Resident mesenchymal cells and fibrosis

Fibrosis is a major clinical problem associated with as many as 45% of all natural deaths in developed nations.It can affect all organs and accumulating evidence indicates that fibrogenesis is not merely a bystander product of injury, but is a central pathological problem directly contributing to loss of organ function. In the majority of clinical cases, fibrogenesis is strongly associated with the recruitment of leukocytes, even in the absence of infection. Although chronic infections are a significant cause of fibrogenesis, in most cases fibrotic disease occurs in the context of sterile injury, such as microvascular disease, toxic epithelial injury or diabetes mellitus. Fibrogenesis is a direct consequence of the activation of extensive, and previously poorly appreciated, populations of mesenchymal cells in our organs which are either wrapped around capillaries and known as ‘pericytes’, or embedded in interstitial spaces between cell structures and known as resident ‘fibroblasts’. Recent fate-mapping and complementary studies in several organs indicate that these cells are the precursors of the scar-forming myofibroblasts that appear in our organs in response to injury. Here we will review the literature supporting a central role for these cells in fibrogenesis, and highlight some of the critical cell to cell interactions that are necessary for the initiation and continuation of the fibrogenic process. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.     

Feedback GAP: pragmatic,cluster-randomized trial of goal setting and action plans to increase the effectiveness of audit and feedback interventions in primary care

Background

Audit and feedback to physicians is a commonly used quality improvement strategy, but its optimal design is unknown. This trial tested the effects of a theory-informed worksheet to facilitate goal setting and action planning, appended to feedback reports on chronic disease management, compared to feedback reports provided without these worksheets.

Methods

A two-arm pragmatic cluster randomized trial was conducted, with allocation at the level of primary care clinics. Participants were family physicians who contributed data from their electronic medical records. The ‘usual feedback’ arm received feedback every six months for two years regarding the proportion of their patients meeting quality targets for diabetes and/or ischemic heart disease. The intervention arm received these same reports plus a worksheet designed to facilitate goal setting and action plan development in response to the feedback reports. Blood pressure (BP) and low-density lipoprotein cholesterol (LDL) values were compared after two years as the primary outcomes. Process outcomes measured the proportion of guideline-recommended actions (e.g., testing and prescribing) conducted within the appropriate timeframe. Intention-to-treat analysis was performed.

Results

Outcomes were similar across groups at baseline. Final analysis included 20 physicians from seven clinics and 1,832 patients in the intervention arm (15% loss to follow up) and 29 physicians from seven clinics and 2,223 patients in the usual feedback arm (10% loss to follow up). Ten of 20 physicians completed the worksheet at least once during the study. Mean BP was 128/72 in the feedback plus worksheet arm and 128/73 in the feedback alone arm, while LDL was 2.1 and 2.0, respectively. Thus, no significant differences were observed across groups in the primary outcomes, but mean haemoglobin A1c was lower in the feedback plus worksheet arm (7.2% versus 7.4%, p<0.001). Improvements in both arms were noted over time for one-half of the process outcomes.

Discussion

Appending a theory-informed goal setting and action planning worksheet to an externally produced audit and feedback intervention did not lead to improvements in patient outcomes. The results may be explained in part by passive dissemination of the worksheet leading to inadequate engagement with the intervention.

Trial registration

ClinicalTrials.gov NCT00996645

     

Universal soldier: Pseudomonas aeruginosa — an opportunistic generalist

The opportunistic pathogen Pseudomonas aeruginosa commonly causes chronic and ultimately deadly lung infections in individuals with the genetic disease cystic fibrosis (CF). P. aeruginosa is metabolically diverse; it displays a remarkable ability to adapt to and successfully occupy almost any niche, including the ecologically complex CF lung. These P. aeruginosa lung infections are a fascinating example of microbial evolution within a “natural” ecosystem. Initially, P. aeruginosa shares the lung niche with a plethora of other microorganisms and is vulnerable to antibiotic challenges. Over time, adaptive evolution leads to certain commonly-observed phenotypic changes within the P. aeruginosa population, some of which render it resistant to antibiotics and apparently help it to out-compete the other species that co-habit the airways. Improving genomics techniques continue to elucidate the evolutionary mechanisms of P. aeruginosa within the CF lung and will hopefully identify new vulnerabilities in this robust and versatile pathogen.     

