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Evaluation of drive mechanisms (including transgenes and drivers) in different environmental conditions and genetic backgrounds
Three major objectives, develop viable gene drive mechanisms, identify the epidemiologically significant vectors of pathogens in specific transmission zones, and introgress effector genes into specific populations, must be met in order to move to the field laboratory advances in genetic control strategies. © 2006 Springer. All Rights Reserved.
Respiratory symptoms, lung function, smoking and allergy in a central australian aboriginal community
Aboriginal Australians have lower levels of lung function than normal and greater rates of decline (Bremner et al. AJRCCM 1998;158:1724). We examined markers of respiratory disease in a central Australian aboriginal community and compared them with tropical aboriginal (TA) and nonaboriginal (NA) communities Questionnaires, FEV1, AHR (methacholine) and prick skin tests were performed on 86 of 169 subjects 10 yrs of age registered in the community. Results: Children (< 18 years) Adults ( > 18 years) females u H males (151 females (34) males 126) Age,yrs 14 ± 2 13 ± 3 38 ± 13 39 ± 15 Cough, % 50 40 45 69 Dyspnoea, % 45 33 50 46 Wheeze (ever), % 18 7 44 38 Asthma (Dr), % 0 7 26 16 Smoker (ever), % 9 40 38 65 Any skin test+,% 36 60 47 54 FEVl,%pred.(*) 96 ± 13 96 ±15 92 ± 20 90 ± 28 AHR,% 11 27 12 10 Symptoms, asthma or smoking were not related to skin tests, AHR or FEV1%. Compared with TA and NA symptoms (except wheeze) were more frequent in children, smoking in adults less (TA), asthma more common in adults (TA), less in children (NA) and similar in adults (NA), + skin tests more frequent than TA but similar to N A in all groups, FEV1 lower in adults and AHR was less than TA but similar to NA.
Maternal cigarette smoking and hla-dr expression in alveolar macrophages in infants
Macrophages are important in host defences in the lung via phagocytic activity, antigen presentation and secretion of inhibitory and pro-inflammatory mediators. The expression of HLADR, a marker of immune function, on alveolar macrophages, is reduced in cigarette smokers and this may alter their immune function. We hypothesised that infants exposed to maternal cigarette smoke will also have reduced expression of HLA-DR on alveolar macrophages. To examine this we compared HLA-DR expression using immunohistochemistry on lung tissue from infants (n=5) who died of SIDS who were exposed to maternal cigarette smoke ( 10 cigarettes a day) with infants (n=6) who also died of SIDS but had no maternal cigarette smoke exposure. Maternal smoking history was obtained by direct interview within 4 weeks of the infants death. We determined the density of alveolar macrophages in the lung by point counting. Points falling on alveolar walls and on HLA-DR + and - alveolar macrophages were counted in five random high power fields (x400). Total macrophages, as a percent of all points counted, and the percent of those macrophages with HLA-DR + staining are shown in the table. Results are expressed as mean SE. Gestation Birth weight age Macrophages HLA-DR + (week) (kg) (mths) (%) (%) Non smoke 40 + 0.5 3.8 + 0.2 6 + 3 9%+ 2 40%+ 8 Smoke exp 40 + 0.3 3.3 + 0.3 5 + 1 14%+ 2 28%+ 4 p value 0.8 0.2 0.7 0.09 0.2 These findings suggest in infants, that the number of alveolar macrophages and the expression of HLA-DR is not altered by maternal cigarette smoking.
