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Biomedical subjects

L Abel

Publications and source records attributed to L Abel.

At least 91 records · Page 5Linked to original sources
PubMed1996

[The genetic susceptibility to leprosy in humans].

The capacity of certain individuals to resist certain diseases, including leprosy, has for a long time been considered as being influenced by genetic factors. The clinical and pathological spectrum of leprosy, epidemiological heterogeneity, both geographic and ethnic, in the prevalence of polar forms, may be explained by genetic differences in host resistance. While the specific genes in question have not been identified, recent studies suggest a genetic basis for differences in the capacity of macrophages in the host to reduce bacterial multiplication. Experimental models analyzing the reactions of antimycobacterial defence have underscored at existing differences in resistance or vulnerability to infection (M. bovis, BCG, M. lepraemurium, M. tuberculosis) were guided by a dominant gene which exists in two allelic forms, bcgr and bcg5. The bcgr allele confers resistance and is more dominant than the bcgs allele which represents greater vulnerability to infection. The murine candidate gene for the bcg gene has been named NRAMP (Natural Resistance-associated Macrophage Protein). Even though the exact function of NRAMP is not currently known, it has been demonstrated that this gene is expressed mainly in macrophages, and that it brings about increased bacteriostatic capacity in these cells. NRAMP is structurally homologous to the family of membranous proteins having a transport function linking ATP. NRAMP is similar to the membranous bacterial system transporting nitrites. The NRAMP protein is also involved as a signal of transduction during the activation of macrophages. It is therefore possible to conceive of genetic polymorphism at this locus intervening in specific and non-specific immune responses to infection. Apart from such potential polymorphism during the initial phase of infection, immunogenetic studies suggest that the polymorphism of class II HLA molecules could intervene in the evolution of secondary immune response to M. leprae. Knowing that HLA molecules are expressed in a co-dominant form, and attributing extraordinary allelic polymorphism to this locus, there may be a rather wide range of immune responses to the M. leprae antigens in subjects with discordant HLA and in populations which have varied genetic profiles. In general it has been acknowledged that HLA-DR isotypes are associated with protective response, while HLA-DQ isotypes are said to be associated with multibacillary lepromatous forms. The chief role of the HLA systems controlling cell-mediated immunity leads to the probability that differences in HLA haplotypes could contribute to the wide spectrum of immune responses observed in leprosy. Genetic determinants of resistance to leprosy cannot be described in a straightforward manner using a classic approach because the complex mechanisms of resistance, yet to be clarified and for which at least two loci are believed to be contributory, may be re-assessed like a multifactorial, multigenetic complex in which environmental events linked to the transmission of M. leprae, its duration, intensity and host factors, varying as a function of time, intervene. A close study of each element and better understanding of the physiological and pathological mechanisms of infection and disease are necessary in order to state the influence of genetic factors on each of them with greater precision.

Adenosine Triphosphate↗
PubMed1995

Lymphocyte development in irradiated thymuses: dynamics of colonization by progenitor cells and regeneration of resident cells.

Lymphocyte development in irradiated thymuses was analyzed using two complementary strategies: an in vitro experimental model and computer simulations. In the in vitro model, fetal thymus lobes were irradiated and the regeneration of cells that survived irradiation were examined, with the results compared to those of reconstitution of the thymus by donor bone marrow cells and their competition with the thymic resident cells. In vitro measurements of resident cell kinetics showed that cell proliferation is slowed down significantly after a relatively low (10 Gy) irradiation dose. Although the number of thymocytes that survived irradiation remained low for several days post-irradiation, further colonization by donor cells was not possible, unless performed within 6 h after irradiation. These experimental results, coupled with the analysis by computer simulations, suggest that bone marrow cell engraftment in the irradiated thymus may be limited by the presence of radiation-surviving thymic resident cells and the reduced availability of seeding niches.

Animals↗
PubMed1995

Complex segregation analysis of leprosy in southern Vietnam.

To investigate the nature of the genetic component controlling susceptibility to leprosy and its subtypes, 402 nuclear families were ascertained through a leprosy patient followed at the Dermatology Hospital in Ho Chi Minh City, Vietnam; 285 families were of Vietnamese origin and 117 were of Chinese origin with a higher proportion of lepromatous forms among Chinese patients. Segregation analyses were conducted using the model developed by Abel and Bonney [(1990) Genet Epidemiol 7:391-407], which accounted for variable age of onset and time-dependent covariates. Three phenotypes were considered: leprosy per se (all forms of leprosy together), nonlepromatous leprosy, and lepromatous leprosy. For each of this phenotype, analyses were performed on the whole sample and separately on the Vietnamese and the Chinese families. The results showed that a single Mendelian gene could not account for the familial distributions of leprosy per se and its two subtypes in the whole sample. However, these results were different according to the ethnic origin of the families. In the Vietnamese subsample, there was evidence for a codominant major gene with residual familial dependences for the leprosy per se phenotype, and borderline rejection of the Mendelian transmission hypothesis for the nonlepromatous phenotype. In Chinese families, strong rejection of Mendelian transmission was obtained in the analysis of leprosy per se, and no evidence for a familial component in the distribution of the nonlepromatous phenotype was observed. For the lepromatous phenotype, the discrimination between models was poor, and no definitive conclusion could be reached. Referring to immunological data, we suggest that these results could be explained by a heterogeneity in the definition of the lepromatous phenotype. It is likely that progress in the understanding of the genetic components involved in the expression of leprosy will come from a better definition of the phenotype under study, and immunological studies are ongoing in this population to investigate this hypothesis.

