Biomedical subjects
L Abel
Publications and source records attributed to L Abel.
All bull. part II: Just "B Kool".
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Genetic analysis of complex diseases.
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Effect of sertraline on regional metabolic rate in patients with affective disorder.
Seventeen patients with major affective disorder completed a 10-week, placebo-controlled, randomized trial of the serotonin reuptake inhibitor sertraline. Patients underwent positron emission tomography with 18F-deoxyglucose and were assessed with the Hamilton Depression Rating Scale at baseline and 10 weeks after treatment with sertraline or placebo. The middle frontal gyrus, an area previously characterized by decreased metabolic activity in depressive patients, showed relatively increased activity on both sides after sertraline when contrasted with temporal and some occipital areas. Sertraline was associated with a significantly increased relative metabolic rate in right parietal lobe and in left occipital area 19, and a decreased metabolic rate in right occipital area 18. Other areas that differed between controls and a larger cohort of 39 depressive patients--including medial frontal lobe, cingulate gyrus, and thalamus--also showed a normalization of metabolic rate after sertraline.
Thymocyte progenitors and T cell development in aging.
Dysfunction of T lymphocytes in aging has been causally related to a gradual loss of the thymic microenvironmental function. However, in view of the fact that T cells are generated from bone marrow-derived stem cells that settle in the thymus, we have investigated the possibility that aging effects on the bone marrow have an impact on T cell development. Our approach was based on seeding of bone marrow cells, from young and old mice, onto lymphoid-depleted fetal thymus explants, and examining the patterns of T lymphocyte development under organ culture conditions. The results indicate multifactorial effects of aging, on pre-thymic and intra-thymic development processes, as well as on feedback regulation by mature T cells.
The impact of host genetics on susceptibility to human infectious diseases.
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 involved in human infectious diseases. Within the past year, highlights include the mapping of a locus controlling the intensity of infection by Schistosoma mansoni, the demonstration that mutations in the interferon-gamma receptor 1 gene are causative of disseminated infection due to weakly pathogenic mycobacteria, and the identification, in the CCR5 gene, of a deletion which provides high protection against HIV-1 infection. The impact of these findings on the understanding of infectious disease pathogenesis and on the design of future preventive and therapeutic strategies should be considerable.
Evidence for a major gene controlling susceptibility to tegumentary leishmaniasis in a recently exposed Bolivian population.
Tegumentary leishmaniasis due to Leishmania braziliensis is a parasitic disease that occurs in two stages after the infected sandfly bite: (1) a primary cutaneous lesion followed by (2) a secondary mucosal involvement generally resulting in severe facial deformities. In order to investigate the genetic and environmental factors involved in the development of the cutaneous lesion, a familial study was performed in a region of Bolivia in which the disease is endemic. Complete selection of 118 nuclear families (703 subjects, with 241 patients), each with at least one cutaneous affected subject, was achieved; 41 families were of native origin, and 77 (herein designated "migrant") recently had settled in the area. For the analysis, the trait under study was the time to onset of the primary cutaneous lesion. The start of the follow-up was birth, for native population, or date of arrival in the endemic area, for migrant population. Segregation analysis was performed by use of a model based on survival analysis methods that allows joint estimation of genetic and environmental effects and accounts for gene x covariate interactions. A significant effect of gender, home-forest distance, and forest-related activity was found. In the 77 migrant families there was evidence for a recessive major gene controlling the onset of the primary cutaneous lesion, with residual familial dependences and age x genotype interaction. Penetrance estimations show that young subjects are genetically more susceptible than older subjects, suggesting that this genetic component could concern mechanisms involved in the development of individual protection during childhood. There was also a significant genetic heterogeneity of the sample according to the native/migrant origin of the families, and no major-gene effect was found in the native subsample.
Risk factors for onset of cutaneous and mucocutaneous leishmaniasis in Bolivia.
A survival analysis was performed on data from an endemic area of Bolivia where two populations, natives and highland migrants, were living, to investigate risk factors for onset of cutaneous leishmaniasis (CL) and its mucosal form (MCL). In a first data set (703 subjects with 242 CL patients), significant risk factors for CL were gender, native/migrant status, activity, and home-forest distance. The instantaneous risk of CL increased until adolescence in both populations, and rapidly decreased thereafter. This risk was 3-10 times higher in migrants than in natives until 20 years of age, and became similar thereafter. Environmental and behavioral factors did not seem sufficient to explain this contrast between the two populations, and this evolution with age may suggest differences in the mechanisms involved in the development of individual protection during childhood. In a second data set (446 CL patients with 34 mucosal forms) the native/migrant status was the main factor associated with the onset of mucosal form.
