Search results
Found 16089 matches for
Gibbs sampling-based segregation analysis of asthma-associated quantitative traits in a population-based sample of nuclear families.
Asthma is a common, complex human disease. Elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts, and increased airway responsiveness are physiological traits that are characteristic of asthma. Few studies have investigated major gene effects for these traits in a population-based sample. Further, it is not known if any putative major genes may be common to two or more of these traits. We investigated the existence and nature of major genes modulating asthma-associated quantitative traits in an Australian population-based sample of 210 Caucasian nuclear families. The sharing of these major genes was also investigated. Segregation analysis was based upon a Markov Chain Monte Carlo (Gibbs sampling) approach as implemented in the program BUGS v0.6. All models included adjustment for age, height, tobacco smoke exposure, and gender. The segregation of total IgE levels, blood eosinophil counts, and dose-response slope (DRS) of methacholine challenge were all consistent with major loci at which a recessive allele acted to increase or decrease the phenotype. The respective estimated frequencies of the recessive alleles were 68% (total IgE), 10% (blood eosinophil count), and 27% (DRS). Extensive modelling suggested that the major loci controlling total serum IgE levels, blood eosinophil counts, and airway responsiveness represent different genes. These data provide evidence, for the first time, of the existence of at least 3 distinct genetic pathways involving major gene effects on physiological traits closely associated with asthma. These results have implications for gene discovery programs.
Familial aggregation and heritability of adult lung function: results from the Busselton Health Study.
Decreased spirometric indices are characteristic of asthma and other respiratory diseases. The aim of this study was to investigate the genetic and environmental components of variance of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) measured in adulthood in an Australian population-based sample of 468 Caucasian nuclear families. The inter-relationships of the genetic determinants of these traits with asthma and atopic rhinitis were also investigated. Serial cross-sectional studies were conducted in the town of Busselton in Western Australia between 1966 and 1981 and follow-up of previous attendees was undertaken in 1995. Data from each subject included in this study were from a single survey in adulthood (25-60 yrs of age) when the subject was as close to age 45 yrs as possible. Multivariate analysis suggested that FEV1 and FVC levels were associated with age, sex, height, tobacco smoke exposure, asthma and atopic rhinitis. After adjustment for relevant covariates, FEV1 levels had a narrow-sense heritability (h2N) of 38.9% (SE 9.1%). FVC levels had an h2N of 40.6% (SE 8.9%). Extended modelling demonstrated little overlap in the genetic determinants of asthma or atopic rhinitis and either FEV1 or FVC levels. The results of this study were consistent with the existence of important genetic determinants of adult lung function that are independent of asthma or other atopic disease, cigarette smoking, height, age or sex.
Airway smooth muscle in health and disease; methods of measurement and relation to function.
Smooth muscle is present and probably functional in the airways in utero and increases in absolute area during growth with little further change during adulthood. It encircles the entire airway below the level of the main bronchus, in a roughly circular orientation, except at high lung volumes. It occupies relatively more of the airway wall in the peripheral airways, reaching a maximum in the membranous bronchioles. Measurement of smooth muscle area in the airway wall is confounded by clinical classification of cases, methods of tissue retrieval and preparation, staining and orientation of sections, magnification, image analysis and statistical methods of comparison between groups. Airway smooth muscle area is pathologically increased in inflammatory conditions of the airways such as chronic obstructive pulmonary disease, in relation to airways obstruction, and asthma, in relation to severity and airway size (between 25 and 250% compared with control cases). It is increased in sudden infant death syndrome, but there are few studies in other conditions such as bronchiectasis. In asthma, smooth muscle must shorten (not necessarily to an abnormal degree) for the structural abnormalities of the airway to manifest as excessive airway narrowing. Not surprisingly there is renewed interest in the relationships between the mechanical and contractile properties of smooth muscle, parenchymal properties and lung volume and how these interact to determine smooth muscle length. The relative importance of smooth muscle area and mechanical properties, altered airway structure and airway inflammation in disease are yet to be determined.
Expression patterns of the larval and adult hexamerin genes of Musca domestica.
