1991: the year in medicine with bold predictions for 1992.
Explore the source record for details and available documents.
Forecasting↗
Biomedical subjects
L Abel
Publications and source records attributed to L Abel.
Segregation analysis detects a major gene controlling blood infection levels in human malaria.
The profound influence that the genetic makeup of the host has on resistance to malaria infection has been established in numerous animal studies. This genetic heterogeneity is one of the main causes of the difficulties in developing an effective malaria vaccine. Segregation analysis is the first step in identifying the nature of genetic factors involved in the expression of human complex diseases, as infectious diseases. To assess the role of host genes in human malaria, we performed segregation analysis of blood parasite densities in 42 Cameroonian families by using both the unified mixed model and the class D regressive model of analysis. The results provide clear evidence for the presence of a recessive major gene controlling the degree of infection in human malaria. Parameter estimates show a frequency of .44-.48 for the deleterious allele, indicating that about 21% of the population is predisposed to high levels of infection.
Adolescent↗
Effects of clozapine and thiothixene on glucose metabolic rate in schizophrenia.
Twelve patients with schizophrenia received positron emission tomography scans with 18F-deoxyglucose before and after 4 to 6 weeks of treatment with clozapine or thiothixene. Both stereotaxic and magnetic resonance image template methods were used to position regions of interest for metabolic rate analysis. Clozapine increased and thiothixene decreased metabolic rates in the basal ganglia; these effects were most marked on the right side. Within the basal ganglia, a superior to inferior gradient in drug effect was found for thiothixene but not clozapine. This gradient resembled in some respects observations on regional differences in D2 receptors in human autoradiography. Baseline metabolic rates also predicted clinical medication response, with right inferior caudate metabolic rates differentiating clozapine and thiothixene responders. Larger sample studies are needed to replicate and extend these initial findings.
Adult↗
Doctor traps.
Explore the source record for details and available documents.
Physician-Patient Relations↗
Thymocyte development in an in vitro constructed chimera of irradiated fetal thymus and lymphohemopoietic cells.
An in vitro model of irradiated thymus-BM chimera was constructed to analyze the developmental interactions of donor and recipient type thymocytes. The experimental system was based on exposing 14-day fetal mouse thymuses to graded doses of irradiation and then reconstituting them with cells from various lymphohemopoietic origins. Values of donor vs. recipient type cells in chimeric thymuses varied with radiation dose, cell inoculum size and time between irradiation and cell seeding. During an 11 day organ culture period, thymocyte progenitors differentiated in this thymic microenvironment and expressed T-cell surface markers. The pattern of expression of T-cell surface markers in these cultures was similar to that in intact fetal thymic explants.
Animals↗
The placebo effect and affect.
Explore the source record for details and available documents.
Double-Blind Method↗
Ready or not, here they (eventually) come: medical practice guidelines.
Explore the source record for details and available documents.
Clinical Protocols↗
Evidence for the segregation of a major gene in human susceptibility/resistance to infection by Schistosoma mansoni.
Severe clinical disease caused by the major human parasite Schistosoma mansoni is the consequence of high and prolonged infections. Epidemiological studies indicate that, for individuals having frequent contacts with cercaria-infested waters, both infection intensities and reinfection after treatment depend, in large part, on their intrinsic susceptibility/resistance to infection, suggesting the role of genetic factors in human resistance to S. mansoni. To investigate whether a major gene controls human susceptibility/resistance to infection by S. mansoni, segregation analysis of infection intensities, adjusted for the factors relevant in schistosomiasis (water contact, age, sex), was performed on 20 Brazilian pedigrees (269 individuals), using both the unified mixed model and the regressive model of analysis. The results are consistent with the hypothesis that there is a codominant major gene controlling human susceptibility/resistance to infection by S. mansoni. Parameter estimates indicate a frequency of .20-.25 for the deleterious allele; thus, about 5% of the population is predisposed to high infections, 60% is resistant, and 35% has an intermediate, although fairly good, level of resistance. These findings provide a genetic basis for earlier observations on the lower resistance and the predisposition to reinfection of certain individuals. In addition to the detection of a major gene effect, the data suggest that immunity to S. mansoni develops progressively during childhood to reach a maximum around the age of puberty. The implications of these results for the strategy to be used in endemic areas to reduce morbidity and to control parasite transmission are discussed.
Age Factors↗
Leprosy and BCG in southern Vietnam.
Explore the source record for details and available documents.
Adult↗
A time-dependent logistic hazard function for modeling variable age of onset in analysis of familial diseases.
