Pathogenesis of hyperinflation in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable lung disease characterized by airflow limitation that is not fully reversible. In a significant proportion of patients with COPD, reduced lung elastic recoil combined with expiratory flow limitation leads to lung hyperinflation during the course of the disease. Development of hyperinflation during the course of COPD is insidious. Dynamic hyperinflation is highly prevalent in the advanced stages of COPD, and new evidence suggests that it also occurs in many patients with mild disease, independently of the presence of resting hyperinflation. Hyperinflation is clinically relevant for patients with COPD mainly because it contributes to dyspnea, exercise intolerance, skeletal muscle limitations, morbidity, and reduced physical activity levels associated with the disease. Various pharmacological and nonpharmacological interventions have been shown to reduce hyperinflation and delay the onset of ventilatory limitation in patients with COPD. The aim of this review is to address the more recent literature regarding the pathogenesis, assessment, and management of both static and dynamic lung hyperinflation in patients with COPD. We also address the influence of biological sex and obesity and new developments in our understanding of hyperinflation in patients with mild COPD and its evolution during progression of the disease

A model for reactive porous transport during re-wetting of hardened concrete

A mathematical model is developed that captures the transport of liquid water in hardened concrete, as well as the chemical reactions that occur between the imbibed water and the residual calcium silicate compounds residing in the porous concrete matrix. The main hypothesis in this model is that the reaction product -- calcium silicate hydrate gel -- clogs the pores within the concrete thereby hindering water transport. Numerical simulations are employed to determine the sensitivity of the model solution to changes in various physical parameters, and compare to experimental results available in the literature.Comment: 30 page

MiR-10 Represses HoxB1a and HoxB3a in Zebrafish

BACKGROUND: The Hox genes are involved in patterning the anterior-posterior axis. In addition to the protein coding Hox genes, the miR-10, miR-196 and miR-615 families of microRNA genes are conserved within the vertebrate Hox clusters. The members of the miR-10 family are located at positions associated with Hox-4 paralogues. No function is yet known for this microRNA family but the genomic positions of its members suggest a role in anterior-posterior patterning. METHODOLOGY/PRINCIPAL FINDINGS: Using sensor constructs, overexpression and morpholino knockdown, we show in Zebrafish that miR-10 targets HoxB1a and HoxB3a and synergizes with HoxB4 in the repression of these target genes. Overexpression of miR-10 also induces specific phenotypes related to the loss of function of these targets. HoxB1a and HoxB3a have a dominant hindbrain expression domain anterior to that of miR-10 but overlap in a weaker expression domain in the spinal cord. In this latter domain, miR-10 knockdown results in upregulation of the target genes. In the case of a HoxB3a splice variant that includes miR-10c within its primary transcript, we show that the microRNA acts in an autoregulatory fashion. CONCLUSIONS/SIGNIFICANCE: We find that miR-10 acts to repress HoxB1a and HoxB3a within the spinal cord and show that this repression works cooperatively with HoxB4. As with the previously described interactions between miR-196 and HoxA7 and Hox-8 paralogues, the target genes are located in close proximity to the microRNA. We present a model in which we postulate a link between the clustering of Hox genes and post-transcriptional gene regulation. We speculate that the high density of transcription units and enhancers within the Hox clusters places constraints on the precision of the transcriptional control that can be achieved within these clusters and requires the involvement of post-transcriptional gene silencing to define functional domains of genes appropriately

