Impact of surgical and of bronchoscopic lung volume reductions in patients with emphysema and hyperinflation on lung structure, function and inflammation

Background – A robust biomarker for predicting and evaluating the response to lung volume reduction (LVR) interventions remains elusive. We investigated the hypothesis that LVR will be accompanied by measurable changes in novel indices of lung structure, function, and inflammation that can be correlated with changes to the conventional clinical parameters and that reliable identifiers of baseline predictors of therapeutic response (minimal clinically important difference, MCID, of at least 10% reduction of residual volume) will be identified. Methods – 72 consecutive subjects with severe emphysema and hyperinflation scheduled for lung volume reductions were recruited: lung volume reduction surgery (LVRS) – 15; Endobronchial valve (EBV) – 29, Endobronchial coil (EBC) – 28. All underwent detailed clinical phenotyping comprising demographics, symptom scores, computed tomography imaging, exercise capacity and lung function measurements during exacerbation-free periods at baseline and at three months after intervention. Novel techniques including quantitative computed tomography (qCT), impulse oscillometry (IOS) and multiple breath nitrogen washout (MBNW), and microvesicle quantification were employed to assess changes in lung structure, function and inflammation, respectively. Results – Surgery achieved the greatest lung volume reductions, △residual volume (RV) of -1.26 ± 0.58 litres (p<0.01), and more than 90% of recipients met the MCID of ≥10% RV reduction. It was the only intervention to be accompanied by improvements in functional gas trapping on CT, IOS expiratory airways resistance at 5Hz, expiratory and within-breath reactance at 5Hz, and peripheral resonant frequency, attributable to recovery of small airways function. Valve implantations reduced residual volume by -0.91 ± 0.66 litres (p<0.01) and 62% of recipients attained the MCID of ≥10% RV reduction. This was in addition to a smaller reduction in IOS expiratory and within-breath reactance at 5Hz without an accompanying signal in resistance, resonant frequency, or functional gas trapping on CT. Modest improvements to alveolar gas mixing (AME) and small airways function (Sacin) were measured using MBNW in a subset of patients. These data suggest the impact of valves on the peripheral airway compartment was less pronounced than with surgery and was achieved predominantly by deflation of emphysematous lung tissue and restoration of the mechanical pump. Coil implantations resulted in modest volume reductions, △residual volume of -0.31 ± 0.60L (p=0.01): Only 35% of subjects achieved the MCID of ≥10% RV reduction. Three-month physiological outcomes were similarly disappointing with improvements limited to CT-intraparenchymal blood vessel volume (perhaps due to greater radial traction exerted by the coils on the surrounding parenchyma) and the area under reactance during expiration (AXex) on IOS. The comparatively minor degree of volume reduction achieved (and the fall in gas transfer) using this technique may explain the relatively small impact on peripheral airways function. An inflammatory sub-study identified a variety of microvesicle (MV) populations in bronchoalveolar lavage fluid (BALF) and in the plasma of patients with mild to very severe COPD. Of these, polymorphouclear (neutrophil)-derived MVs were found to be substantially increased in BALF and their numbers correlated with airflow limitation, reduced exercise capacity, impaired of quality of life, and the BODE index. BALF neutrophil-derived MVs correlated with BALF neutrophil cell numbers but not with circulating neutrophil MV numbers, implying local alveolar release rather than translocation from the circulation. BALF neutrophil-derived MVs were also shown to be a more robust biomarker of disease severity than BALF neutrophil cell and cytokine levels. In a subset of valve and coil recipients, BALF-neutrophil derived MV levels were evaluated before and after intervention. Mean volume reduction in the coil recipients was exceeded threefold by that of the valve beneficiaries. Unexpectedly there was no statistically significant change in MV numbers at three months in the valve arm. Possible explanations include contamination from more proximal airway sampling / spill over from the ipsilateral lobe(s) or induction of a localised inflammatory response to biofilm formation overlying the nitinol-silicone implants. In contrast, a statistically significant fall in MV numbers was observed in the coil cohort in the absence of clinically meaningful volume reduction. It must however be borne in mind that despite the thin profile of the nitinol endobronchial coil, the surface area of the airway epithelium exposed to sampling is reduced. There were no identifiable predictors of therapeutic response among the novel indices of lung structure, function, and inflammation analysed. Conclusions – The degree of lung volume reduction achieved is critical in determining favourable clinical outcomes for patients with severe emphysema and hyperinflation. Similarly, the structural and functional impacts of lung volume reduction on the small airways compartment, the principal site of airflow obstruction, are proportional to the degree of volume reduction achieved (surgery > valves > coils). The impact of these therapies on airways inflammation requires further scrutiny. qCT and IOS qualify as structural and functional biomarkers, respectively, for evaluating volume reduction – however, their predictive value for therapeutic response is not established from this small dataset. BALF neutrophil-derived MV observations are potentially useful contributors to disease phenotyping alongside lung function tests and qCT imaging – their role as biomarkers for predicting and assessing therapeutic response remains to be seen. Larger randomised controlled trial designs are recommended to further investigate these preliminary findings.Open Acces