The paper presents an extension of the regressive logistic models proposed by Bonney [Biometrics 42:611-625, 1986], to address the problems of variable age-of-onset and time-dependent covariates in analysis of familial diseases. This goal is achieved by using failure time data analysis methods, and partitioning the time of follow up in K mutually exclusive intervals. The conditional probability of being affected within the kth interval (k = 1...K) given not affected before represents the hazard function in this discrete formulation. A logistic model is used to specify a regression relationship between this hazard function and a set of explanatory variables including genotype, phenotypes of ancestors, and other covariates which can be time dependent. The probability that a given person either becomes affected within the kth interval (i.e., interval k includes age of onset of the person) or remains unaffected by the end of the kth interval (i.e., interval k includes age at examination of the person) are derived from the general results of failure time data analysis and used for the likelihood formulation. This proposed approach can be used in any genetic segregation and linkage analysis in which a penetrance function needs to be defined. Application of the method to familial leprosy data leads to results consistent with our previous analysis performed using the unified mixed model [Abel and Demenais, Am J Hum Genet 42:256-266, 1988], i.e., the presence of a recessive major gene controlling susceptibility to leprosy. Furthermore, a simulation study shows the capability of the new model to detect major gene effects and to provide accurate parameter estimates in a situation of complete ascertainment.
Adolescent↗
Quantitative analysis of bone marrow thymic progenitors in young and aged mice.
Our studies on the capacity of bone marrow (BM) to generate T lymphocytes in aging have revealed that under the competitive conditions of thymic reconstitution, cells of aged mice are significantly inferior to those of the young. The present study was designed to further investigate the basis of this age-related change. Two mechanisms were considered: (a) The potential of BM-derived T cell precursors from aged mice to proliferate and differentiate in the thymic microenvironment is impaired. (b) The frequency of T cell precursors is reduced in BM of aged mice, thus affecting their ability to compete efficiently in reconstituting the thymus. These possibilities were studied in vitro by colonizing thymocyte-depleted fetal thymic lobes with BM cells from aged (24-month) and young (3-month) C57BL/6 mice. By determining the cell cycle duration of BM-derived cells which have seeded the thymic lobes, we found that cells originating from aged mice proliferate in the thymus at the same rate as those from young mice. Reconstitution with limiting numbers of BM cells indicated that the frequency of thymic progenitors in the BM is significantly reduced in aged as compared to young mice. We thus conclude that aging is associated with a quantitative reduction in the frequency of thymic progenitors in the BM.
Aging↗
Syngeneic preference manifested by thymic stroma during development of thymocytes from bone marrow cells.
The question whether major histocompatibility complex (MHC) recognition is expressed in interactions between thymocyte progenitors and thymic stroma cells was investigated in an organ culture system, in which inductive interactions between thymic stroma cells and thymocyte progenitors of different MHC haplotypes could be measured. Thymocyte-depleted fetal thymuses were reconstituted with mixtures of syngeneic and allogeneic bone marrow cells, which also differed in their Thy-1 allele. The relative repopulating ability of the cells was estimated by determining the percentage of emerging Thy-1.1+ vs. Thy-1.2+ thymocytes. Similar values of Thy-1+ cells of the bone marrow donor type developed when the thymus were reconstituted by bone marrow from donors which were either syngeneic or allogeneic to the thymic explants. However, when a 1:1 mixture of syngeneic and allogeneic cells was applied to the thymus, a syngeneic preference was manifested in development of Thy-1+ cells. When mixtures of bone marrow cells from C57BL/Ka (Thy-1.1) and B10.A MHC-congenic (Thy-1.2) mice were used, this developmental preference was found to map to the I-E region. Thymocytes derived from bone marrow cells allogeneic to the stroma, seeded on their own, manifested an advantage over allogeneic bone marrow cells from a different MHC haplotype, in a secondary reconstitution. This suggested that allogeneic bone marrow progenitor cells can be "educated" by the host thymic stroma to behave, in the competitive reconstitution, like syngeneic cells.
Animals↗
Robustness of the unified model to shared environmental effects in the analysis of dichotomous traits.
