Chronic lung disease in adult recurrent tuberculosis survivors in Zimbabwe: a cohort study.

OBJECTIVE: To examine the prevalence and magnitude of chronic lung disease (CLD) and its association with empiric anti-tuberculosis treatment (due to lack of bacteriologic confirmation) among recurrent tuberculosis (TB) survivors in a human immunodeficiency virus (HIV) prevalent setting. METHODS: Prospective cohort study of retreatment TB survivors in Harare, Zimbabwe. At median follow-up of 2 years post-treatment initiation, we characterized mortality, respiratory impairment, and mental health. RESULTS: Among 175 retreatment TB survivors, 65% of whom were HIV-positive and 21% had been empirically treated, multiparameter CLD was noted at follow-up among 14% of patients (95%CI 9.0-19.7), with a six-fold increase in age-adjusted death in the first year following treatment completion. Empirically treated TB (relative risk [RR] 3.4, 95%CI 1.4-8.3) was associated with CLD, as was the number of previous anti-tuberculosis treatment courses in dose-dependent fashion (three vs. one, RR 6.2, 95%CI 1.7-22.1). Among retreatment TB survivors, 33% (95%CI 26.0-40.1) had persistent respiratory symptoms (Chronic Obstructive Pulmonary Disease Assessment Test score 10); 26% (95%CI 19.8-33.0) significant deficits in exercise capacity (median incremental shuttle walk test distance, 550 m; Q1-Q3 440-730 m); 83% (95%CI 75.7-89.7) residual radiographic abnormalities on chest X-ray; 12% (95%CI 6.6-16.1%) moderate-to-severe obstruction on spirometry; and 13% (95%CI 7.6-17.5%) major depression. CONCLUSIONS: Despite successful treatment, retreatment TB survivors retain a substantial risk of morbidity and mortality.

Corticosteroid and long-acting ß-agonist therapy reduces epithelial goblet cell metaplasia.

BACKGROUND: Bronchial epithelial goblet cell metaplasia (GCM) with hyperplasia is a prominent feature of asthma, but the effects of treatment with corticosteroids alone or in combination with a long-acting ß2 -adrenergic receptor agonist (LABA) on GCM in the bronchial epithelium are unknown. OBJECTIVES: To determine whether corticosteroid alone or in combination with a LABA alters protein and gene expression pathways associated with IL-13-induced goblet cell metaplasia. RESULTS: We evaluated the effects of fluticasone propionate (FP) and of salmeterol (SM), on the response of well-differentiated cultured bronchial epithelial cells to interleukin-13 (IL-13). Outcome measures included gene expression of SPDEF/FOXa2, gene expression and protein production of MUC5AC/MUC5B and morphologic appearance of cultured epithelial cell sheets. We additionally analysed expression of these genes in bronchial epithelial brushings from healthy, steroid-naïve asthmatic and steroid-treated asthmatic subjects. In cultured airway epithelial cells, FP treatment inhibited IL-13-induced suppression of FOXa2 gene expression and up-regulation of SPDEF, alterations in gene and protein measures of MUC5AC and MUC5B and induction of GCM. The addition of SM synergistically modified the effects of FP modestly-only for gel-forming mucin MUC5AC. In bronchial epithelial cells recovered from asthmatic vs healthy human subjects, we found FOXa2 and MUC5B gene expression to be reduced and SPDEF and MUC5AC gene expression to be increased; these alterations were not observed in bronchial epithelial cells recovered after treatment with inhaled corticosteroids. CONCLUSION AND CLINICAL RELEVANCE: Corticosteroid treatment inhibits IL-13-induced GCM of the airways in asthma, possibly through its effects on SPDEF and FOXa2 regulation of mucin gene expression. These effects are modestly augmented by the addition of a long-acting ß-agonist. As we found evidence for drug treatment counteracting the effects of IL-13 on the epithelium, we conclude that further exploration into the mechanisms by which corticosteroids and long-acting ß2 -adrenergic agonists confer protection against pathologic airway changes is warranted.