Food for profit, food for thought.
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Weight loss, nutrition & preventive medicine. A guide for patients.
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Brain glucose metabolism during non-rapid eye movement sleep in major depression. A positron emission tomography study.
BACKGROUND: Depression is characterized by several sleep-related abnormalities shortly before and after sleep onset, such as prolonged sleep latency, loss of stage 3-4 sleep, reduced rapid eye movement (REM) latency, increased nocturnal core body temperature, and abnormal hormone secretion patterns. Sleep deprivation is associated with a temporary improvement in depression. We hypothesized that depressed patients may be "overaroused" and that absolute cerebral glucose metabolism would be elevated during the first nocturnal non-REM sleep period in depressed patients compared with normal controls. In addition, since hypofrontality (greater metabolic activity in occipital compared with frontal cortical activity) has been reported in waking positron emission tomographic studies of depressed patients compared with controls, we predicted significant hypofrontality in depressed patients during the first non-REM period. METHODS: Positron emission tomography with fludeoxy-glucose F 18 was used to compare 10 unmedicated men with unipolar depression with 12 normal men during the first non-REM sleep period at normal bedtime. RESULTS: Whole-brain absolute metabolic rate during non-REM sleep was significantly elevated (+47%) in patients compared with controls. Mean absolute cerebral glucose metabolic rate was also higher in every area of the brain in patients compared with normal controls. The greatest significant mean increases were in the posterior cingulate and amygdala (+44%), hippocampus (+37% to +43%), occipital and temporal cortex (+33% to +34%), and pons (+33%). Relative metabolic rates in specific neroanatomical areas, however, varied considerably both within the patient group and between patients and controls. Patients showed significant hypofrontality, particularly in the medio-orbital frontal cortex, compared with controls. Patients also showed significant reductions of relative metabolic rate in the anterior cingulate, caudate, and medial thalamus compared with controls. CONCLUSIONS: These findings provide further support for the hyperarousal hypothesis of some types of major depressive disorder. Abnormal patterns of cerebral metabolism during non-REM sleep in depressed patients confirmed earlier waking findings of decreased relative frontal and abnormal limbic metabolic activity and striatal metabolism in association with posterior cortical increases.
Improving the robustness of the weighted pairwise correlation test for linkage analysis.
The weighted pairwise correlation (WPC) approach provides simple and flexible tests for genetic linkage which may be adapted to qualitative, quantitative, or age-dependent traits. These tests also seem to have good power. However, when working with large pedigrees, a disease susceptibility gene not linked to the marker studied induces correlations of the trait values, leading to inflated type-I errors for these tests. Thus, in its first version, the WPC approach is reliable when using sibships but not when using larger pedigrees. We propose a way for correcting the variances of the WPC statistics to take these correlations into account. A simulation study shows that the type I errors of the corrected statistics are good. The approach is based on a transformation which yields uncorrelated residuals. We study three statistics, based on the permutation distributions of residuals: one based on ordinary residuals adapted to quantitative traits, another based on martingale residuals adapted to survival data, and one based on rank residuals which can be used in both situations. We apply the corrected WPC tests to pedigrees of Alzheimer's disease previously analyzed with the first version of the method (WRPC).
Genetic localization of 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 around 200,000 die each year of this disease. Severe clinical disease in schistosomiasis is often the consequence of heavy infection which, in several endemic areas, are determined largely by the susceptibility/resistance of individuals. Previously, we reported evidence, based on a segregation analysis in Brazilian pedigrees, that intensity of infection by Schistosoma mansoni was influenced by a major gene, indicating that host genetic factors are probably critical in controlling schistosome infection and disease development. To localize this gene, referred to as SM1, we performed a genome-wide study on 142 Brazilian subjects belonging to 11 informative families Our results show a linkage to only one region, on chromosome 5q31-q33, with maximum two-point lod scores of +4.74 and +4.52 for D5S636 and the colony stimulating factor-1 receptor marker (CSF1R), respectively. This was corroborated by multipoint analysis, indicating a close proximity to CSF1R as the most likely location of SM1. This region contains several candidate genes encoding immunological molecules that were shown to play important roles in human protection against schistosomes.
Intraspinal epidural sarcoidosis: case report.
