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L Abel

Publications and source records attributed to L Abel.

At least 19 recordsLinked to original sources
PubMed2005

[Genetics and immunity of tuberculosis].

Tuberculosis, caused by Mycobacterium tuberculosis, is the most common mycobacterial disease in the world and remains a leading public health problem. Numerous other mycobacterial species are present in the environment and are most often termed atypical or nontuberculous mycobacteria. Like the attenuated vaccine Bacille Calmette-Guérin (BCG) they are generally poorly virulent, even so they can be at the origin of severe infections if the host immune response is impaired. It has been clearly demonstrated that the intrinsic virulence of a mycobacterial species is not the only factor determining disease severity, which is illustrated by the observation that the majority of individuals infected with M. tuberculosis do not develop clinical disease. Numerous arguments suggest that disease severity depends largely on susceptibility/resistance determined by the host genetic make up. In the following review we will discuss the studies on the genes implicated in complex predisposition to tuberculosis and Mendelian predisposition to disease caused by less virulent mycobacteria, proposing a continuous spectrum between those two types of predisposition.

Child↗
PubMed2003

Segregation of HLA/TNF region is linked to leprosy clinical spectrum in families displaying mixed leprosy subtypes.

Each year an estimated 600000 new leprosy cases are diagnosed worldwide. The spectrum of the disease varies widely from limited tuberculoid forms to extensive lepromatous forms. A measure of the risk to develop lepromatous forms of leprosy is provided by the extent of skin reactivity to lepromin (Mitsuda reaction). To address a postulated oligogenic control of leprosy pathogenesis, we investigated in the present study linkage of leprosy susceptibility, leprosy clinical subtypes, and extent of the Mitsuda reaction to six chromosomal regions carrying known or suspected leprosy susceptibility loci. The only significant result obtained was linkage of leprosy clinical subtype to the HLA/TNF region on human chromosome 6p21 (P(corrected)=0.00126). In addition, we established that within the same family different HLA/TNF haplotypes segregate into patients with different leprosy subtypes directly demonstrating the importance of this genome region for the control of clinical leprosy presentation.

Chromosomes, Human, Pair 6↗
PubMed2003

Genetic control of visceral leishmaniasis in a Sudanese population: candidate gene testing indicates a linkage to the NRAMP1 region.

There is some evidence showing that genetic factors are involved in human susceptibility to parasitic diseases such as schistosomiasis and malaria. Studies have shown that the Nramp1 and H-2 genes are implicated in the control of Leishmania donovani infection in mice. We sought genetic loci involved in the control of susceptibility to visceral disease caused by L. donovani in humans. We studied 37 families with at least two affected sibs living in a village in eastern Sudan, where an outbreak of visceral leishmaniasis occurred between 1995 and 2000. The genetic markers located in five chromosomal regions containing candidate genes were typed: 2q35 (NRAMP1), 5q31-q33 (Th2 cytokine cluster), 6p21 (HLA/TNF-alpha), 6q23 (INFGRI) and 12q15 (INF-gamma). Linkage (multipoint lod-score=1.08; P=0.01) was observed for the 5'(CA) repeat polymorphism in the NRAMP1 promoter. This suggests that genetic variations of this gene affect susceptibility to visceral leishmaniasis in this population.

Adolescent↗
PubMed2003

Variants of the human NRAMP1 gene and susceptibility to tuberculosis in Morocco.

It has been well established that the host genetic background is an important modulator of tuberculosis susceptibility. The NRAMP1 (alias SLC11A1) gene has been associated with tuberculosis susceptibility in several ethnic groups. Here we studied the association and linkage of NRAMP1 with tuberculosis in 116 nuclear families, comprising 211 affected offspring, from Casablanca, Morocco. All enrolled tuberculosis cases were culture-positive. No evidence was found of linkage or association of NRAMP1 with tuberculosis. These findings suggest heterogeneity in the genetic control of tuberculosis susceptibility.

Adolescent↗
PubMed2002

[Human mycobacterial infections: impact of host genetic factors].

Humans are exposed worldwide to a variety of environmental mycobacteria (EM) and most children are inoculated with live Bacille Calmette-Guérin (BCG) vaccine. Although rarely pathogenic, poorly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. M. tuberculosis and M. leprae are more virulent, causing tuberculosis, and leprosy, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. There is now accumulating evidence that the large interindividual variability of clinical outcome results in part from variability in the human genes that control host defense. We review here in current knowledge about genetic predisposition to common (leprosy and tuberculosis) and rare (BCG and EM infections) mycobacterial infections.

Genetic Predisposition to Disease↗
PubMed2001

SMN interacts with a novel family of hnRNP and spliceosomal proteins.

