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The use of the internal perimeter to compare airway size and to calculate smooth muscle shortening.
Previous studies from our laboratory suggest that the internal airway perimeter (Pi) defined by the folded epithelial surface remains constant as the airways narrow. To test this hypothesis, we treated adjacent slices of resected lung lobes with either theophylline or carbachol and determined the dimensions of the airways in these lung slices. Transverse sections of contracted (n = 58) and relaxed (n = 55) airways were used to measure the Pi defined by the epithelial surface, lumen area (Ai), external perimeter (Pe) defined by the outer edge of the smooth muscle layer, and the external area (Ae). Wall area (WA = Ae - Ai) was calculated. The frequency distribution of internal perimeters was not significantly different for the contracted and relaxed airways, and when the square root of wall area was plotted against Pi, the regression lines for the contracted and relaxed airways were almost identical. The "relaxed" external perimeter was calculated Per = square root Pi2 + (4 pi WA), and the percentage of muscle shortening (PMS) was determined: PMS = [(Per - Pe)/Per] x 100. We conclude that Pi and WA are constant in airways whether the smooth muscle is relaxed or contracted and that Pi can be used as a marker of airway size and, under controlled conditions, can be used to calculate the smooth muscle shortening present in a given airway.
The future of child and adolescent clinical psychopharmacology: A systematic review of phase 2, 3, or 4 randomized controlled trials of pharmacologic agents without regulatory approval or for unapproved indications.
We aimed to identify promising novel medications for child and adolescent mental health problems. We systematically searched https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ (from 01/01/2010-08/23/2022) for phase 2 or 3 randomized controlled trials (RCTs) of medications without regulatory approval in the US, Europe or Asia, including also RCTs of dietary interventions/probiotics. Additionally, we searched phase 4 RCTs of agents targeting unlicensed indications for children/adolescents with mental health disorders. We retrieved 234 ongoing or completed RCTs, including 26 (11%) with positive findings on ≥ 1 primary outcome, 43 (18%) with negative/unavailable results on every primary outcome, and 165 (70%) without publicly available statistical results. The only two compounds with evidence of significant effects that were replicated in ≥ 1 additional RCT without any negative RCTs were dasotraline for attention-deficit/hyperactivity disorder, and carbetocin for hyperphagia in Prader-Willi syndrome. Among other strategies, targeting specific symptom dimensions in samples stratified based on clinical characteristics or established biomarkers may increase chances of success in future development programmes.
White matter abnormalities in paediatric obsessive-compulsive disorder: a systematic review of diffusion tensor imaging studies.
Microstructural alterations in white matter are evident in obsessive-compulsive disorder (OCD) both in adult and paediatric populations. Paediatric patients go through the process of maturation and thus may undergo different pathophysiology than adult OCD. Findings from studies in paediatric obsessive-compulsive disorder have been inconsistent, possibly due to their small sample size or heterogeneous populations. The aim of this review is to provide a comprehensive overview of white matter structures in paediatric obsessive-compulsive disorder and their correlation with clinical features. Based on PRISMA guidelines, we performed a systematic search on diffusion tensor imaging studies that reported fractional anisotropy, mean diffusivity, radial diffusivity, or axial diffusivity alterations between paediatric patients with obsessive-compulsive disorder and healthy controls using voxel-based analysis, or tract-based spatial statistics. We identified fifteen relevant studies. Most studies reported changes predominantly in the corpus callosum, cingulum, arcuate fasciculus, uncinate fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tract, forceps minor and major, and the cerebellum in paediatric obsessive-compulsive disorder. These alterations included increased and decreased fractional anisotropy and radial diffusivity, and increased mean and axial diffusivity in different white matter tracts. These changes were associated with obsessive-compulsive disorder symptoms. Moreover, specific genetic polymorphisms were linked with cerebellar white matter changes in paediatric obsessive-compulsive disorder. White matter changes are widespread in paediatric OCD patients. These changes are often associated with symptoms however there are controversies in the direction of changes in some tracts.
Hemizygous mutations in L1CAM in two unrelated male probands with childhood onset psychosis.
OBJECTIVE: To identify genes underlying childhood onset psychosis. METHODS: Patients with onset of psychosis at age 13 or younger were identified from clinics across England, and they and their parents were exome sequenced and analysed for possible highly penetrant genetic contributors. RESULTS: We report two male childhood onset psychosis patients of different ancestries carrying hemizygous very rare possibly damaging missense variants (p.Arg846His and p.Pro145Ser) in the L1CAM gene. L1CAM is an X-linked Mendelian disease gene in which both missense and loss of function variants are associated with syndromic forms of intellectual disability and developmental disorder. CONCLUSIONS: This is the first study reporting a possible extension of the phenotype of L1CAM variant carriers to childhood onset psychosis. The family history and presence of other significant rare genetic variants in the patients suggest that there may be genetic interactions modulating the presentation.
Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.
[This corrects the article DOI: 10.1371/journal.pgen.1005378.].
Gyrification of Broca's region is anomalously lateralized at onset of schizophrenia in adolescence and regresses at 2 year follow-up.
Gyrification of the human cerebral cortex starts in the foetus and progresses in early infancy; the pattern of folding in later life provides a lead to early developmental aberration. By studying gyrification at illness onset in adolescence we hoped to clarify the pathophysiology of schizophrenia. Here we find 1) an area of hypergyria includes Broca's area and extends into the Sylvian fissure to encroach on the anterior insula in the left hemisphere, and 2) an area of hypogyria in the superior temporal lobe approximates to Wernicke's area but is located in the right hemisphere and encroaches on the posterior insula. In Broca's/anterior insula area, right lateralization was present in healthy controls but patients were left lateralized: at two year follow-up gyrification had decreased in patients while it increased in controls, and the reduction predicted impaired category fluency. Progressive change was unaccompanied by cortical thinning (investigated only in the brain regions showing baseline changes in gyrification) indicating that the disease process affecting these brain regions (insula, inferior frontal and superior temporal) is not primarily degenerative. A deviation in the lateralized development of peri-Sylvian areas for language production and comprehension appears critical to the pathophysiology of schizophrenia and may point to its species-specific origin.
Towards a framework for community engagement in global health research.
New technologies for global public health are spurring critical evaluations of the role of communities in research and what they receive in exchange for their participation. Community engagement activities resulting from these evaluations are most challenging for novel scientific ventures, particularly those involving controversial strategies and those in which some risks are poorly understood or determined. Remarkably, there is no explicit body of community engagement knowledge to which researchers can turn for guidance about approaches that are most likely to be effective in different contexts, and why. We describe here a framework that provides a starting point for broader discussions of community engagement in global health research, particularly as it relates to the development, evaluation and application of new technologies.
Cerebral palsy and juvenile-onset bipolar disorder. A preliminary report.
Cerebral palsy refers to a heterogeneous group of congenital and early acquired brain disorders. Children with cerebral palsy and other brain disorders have an increased rate of psychiatric disorder. The pattern of disorder is not particularly distinctive and no specific association has been found. We report two cases of spastic diplegia of prematurity comorbid with juvenile onset bipolar disorder, which highlight some of the diagnostic difficulties in these cases. An interesting association between the periventricular leucomalacia as an aetiological factor in cerebral palsy and the white matter lesions seen on magnetic resonance imaging in cases of bipolar disorder is noted.
Independent inheritance of serum immunoglobulin E concentrations and airway responsiveness.
Elevated serum Immunoglobulin E (IgE) levels and increased airway responsiveness (AR) are correlated traits that are characteristic of asthma. It is not known to what extent these traits arise from distinct or shared genetic determinants. We investigated the genetic and environmental components of variance of serum total and specific IgE levels and AR in an Australian population-based sample of 232 Caucasian nuclear families. The inter-relationships of the genetic determinants of these traits were also investigated. Log(e) total serum IgE levels had a narrow-sense heritability (h(2)(N)) of 47.3% (SE = 10.0%). Specific serum IgE levels against house dust mite and timothy grass, measured as a RAST Index, ad a h(2)(N) of 33.8% (SE = 7.3%). AR, quantified by the log(e) dose-response slope to methacholine (DRS), had a h(2)(N) of 30.0% (SE = 12.3%). Extended modeling demonstrated an approximate 70% overlap in the genetic determinants of total and specific serum IgE levels. The genetic determinants of serum IgE levels and AR exhibited less than 30% sharing. These data are consistent with the existence of multiple genetic determinants of the pathophysiologic traits associated with asthma, and suggest that AR is genetically distinct from atopy. These results have implications for gene discovery programs.
Evaluation of a randomised controlled trial of adult asthma education in a hospital setting.