Stress improves selective attention towards emotionally neutral left ear stimuli.

Research concerning the impact of psychological stress on visual selective attention has produced mixed results. The current paper describes two experiments which utilise a novel auditory oddball paradigm to test the impact of psychological stress on auditory selective attention. Participants had to report the location of emotionally-neutral auditory stimuli, while ignoring task-irrelevant changes in their content. The results of the first experiment, in which speech stimuli were presented, suggested that stress improves the ability to selectively attend to left, but not right ear stimuli. When this experiment was repeated using tonal stimuli the same result was evident, but only for female participants. Females were also found to experience greater levels of distraction in general across the two experiments. These findings support the goal-shielding theory which suggests that stress improves selective attention by reducing the attentional resources available to process task-irrelevant information. The study also demonstrates, for the first time, that this goal-shielding effect extends to auditory perception.

Neural basis of auditory expectation within temporal cortex.

Predictive coding frameworks of perception propose that neural networks form predictions of expected input and generate prediction errors when the external input does not match expectation. We therefore investigated the processing of unexpected sounds and silence in the auditory cortex using fMRI. Unexpected sounds, when compared to expected sounds, evoked greater activation in large areas of the left temporal and insular cortices. Additionally the left middle temporal gyrus exhibited greater activation to unexpected events in general, whether sounds or silence, when compared to the corresponding expected events. These findings support predictive coding models of perception, which suggest that regions of the temporal cortex function to integrate sensory information with predictive signals during auditory perception.

Clinical and neuropsychological aspects of non-fatal self-harm in schizophrenia.

PURPOSE: To investigate demographic, clinical and neuropsychological aspects of self-harm in schizophrenia and identify which are independently predictive of and therefore the most relevant to clinical intervention. SUBJECTS AND METHODS: Eighty-seven patients with schizophrenia were interviewed regarding substance misuse, depression, hopelessness, negative/positive symptoms and illness insight. Neuropsychological assessment included premorbid IQ, continuous performance test, cognitive-motor and trait impulsivity. A prospective three-month review of medical records was also undertaken. RESULTS: Fifty-nine patients (68%) reported past self-harm (including attempted suicide). Those with past self-harm, compared to those without, were significantly more likely to report depression, hopelessness, impulsivity, a family history of self-harm, polysubstance abuse and had higher premorbid IQ. Logistic regression revealed that depression, higher premorbid IQ and polysubstance abuse were independently linked to self-harm. Five participants attempted self-harm during the 3-month prospective follow-up period. These all had a history of past self-harm and were significantly more likely to have been depressed at the initial interview than those who did not go on to self-harm. DISCUSSION AND CONCLUSIONS: Independent predictors of self-harm in schizophrenia are premorbid IQ and polysubstance abuse. In addition, depression was both independently associated with past self-harm and predictive of self-harm in the follow-up period.

Where does transcranial magnetic stimulation (TMS) stimulate? Modelling of induced field maps for some common cortical and cerebellar targets.

Computational models have been be used to estimate the electric and magnetic fields induced by transcranial magnetic stimulation (TMS) and can provide valuable insights into the location and spatial distribution of TMS stimulation. However, there has been little translation of these findings into practical TMS research. This study uses the International 10-20 EEG electrode placement system to position a standard figure-of-eight TMS coil over 13 commonly adopted targets. Using a finite element method and an anatomically detailed and realistic head model, this study provides the first pictorial and numerical atlas of TMS-induced electric fields for a range of coil positions. The results highlight the importance of subject-specific gyral folding patterns and of local thickness of subarachnoid cerebrospinal fluid (CSF). Our modelling shows that high electric fields occur primarily on the peaks of those gyri which have only a thin layer of CSF above them. These findings have important implications for inter-individual generalizability of the TMS-induced electric field. We propose that, in order to determine with accuracy the site of stimulation for an individual subject, it is necessary to solve the electric field distribution using subject-specific anatomy obtained from a high-resolution imaging modality such as MRI.