Spinal muscular atrophy (SMA) is a common neurodegenerative disease caused by deletion or loss-of-function mutations of the survival of motor neurons (SMN) protein. SMN is in a complex with several proteins, including Gemin2, Gemin3 and Gemin4, and it plays important roles in small nuclear ribonucleoprotein (snRNP) biogenesis and in pre-mRNA splicing. Here, we characterize three new hnRNP proteins, collectively referred to as hnRNP Qs, which are derived from alternative splicing of a single gene. The hnRNP Q proteins interact with SMN, and the most common SMN mutant found in SMA patients is defective in its interactions with them. We further demonstrate that hnRNP Qs are required for efficient pre-mRNA splicing in vitro. The hnRNP Q proteins may provide a molecular link between the SMN complex and splicing.

Amino Acid Sequence↗
PubMed2001

The Y14 protein communicates to the cytoplasm the position of exon-exon junctions.

We recently described an RNA-binding protein, Y14, that binds preferentially to spliced mRNAs and persists in the cytoplasm. Y14 is part of a multi-protein complex that also contains the mRNA export factor TAP. This suggests that splicing imprints the mRNA with a unique set of proteins that communicate the history of the transcript to the cytoplasm. Here, using microinjection of pre-mRNAs into Xenopus oocyte nuclei followed by immunoprecipitation of RNase-fragmented mRNAs from the cytoplasm, we show that Y14 is stably bound to sequences immediately upstream of exon-exon junctions. This feature appears to be unique to Y14. Using monoclonal antibodies that we produced against Aly/REF, another component recently reported to be an mRNA export factor, we show that Aly/REF is associated with spliced mRNAs in the nucleus but is not detectable on mRNAs in the cytoplasm. Thus, we propose that the splicing- dependent binding of Y14 provides a position-specific molecular memory that communicates to the cytoplasm the location of exon and intron boundaries. This novel mechanism may play an important role in post-splicing events.

Active Transport, Cell Nucleus↗
PubMed2001

Patterns of cortical activity and memory performance in Alzheimer's disease.

BACKGROUND: Declarative memory changes are the hallmark of Alzheimer's disease, although their functional neuroanatomy is not restricted to a single structure. Factor analysis provides statistical methods for evaluating patterns of cerebral changes in regional glucose uptake. METHODS: Thirty-three Alzheimer's patients and 33 age- and gender-matched control subjects were studied with magnetic resonance imaging and positron emission tomography with [(18)F] deoxyglucose. During the tracer-uptake period, subjects performed a serial verbal learning task. Cortical activity was measured in 32 regions of interest, four in each lobe on both hemispheres. RESULTS: Factor analysis with varimax rotation identified seven factors explaining 80% of the variance ("parietal cortex," "occipital cortex," "right temporo-prefrontal areas," "frontal cortex," "motor strip," "left temporal cortex," and "posterior temporal cortex"). Relative to control subjects, Alzheimer's patients showed significantly reduced values on the factors occipital cortex, right temporo-prefrontal areas, frontal cortex, and left temporal cortex. The factor temporo-prefrontal areas showed large differences between patients with good and poor performance, but little difference when control subjects were similarly divided. CONCLUSIONS: Findings suggest that Alzheimer's disease is characterized by altered patterns of cortical activity, rather than deficits in a single location, and emphasize the importance of right temporo-prefrontal circuitry for understanding memory deficits.

Aged↗
PubMed2001

Multipoint development of the weighted pairwise correlation (WPC) linkage method for pedigrees of arbitrary size and application to the analysis of breast cancer and alcoholism familial data.

The weighted pairwise correlation (WPC) method is a simple and powerful model-free method of linkage analysis that has the advantages of being applicable to binary, ordered categorical, quantitative, or censored traits, and to consider all pairs of relatives in large pedigrees. The originally implemented approach was limited to the use of the identical by state (IBS) information, and we recently extended the WPC method to incorporate the identical by descent (IBD) information for two-point linkage analysis. Here, we develop a multipoint WPC method suitable for pedigrees of arbitrary size and large number of markers. The multipoint IBD estimation procedure for relative pairs is based on the efficient regression approach developed for pedigrees implemented in SOLAR. A robust and fast Monte-Carlo procedure is used to determine reliable P values. Application of the method to the 214 pedigrees from the Breast Cancer Linkage Consortium provided for the Genetic Analysis Workshop (GAW) 9 shows that multipoint WPC statistic values were not far from two-point maximum lod-score values obtained by the classical parametric linkage method and were higher than multipoint variance component analysis lod-scores obtained with SOLAR. The multipoint WPC method is also used to analyze the familial Collaborative Study of the Genetics of Alcoholism data on alcoholism released for GAW11. It allows a better specification of the linkage results previously obtained within the chromosome 4 region.