Hexamerins are proteins found in high abundance in the haemolymph of larval and adult insects. The expression patterns of the genes encoding the house fly, Musca domestica, hexamerins were determined by Northern analyses using cDNAs as probes. A cDNA, A1, hybridized to a fat body-specific messenger RNA (mRNA) which is detectable in larvae until pupation. Antibodies raised to the larval-specific hexamerin, Hex-L, bind recombinant protein encoded by a 5' rapid amplification of cDNA ends (RACE) product of A1, A2, indicating that the A cDNAs likely represent the genes encoding Hex-L. The F1, F2 and F3 cDNAs, corresponding to genes encoding an adult, female-enriched hexamerin, Hex-F, hybridized with an mRNA isolated from protein-fed females which has a temporal expression profile similar to that observed for the accumulation of Hex-F. Furthermore, expression of the mRNAs hybridizing to the F cDNAs is correlated with the abundance of Hex-F protein during the gonotrophic cycles. The mRNA transcription profiles indicate that the Hex-L and Hex-F genes are regulated in a sex-, tissue- and developmental phase-dependent manner. This stage-specific expression of hexamerins contrasts with the expression patterns of hexamerins seen in other insects. The conceptual translation products of larval hexamerin cDNAs showed identity with larval serum protein 1 (LSP1)-type hexamerins while the deduced products of the female hexamerin cDNAs showed the highest identity with LSP2-type hexamerins. Genomic analyses showed that the larval hexamerin and female hexamerin genes from M. domestica belong to two distinct multigenic families.
Virus-expressed, recombinant single-chain antibody blocks sporozoite infection of salivary glands in Plasmodium gallinaceum-infected Aedes aegypti.
Transgenic mosquitoes resistant to malaria parasites are being developed to test the hypothesis that they may be used to control disease transmission. We have developed an effector portion of an antiparasite gene that can be used to test malaria resistance in transgenic mosquitoes. Mouse monoclonal antibodies that recognize the circumsporozoite protein of Plasmodium gallinaceum can block sporozoite invasion of Aedes aegypti salivary glands. An anti-circumsporozoite monoclonal antibody, N2H6D5, whose corresponding heavy- and light-chain gene variable regions were engineered as a single-chain antibody construct, binds to P. gallinaceum sporozoites and prevents infection of Ae. aegypti salivary glands when expressed from a Sindbis virus. Mean intensities of sporozoite infections of salivary glands in mosquitoes expressing N2scFv were reduced as much as 99.9% when compared to controls.
Decline in lung function and mortality: the Busselton Health Study.
BACKGROUND: There is a direct association between level of lung function, measured by forced expiratory volume in 1 second (FEV1) and mortality rates. A low FEV may result from an increased decline in FEV1 with age, which may be an independent predictor of mortality. OBJECTIVE: To examine the association between decline in FEV1 and mortality in a cohort from a community health study. SETTING AND METHODS: From five cross sectional studies in Busselton between 1969 and 1981 a cohort of 751 men and 940 women was identified who had three assessments of lung function over a six year period and had other health related data collected. Each subject's average FEV1 and decline in FEV1 (litre/year) were calculated from these three measurements. Mortality follow up to December 1995 was obtained. Cause of death was taken as the certified cause of death from the death certificate using ICD9 categories. RESULTS: The average decline in FEV1 was 0.04 litre per year (SD = 0.07) for men and 0.03 litre per year (SD = 0.06) for women. Average FEV1 was significantly associated with all cause and cardiovascular disease mortality in both sexes. In women there was a significant association between decline in FEV1 and death from all causes, after adjusting for average FEV1, age, smoking, coronary heart disease, and cardiovascular disease risk factors; a 0.05 litre per year increase in the rate of decline of FEV1 increased the risk of death for all causes by 1.23 (95% confidence interval 1.06, 1.44). In men the effect of decline in FEV1 on death rate was less; for all men the hazard ratio for a 0.05 litre/year greater decline in FEV1 was 1.19 (0.99, 1.21). CONCLUSION: Decline in lung function, measured by FEV1 is a predictor of death, independent of average FEV1 and risk factors for cardiovascular disease.
Borderline personality disorder: study in adolescence.
The study of the presentation, symptomatology and family characteristics of an exclusively adolescent sample of patients with borderline personality disorder (BPD) was undertaken. Twenty-four cases of borderline personality disorder, 20 females, 4 males, identified using chart review and meeting the criteria of the Diagnostic Interview for Borderlines (DIB) and DSM III-R, were matched with psychiatric controls. Adolescents with borderline personality disorder were found to have high rates of affective symptomatology with Axis I diagnosis of major depressive disorder MDD (DSM-III-R), and high rates of interpersonal psychopathology, i.e., manipulation, devaluation, and a pervasive sense of boredom. The latter seem to be characteristic as for adults with borderline personality disorder. The families were particularly angry and volatile.