OBJECTIVE AND IMPORTANCE: A rare case of lumbar intraspinal epidural sarcoidosis is identified. The rarity of this condition and its clinical presentation are stressed. CLINICAL PRESENTATION: A young Caucasian man presented with the progressive onset of cauda equina syndrome as a result of an expanding mass in the lumbar epidural space compromising the lumbar dural tube from L1 to S1. The patient presented with motor, sensory, and sphincteric dysfunction as a result of this large intraspinal epidural mass. No evidence of systemic illness was noted concomitant with the patient's onset of neurological symptomatology. The patient underwent surgical extirpation of a lumbar intraspinal epidural mass, which was identified histopathologically as sarcoid granuloma. The postoperative work-up included the identification of a mediastinal adenopathy, which was subsequently biopsied and confirmed the diagnosis of sarcoid disease. The patient was treated postoperatively with oral prednisone over a 4-month period. At 7 months postoperatively, the patient had regained gainful employment, the results of his neurological examination were normal, and he was pain-free. INTERVENTION: The patient underwent a multilevel bilateral lumbar laminectomy with facet preservation, extending from L1 to S1, allowing for a gross total removal of the epidural mass. Postoperative oral prednisone was administered as adjuvant therapy for the treatment of multisystem sarcoid disease. CONCLUSION: Aggressive surgical management involving the removal of an extensive epidural mass of the lumbar canal, which was diagnosed as sarcoid disease, coupled with the adjuvant use of oral prednisone has resulted in an excellent outcome for the patient. The results of his clinical examination are now normal, and postoperative radiological imaging reveals no evidence of recurrent or residual disease in the lumbar epidural space. In the unusual case of intraspinal epidural sarcoidosis, the surgical resection of accessible intraspinal epidural masses is recommended, as is the use of oral prednisone postoperatively.
PET and MRI of the thalamus in never-medicated patients with schizophrenia.
OBJECTIVE: This study reports the first paired measurements of glucose metabolism and size of thalamic regions in never-medicated schizophrenic patients using coregistered magnetic resonance imaging (MRI) templates. METHOD: Positron emission tomography with [18F]fluorodeoxyglucose and matching MRI scans were obtained in 20 never-medicated patients with schizophrenia and 15 normal volunteers. Methods for thalamic edge finding, statistical testing of shape differences with chi-square maps, and MRI localization of major thalamic subregions were developed. RESULTS: Patients with schizophrenia showed a diminished metabolic rate in the right thalamus, with a loss of the normal pattern of right greater than left asymmetry. Division into anterior/posterior segments revealed that the left anterior and right posterior showed the decrease. Differences were greater for metabolism in the weighted thalamic area (ratexarea) than for rate per unit area, a finding consistent with reported greater decreases in total neuron number than of neuron density in the thalami of schizophrenic patients. The area of the thalamus was smaller in the patients than in the volunteers, and this difference was greatest in the left anterior region. CONCLUSIONS: The reduced thalamic activity observed in this study lends further support to the concept of deficits in sensory filtering in schizophrenia.
Segregation analysis indicates a major gene in the control of interleukine-5 production in humans infected with Schistosoma mansoni.
The interleukine-5 (IL-5) is a hormone of the immune system that is the main regulator of eosinopoiesis, eosinophil maturation and activation, and immunoglobulin A production. Thus, IL-5 contributes in several ways to human immune defenses against various pathogens, including helminths and infectious agents of the digestive and respiratory tracts. On the other hand, the increase in eosinophil number and the activation of these cells, which both have been related to elevated IL-5 production, are the cause of severe pathological disorders, as in asthma or hypereosinophilic syndromes. Although the immunological pathways leading to IL-5 synthesis have been identified, the reasons for the large variability observed in IL-5 production among subjects exposed to comparable antigenic stimulation are unknown. To investigate the role of genetic factors in this variability, we conducted a segregation analysis in a Brazilian population infected by the helminth parasite Schistosoma mansoni. The analysis was performed on IL-5 levels produced by blood mononuclear cells of these subjects after in vitro restimulation with either parasite extracts (IL-5/schistosomula sonicates [SS] phenotype) or a T-lymphocyte mitogen (IL-5/phytohemagglutin [PHA]). The results provide clear evidence for the segregation of a codominant major gene controlling IL-5/SS and IL-5/PHA production and accounting for 70% and 73% of the phenotypic variance, respectively; the frequency of the allele predisposing to low IL-5 production was approximately .22 for both phenotypes. No significant relationship was found between these genes and the gene controlling infection intensities by S. mansoni detected in a previous study. Linkage studies are ongoing to locate those genes that would help to characterize the genetic factors involved in pathological conditions such as severe helminth infections and allergic diseases.
The news and weather report: bad moon rising and ill winds blowing.
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Reduction of contaminated urine specimens in pregnant women.
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