Pathological and phylogenetic characterization of Amphibiothecum sp. infection in an isolated amphibian (Lissotriton helveticus) population on the island of Rum (Scotland)

Outbreaks of cutaneous infectious disease in amphibians are increasingly being attributed to an overlooked group of fungal-like pathogens, the Dermocystids. During the last 10 years on the Isle of Rum, Scotland, palmate newts (Lissotriton helveticus) have been reportedly afflicted by unusual skin lesions. Here we present pathological and molecular findings confirming that the pathogen associated with these lesions is a novel organism of the order Dermocystida, and represents the first formally reported, and potentially lethal, case of amphibian Dermocystid infection in the UK. Whilst the gross pathology and the parasite cyst morphology were synonymous to those described in a study from infected L. helveticus in France, we observed a more extreme clinical outcome on Rum involving severe subcutaneous oedema. Phylogenetic topologies supported synonymy between Dermocystid sequences from Rum and France and as well as their distinction from Amphibiocystidium spp. Phylogenetic analysis also suggested that the amphibian-infecting Dermocystids are not monophyletic. We conclude that the L. helveticusinfecting pathogen represents a single, novel species; Amphibiothecum meredithae

Personality Traits in Juvenile Delinquents: Associations with Peer and Family Relations

Objective: To establish family and peer correlates of personality traits shown to be predictive of future criminal recidivism. Method: 137 incarcerated boys aged 13-18 (x = 16 ± 1.2), 35% black, 21% Hispanic, 43% white, and 1% other completed the Weinberger Adjustment Inventory (WAI) and a psychosocial history obtained by a social worker. Records were summarized using two raters who assigned numerical ratings to dimensions of family and peer relations. Results: As expected, observer ratings of family and peer relationships were correlated with the personality characteristics of distress, denial and restraint as measured by the WAI. Conclusion: Family and peer relations are associated with certain personality traits that are predictive of criminal recidivism in delinquents. This study further expands the knowledge base regarding the social and interpersonal correlates of individual traits predicting criminal recidivism

Psychiatric Aspects of the Treatment of Mild to Moderate Facial Acne

The improvement of acne appears to be associated with decreased depression and anxiety and greater satisfaction with aspects of body image that are generally unrelated to the appearance of the skin, ie, body shape and weight. The latter emphasizes the profound effect of the appearance of the skin upon the patient's overall body image. Our preliminary findings underline the need for larger controlled studies of psychosomatic factors among patients with mild to moderate acne.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65635/1/j.1365-4362.1990.tb03777.x.pd

Infections on the move: how transient phases of host movement influence disease spread.

Animal movement impacts the spread of human and wildlife diseases, and there is significant interest in understanding the role of migrations, biological invasions and other wildlife movements in spatial infection dynamics. However, the influence of processes acting on infections during transient phases of host movement is poorly understood. We propose a conceptual framework that explicitly considers infection dynamics during transient phases of host movement to better predict infection spread through spatial host networks. Accounting for host transient movement captures key processes that occur while hosts move between locations, which together determine the rate at which hosts spread infections through networks. We review theoretical and empirical studies of host movement and infection spread, highlighting the multiple factors that impact the infection status of hosts. We then outline characteristics of hosts, parasites and the environment that influence these dynamics. Recent technological advances provide disease ecologists unprecedented ability to track the fine-scale movement of organisms. These, in conjunction with experimental testing of the factors driving infection dynamics during host movement, can inform models of infection spread based on constituent biological processes

Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis

Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc) produce low levels of prostaglandin (PG) E(2), due to a limited capacity to up-regulate cyclooxygenase-2 (COX-2). This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood. In the present study, we examined whether the reduced level of COX-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5-aza-2′-deoxycytidine (5AZA) restored COX-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of PGE(2) production, collagen mRNA expression and sensitivity to apoptosis. COX-2 methylation assessed by bisulfite sequencing and methylation microarrays was not different in fibrotic fibroblasts compared with controls. However, further analysis of the methylation array data identified a transcriptional regulator, chromosome 8 open reading frame 4 (thyroid cancer protein 1, TC-1) (c8orf4), which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knockdown of c8orf4 in control fibroblasts down-regulated COX-2 and PGE(2) production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates COX-2 expression in lung fibroblasts through binding of the proximal promoter. We conclude that the decreased capacity of fibrotic lung fibroblasts to up-regulate COX-2 expression and COX-2-derived PGE(2) synthesis is due to an indirect epigenetic mechanism involving hypermethylation of the transcriptional regulator, c8orf4