Alcoholism↗
PubMed2001

An autosome-wide search for loci underlying wheezing age of onset in German asthmatic children identifies a new region of interest on 6q24-q25.

While numerous familial studies of asthma have identified several distinct chromosomal regions, no linkage studies have been performed taking into account the age of onset of disease. Here, we performed a genome-wide scan to search for loci linked either to asthma or wheezing age of onset in a population of German asthmatic children by incorporating survival analysis techniques in the maximum-likelihood-binomial approach. In addition to several regions already reported in asthma, wheezing age of onset was found to be strongly linked to chromosome 6q24-q25 (lod score = 3.56). Interestingly, this region contains some candidates genes such as the gene coding for the IFN-gamma receptor ligand-binding chain.

Adolescent↗
PubMed2001

Incorporation of covariates in multipoint model-free linkage analysis of binary traits: how important are unaffecteds?

When the mode of inheritance is unknown, genetic linkage analysis of binary trait is commonly performed using affected-sib-pair approaches. When there is evidence that some covariates influence the phenotype, incorporation of this information is expected to increase the power of the analysis since it allows (1) a better specification of the phenotype and (2) to take into account unaffected subjects. Here, we show how to account for covariates in the sibship-oriented Maximum-Likelihood-Binomial (MLB) linkage method by means of Pearson's logistic regression residuals which are computed using phenotypic and covariate information on both affected and unaffected subjects. These residuals are subsequently analysed as a quantitative phenotype with the corresponding extension of the MLB approach which can be used without any assumption on the distribution of these residuals. Then, a large simulation study is performed to study the relative power of incorporating or not unaffected sibs. To this aim, two different strategies in the multipoint analysis of family data are compared: (1) using residuals of the whole sibships (ie both covariate and genotypic information on unaffecteds is needed), and (2) using affecteds only (no information on unaffecteds is needed), under different generating models according to genetic and covariate effects. The results show that there is a clear increment in the power to detect the susceptibility locus when making use of the information carried by unaffecteds, in particular for dominant mode of inheritance and when values of the covariates influencing the disease are shared by all the members of the family.

Analysis of Variance↗
PubMed2001

Eeg alpha rhythm and glucose metabolic rate in the thalamus in schizophrenia.

Positron emission tomography with uptake of [(18)F]fluorodeoxyglucose (FDG) and quantitative EEG were simultaneously performed in 18 medication-free patients with schizophrenia and in 13 normal volunteers. Subjects performed the Continuous Performance Task (CPT) during FDG uptake. Correlations were calculated between alpha power during the CPT and glucose metabolic rate (GMR) in thalamic regions and between alpha power during the CPT and GMR in occipital cortices. Regression analyses were used to describe the prediction of GMR in the occipital cortices and in the thalamic regions of occipital alpha power. In normal controls, we found (1) significant negative correlations between absolute alpha power and GMR in the left occipital cortex, (2) significant positive correlations between normalized alpha power and GMR in the right and left lateral thalamus and (3) combined effects of GMR in the thalamic regions and the occipital cortices on alpha power, which accounted for 98% of the variance of alpha power. In patients with schizophrenia, we found no significant correlations between alpha power and GMR in the occipital cortices or between alpha power and GMR in the thalamic regions. Correlation coefficients between absolute alpha power and GMR in the left occipital cortex and between normalized alpha power and GMR in the left lateral thalamus were significantly different in normal subjects compared to schizophrenic patients. The present findings provide evidence for involvement of the thalamus in the generation of alpha rhythm in humans. Furthermore, the present results suggest differences in thalamocortical circuits between normal controls and schizophrenic subjects.

Adult↗
PubMed2001

Genome search for additional human loci controlling infection levels by Schistosoma mansoni.

Schistosomiasis is a major public health problem in many developing countries. Previous studies have shown that infection levels by Schistosoma mansoni in a Brazilian population is controlled by a major gene, denoted as SM1, which was mapped to chromosome 5q31-q33 by use of a model-based (logarithm of the odds [lod] score) analysis method. The present study is an autosome-wide scan searching for additional human loci implicated in the regulation of S. mansoni infection intensities. The weighted pairwise correlation model-free linkage method was used in order to consider large pedigrees and to conduct a 2-locus analysis (i.e., to search for a second locus taking into account linkage to 5q31-q33). The most significant linkage results were again obtained in the 5q31-q33 region. Two additional regions provided linkage results with significance levels around 0.001, 1p21-q23 (results independent of 5q31-q33) and 6p21-q21 (results in interaction with 5q31-q33). The investigation of these regions, which contain some candidate genes, is ongoing in other populations to confirm the role of these regions.

Adult↗