Maternal cigarette smoking and alveolar wall elastin in the infant lung
The harmful effects of maternal cigarette smoking to infants include reduced lung function in the neonatal period, increased airway responsiveness to inhaled agonists, and increased frequency of asthma exacerbations. Animal models of in utero smoke exposure have shown reduced amounts of elastin in alveolar walls with an increase in size, but a reduction in the number, of saccules in the lungs of smoke-exposed animals (Pediatr.Res. 1985:19:408-412). We hypothesised that infants exposed to maternal cigarette smoke would have reduced elastin in their alveolar walls. We measured the amount of elastin in the alveolar walls of infants (n=12) who died of SIDS and had been exposed to maternal cigarette smoke (20 cigarettes a day) during pregnancy and up to the time of death and compared these findings with those from infants (n=9) who also died of SIDS but had no maternal cigarette smoke exposure. Sections of lung parenchyma were stained with Resorcin-Fuchsin. The percentage of elastin in the alveolar wall was determined by point counting on 10 random high power fields (x400). The ratio of airspace to tissue (a marker of inflation) was also estimated. Results are expressed as mean standard error. Gestation Birth weight age Airspace Elastin (week) (kg) (mehs) (%) (%) Non smoke 39 ± 0.6 3.9 ± 0.6 5 ± 0.9 64 ± 2 10 ± 0.6 Smoke exp 38 ±0.5 3.0 ±0.1 4 ± 0.9 64 ±2 9.5 ± 0.6 p value n.s. n.s. n.s. n.s. n.s. These findings suggest that maternal cigarette smoke exposure does not have a significant effect on the amount of elastin in the alveolar wall in infants.
Mast cell degranulation is related to asthma severity and varies in different airway wall compartments in asthma
Asthma is characterised by excessive ainvay narrowing, airway inflammation and airwa\ remodelling. Mast cells (MC's) can be considered to be a tissue resident cell capable of playing a role in acute and chronic aspects of asthma via secretion and synthesis of a range of chemical mediators. Mast cells contain or synthesise histamine. which contracts smooth muscle, tryptase and chymase that are potent secretagogues and 1L-4 and IL-5 which are important in allergic inflammation. Thus their distribution and activation in different airway wall compartments may relate to the pathophysiological features of asthma. Transverse sections of large and small airways from controls (CO), mild (nonfatal - NFA) and severe (fatal - FA) asthma, n=8 in each group, were stained with the AAI (MC tryptase) monoclonal antibody. MC's (intact and degranulated) were counted in the lumen (LU), epithelium (EP1), inner airway wall (WAi), smooth muscle (ASM), submucosal mucous glands (SMG) and outer airway wall (WAo) and expressed as cells per mm- of the measured area. Degranulated MC's were expressed as a % of total MC's in the different airway compartments. MC density was 5 fold higher in small airways compared ith large airways and highest on the ASM of all airwa) compartments. MC density as increased (p<0.05) in CO and NFA compared with FA in large airways and in NFA and FA compared with CO in small airways. MC density was highest in ASM and SMG in large airways and in the ASM and WAo in small airways. Degranulation was greater (P<0.05) in FA than in NFA and greater in NFA than CO in large and small airways. Degranulation was highest on ASM and SMG in FA and greater than in NFA and CO. We conclude that MC density varies between large and small airways and between airway compartments. Increased numbers of degranulated MC's on ASM and Gland in FA is likely to play a role in excessive airway narrowine.
Risk factors for chronic airflow limitation in the busselton community
Smoking and asthma both lead to chronic airflow limitation (CAL); the relative effect of each should be determined. AIM: To determine the risk conferred by asthma and cigarette smoking on the development of CAL in a community sample. METHODS: Subjects studied in both 1981 and 1995 health surveys in Busselton were identified. Information on respiratory symptoms, past illnesses and smoking was obtained by questionnaire and FEVi and FVC measured. CAL was defined as FEVi <80% predicted and a FEWFVC ratio <90% predicted in 1995. Predicted values were derived from the Busselton population. RESULTS: About 10% of 778 men and 7.2% of 1029 women who attended both surveys had CAL in 1995. After adjusting for level of lung function in 1981, using stepwise regression analysis, the associations between the presence of subject characteristics in 1981 and CAL in 1995 were, 1981 Characteristic Odds Ratio (95% Confidence interval) Men Women Age 1.06 (1.03-1.09) 1.04 (1.02-1.07) Asthma 4.84 (1.86-12.56) 3.77 (1.81-7.83) Cough and phlegm 3.06 (1.48-6.30) 2.92 (1.32-6.43) Smoking Never 1.00 1.00 Exsmoker 3.91 (1.46-10.50) 0.45 (0.19-1.12) light(<20/d) 9.58 (2.81-32.58) 2.57 (0.95-6.93) Heavy (>20/d) 16.97 (5.74-50.20) 5.05 (2.34-10.93) CONCLUSION: Asthma is a strong risk factor for CAL in this population with a similar level of effect to being a light smoker. Improvements in the treatment of asthma may reduce this risk.