Airway structure and inflammatory cells in fatal attacks of asthma.
Fatal attacks of asthma usually occur against a background of chronic persistent symptoms, presumably due to chronic airway inflammation and changes in airway wall structure. Death from asthma is usually attributed to excessive airway narrowing due to a combination of muscle spasm and mucous plugging. To test the hypothesis that airway wall structure and/or the inflammatory cell profile are related to the duration of a fatal attack of asthma, inflammatory cell profiles and airway structure were examined in cases of fatal asthma and related to the duration of the fatal attack. In transverse sections of large and small airways from subjects dying from asthma, the numbers of eosinophils, neutrophils and lymphomononuclear cells were counted. The amount of smooth muscle shortening, the areas of airway wall, smooth muscle, mucous gland and cartilage were measured. Cell counts, airway dimensions and muscle shortening were compared in cases dying within 2 h of the fatal attack (short duration) and those dying more than 5 h after the onset of the fatal attack (long duration). In cases with fatal attacks of short duration, the numbers of neutrophils and the mucous gland area were increased and the numbers of eosinophils were reduced compared to cases with fatal attacks of long duration. Lymphocyte numbers, airway wall thickness, the areas of smooth muscle and cartilage and the amount of smooth muscle shortening were similar in the two groups. These findings suggest fatal attacks of asthma may be triggered by an inflammatory stimulus and suggest that increased production of mucous may contribute to sudden death in such cases.
In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis.
Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age = 16.6 years, interquartile range (IQR) = 2.14, 46.4% females) and 265 adolescent healthy controls (median age = 16.2 years, IQR = 2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen's d = 0.37), posterior corona radiata (d = 0.32), and superior fronto-occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.
Reduced Antiviral Interferon Production in Poorly Controlled Asthma Is Associated With Neutrophilic Inflammation and High-Dose Inhaled Corticosteroids.
BACKGROUND: Asthma is a heterogeneous chronic inflammatory disease in which host defense against respiratory viruses such as human rhinovirus (HRV) may be abnormal. This is a matter of some controversy, with some investigators reporting reduced type I interferon (IFN) synthesis and others suggesting that type I IFN synthesis is relatively normal in asthma. OBJECTIVE: The objective of this study was to examine the responsiveness of circulating mononuclear cells to HRV in a large cohort of participants with poorly controlled asthma and determine whether IFN-α and IFN-β synthesis varies across different inflammatory phenotypes. METHODS: Eligible adults with asthma (n = 86) underwent clinical assessment, sputum induction, and blood sampling. Asthma inflammatory subtypes were defined by sputum cell count, and supernatant assessed for IL-1β. Peripheral blood mononuclear cells (PBMCs) were exposed to HRV serotype 1b, and IFN-α and IFN-β release was measured by enzyme-linked immunosorbent assay. RESULTS: Participants (mean age, 59 years; atopy, 76%) had suboptimal asthma control (mean asthma control questionnaire 6, 1.7). In those with neutrophilic asthma (n = 12), HRV1b-stimulated PBMCs produced significantly less IFN-α than PBMCs from participants with eosinophilic (n = 35) and paucigranulocytic asthma (n = 35). Sputum neutrophil proportion and the dose of inhaled corticosteroids were independent predictors of reduced IFN-α production after HRV1b exposure. CONCLUSIONS: Antiviral type I IFN production is impaired in those with neutrophilic airway inflammation and in those prescribed high doses of inhaled corticosteroids. Our study is an important step toward identifying those with poorly controlled asthma who might respond best to inhaled IFN therapy during exacerbations.
Longitudinal brain changes in early-onset psychosis.