BACKGROUND: Although patient education is a key step in the Australian Asthma Management Plan, its impact has not been assessed in a hospital outpatient asthma clinic. METHODS: A controlled trial was undertaken in 125 adults with asthma recruited from the Alfred Hospital Asthma and Allergy Clinic and randomly allocated to an intervention (n = 64) or control (n = 61) group. Subjects in the intervention group attended three education sessions, each of 90 minutes duration, spread over three successive weeks. Asthma knowledge, quality of life, self-management skills, and attitudes and beliefs about asthma were assessed by questionnaires at baseline and after six months. The intervention group was also assessed immediately after the three education sessions. The control group was evaluated after six months of usual care. RESULTS: Asthma knowledge improved significantly in the intervention group after three education sessions (p = 0.0001) and this was retained six months later (p = 0.03). The impact of asthma on quality of life decreased significantly immediately after intervention (p = 0.03) but this was not maintained six months later (p = 0.35). On the other hand, the intervention had little impact on self-management skills or attitudes and beliefs about asthma. However, the control group had also improved their knowledge, quality of life and self-management skills after six months of usual care. The difference in mean change in knowledge score at six months between the intervention and control groups was not significant (p = 0.51). CONCLUSIONS: In contrast to some other studies, a limited asthma education programme in a hospital outpatient setting had a positive impact on patients' knowledge of asthma, but not on their quality of life, self-management skills, or attitudes and beliefs about asthma.
Juvenile sexual offending: one-year period prevalence study within Oxfordshire.
An epidemiological survey using a postal questionnaire revealed a 1-year period prevalence rate of 1.5 official juvenile sexual offenders per 1,000 males aged 12-17 within Oxfordshire (.85 per 1,000 12-17 year olds overall). The majority of sexually abusive youth were male, with a family history of neglect, physical, and/or sexual abuse. Behavioral and psychological problems were common.
A model of airway narrowing in asthma and in chronic obstructive pulmonary disease.
We have examined the effect of airway wall thickening, loss of lung recoil, and airway smooth muscle shortening on the increase in airway resistance using a model of the human tracheobronchial tree. The values for airway wall thickening were determined morphometrically on the postmortem or surgically resected lungs of normal subjects, patients with moderate chronic obstructive pulmonary disease, and patients with severe asthma. Loss of recoil was simulated by deflating airways along their pressure-area curves by 1 to 3 cm H2O. 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 have little effect on baseline resistance, can profoundly affect 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 can partially explain the airway hyperresponsiveness observed in patients with chronic obstructive lung disease and asthma.
Characterization of the extracellular free water signal in schizophrenia using multi-site diffusion MRI harmonization.
Studies applying Free Water Imaging have consistently reported significant global increases in extracellular free water (FW) in populations of individuals with early psychosis. However, these published studies focused on homogenous clinical participant groups (e.g., only first episode or chronic), thereby limiting our understanding of the time course of free water elevations across illness stages. Moreover, the relationship between FW and duration of illness has yet to be directly tested. Leveraging our multi-site diffusion magnetic resonance imaging(dMRI) harmonization approach, we analyzed dMRI scans collected by 12 international sites from 441 healthy controls and 434 individuals diagnosed with schizophrenia-spectrum disorders at different illness stages and ages (15-58 years). We characterized the pattern of age-related FW changes by assessing whole brain white matter in individuals with schizophrenia and healthy controls. In individuals with schizophrenia, average whole brain FW was higher than in controls across all ages, with the greatest FW values observed from 15 to 23 years (effect size range = [0.70-0.87]). Following this peak, FW exhibited a monotonic decrease until reaching a minima at the age of 39 years. After 39 years, an attenuated monotonic increase in FW was observed, but with markedly smaller effect sizes when compared to younger patients (effect size range = [0.32-0.43]). Importantly, FW was found to be negatively associated with duration of illness in schizophrenia (p = 0.006), independent of the effects of other clinical and demographic data. In summary, our study finds in a large, age-diverse sample that participants with schizophrenia with a shorter duration of illness showed higher FW values compared to participants with more prolonged illness. Our findings provide further evidence that elevations in the FW are present in individuals with schizophrenia, with the greatest differences in the FW being observed in those at the early stages of the disorder, which might suggest acute extracellular processes.
Abnormal frontostriatal connectivity in adolescent-onset schizophrenia and its relationship to cognitive functioning.