Localisation of oncostatin M receptors (OSMR) in human airways by immunohistochemistry: Altered pattern of distribution in asthma
Oncostatin M (OSM) is a member of the IL-6 family of cytokines and to date has been demonstrated to be released by activated T-cells and macrophages. OSM is a potent inducer of epithelial anti-proteinases as well as tissue inhibitor of metalloproteinases, suggesting an anti-proteolytic function. However, the distribution of OSMR in human airways is unknown. We hypothesised that due to these effects, OSMR would be present in human airway epithelium and that the expression and pattern of OSMR distribution would be upregulated in asthma. Methods: Transverse sections (n=3) of large airways were obtained at autopsy from cases of fatal asthma (FA, n=7) and from non-smoking controls (con, n=4). Sections were stained for OSMR using a specific polyclonal antibody (provided by Immunex, Seattle, WA). Positive staining for OSMR was scored semi-quantitatively for intensity (0-4) and distribution (0-4) in the epithelium (epi), basement membrane (bm), smooth muscle (asm), sub-mucosal glands (smg), vasculature (bv), mononuclear (mono) and multinuclear cells (poly) Results: The mean ±S.D. scoring intensity is shown below. epi bm asm smg bv mono, poly FA T3±1.3# T5±1.6 2.8±1.8# 1.4±0.7 1.9±1~5~ 2.0±12~ 0.3±1.1 Con 0.6±1.2 1.4±1.6 1.1±1.8 1.2±1.8 1.3+1.8 1.6±1.5 0.3±1.1 #P<0.01 vs con. The distribution of staining score showed similar trends. Conclusion: These results show for the first time that OSMR are present in human airways and that the pattern of expression is altered in asthma. The distribution of staining suggests that OSM may play an important role in airway inflammation associated with asthma.
Fibroblasts in patients with fatal asthma (FA), chronic obstructive pulmonary disease (COPD) and controls
Asthma and COPD are characterised by persistent airway inflammation and airway fibrosis. We have hypothesised that the inflammation is due to persistent immune stimulation by exogenous cigarette smoke in COPD and by activated airway resident cells, such as fibroblasts, in asthma. The numbers of fibroblasts in the airway wall in patients with asthma and COPD has not been reported and there are currently no specific markers for fibroblasts available for use in formalin fixed tissue. Aim: To compare numbers of fibroblasts in FA and COPD and in smoking (SC) and nonsmoking controls (NC) without airflow obstruction. Methods: Transversesections of large airways were obtained at autopsy (FA, NC), at surgical resection (SC - FEV1>80%, mild COPD - FEV1<80%) and at transplantation (severe COPD - FEV1<20%). Sections were stained with HAM56 (Dako -alveolar and tissue macrophages). Cells with a long spindle shaped nucleus and cytoplasm, not staining positively for HAM56 (tissue resident macrophages) were defined as fibroblasts. Positively stained cells were counted in the submucosa (away from the smooth muscle) and were expressed per mm of the basement membrane. Results: NC SC FA COPD COPD (mild) (severe) Fibroblasts 2.4±2.5* 6.4±3.3** T4.2±7.8 7.1±3.2# 11.5±4.5 p<0.05NC v FA&COPD (severe), **SC v FA, # COPD (mild) v FA Conclusions: In FA, submucosal fibroblasts were increased in number compared with controls (smoking or not) and mild COPD. Only severe COPD differed from nonsmoking controls. Therefore, the number of fibroblasts may be related to the degree of airway inflammation and/or obstruction.