Short term effects of exercise training on exercise capacity and quality of life in patients with pulmonary arterial hypertension: protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Advances in the understanding and management of pulmonary arterial hypertension have enabled earlier diagnosis and improved prognosis. However, despite best available therapy, symptoms of exertional dyspnoea and fatigue are commonly reported and result in a reduced capacity to perform daily activities and impaired quality of life. Exercise training has demonstrated efficacy in individuals with other respiratory and cardiovascular diseases. Historically, however, exercise training has not been utilised as a form of therapy in pulmonary arterial hypertension due to the perceived risk of sudden cardiac death and the theoretical possibility that exercise would lead to worsening pulmonary vascular haemodynamics and deterioration in right heart function. Now, with the advances in pharmaceutical management, determining the safety and benefits of exercise training in this population has become more relevant. Only three studies of supervised exercise training in pulmonary arterial hypertension have been published. These studies demonstrated improvements in exercise capacity and quality of life, in the absence of adverse events or clinical deterioration. However, these studies have not utilised an outpatient-based, whole body exercise training program, the most common format for exercise programs within Australia. It is uncertain whether this form of training is beneficial and capable of producing sustained benefits in exercise capacity and quality of life in this population.</p> <p>Design/Methods</p> <p>This randomised controlled trial will determine whether a 12 week, outpatient-based, supervised, whole body exercise training program, followed by a home-based exercise program, is safe and improves exercise capacity and quality of life in individuals with pulmonary arterial hypertension. This study aims to recruit 34 subjects who will be randomly allocated to the exercise group (supervised exercise training 3 times a week for 12 weeks, followed by 3 sessions per week of home exercise for 12 weeks) or the control group (usual medical care). Subjects will be assessed at baseline, 12 weeks and 24 weeks.</p> <p>Discussion</p> <p>This study will determine whether outpatient-based, whole body exercise training is beneficial and safe in individuals with pulmonary arterial hypertension. Additionally, this study will contribute to clinical practice guidelines for this patient population.</p> <p>Trial registration</p> <p>Australia and New Zealand Clinical Trials Register (ANZCTR): <a href="http://www.anzctr.org.au/ACTRN12609000502235.aspx">ACTRN12609000502235</a></p

Limited diversity associated with duplicated class II MHC-DRB genes in the red squirrel population in the United Kingdom compared with continental Europe

The red squirrel (Sciurus vulgaris) population in the United Kingdom has declined over the last century and is now on the UK endangered species list. This is the result of competition from the eastern grey squirrel (S. carolinensis) which was introduced in the 19th century. However, recent evidence suggests that the rate of population decline is enhanced by squirrelpox disease, caused by a viral infection carried asymptomatically by grey squirrels but to which red squirrels are highly susceptible. Population genetic diversity provides some resilience to rapidly evolving or exotic pathogens. There is currently no data on genetic diversity of extant UK squirrel populations with respect to genes involved in disease resistance. Diversity is highest at loci involved in the immune response including genes clustered within the major histocompatibility complex (MHC). Using the class II DRB locus as a marker for diversity across the MHC region we genotyped 110 red squirrels from locations in the UK and continentalEurope. Twenty four Scvu-DRB alleles at two functional loci; Scvu-DRB1 and Scvu- DRB2, were identified. High levels of diversity were identified at both loci in the continental populations. In contrast, no diversity was observed at the Scvu-DRB2 locus in the mainland UK population while a high level of homozygosity was observed at the Scvu-DRB1 locus. The red squirrel population in the UK appears to lack the extensive MHC diversity associated with continental populations, a feature which may have contributed to their rapid decline

Multiple Promoters and Alternative Splicing: Hoxa5 Transcriptional Complexity in the Mouse Embryo

The genomic organization of Hox clusters is fundamental for the precise spatio-temporal regulation and the function of each Hox gene, and hence for correct embryo patterning. Multiple overlapping transcriptional units exist at the Hoxa5 locus reflecting the complexity of Hox clustering: a major form of 1.8 kb corresponding to the two characterized exons of the gene and polyadenylated RNA species of 5.0, 9.5 and 11.0 kb. This transcriptional intricacy raises the question of the involvement of the larger transcripts in Hox function and regulation.We have undertaken the molecular characterization of the Hoxa5 larger transcripts. They initiate from two highly conserved distal promoters, one corresponding to the putative Hoxa6 promoter, and a second located nearby Hoxa7. Alternative splicing is also involved in the generation of the different transcripts. No functional polyadenylation sequence was found at the Hoxa6 locus and all larger transcripts use the polyadenylation site of the Hoxa5 gene. Some larger transcripts are potential Hoxa6/Hoxa5 bicistronic units. However, even though all transcripts could produce the genuine 270 a.a. HOXA5 protein, only the 1.8 kb form is translated into the protein, indicative of its essential role in Hoxa5 gene function. The Hoxa6 mutation disrupts the larger transcripts without major phenotypic impact on axial specification in their expression domain. However, Hoxa5-like skeletal anomalies are observed in Hoxa6 mutants and these defects can be explained by the loss of expression of the 1.8 kb transcript. Our data raise the possibility that the larger transcripts may be involved in Hoxa5 gene regulation.Our observation that the Hoxa5 larger transcripts possess a developmentally-regulated expression combined to the increasing sum of data on the role of long noncoding RNAs in transcriptional regulation suggest that the Hoxa5 larger transcripts may participate in the control of Hox gene expression

