise Correlation (WPC) has been proposed by Commenges [1994], and extended to incorporate identity-by-descent (IBD) information [Zinn-Justin and Abel, 1999]. We performed an autosome-wide scan in the Collaborative Study on the Genetics of Alcoholism data using the WPC-IBD method, considering two phenotypes related to alcohol dependence defined as residuals of binary traits adjusted for age and sex. Three chromosome 4 markers located in a region of 50 cM spanning from GABRB1 to D4S1651 provided Monte Carlo (MC) p-values lower than 0.005, confirming the possible influence of beta 1 GABA receptor and ADH genes in alcoholism. Furthermore, marker D15S642, not far from the ALDH6 gene, provided an MC p-value of 0.0005 in ethnic groups "White, Hispanic" and "White, non-Hispanic."

Alcoholism↗
PubMed1999

Genetic model-free linkage analysis using the maximum-likelihood-binomial method for categorical traits.

Within the simulated data of the 11th Genetic Analysis Workshop, we searched for the genes controlling the disease. We analyzed 200 families from Studies 2 and 3 presenting both mild and severe forms of disease. Linkage analysis was performed using the recently developed genetic model-free maximum-likelihood-binomial (MLB) method which overcomes the problem of multiple sibs by considering the sibship as a whole. The MLB allowed us to consider the disease as either a binary (affected/unaffected) or an ordered categorical (differentiating the two forms of disease and including effects of environmental factors) phenotype. In both studies, two regions provided evidence for linkage at a significance level below 10(-4). One is located on chromosome 3 (from D3G041 to D3G047), and the other on chromosome 5 (from D5G034 to D5G041). In Study 2, the most significant results were obtained by combining both forms of disease, suggesting that they are under the same genetic control, while in Study 3, the stronger results were obtained when considering severe subjects alone, suggesting that only the severe form is under the control of both locus B and C. The subsequent knowledge of the true model allowed a posterior interpretation of our results, in particular the difference in optimal coding schemes observed between Studies 2 and 3, and the failure to locate locus A.

Alleles↗
PubMed1999

Differential effects of CD4+ and CD8+ cells on lymphocyte development from human cord blood cells in murine fetal thymus explants.

The possibility that mature lymphocytes play a role in the regulation of human T cell development was studied in the experimental model of fetal thymus organ cultures (FTOC), by reconstituting lymphocyte-depleted murine fetal thymus (FT) lobe with cells isolated from human umbilical cord blood (CB). Cultures were incubated with human cytokines (IL-7, FLT-3 ligand and Steel Factor), or remained untreated. When CD4+, or CD8+ CB cells, were co-cultured with FT explants, they expanded and maintained their original phenotypic markers, with no significant effect of the cytokines. Cultures of human hematopoietic stem cells (CD34+) gave rise to CD4+CD8- cells, which were mainly CD3-, with no indication of further intermediate developmental stages. However, a limited number of CD4+CD8+ (double positive [DP]) cells were detected when the CD34- cells were co-cultured with CD4+ cells from the same CB samples. In contrast, FT with unseparated CB cells resulted in the different CD4/CD8 subsets, and their numbers increased in the presence of cytokines. The appearance of DP cells depended on the presence of either CD4+ or CD8+ cells in the cultured CB samples. Hence, DP cells were not detected when the CB was depleted of CD4+ and CD8- cells ("depCB") before culture, and they appeared when depCB were co-cultured with either CD4+ or CD8+ cells. In contrast, CD4+ cells inhibited the development of CD8+CD3+ cells, and this was most pronounced in the absence of the cytokines. There was no symmetrical down-regulatory effect of CD8+ cells on the development of CD4+CD3+ cells. Addition of IL-15 to the cytokine mixture led to an increased proportion of CD56+ cells in cultures of CD34+ cells. The presence of CD4+, and not CD8+ cells, interfered with this process. Our results thus imply differential effects of CD4+ and CD8+ cells on thymocytopoiesis.

ADP-ribosyl Cyclase↗
PubMed1999

Full results of the genome-wide scan which localises a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33.