Auditory hallucinations: expectation-perception model.

In this paper, we aimed to present a hypothesis that would explain the mechanism of auditory hallucinations, one of the main symptoms of schizophrenia. We propose that auditory hallucinations arise from abnormalities in the predictive coding which underlies normal perception, specifically, from the absence or attenuation of prediction error. The suggested deficiencies in processing prediction error could arise from (1) abnormal modulation of thalamus by prefrontal cortex, (2) absence or impaired transmission of external input, (3) dysfunction of the auditory and association cortex, (4) neurotransmitter dysfunction and abnormal connectivity, and (5) hyperactivity activity in auditory cortex and broad prior probability. If there is no prediction error, the initially vague prior probability develops into an explicit percept in the absence of external input, as a result of a recursive pathological exchange between auditory and prefrontal cortex. Unlike existing explanations of auditory hallucinations, we propose concrete mechanisms which underlie the imbalance between perceptual expectation and external input. Impaired processing of prediction error is reflected in reduced mismatch negativity and increased tendency to report non-existing meaningful language stimuli in white noise, shown by those suffering from auditory hallucinations. We believe that the expectation-perception model of auditory hallucinations offers a comprehensive explanation of the underpinnings of auditory hallucinations in both patients and those not diagnosed with mental illness. Therefore, our hypothesis has the potential to fill the gaps in the existing knowledge about this distressing phenomenon and contribute to improved effectiveness of treatments, targeting specific mechanisms.

A protective role for periostin and TGF-ß in IgE-mediated allergy and airway hyperresponsiveness.

BACKGROUND: The pathophysiology of asthma involves allergic inflammation and remodelling in the airway and airway hyperresponsiveness (AHR) to cholinergic stimuli, but many details of the specific underlying cellular and molecular mechanisms remain unknown. Periostin is a matricellular protein with roles in tissue repair following injury in both the skin and heart. It has recently been shown to be up-regulated in the airway epithelium of asthmatics and to increase active TGF-ß. Though one might expect periostin to play a deleterious role in asthma pathogenesis, to date its biological role in the airway is unknown. OBJECTIVE: To determine the effect of periostin deficiency on airway responses to inhaled allergen. METHODS: In vivo measures of airway responsiveness, inflammation, and remodelling were made in periostin deficient mice and wild-type controls following repeated intranasal challenge with Aspergillus fumigatus antigen. In vitro studies of the effects of epithelial cell-derived periostin on murine T cells were also performed. RESULTS: Surprisingly, compared with wild-type controls, periostin deficient mice developed increased AHR and serum IgE levels following allergen challenge without differences in two outcomes of airway remodelling (mucus metaplasia and peribronchial fibrosis). These changes were associated with decreased expression of TGF-ß1 and Foxp3 in the lungs of periostin deficient mice. Airway epithelial cell-derived periostin-induced conversion of CD4(+) CD25(-) cells into CD25(+) , Foxp3(+) T cells in vitro in a TGF-ß dependent manner. CONCLUSIONS AND CLINICAL RELEVANCE: Allergen-induced increases in serum IgE and bronchial hyperresponsiveness are exaggerated in periostin deficient mice challenged with inhaled aeroallergen. The mechanism of periostin's effect as a brake on allergen-induced responses may involve augmentation of TGF-ß-induced T regulatory cell differentiation.

The state of tranquility: subjective perception is shaped by contextual modulation of auditory connectivity.