Primitive Duplicate Hox Clusters in the European Eel's Genome

The enigmatic life cycle and elongated body of the European eel (Anguilla anguilla L., 1758) have long motivated scientific enquiry. Recently, eel research has gained in urgency, as the population has dwindled to the point of critical endangerment. We have assembled a draft genome in order to facilitate advances in all provinces of eel biology. Here, we use the genome to investigate the eel's complement of the Hox developmental transcription factors. We show that unlike any other teleost fish, the eel retains fully populated, duplicate Hox clusters, which originated at the teleost-specific genome duplication. Using mRNA-sequencing and in situ hybridizations, we demonstrate that all copies are expressed in early embryos. Theories of vertebrate evolution predict that the retention of functional, duplicate Hox genes can give rise to additional developmental complexity, which is not immediately apparent in the adult. However, the key morphological innovation elsewhere in the eel's life history coincides with the evolutionary origin of its Hox repertoire

Assortative Mating in Fallow Deer Reduces the Strength of Sexual Selection

Background: Assortative mating can help explain how genetic variation for male quality is maintained even in highly polygynous species. Here, we present a longitudinal study examining how female and male ages, as well as male social dominance, affect assortative mating in fallow deer (Dama dama) over 10 years. Assortative mating could help explain the substantial proportion of females that do not mate with prime-aged, high ranking males, despite very high mating skew. We investigated the temporal pattern of female and male matings, and the relationship between female age and the age and dominance of their mates. Results: The peak of yearling female matings was four days later than the peak for older females. Younger females, and especially yearlings, mated with younger and lower-ranking males than older females. Similarly, young males and lowerranking males mated with younger females than older males and higher-ranking males. Furthermore, the timing of matings by young males coincided with the peak of yearling female matings, whereas the timing of older male matings (irrespective of rank) coincided with the peak of older female matings. Conclusions: Assortative mating, through a combination of indirect and/or direct female mate choice, can help explain th

The interest of gait markers in the identification of subgroups among fibromyalgia patients

<p>Abstract</p> <p>Background</p> <p>Fibromyalgia (FM) is a heterogeneous syndrome and its classification into subgroups calls for broad-based discussion. FM subgrouping, which aims to adapt treatment according to different subgroups, relies in part, on psychological and cognitive dysfunctions. Since motor control of gait is closely related to cognitive function, we hypothesized that gait markers could be of interest in the identification of FM patients' subgroups. This controlled study aimed at characterizing gait disorders in FM, and subgrouping FM patients according to gait markers such as stride frequency (SF), stride regularity (SR), and cranio-caudal power (CCP) which measures kinesia.</p> <p>Methods</p> <p>A multicentre, observational open trial enrolled patients with primary FM (44.1 ± 8.1 y), and matched controls (44.1 ± 7.3 y). Outcome measurements and gait analyses were available for 52 pairs. A 3-step statistical analysis was carried out. A preliminary single blind analysis using k-means cluster was performed as an initial validation of gait markers. Then in order to quantify FM patients according to psychometric and gait variables an open descriptive analysis comparing patients and controls were made, and correlations between gait variables and main outcomes were calculated. Finally using cluster analysis, we described subgroups for each gait variable and looked for significant differences in self-reported assessments.</p> <p>Results</p> <p>SF was the most discriminating gait variable (73% of patients and controls). SF, SR, and CCP were different between patients and controls. There was a non-significant association between SF, FIQ and physical components from Short-Form 36 (p = 0.06). SR was correlated to FIQ (p = 0.01) and catastrophizing (p = 0.05) while CCP was correlated to pain (p = 0.01). The SF cluster identified 3 subgroups with a particular one characterized by normal SF, low pain, high activity and hyperkinesia. The SR cluster identified 2 distinct subgroups: the one with a reduced SR was distinguished by high FIQ, poor coping and altered affective status.</p> <p>Conclusion</p> <p>Gait analysis may provide additional information in the identification of subgroups among fibromyalgia patients. Gait analysis provided relevant information about physical and cognitive status, and pain behavior. Further studies are needed to better understand gait analysis implications in FM.</p