Airway inflammation and best lung function in asthma
Asthma can cause irreversible airflow obstruction (Brown et.al. Thorax 1984;39:131) which may be due to chronic inflammation of airway walls with resultant structural changes over time. A relationship between airway inflammation and ventilatory function and its decline with time has not been established. To examine the hypothesis that chronic inflammation of airways and progressive airflow obstruction are related we examined smears of sputum obtained from 20 chronic asthmatics while on their usual treatment. Smears were stained with haematoxylin and eosin and the percentages of eosinophils (E), neutrophils (N), lymphocytes (L) and macrophages (M) were calculated. The subjects were from a cohort of 44 asthmatics studied in 1980 and 1997. In both studies FEV1 was measured at enrolment and after 2 weeks each of usual treatment, high dose inhaled corticosteroids (ICS) and prednisolone 0.6mg/kg/day. Peak flows (PEF) were measured daily and symptoms, usual severity of asthma and treatment were assessed by questionnaire. Results: The best FEV1 with maximum treatment in the 20 subjects was 80±25 % predicted and decline in FEV1 was 40±15 mls/yr. Sputum cell counts (%) were: E = 14.5±19.9,N=34.3±25.0,L=0.8±0.8, M= 44.7±24.6;none were related to worst or best FEVi, change in FEVi with treatment, PEF variability, treatment scores, dose of ICS or to asthma severity or decline in FEVi from 1980-1997. Conclusion: In this group of asthmatics, airway eosinophils and neutrophils were increased compared with reported values for normal subjects (Pizichini et.al. AJRCCM 1996;154:308). The independence of inflammatory cell numbers and best FEV1 and its decline with time suggests that inflammation is determined by acute, variable factors and may not determine the structural changes which cause persistent airflow obstruction.
CC16 genotype frequencies: Differences between two western Australian populations
An adenine to guanine substitution at position 38 of the Clara cell secretory protein (CC16) gene (A38G) has shown an association between the 38A genotype and an increased risk of asthma. Aim: To compare the A38G genotype frequency, and identify possible associations between the A38G genotype, asthma and lung function parameters in two Western Australian (WA) populations. Subjects: (1) 266 individuals from 76 nuclear families living in Perth, and (2) 237 individuals from an isolated indigenous community in the tropical north of WA. Genomic methods: PCR products of the CC16 exon 1 were genotyped by Sau 96 I restriction digestion which were confirmed in 10% of the samples by DMA sequencing. Results: Population 1 had 27 (10.2%) homozygous for the published sequence (38A/38A), 123 (46.2%) were heterozygous (38A/38G), and 116 (43.6%) were homozygous for the polymorphism (38G/38G). In contrast, population 2 had 149 (62.9%) with 38A/38A, 75 (31.6%) 38A/38G, and only 13 (5.5%) with the 38G/38G genotype. An association was observed between the 38A allele and an increased risk of asthma in population 1 (p=0.02). In population 2, the 38AAM genotype was associated with reduced FEVi (p=0.033). Conclusions: The marked difference in the CC16 genotype frequencies between the two populations may be due to environmental selective pressures, but is more likely a consequence of founder effect and random genetic drift. Despite these differences, this work provides evidence from both populations that the 38A allele may be associated with an increased risk of expressing asthma-related traits. We gratefully acknowledge all the people who participated in this study.