Adolescent↗
PubMed1995

Complex segregation analysis of familial diseases with variable age of onset: comparison of different methods by a simulation study.

Standard methods of segregation analysis, such as originally developed in the unified model (UM) or the regressive logistic model (RLM) do not account for age of onset, and use instead age at examination. To take into account age of onset, models should be formulated using survival analysis concepts, as it was recently proposed with a model based on a logistic hazard function (LHM). A simulation study was conducted to compare the performances of the three methods (UM, RLM, and LHM) in analyzing generated familial data with variable age of onset. When the data were simulated under a polygenic hypothesis, all analysis models were robust with respect to the false conclusion of a major gene, if the tests of transmission probabilities were performed properly. When the data were generated under a major gene hypothesis, two main results were observed: 1) the use of the LHM markedly increased the power to detect a major gene, in particular when a genotype by age interaction was introduced in the model; and 2) in the situation of disease-specific mortality, the use of either UM (whether specific mortality was accounted for or not) or RLM led to both spurious conclusions and bias in parameter estimates. These latter results obtained with the UM and the RLM can be explained by the violation of one constraint of both models observed in a situation of disease-specific mortality, i.e., given all covariates, the probability of being affected and that of not being affected should sum to 1. The use of methods based on survival analysis concepts is recommended in the study of familial diseases with variable age of onset, especially in the case of a correlation between age of onset and age at examination which is induced by disease-specific mortality.

Adult↗
PubMed1995

How can maximum likelihood methods reveal candidate gene effects on a quantitative trait?

Different maximum likelihood approaches were used to explore the role of candidate genes in the variability of quantitative trait Q1 while accounting for the effects of age, Q2, and Q3. Segregation analysis, under the class D regressive model, provides evidence for a Mendelian gene effect on the adjusted trait Q1. Results of gene mapping through lod-score analyses remain puzzling. Pairwise lod scores indicate a possible linkage with the candidate gene C5 which is excluded when using tightly linked informative marker loci. Finally, our combined segregation and linkage analysis clearly shows that a C5 linked gene is involved in Q1 variability. However, given the lod-score results within the C5 region, we postulate a more complex mechanism for Q1 than a single di-allelic C5 linked gene. The knowledge of the true model (C5 is MG1 and has three alleles) permits a partial explanation of our results. This study demonstrates the advantages of using complementary approaches to reveal the role of candidate genes in complex traits, and the value of simultaneous estimation of linkage and segregation parameters.

Alleles↗
PubMed1995

Glucose metabolic correlates of continuous performance test performance in adults with a history of infantile autism, schizophrenics, and controls.

Twenty-five schizophrenic patients, fourteen adults with a history of infantile autism, and twenty normal controls performed a test of sustained attention, the degraded stimulus continuous performance test (CPT), during the 35 minute 18-fluoro-2-deoxyglucose uptake period preceding positron emission tomographic (PET) scan acquisition. This is the first analysis comparing correlations between glucose metabolic rate (GMR) for selected regions and CPT performance. CPT performance differed in controls and schizophrenics, but autistics did not differ from either group. In controls and schizophrenic patients, task performance correlated with GMR in medial superior frontal gyrus and lateral inferior temporal gyrus, suggesting that activation of those regions is important in the normal performance of the task and that damage to those regions, which also showed low GMR in schizophrenics, contributes to the attentional dysfunction in schizophrenia. Also, schizophrenics showed negative correlations of task performance with anterior cingulate activity suggesting that overactivity of that region, which is involved in mental effort and whose GMR was low in our larger study of schizophrenia, impairs task performance in schizophrenics. Autistic patients showed negative correlations of medial frontal cortical GMR with attentional performance, suggesting that neuronal inefficiency in that region may contribute to poor performance.

Adolescent↗
PubMed1995

Genetic epidemiology of breast cancer: interest of survival analysis methods.