Molecular Dynamics Analysis of Apolipoprotein-D - Lipid Hydroperoxide Interactions: Mechanism for Selective Oxidation of Met-93

Background: Recent studies suggest reduction of radical-propagating fatty acid hydroperoxides to inert hydroxides by interaction with apolipoprotein-D (apoD) Met93 may represent an antioxidant function for apoD. The nature and structural consequences of this selective interaction are unknown. Methodology/Principal Findings: Herein we used molecular dynamics (MD) analysis to address these issues. Longtimescale simulations of apoD suggest lipid molecules are bound flexibly, with the molecules free to explore multiple conformations in a binding site at the entrance to the classical lipocalin ligand-binding pocket. Models of 5s- 12s- and 15s hydroperoxyeicosatetraenoic acids were created and the lipids found to wrap around Met93 thus providing a plausible mechanism by which eicosatetraenoic acids bearing hydroperoxides on different carbon atoms can interact with Met93 to yield Met93 sulfoxide (Met93SO). Simulations of glycosylated apoD indicated that a second solvent exposed Met at position 49 was shielded by a triantennerary N-glycan attached to Asn45 thereby precluding lipid interactions. MD simulations of apoD showed B-factors of the loop containing Met93SO were higher in the oxidized protein, indicating increased flexibility that is predicted to destabilize the protein and promote self-association. Conclusions/Significance: These studies provide novel insights into the mechanisms that may contribute to the antioxidant function of apoD and the structural consequences that result if Met93SO is not redox-cycled back to its native state

Body image, body dissatisfaction and weight status in south asian children: a cross-sectional study

Background Childhood obesity is a continuing problem in the UK and South Asian children represent a group that are particularly vulnerable to its health consequences. The relationship between body dissatisfaction and obesity is well documented in older children and adults, but is less clear in young children, particularly South Asians. A better understanding of this relationship in young South Asian children will inform the design and delivery of obesity intervention programmes. The aim of this study is to describe body image size perception and dissatisfaction, and their relationship to weight status in primary school aged UK South Asian children. Methods Objective measures of height and weight were undertaken on 574 predominantly South Asian children aged 5-7 (296 boys and 278 girls). BMI z-scores, and weight status (underweight, healthy weight, overweight or obese) were calculated based on the UK 1990 BMI reference charts. Figure rating scales were used to assess perceived body image size (asking children to identify their perceived body size) and dissatisfaction (difference between perceived current and ideal body size). The relationship between these and weight status were examined using multivariate analyses. Results Perceived body image size was positively associated with weight status (partial regression coefficient for overweight/obese vs. non-overweight/obese was 0.63 (95% CI 0.26-0.99) and for BMI z-score was 0.21 (95% CI 0.10-0.31), adjusted for sex, age and ethnicity). Body dissatisfaction was also associated with weight status, with overweight and obese children more likely to select thinner ideal body size than healthy weight children (adjusted partial regression coefficient for overweight/obese vs. non-overweight/obese was 1.47 (95% CI 0.99-1.96) and for BMI z-score was 0.54 (95% CI 0.40-0.67)). Conclusions Awareness of body image size and increasing body dissatisfaction with higher weight status is established at a young age in this population. This needs to be considered when designing interventions to reduce obesity in young children, in terms of both benefits and harms

Inhalation Therapy in Patients Receiving Mechanical Ventilation: An Update

Incremental gains in understanding the influence of various factors on aerosol delivery in concert with technological advancements over the past 2 decades have fueled an ever burgeoning literature on aerosol therapy during mechanical ventilation. In-line use of pressurized metered-dose inhalers (pMDIs) and nebulizers is influenced by a host of factors, some of which are unique to ventilator-supported patients. This article reviews the impact of various factors on aerosol delivery with pMDIs and nebulizers, and elucidates the correlation between in-vitro estimates and in-vivo measurement of aerosol deposition in the lung. Aerosolized bronchodilator therapy with pMDIs and nebulizers is commonly employed in intensive care units (ICUs), and bronchodilators are among the most frequently used therapies in mechanically ventilated patients. The use of inhaled bronchodilators is not restricted to mechanically ventilated patients with chronic obstructive pulmonary disease (COPD) and asthma, as they are routinely employed in other ventilator-dependent patients without confirmed airflow obstruction. The efficacy and safety of bronchodilator therapy has generated a great deal of interest in employing other inhaled therapies, such as surfactant, antibiotics, prostacyclins, diuretics, anticoagulants and mucoactive agents, among others, in attempts to improve outcomes in critically ill ICU patients receiving mechanical ventilation