Musca domestica hexamerins
During the Musca life cycle a larval hexamerin (arylphorin) and an adult female hexamerin (NVFP) was characterized, cDNAs from Musca hexamerins were cloned and characterized. The larval hexamerin (Hex-L) cDNA (A1,378 bp) showed similarityI with calliphorin from C.vicina and LSP1 from D.melanogaster. This eDNA recognizes a larval fat body specific mRNA (2.6 kb) with a temporal expression profile suggesting that expression of Hex-L is controlled at level of transcription. A female-specific non-vitellogenic Musca protein (Hex-F) was characterized. It is a 430 kDa hexamer made up of 7() kDa subunits. Amino acid analyses of Hex-F show a moderate aromatic amino acid content (12%) and a low methionine content (10%) in relation with other hexamerins of arylphorin group. Three main Hex-F eDNA-clones were characterized: F1(912 bp), F2 (2,202 bp)and (F3 2,100 bp). The sequence of these three clones reveals a homology with other insect hexamerin genes. The highest similarity has been obtained with the LSP2 gene of D.rnelanogaster. The temporal expression profiles of mRNAs that hybridize with the F1, F2 and F3 clones, as well as the recognition of an F2-derived recombinant protein by anti-Hex-F serum allows us to conclude that these cDNAs are partial eDNA clones of Musca Hex-F genes. Southern blot experiments show that Hex-L and Hex-F genes of M.domestica belong to two distinct multigenic ramifies. Our data support the assumption that Hex-F (and LSP2 from D.melanogaster) are hexamerins with a yet not well understood function in the vitellogenesis process.
Model of airway narrowing in asthma and chronic obstructive pulmonary disease
Exaggerated airway narrowing in response to a wide variety of nonspecific stimuli is a characteristic feature of asthma and occurs in some patients who have chronic obstructive pulmonary disease. We have developed a computational model of the human bronchial tree which allows us to investigate the effect of volume changes, airway smooth muscle shortening and airway wall thickening on airways resistance. This model is based on Weibel's symmetric lung geometry, pressure-area curves by 1-3 cmH2O. Values of smooth muscle shortening between 20 and 40% were used in the model to generate sigmoidal shaped 'dose' response curves. The analysis shows that moderate amounts of airway wall thickening, which has little effect on baseline resistance, can profoundly effect the airway narrowing caused by smooth muscle shortening - especially if the wall thickening is localized in peripheral airways. The combination of a loss of recoil and airway wall thickening are more than additive in their effect on simulated airway responsiveness. We conclude that airway wall thickening and a loss of lung recoil would explain in part the airway hyperresponsiveness characteristics of patients with chronic obstructive lung disease and asthma.
Paediatric psychopharmacology in schizophrenia
The evidence for the use of antipsychotic medication in the treatment of early-onset schizophrenia (onset at age less than 18 years), based on an increasing number of randomized controlled trials, points to therapeutic efficacy with moderate-to-large effect sizes. Some of the trials, however, were of short duration and a few were industry funded. Medication with both first-generation (FGA) and second-generation (SGA) antipsychotics is also associated with considerable side effects. Nevertheless, cautious use alongside psychosocial interventions can be recommended, provided there is continued, careful monitoring. © 2008 Elsevier Ltd. All rights reserved.
Improving the predictive potential of diffusion MRI in schizophrenia using normative models-Towards subject-level classification.
Diffusion MRI studies consistently report group differences in white matter between individuals diagnosed with schizophrenia and healthy controls. Nevertheless, the abnormalities found at the group-level are often not observed at the individual level. Among the different approaches aiming to study white matter abnormalities at the subject level, normative modeling analysis takes a step towards subject-level predictions by identifying affected brain locations in individual subjects based on extreme deviations from a normative range. Here, we leveraged a large harmonized diffusion MRI dataset from 512 healthy controls and 601 individuals diagnosed with schizophrenia, to study whether normative modeling can improve subject-level predictions from a binary classifier. To this aim, individual deviations from a normative model of standard (fractional anisotropy) and advanced (free-water) dMRI measures, were calculated by means of age and sex-adjusted z-scores relative to control data, in 18 white matter regions. Even though larger effect sizes are found when testing for group differences in z-scores than are found with raw values (p
Effect of five genetic variants associated with lung function on the risk of chronic obstructive lung disease, and their joint effects on lung function.