Progressive losses of cortical gray matter volumes and increases in ventricular volumes have been reported in patients with childhood-onset schizophrenia (COS) during adolescence. Longitudinal studies suggest that the rate of cortical loss seen in COS during adolescence plateaus during early adulthood. Patients with first-episode adolescent-onset schizophrenia show less marked progressive changes, although the number of studies in this population is small. Some studies show that, although less exaggerated, progressive changes are also present in nonschizophrenia early-onset psychosis. The greater loss of brain tissue seen in COS, even some years after the first episode, as compared to adolescent- or adult-onset schizophrenia may be due to variables such as sample bias (more severe, treatment refractory sample of childhood-onset patients studied), a process uniquely related to adolescent development in COS, differential brain effects of drug treatment in this population, clinical outcome, or interactions among these variables. Findings from both cross-sectional studies of first-episode patients and longitudinal studies in COS and adolescent onset support the concept of early-onset schizophrenia as a progressive neurodevelopmental disorder with both early and late developmental abnormalities. Future studies should look for correlates at a cellular level and for pathophysiological explanations of volume changes in these populations. The association of risk genes involved in circuitries associated with schizophrenia and their relationship to developmental trajectories is another promising area of future research.
Variability of airway structure and inflammation in normal subjects and in cases of nonfatal and fatal asthma.
The quantitative assessment of airway inflammation in patients with apparently similar clinical severity of asthma has yielded variable results. The aim of this study was to assess the variability of inflammatory cell counts and airway structure in large and small airways from subjects with and without asthma, and to calculate the number of cases required to detect significant differences between disease groups. Three serial transverse sections, 20 microns apart, were examined from cartilaginous and membranous bronchioles. Airway dimensions measured were the areas and perimeters defined by the luminal surface of the airway epithelium, basement membrane, outer border of airway smooth muscle, and surrounding border of the airway adventitia. Airway wall components measured were the areas of airway smooth muscle, mucous glands and cartilage. The numbers (per mm of basement membrane) of lymphocytes, eosinophils, neutrophils and plasma cells were counted using haematoxylin and eosin staining and mast cells were counted in sections stained with Toluidine blue. Measurements were repeated by two or three observers. The coefficient of variation (CV) was used to assess intraairway, intraobserver and interobserver variability. For airway dimensions the mean (+/- SD) CV within airways was 3.8% +/- 2.1%, within observers was 3.7% +/- 1.8% and between observers, 3.4% +/- 1.8%. For airway wall components, the CV within airways was 10.7% +/- 4.6%, and between observers was 8.8% +/- 2.2%. For cell counts, the CV within airways was 20.8% +/- 12.5%, within observers was 8.3% +/- 3.7% and between observers, 9.6% +/- 4.6%. There were no significant differences in variability between cases with and without asthma. Intra-airway variability was higher (p < 0.05) in membranous airways (5.6% +/- 1.7%) than in large cartilaginous airways (2.3% +/- 1.1%). We estimate that between 5 and 15 cases in each group would be required to detect differences of 50-100% between groups, depending on the parameter being compared. These findings suggest that airway structure and inflammatory cell numbers are uniform throughout the bronchial tree in normal and asthmatic cases, and that small samples of large or small airways are likely to be representative when comparing cases.
Sex differences in the hyperkinetic syndrome of childhood.
Among a clinic sample of 6525 subjects, 61 males and 18 females with an ICD-9 diagnosis of the hyperkinetic syndrome of childhood were identified. Hyperactive girls had a lower IQ and significantly higher rates of language disorders and neurological disorders, suggesting a possible neurological basis for hyperactivity in females. In contrast, there was a population of male hyperactives with less evidence of brain dysfunction and a normal IQ, evidence compatible with the model of greater male constitutional variability. There was little evidence for the polygenetic multiple threshold model of sex inheritance.
Effects of lung volume, bronchoconstriction, and cigarette smoke on morphometric airway dimensions.
To examine the role of airway wall thickening in the bronchial hyperresponsiveness observed after exposure to cigarette smoke, we compared the airway dimensions of guinea pigs exposed to smoke (n = 7) or air (n = 7). After exposure the animals were anesthetized with urethan, pulmonary resistance was measured, and the lungs were removed, distended with Formalin, and fixed near functional residual capacity. The effects of lung inflation and bronchoconstriction on airway dimensions were studied separately by distending and fixing lungs with Formalin at total lung capacity (TLC) (n = 3), 50% TLC (n = 3), and 25% TLC (n = 3) or near residual volume after bronchoconstriction (n = 3). On transverse sections of extraparenchymal and intraparenchymal airways the following dimensions were measured: the internal area (Ai) and internal perimeter (Pi), defined by the epithelium, and the external area (Ae) and external perimeter (Pe), defined by the outer border of smooth muscle. Airway wall area (WA) was then calculated, WA = Ae - Ai. Ai, Pe, and Ae decreased with decreasing lung volume and after bronchoconstriction. However, WA and Pi did not change significantly with lung volume or after bronchoconstriction. After cigarette smoke exposure airway resistance was increased (P less than 0.05); however, there was no difference in WA between the smoke- and air-exposed groups when the airways were matched by Pi. We conclude that Pi and WA are constant despite changes in lung volume and smooth muscle tone and that airway hyperresponsiveness induced by cigarette smoke is not mediated by increased airway wall thickness.