In an attempt to explain the controversy resulting from the analysis of the breast cancer data collected by Jacobsen, a segregation analysis was performed using successively the unified mixed model (UM) and the logistic hazard function model (LHM) (Abel & Bonney, 1990). Under the UM, age of onset of the disease cannot be taken into account, each individual being assigned to a liability class according to his age at examination, whereas, in the LHM, variable age of onset is modelled using survival analysis methods. Under the UM, we confirmed the results of Demenais et al. (1986b), i.e. the transmission probabilities are significantly different from Mendelian expectations. The same results were obtained when taking into account the specific mortality for the computation of the morbid risk observed in a given liability class. Under the LHM, the analysis provides evidence for a monogenic autosomal model with a rare dominant allele responsible for the disease, and transmission probabilities compatible with Mendelian expectations. This study shows that the rejection of the Mendelian transmission under the UM can be due to a violation of a constraint of this model (i.e. the probability of being and not being affected in a given liability class should sum to 1) when a specific mortality is induced by the disease as in breast cancer. Survival analysis methods avoid these problems by taking into account the onset of the disease as the failure time event and are more suitable when studying a complex trait such as breast cancer.

Breast Neoplasms↗
PubMed1995

MHC-linked colonization of the thymus and thymocyte development: effects of mature T lymphocytes.

Effects of mature T lymphocytes on thymic colonization by lymphohemopoietic cells were investigated in an in vitro experimental model, using a variety of experimental strategies. Lymphoid-depleted fetal thymus (FT) explants (C57BL/Ka, Thy1.1, H-2b) were incubated with bone marrow (BM) cells from syngeneic (C57BL/Ka; SBM) and allogeneic (BALB/c, Thy1.2, H-2d; ABM) donors. Cocultures of FT with SBM and ABM, depleted of Thy1+ or of CD3+ cells, resulted in equal proportions of lymphocytes from both BM donors. When peripheral blood lymphocytes (PBL) from synegenic or semi-allogeneic donors (F1[C57BL/Ka x C57BL/6J], Thy1.1/Thy1.2); or F1[C57BL/Ka x BALB/c], Thy1.1/Thy1.2, respectively) were added to these cultures, the total lymphocyte count per thymic lobe decreased and a developmental preference of the SBM-derived cells, as compared to the ABM-derived cells, was noted. Cells of the PBL types were also observed in the cultures. Cocultures of FT with ABM and PBL showed reduced proportions of ABM-derived cells and occurrence of cells of the PBL type. Finally, FT explants partially depleted of lymphocytes by irradiation (6 Gy), were cocultured with PBL from either syngeneic or allogeneic donors. In the presence of syngeneic PBL, the total number of cells and the proportion of double-positive (CD4+CD8+) T cells were similar to those in the FT cultured by itself, whereas in the presence of allogeneic PBL these values were reduced. The study suggests that mature T lymphocytes may play a role in the developmental processes in the thymus, and points to MHC-linked selective effects.

Animals↗
PubMed1995

Longitudinal survey of Loa loa filariasis in southern Cameroon: long-term stability and factors influencing individual microfilarial status.

A longitudinal, one-year survey of Loa loa infection was carried out in an endemic area of southern Cameroon. Parasitologic samplings (calibrated thick blood smears) were performed every two months to study the evolution of loiasis infection at both the population and the individual level. The mean number of measurements by subject was 3.8 (range 1-6). At the population level, prevalence of infection and microfilarial load were found to be very stable over time. This observation is consistent with the existence of an important reserve of parasitic material available for vectors and the maintenance of high levels of transmission. At the individual level, both the microfilarial status (microfilaremic/nonmicrofilaremic) and the level of parasitemia showed a remarkable stability over time. Age was the relevant factor that influenced the individual microfilarial status in the whole population. When only microfilaremic individuals were taken into account, age did not influence the level of microfilaremia, suggesting that loiasis could be considered as a noncumulative disease. The stability of individual microfilarial status and the pattern of infection variations observed with age support the view that genetic factors might be involved in host defense mechanisms against loiasis infection.

Adolescent↗
PubMed1995

[Role of genetic epidemiology in the study of infectious diseases. The example of malaria].

Genetic epidemiology is a new tool for the study of malaria, with interesting incidence in the comprehension of host/parasite interrelations. The existence of a co-dominant major gene, with a mendelian transmission, controlling the levels of parasitemia has been found out. This allele has a frequency of 24% which means that about 6% of the population is predisposed to high parasitemias. These studies show the interest to integrate the existence of a genetical variability in the development and the evaluation of malaria control programmes. They are offering new perspectives in therapeutics and in the elaboration of vaccinal strategies.

Animals↗
PubMed1994

Selective reductions in prefrontal glucose metabolism in murderers.