In this study, we investigated brain mechanisms for the generation of subjective experience from objective sensory inputs. Our experimental construct was subjective tranquility. Tranquility is a mental state more likely to occur in the presence of objective sensory inputs that arise from natural features in the environment. We used functional magnetic resonance imaging to examine the neural response to scenes that were visually distinct (beach images vs. freeway images) and experienced as tranquil (beach) or non-tranquil (freeway). Both sets of scenes had the same auditory component because waves breaking on a beach and vehicles moving on a freeway can produce similar auditory spectral and temporal characteristics, perceived as a constant roar. Compared with scenes experienced as non-tranquil, we found that subjectively tranquil scenes were associated with significantly greater effective connectivity between the auditory cortex and medial prefrontal cortex, a region implicated in the evaluation of mental states. Similarly enhanced connectivity was also observed between the auditory cortex and posterior cingulate gyrus, temporoparietal cortex and thalamus. These findings demonstrate that visual context can modulate connectivity of the auditory cortex with regions implicated in the generation of subjective states. Importantly, this effect arises under conditions of identical auditory input. Hence, the same sound may be associated with different percepts reflecting varying connectivity between the auditory cortex and other brain regions. This suggests that subjective experience is more closely linked to the connectivity state of the auditory cortex than to its basic sensory inputs.

The development of a clinically useful tool for predicting the development of psychological disorder following injury.

OBJECTIVES: To identify factors significantly associated with post-traumatic stress disorder (PTSD), anxiety, and depression at 3 months post-injury; to develop a generic model to predict the occurrence of PTSD, anxiety, and depression at 3 months post-injury; and to validate this model in a test data set of patients. DESIGN: Prospective cohort study. METHODS: Participants were 823 patients attending an emergency department (ED) following accidental injury. Baseline questionnaires were completed, with 1 and 3 months postal follow-ups. Predictor variables demonstrating significant associations with two of the three outcome measures (3-month HAD anxiety and depression scores and PTSD symptoms) were included in multivariate regression models for each outcome. Non-significant predictor variables were removed until all remaining independent variables made the most significant contribution to each of the three models. Models were validated using a test dataset. RESULTS: Previous history of mental health problems, neuroticism score and having PTSD symptoms at 1 month predicted adverse outcomes at 3 months. When used on the test datasets, the areas under the receiver operating curve (ROC) curve for the models predicting outcomes at 3 months were: PTSD=0.91 (sensitivity=88.5%); anxiety=0.87 (sensitivity=93.7%); and depression=0.87 (sensitivity=96.7%). CONCLUSIONS: The final model performed moderately well across the three outcomes and may be useful clinically as a generic rule-out tool to identify those who will not require follow up, watchful waiting or intervention.

Cognitive performance and grey matter density in psychosis: functional relevance of a structural endophenotype.

BACKGROUND: Structural brain changes and cognitive impairments have been identified as indicators of genetic risk for schizophrenia. However, the pattern of associations between such structural and functional liability markers has been less well investigated. METHODS: Magnetic resonance imaging data and cognitive assessments were acquired in 31 patients with psychosis, 32 non-psychotic first-degree relatives and 28 controls. The relationship between cerebral grey matter density and cognitive performance was examined using computational morphometry. RESULTS: Two out of 6 cognitive tests revealed significant associations with grey matter density in regions of the frontal lobe, basal ganglia, thalamus and cerebellum in patients and relatives. In patients, poorer executive functioning was associated with cerebellar grey matter density deficits. In relatives, poorer executive functioning was associated with increased grey matter density in the cerebellum and frontal lobe. In both patients and relatives, strategic retrieval from semantic memory was positively associated with grey matter density in basal ganglia structures. Some additional negative associations in the patients differentiated this group from relatives. CONCLUSIONS: The overlap in structure-function relationships in individuals with schizophrenia and those with liability for the disorder may suggest that regional grey matter density alterations functionally alter particular neurocircuits, which could lead to cognitive deficits. The non-overlapping structure-function correlations may reflect disease-related or compensatory mechanisms.

Humour experience in schizophrenia: relationship with executive dysfunction and psychosocial impairment.