Comparative neuropsychiatry: white matter abnormalities in children and adolescents with schizophrenia, bipolar affective disorder, and obsessive-compulsive disorder.
BACKGROUND: There is considerable evidence that white matter abnormalities play a key role in the pathogenesis of a number of major psychiatric disorders, including schizophrenia, bipolar affective disorder, and obsessive-compulsive disorder. Few studies, however, have compared white matter abnormalities early in the course of the illness. METHODS: A total of 102 children and adolescents participated in the study, including 43 with early-onset schizophrenia, 13 with early-onset bipolar affective disorder, 17 with obsessive-compulsive disorder, and 29 healthy controls. Diffusion tensor imaging scans were obtained on all children and the images were assessed for the presence of non-spatially overlapping regions of white matter differences, a novel algorithm known as the pothole approach. RESULTS: Patients with early-onset schizophrenia and early-onset bipolar affective disorder had a significantly greater number of white matter potholes compared to controls, but the total number of potholes did not differ between the two groups. The volumes of the potholes were significantly larger in patients with early-onset bipolar affective disorder compared to the early-onset schizophrenia group. Children and adolescents with obsessive-compulsive disorder showed no differences in the total number of white matter potholes compared to controls. CONCLUSIONS: White matter abnormalities in early-onset schizophrenia and bipolar affective disorder are more global in nature, whereas children and adolescents with obsessive-compulsive disorder do not show widespread differences in FA.
A Preliminary Study of an Extension of a Community Dialectic Behaviour Therapy (DBT) Programme to Adolescents in the Looked After Care System.
BACKGROUND: Adolescents in the Looked After Care (LAC) system demonstrate high rates of psychiatric disorder and self-harm; however, there is little evidence for therapies reducing self-harm in this population. METHOD: An open evaluation of DBT for adolescents with repeated serious self-harm in the LAC system was undertaken. RESULTS: An intention-to-treat (ITT) analysis showed that DBT was successful at reducing the core elements of depression, hopelessness and self-harm; however, 35% (7/20) failed to engage. CONCLUSION: DBT is a useful treatment option; the failure, however, of some adolescents to engage in therapy may be due to their higher initial rates of depression and hopelessness.
Functional haplotypes in the PTGDR gene fail to associate with asthma in two Australian populations.
BACKGROUND AND OBJECTIVE: Haplotypes in the promoter region of the prostanoid DP receptor (PTGDR) gene have been shown to functionally influence gene transcription and to be associated with asthma in two previous case-control studies in Caucasians. This study tested the association of PTGDR haplotypes with asthma phenotypes in two large Caucasian-Australian populations. These results were incorporated in a meta-analysis with previously published data to determine the overall role for these haplotypes in the risk of asthma. METHODS: Three PTGDR promoter-region single nucleotide polymorphisms (SNP) were genotyped in 368 individuals from the Western Australian Twin Child Health study and 2988 individuals from the Busselton Health Study. Logistic regression and transition disequilibrium tests were used to assess whether SNP genotypes and three SNP haplotypes were associated with doctor-diagnosed asthma or intermediate quantitative traits. Longitudinal data from the Busselton Health Study were used to examine whether PTGDR influences changes in lung function over time. Meta-analysis incorporated the findings of this study with those of two previous studies in Caucasian populations. RESULTS: Cross-sectional associations between PTGDR haplotypes and asthma phenotypes were non-significant (P > 0.05) in both populations. Longitudinal analyses of PTGDR and lung function were also non-significant. Meta-analysis, however, suggested that haplotype TCT was significantly associated with decreased risk of asthma (OR = 0.76; P = 0.02) while haplotype CCC was not significantly associated with asthma (OR = 1.30; P = 0.07). CONCLUSIONS: These results suggest that despite the non-significant findings in the present study populations, PTGDR promoter haplotypes may account for a small but significant proportion of the risk of asthma in Caucasian populations.