Three hundred million individuals are at risk of infection by schistosomes, and thousands die each year of severe hepatic disease. Previous studies have shown that the intensity of infection by Schistosoma mansoni in a Brazilian population is controlled by a major gene, denoted as SM1. We report here the full results of a genome-wide search that was performed on this population to localise SM1. Two hundred and forty-six microsatellites were used for the primary map, and only one region in 5q31-q33 provided significant evidence of linkage. SM1 was subsequently mapped to this region, which contains several genes encoding cytokines or cytokine receptors which are involved in protection against schistosomes. Three additional regions, 1p22.2, 7q36 and 21q22-22-qter, yielded promising, although not significant, lod-score values. These regions contain candidate genes encoding cytokines or molecules relevant to anti-schistosome immunity.

Animals↗
PubMed1999

Genetic epidemiology of host predisposition microfilaraemia in human loiasis.

Evidence is accumulating from experimental and human studies that genetic factors are involved both in the control of infectious diseases and in the regulation of infection levels and clinical presentation. So far few studies have investigated the role of these genetic factors in human infection by the filarial parasite Loa loa. We present a segregation analysis on 74 nuclear families who live in the tropical rainforest of southern Cameroun and are exposed to homogeneous loiasis transmission. The results indicate that there is a genetic predisposition to be microfilaraemic and that predisposed subjects might be genetically unable to mount an efficient immune response against loiasis antigens. This individual susceptibility could explain at least in part why the prevalence of infection (microfilaraemic individuals) does not usually exceed 30% of the exposed population in hyperendemic regions. Further genetic studies, based on linkage analysis using both familial information and genetic markers, will help to identify the nature of the genetic factors predisposing to microfilaraemia.

Adolescent↗
PubMed1999

Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene.

Lethal disease due to hepatic periportal fibrosis occurs in 2%-10% of subjects infected by Schistosoma mansoni in endemic regions such as Sudan. It is unknown why few infected individuals present with severe disease, and inherited factors may play a role in fibrosis development. Schistosoma mansoni infection levels have been shown to be controlled by a locus that maps to chromosome 5q31-q33. To investigate the genetic control of severe hepatic fibrosis (assessed by ultrasound examination) causing portal hypertension, a segregation analysis was performed in 65 Sudanese pedigrees from the same village. Results provide evidence for a codominant major gene, with.16 as the estimated allele A frequency predisposing to advanced periportal fibrosis. For AA males, AA females, and Aa males a 50% penetrance is reached after, respectively, 9, 14, and 19 years of residency in the area, whereas for other subjects the penetrance remains <.02 after 20 years of exposure. Linkage analysis performed in four candidate regions shows that this major locus maps to chromosome 6q22-q23 and that it is closely linked (multipoint LOD score 3.12) to the IFN-gammaR1 gene encoding the receptor of the strongly antifibrogenic cytokine interferon-gamma. These results show that infection levels and advanced hepatic fibrosis in human schistosomiasis are controlled by distinct loci; they suggest that polymorphisms within the IFN-gammaR1 gene could determine severe hepatic disease due to S. mansoni infection and that the IFN-gammaR1 gene is a strong candidate for the control of abnormal fibrosis observed in other diseases.

Adolescent↗
PubMed1999

Susceptibility to periportal (Symmers) fibrosis in human schistosoma mansoni infections: evidence that intensity and duration of infection, gender, and inherited factors are critical in disease progression.

Lethal disease in Schistosoma mansoni infections is mostly due to portal hypertension caused by hepatic periportal fibrosis. To evaluate the factors that may determine severe disease, livers and spleens were examined by ultrasound in a Sudanese population living in a village where S. mansoni is endemic. Early (FI), moderate (FII), or advanced (FIII) fibrosis was observed in 58%, 9%, and 3% of the population, respectively. Although FI affected 50%-70% of the children and adolescents, FII prevalence was low in subjects </=20 years old but increased sharply (45%-58%) in men 21-30 years old and was associated with the highest infections. Portal and splenic vein diameters were increased in one-third of persons with FII and in almost all with FIII disease. Severe disease, FII or FIII with portal hypertension, affected 6% of the population, was associated with splenomegaly, occurred mostly in adult men, and was clustered in a few pedigrees. These observations suggest that infection intensity and duration, gender-related factors, and inherited factors are important in fibrosis development.

Adolescent↗