This study tests the hypothesis that seriously violent offenders pleading not guilty by reason of insanity or incompetent to stand trial are characterized by prefrontal dysfunction. This hypothesis was tested in a group of 22 subjects accused of murder and 22 age-matched and gender-matched controls by measuring local cerebral uptake of glucose using positron emission tomography during the continuous performance task. Murderers had significantly lower glucose metabolism in both lateral and medial prefrontal cortex relative to controls. No group differences were observed for posterior frontal, temporal, and parietal glucose metabolism, indicating regional specificity for the prefrontal deficit. Group differences were not found to be a function of raised levels of left-handedness, schizophrenia, ethnic minority status, head injury, or motivation deficits in the murder group. These preliminary results suggest that deficits localized to the prefrontal cortex may be related to violence in a selected group of offenders, although further studies are needed to establish the generalizability of these findings to violent offenders in the community.

Adult↗
PubMed1994

Mutations of the RET proto-oncogene in Hirschsprung's disease.

Hirschsprung's disease (HSCR) is a common condition (1 in 5,000 live births) resulting in intestinal obstruction in neonates and megacolon in infants and adults. This disease has been ascribed to the absence of autonomic ganglion cells, which are derived from the neural crest, in the terminal hindgut. Segregation analyses have suggested incompletely penetrant dominant inheritance in familial HSCR. Recently, a gene for HSCR has been mapped to chromosome 10q11.2 (refs 6, 7). No recombination was observed between the disease locus and the locus for the RET proto-oncogene, a protein tyrosine kinase gene expressed in the cells derived from the neural crest. Here we report nonsense and missense mutations in the extracellular domain of RET protein (exons 2, 3, 5 and 6) in six unrelated probands and show that the mutant genotypes segregate with the disease in HSCR families. Mutations of RET have been previously reported in multiple endocrine neoplasia type 2A (MEN 2A). Thus, germ-line mutations of the RET gene may contribute either to developmental anomalies in HSCR or to inherited predisposition to cancer in MEN 2A.

Base Sequence↗
PubMed1994

Developmental interactions of CD4 T cells and thymocytes: age-related differential effects.

The study was designed to determine whether the developmental potential of immature thymocytes in the thymus is altered in aging, and whether concomitantly present mature T cells have any feedback effect. The strategy was to seed sorted double negative, CD4-CD8-(DN) thymocytes on their own, or in the presence of mature T cells, onto lymphoid depleted fetal thymus (FT) explants, and to examine the resulting T cell subsets. Thymocyte donors were young (2-3 months) and old (24 months) C57BL/6J, Thy1.2 mice and splenocytes were from C57BL/Ka, Thy1.1 mice. The DN cells of the old gave rise to lower values of double positive CD4+CD8+ (DP) cells than those of the young. Cocultures containing a mixture of DN thymocytes and CD4+CD8- splenocytes showed higher CD4+CD8- and DN, and lower DP and CD4-CD8+ levels in the old-donor derived cells, as compared with the young ones. Similar results were obtained with CD4+CD8- thymocytes. In contrast, the presence of CD4-CD8+ splenocytes had no effect on the pattern of DN cell development. Our data indicate that differentiation of CD4/CD8 thymocyte phenotypes is affected by CD4+ cells, in an age-associated differential manner.

Aging↗
PubMed1994

Long segment and short segment familial Hirschsprung's disease: variable clinical expression at the RET locus.

Hirschsprung's disease (aganglionic megacolon, HSCR) is a frequent condition of unknown origin (1/5000 live births) resulting in intestinal obstruction in neonates and severe constipation in infants and adults. In the majority of cases (80%), the aganglionic tract involves the rectum and the sigmoid colon only (short segment HSCR), while in 20% of cases it extends toward the proximal end of the colon (long segment HSCR). In a previous study, we mapped a gene for long segment familial HSCR to the proximal long arm of chromosome 10 (10q11.2). Further linkage analyses in familial HSCR have suggested tight linkage of the disease gene to the RET protoncogene mapped to chromosome 10q11.2. Recently, nonsense and missense mutations of RET have been identified in HSCR patients. However, the question of whether mutations of the RET gene account for both long segment and short segment familial HSCR remained unanswered. We have performed genetic linkage analyses in 11 long segment HSCR families and eight short segment HSCR families using microsatellite DNA markers of chromosome 10q. In both anatomical forms, tight pairwise linkage with no recombinant events was observed between the RET proto-oncogene locus and the disease locus (Zmax = 2.16 and Zmax = 5.38 for short segment and long segment HSCR respectively at 0 = 0%) Multipoint linkage analyses performed in the two groups showed that the maximum likelihood estimate was at the RET locus. Moreover, we show that point mutations of the RET proto-oncogene occur either in long segment or in short segment HSCR families and we provide evidence for incomplete penetrance of the disease causing mutation. These data suggest that the two anatomical forms of familial HSCR, which have been separated on the basis of clinical and genetic criteria, may be regarded as the variable clinical expression of mutations at the RET locus.

Chromosome Mapping↗