BACKGROUND: The ability to appreciate humour is essential to successful human interactions. In this study, we hypothesized that individuals with schizophrenia would have diminished ability to recognize and appreciate humour. The relationship between humour experience and clinical symptoms, cognitive and social functioning was examined. METHOD: Thirty patients with a DSM-IV diagnosis of schizophrenia were compared with 30 age-, gender-, IQ- and ethnicity-matched healthy controls. Humour recognition was measured by identification of humorous moments in four silent slapstick comedy film clips and calculated as d-prime (d') according to signal detection theory. Humour appreciation was measured by self-report mood state and funniness ratings. Patients were assessed for clinical symptoms, theory of mind ability, executive function [using the Wisconsin Card Sorting Test (WCST)] and social functioning [using the Life Skills Profile (LSP)]. RESULTS: Patient and control groups did not differ in the funniness ratings they attributed to the video clips. Patients with schizophrenia had a lower d' (humour) compared to the controls, after controlling for (1) the performance of a baseline recognition task with a non-humorous video clip and (2) severity of depressive symptoms. In patients, d' (humour) had significant negative correlation with delusion and depression scores, the perseverative error score of the WCST and the total scores of the LSP. CONCLUSIONS: Compared with controls, patients with schizophrenia were less sensitive at detecting humour but similarly able to appreciate humour. The degree of humour recognition difficulty may be associated with the extent of executive dysfunction and thus contribute to the psychosocial impairment in patients with schizophrenia.

Auditory hallucinations in those populations that do not suffer from schizophrenia.

The following article discusses the phenomenon of auditory hallucinations in those who do not suffer from schizophrenia. Research has shown the occurrence of auditory hallucinations in the general population to such an extent that they cannot be said to be pathognomonic of psychiatric illness. In addition, it has long been known that certain hallucinatory experiences occur in health, such as hypnagogic and hypnopompic hallucinations. However, there are fundamental differences in the characteristics of these experiences. In the psychiatric population, these tend to be frequent, intrusive, and distressing. In contrast, in the nonclinical population, these are often predominantly positive and nonthreatening. The exact mechanism for the occurrence of auditory hallucinations is not yet known, but it is hoped that through the study of those in health, the mechanisms that underpin pathophysiologic processes in clinical conditions also can be elucidated.

Neural activity in speech-sensitive auditory cortex during silence.

That auditory hallucinations are voices heard in the absence of external stimuli implies the existence of endogenous neural activity within the auditory cortex responsible for their perception. Further, auditory hallucinations occur across a range of healthy and disease states that include reduced arousal, hypnosis, drug intoxication, delirium, and psychosis. This suggests that, even in health, the auditory cortex has a propensity to spontaneously "activate" during silence. Here we report the findings of a functional MRI study, designed to examine baseline activity in speech-sensitive auditory regions. During silence, we show that functionally defined speech-sensitive auditory cortex is characterized by intermittent episodes of significantly increased activity in a large proportion (in some cases >30%) of its volume. Bilateral increases in activity are associated with foci of spontaneous activation in the left primary and association auditory cortices and anterior cingulate cortex. We suggest that, within auditory regions, endogenous activity is modulated by anterior cingulate cortex, resulting in spontaneous activation during silence. Hence, an aspect of the brain's "default mode" resembles a (preprepared) substrate for the development of auditory hallucinations. These observations may help explain why such hallucinations are ubiquitous.

Structural changes to airway smooth muscle in cystic fibrosis.

BACKGROUND: Chronic airway obstruction is characteristic of cystic fibrosis (CF) but there are few studies of airway smooth muscle remodelling in CF. METHODS: Airway smooth muscle content and mean airway smooth muscle cell size were measured by applying design-based stereology to bronchoscopic biopsy specimens obtained from seven subjects with CF and 15 healthy controls. RESULTS: The smooth muscle content increased by 63% in subjects with CF (mean (SD) 0.173 (0.08) v 0.106 (0.042) mm(3) smooth muscle/mm(3) submucosa, mean difference -0.067; 95% CI -0.12 to -0.013, p = 0.017) but there was no increase in mean cell size (2705 (351) v 2654 (757) microm(3), mean difference -51; 95% CI -687 to 585, p = 0.87). CONCLUSIONS: These findings indicate hyperplasia of airway smooth muscle cells without hypertrophy and suggest that accumulation of airway smooth muscle cells may contribute to airway narrowing and bronchial hyperresponsiveness in CF.