Simulation studies were conducted to assess to what extent the conclusions of segregation analysis, performed under the unified model, can be affected by the presence of unmeasured environmental factors shared by family members. Dichotomous data were generated on six-member nuclear families under two variants of the mixed model, incorporating environmental effects shared by all family members. When the generating model includes a polygenic component and a shared environmental effect, there is false detection of a major gene, especially when the joint likelihood of parents' and offspring's phenotypes is computed. The proportion of false conclusions increases as the shared environmental effect increases. On the other hand, the presence of a shared environmental effect in addition to a major gene component does not alter the detection of the major gene nor the transmission probability estimates, which are close to the expected Mendelian values. The rejection of the Mendelian transmission hypothesis, as observed in familial analyses of affected disorders, might be the result of mechanisms other than those considered here, such as more complex sources of environmental resemblance or a possible genetic heterogeneity.
Affective Disorders, Psychotic↗
Modeling the age-of-onset function in segregation analysis: a causal scheme for leprosy.
Several methods have been proposed to take into account the variable age of onset of a disease in genetic analysis. A different approach is presented from an etiological point of view. To illustrate the method, we used leprosy, an infectious disease with a variable age of onset depending on both the time of contamination with the bacillus and the latency of the disease; the role of a major gene in the susceptibility to this disease has been recently detected. The age-of-onset function was modeled to account for the two temporal processes: contamination event and incubation period. For genetic analysis, this function was combined with the probability of being susceptible to the disease, which was expressed by the use of regressive models. To test this new approach, ten sets of 500 nuclear families were simulated considering different hypotheses of contamination risks, which were either constant or dependent on contacts with contagious leprosy patients, and varying the extent to which the disease is heritable. Analyses of these data using two versions of the model indicate that the model can detect familial correlations in variable age of onset and discriminate between the different simulated effects.
Adolescent↗
Ferritin H gene polymorphism in idiopathic hemochromatosis.
The authors studied the H ferritin restriction polymorphism in 83 hemochromatosis patients and 84 controls as well as in 19 nuclear families. No significant difference was found with the ten restriction enzymes used (HindIII, EcoRI, EcoRV, PvuII, BamHI, PstI, Bg/I, Bg/II, HincII, and TaqI). Hence, the genomic abnormality responsible for idiopathic hemochromatosis is not a major deletion of an H ferritin gene. A higher frequency of one HindIII fragment, although nonsignificant when the number of comparisons made is taken into account, was observed in the patients. This HindIII fragment hybridizes with the H ferritin probe and with a 28 S ribosomal probe, and its segregation with HLA haplotypes (hence its assignment to chromosome 6) is uncertain. Its possible meaning in the expression of the disease is discussed.
Chromosome Mapping↗
The gene for incontinentia pigmenti is assigned to Xq28.
A linkage study of eight families with incontinentia pigmenti (IP) has been performed, and linkage to site DXS52 has been established. We suggest that the IP locus lies in the Xq terminal region on the long arm of the X chromosome.
Chromosome Mapping↗
Amodiaquine-induced immune agranulocytosis.
This report describes two patients who developed agranulocytosis while receiving prophylactic amodiaquine treatment. The neutrophil counts returned to normal in one after stopping the drug while the other died of sepsis. Amodiaquine-dependent circulating neutrophil IgG antibodies were demonstrated in both patients using the indirect granulocyte immunofluorescence test. The antineutrophil antibody activity was enhanced with the use of the major amodiaquine metabolite, mono-desethyl amodiaquine. Additional studies showed the activity of the sera to be nondialysable, heat stable, active against autologous as well as allogenic cells, and absent from the convalescent sera. There was no growth inhibition of allogenic myeloid committed progenitor cells (CFU-GM) following incubation with the patients' sera, complement and amodiaquine. These results indicate that agranulocytosis can be mediated by a drug-dependent antibody which affects mature blood cells.
Agranulocytosis↗
Genetic susceptibility to leprosy on a Caribbean Island: linkage analysis with five markers.
Our recent segregation analysis, carried out on 27 large pedigrees from a Caribbean island (Desirade), has shown the presence of recessive major gene(s) controlling susceptibility to leprosy per se and nonlepromatous leprosy, respectively. Linkage analysis was performed between each of these two detected genes and each of five markers typed in the Desirade population: HLA, ABO, Rhesus, Gm and Km. No positive significant lod score was observed. However, for leprosy per se close linkage was excluded with Rhesus and Gm (and also with ABO and HLA, considering a lower value for the frequency of the gene controlling susceptibility to leprosy per se). The highest lod score, although not significant, was obtained between the gene for nonlepromatous leprosy and ABO. Our overall results, joined with previous studies and experimental data, suggest that the gene controlling susceptibility to leprosy per se and that controlling susceptibility to nonlepromatous leprosy might be different, acting at successive stages of the immune response to infection with Mycobacterium leprae.
ABO Blood-Group System↗