RATIONALE: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied. OBJECTIVES: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP. METHODS: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD. MEASUREMENTS AND MAIN RESULTS: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10-12 risk alleles was associated with a reduction in FEV1 (β = -72.21 ml, P = 3.90 × 10(-4)) and FEV1/FVC (β = -1.53%, P = 6.35 × 10(-6)), and with COPD (odds ratio = 1.63, P = 1.46 × 10(-5)). CONCLUSIONS: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.
Semantic fluency is impaired but phonemic and design fluency are preserved in early-onset schizophrenia.
Impairments of verbal fluency are recognised in adult-onset schizophrenia but their presence in early-onset schizophrenia is not well established. This study investigated the extent and character of verbal fluency disturbance in young patients close to illness onset. Thirty-three adolescents with DSM-IV schizophrenia and 33 controls completed phonemic and semantic fluency tests and a free design fluency test. Patients had significantly impaired semantic fluency compared to controls but no impairment on phonemic or design fluency. The difference between patients and controls for semantic fluency remained significant when corrected for age and IQ. These results lend support to the hypothesis that impaired semantic fluency may be an early trait marker of schizophrenia that is potentially related to a failure of lateralisation of language.
Resistant depression in childhood and adolescence
A proportion of children and adolescents with major depressive disorder (MDD; DSM-IV) fail to respond to first-line psychological therapies. This article outlines the available biological therapies and their usage.
Subcortical Brain Volume, Regional Cortical Thickness, and Cortical Surface Area Across Disorders: Findings From the ENIGMA ADHD, ASD, and OCD Working Groups.
OBJECTIVE: Attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. The authors sought to directly compare these disorders using structural brain imaging data from ENIGMA consortium data. METHODS: Structural T1-weighted whole-brain MRI data from healthy control subjects (N=5,827) and from patients with ADHD (N=2,271), ASD (N=1,777), and OCD (N=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. The authors examined subcortical volume, cortical thickness, and cortical surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults, using linear mixed-effects models adjusting for age, sex, and site (and intracranial volume for subcortical and surface area measures). RESULTS: No shared differences were found among all three disorders, and shared differences between any two disorders did not survive correction for multiple comparisons. Children with ADHD compared with those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller intracranial volume than control subjects and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared with adult control subjects and other clinical groups. No OCD-specific differences were observed across different age groups and surface area differences among all disorders in childhood and adulthood. CONCLUSIONS: The study findings suggest robust but subtle differences across different age groups among ADHD, ASD, and OCD. ADHD-specific intracranial volume and hippocampal differences in children and adolescents, and ASD-specific cortical thickness differences in the frontal cortex in adults, support previous work emphasizing structural brain differences in these disorders.
Fear responses to safety cues in anxious adolescents: Preliminary evidence for atypical age-associated trajectories of functional neural circuits
Adolescent anxiety is common and impairing and often persists into adulthood. There is growing evidence that adult anxiety is characterized by abnormal fear responses to threat and safety cues, along with perturbations in fear-related neural circuits. Although some of this work has been extended to adolescents, with promising results, it is not yet clear whether changes in these circuits across developmental age varies between anxious and non-anxious adolescents. Here we used fMRI to examine how age modulates neural responses as adolescents are exposed to threat and safety cues. Participants were 15 anxious and 11 non-anxious adolescents (age 12-17) who completed a fear conditioning paradigm. The paradigm incorporated a threat cue comprising a neutral face which was paired with a fearful, screaming face, a safety cue comprising a different neutral face, and a control stimulus. Across the whole sample, neural activation to the threat cue (relative to the control cue) correlated positively with age in a number of regions, including the dorsal anterior cingulate and bilateral dorsolateral prefrontal cortex (PFC). However, neural activation to the safety cue (relative to the control cue) was modulated differently by age in the two groups: a more positive association between activation and age was observed in the control group compared to the anxious group in various regions including medial and dorsolateral PFC, anterior insula, and amygdala. These findings suggest that maturation of the neural substrates of fear responses to safety cues may be perturbed in anxious adolescents, potentially contributing to the emergence and maintenance of anxiety disorders in adulthood.