Dopant radiative cooling effects in indirect-drive Ar-doped capsule implosion experiments.

We present results from simulations performed to investigate the effects of dopant radiative cooling in inertial confinement fusion indirect-drive capsule implosion experiments. Using a one-dimensional radiation-hydrodynamics code that includes inline collisional-radiative modeling, we compute in detail the non-local thermodynamic equilibrium atomic kinetics and spectral characteristics for Ar-doped DD fuel. Specifically, we present results from a series of calculations in which the concentration of the Ar is varied, and examine the sensitivity of the fuel conditions (e.g., electron temperature) and neutron yield to the Ar dopant concentration. Simulation results are compared with data obtained in OMEGA indirect-drive experiments in which monochromatic imaging and spectral measurements of Ar Hebeta and Lybeta line emission were recorded. The incident radiation drive on the capsule is computed with a three-dimensional view factor code using the laser beam pointings and powers from the OMEGA experiments. We also examine the sensitivity of the calculated compressed core electron temperatures and neutron yields to the radiation drive on the capsule and to the radiation and atomic modeling in the simulations.

Social cognition, brain networks and schizophrenia.

BACKGROUND: A better understanding of the neural basis of social cognition including mindreading (or theory of mind) and empathy might help to explain some deficits in social functioning in people with schizophrenia. Our aim was to review neuroimaging and neuropsychological studies on social cognition, as they may shed light on the neural mechanisms of social cognition and its dysfunction in patients with schizophrenia. METHOD: A selective literature review was undertaken. RESULTS: Neuroimaging and neuropsychological studies suggest convergence upon specific networks for mindreading and empathy (the temporal cortex, amygdala and the prefrontal cortex). The frontal lobe is likely to play a central role in enabling social cognition, but mindreading and empathic abilities may require relatively different weighting of subcomponents within the same frontal-temporal social cognition network. CONCLUSIONS: Disturbances in social cognition may represent an abnormal interaction between frontal lobe and its functionally connected cortical and subcortical areas. Future studies should seek to explore the heterogeneity of social dysfunction within schizophrenia.

Lateralisation of language function in young adults born very preterm.

OBJECTIVE: To explore, using functional magnetic resonance imaging (MRI), the functional organisation of phonological processing in young adults born very preterm. SUBJECTS: Six right handed male subjects with radiological evidence of thinning of the corpus callosum were selected from a cohort of very preterm subjects. Six normal right handed male volunteers acted as controls. METHOD: Blood oxygenation level dependent contrast echoplanar images were acquired over five minutes at 1.5 T while subjects performed the tasks. During the ON condition, subjects were visually presented with pairs of non-words and asked to press a key when a pair of words rhymed (phonological processing). This task alternated with the OFF condition, which required subjects to make letter case judgments of visually presented pairs of consonant letter strings (orthographic processing). Generic brain activation maps were constructed from individual images by sinusoidal regression and non-parametric testing. Between group differences in the mean power of experimental response were identified on a voxel wise basis by analysis of variance. RESULTS: Compared with controls, the subjects with thinning of the corpus callosum showed significantly reduced power of response in the left hemisphere, including the peristriate cortex and the cerebellum, as well as in the right parietal association area. Significantly increased power of response was observed in the right precentral gyrus and the right supplementary motor area. CONCLUSIONS: The data show evidence of increased frontal and decreased occipital activation in male subjects with neurodevelopmental thinning of the corpus callosum, which may be due to the operation of developmental compensatory mechanisms.