BACKGROUND: Adolescent-onset schizophrenia (AOS) is associated with cognitive impairment and poor clinical outcome. Cognitive dysfunction is hypothesised, in part, to reflect functional dysconnectivity between the frontal cortex and the striatum, although structural abnormalities consistent with this hypothesis have not yet been demonstrated in adolescence. OBJECTIVE: To characterise frontostriatal white matter (WM) tracts in relation to cognition in AOS. DESIGN: A MRI volumetric and diffusion tensor imaging study. PARTICIPANTS: Thirty-seven AOS subjects and 24 age and sex-matched healthy subjects. OUTCOME MEASURES: Using probabilistic tractography, cortical regions with the highest connection probability for each striatal voxel were determined, and correlated with IQ and specific cognitive functions after co-varying for age and sex. Fractional anisotropy (FA) from individual tracts was a secondary measure. RESULTS: Bayesian Structural Equation modeling of FA from 12 frontostriatal tracts showed processing speed to be an intermediary variable for cognition. AOS patients demonstrated generalised cognitive impairment with specific deficits in verbal learning and memory and in processing speed after correction for IQ. Dorsolateral prefrontal cortex connectivity with the striatum correlated positively with these measures and with IQ. DTI voxel-wise comparisons showed lower connectivity between striatum and the motor and lateral orbitofrontal cortices bilaterally, the left amygdalohippocampal complex, right anterior cingulate cortex, left medial orbitofrontal cortex and right dorsolateral prefrontal cortex. CONCLUSIONS: Frontostriatal dysconnectivity in large WM tracts that can explain core cognitive deficits are evident during adolescence. Processing speed, which is affected by alterations in WM connectivity, appears an intermediary variable in the cognitive deficits seen in schizophrenia.
Sexually dimorphic white matter geometry abnormalities in adolescent onset schizophrenia.
The normal human brain is characterized by a pattern of gross anatomical asymmetry. This pattern, known as the "torque", is associated with a sexual dimorphism: The male brain tends to be more asymmetric than that of the female. This fact, along with well-known sex differences in brain development (faster in females) and onset of psychosis (earlier with worse outcome in males), has led to the theory that schizophrenia is a disorder in which sex-dependent abnormalities in the development of brain torque, the correlate of the capacity for language, cause alterations in interhemispheric connectivity, which are causally related to psychosis (Crow TJ, Paez P, Chance SE. 2007. Callosal misconnectivity and the sex difference in psychosis. Int Rev Psychiatry. 19(4):449-457.). To provide evidence toward this theory, we analyze the geometry of interhemispheric white matter connections in adolescent-onset schizophrenia, with a particular focus on sex, using a recently introduced framework for white matter geometry computation in diffusion tensor imaging data (Savadjiev P, Kindlmann GL, Bouix S, Shenton ME, Westin CF. 2010. Local white geometry from diffusion tensor gradients. Neuroimage. 49(4):3175-3186.). Our results reveal a pattern of sex-dependent white matter geometry abnormalities that conform to the predictions of Crow's torque theory and correlate with the severity of patients' symptoms. To the best of our knowledge, this is the first study to associate geometrical differences in white matter connectivity with torque in schizophrenia.
Guidance on the Use of Antidepressants for Depression in Young People: A Survey of the Views of Consultants in Child and Adolescent Psychiatry.
BACKGROUND: The Committee on Safety of Medicines (CSM) and National Institute for Health and Clinical Excellence have issued guidance on antidepressant use in depression in young people. METHOD: An anonymous survey was sent to 692 UK consultants in child and adolescent psychiatry; the response rate was 70.1%. RESULTS: Almost all (95.1%) respondents said fluoxetine was their antidepressant of first choice (29.9% only prescribed fluoxetine), although use of sertraline and citalopram was common. The CSM advice had resulted in 68.4% switching to fluoxetine only, or mostly. CONCLUSIONS: Clinicians appear to be adhering national guidance. Guidance needs to be regularly updated to reflect current evidence.
Mast cell densities in bronchial biopsies and small airways are related.
INTRODUCTION: The study sought to determine whether mast cell counts in endobronchial biopsies of large airways are related to mast cell counts in the small airways. METHODS: Lungs, obtained postmortem from 10 subjects who had died of non-respiratory causes, were fixed in inflation. Mast cell densities (cells/mm(3)), determined with an optical disector, were compared on histological sections (30 μm thick) of biopsies and small airways stained with human anti-mast cell tryptase. RESULTS: Mean mast cell density over the inner airway wall in biopsies was significantly related to mean mast cell density over the total airway wall in the small airways (r=∼0.80, p<0.01). A minimum of three biopsies per case was required to demonstrate this relationship. Within relevant count areas, mast cell density was about 1.6-fold higher in the small airways than in the biopsies. CONCLUSIONS: These findings suggest that when mean counts from at least three biopsies per case are used, intersubject comparisons of mast cell density in the inner airway wall in endobronchial biopsies reflect intersubject comparisons of mast cell density over the total airway wall in small airways. This is despite the observation that mast cell densities are generally higher in the small airways.