Contrasting geographic patterns of genetic variation for molecular markers vs. phenotypic traits in the energy grass Miscanthus sinensis

Species and hybrids of Miscanthus are a promising energy crop, but their outcrossing mating systems and perennial life cycles are serious challenges for breeding programs. One approach to accelerating the domestication of Miscanthus is to harness the tremendous genetic variation that is present within this genus using phenotypic data from extensive field trials, high‐density genotyping and sequencing technologies, and rapidly developing statistical methods of relating phenotype to genotype. The success of this approach, however, hinges on detailed knowledge about the population genetic structure of the germplasm used in the breeding program. We therefore used data for 120 single‐nucleotide polymorphism and 52 simple sequence repeat markers to depict patterns of putatively neutral population structure among 244 Miscanthus genotypes grown in a field trial near Aberystwyth (UK) and delineate a population of 145 M . sinensis genotypes that will be used for association mapping and genomic selection. Comparative multivariate analyses of molecular marker and phenotypic data for 17 traits related to phenology, morphology/biomass, and cell wall composition revealed significant geographic patterns in this population. A longitudinal cline accounted for a substantial proportion of molecular marker variation (R² = 0.60, P = 3.4 × 10^?15). In contrast, genetic variation for phenotypic traits tended to follow latitudinal and altitudinal gradients, with several traits appearing to have been affected by divergent selection (i.e., Q_ST >> F_ST). These contrasting geographic trends are unusual relative to other plants and provide opportunities for powerful studies of phenotype–genotype associations and the evolutionary history of M. sinensis.     

Are Treatments More Effective than Placebos? A Systematic Review and Meta-Analysis

BackgroundPlacebos are widely used in clinical practice in spite of ethical restrictions. Whether such use is justified depends in part on the relative benefit of placebos compared to ‘active’ treatments. A direct test for differences between placebo and ‘active’ treatment effects has not been conducted.ObjectivesWe aimed to test for differences between treatment and placebo effects within similar trial populations.ResultsIn trials with continuous outcomes (n = 115) we found no difference between treatment and placebo effects (MD = −0.29, 95% CI −0.62 to 0.05, P = 0.10). In trials with binary outcomes (n = 37) treatments were significantly more effective than placebos (RRR = 0.72, 95%CI = 0.61 to 0.86, P = 0.0003). Treatment and placebo effects were not different in 22 out of 28 predefined subgroup analyses. Of the six subgroups with differences treatments were more effective than placebos in five. However when all criteria for reducing bias were ruled out (continuous outcomes) placebos were more effective than treatments (MD = 1.59, 95% CI = 0.40 to 2.77, P = 0.009).

Conclusions and Implications

Placebos and treatments often have similar effect sizes. Placebos with comparatively powerful effects can benefit patients either alone or as part of a therapeutic regime, and trials involving such placebos must be adequately blinded.     

Relationships among Musical Aptitude,Digit Ratio and Testosterone in Men and Women

Circulating adult testosterone levels, digit ratio (length of the second finger relative to the fourth finger), and directional asymmetry in digit ratio are considered sexually dimorphic traits in humans. These have been related to spatial abilities in men and women, and because similar brain structures appear to be involved in both spatial and musical abilities, neuroendocrine function may be related to musical as well as spatial cognition. To evaluate relationships among testosterone and musical ability in men and women, saliva samples were collected, testosterone concentrations assessed, and digit ratios calculated using standardized protocols in a sample of university students (N = 61), including both music and non-music majors. Results of Spearman correlations suggest that digit ratio and testosterone levels are statistically related to musical aptitude and performance only within the female sample: A) those females with greater self-reported history of exposure to music (p = 0.016) and instrument proficiency (p = 0.040) scored higher on the Advanced Measures of Music Audiation test, B) those females with higher left hand digit ratio (and perhaps lower fetal testosterone levels) were more highly ranked (p = 0.007) in the orchestra, C) female music students exhibited a trend (p = 0.082) towards higher testosterone levels compared to female non-music students, and D) female music students with higher rank in the orchestra/band had higher testosterone levels (p = 0.003) than lower ranked students. None of these relationships were significant in the male sample, although a lack of statistical power may be one cause. The effects of testosterone are likely a small part of a poorly understood system of biological and environmental stimuli that contribute to musical aptitude. Hormones may play some role in modulating the phenotype of musical ability, and this may be the case for females more so than males.     

Age and sex-dependent effects of landscape cover and trapping on the spatial genetic structure of the stone marten (<Emphasis Type="Italic">Martes foina</Emphasis>)

Maintenance of genetic variation is of critical importance for wild populations since low levels limit the species’ ability to respond to different threats (diseases, predators, environmental changes) in both the long and the short term. Human activities could impact the genetic variation of wild species in multiple ways, including via fragmentation and harvesting. We used an individual-based landscape genetics approach to describe the impact of landscape elements and trapping pressure on the spatial genetic structure of a large sample (n = 370) of the stone marten (Martes foina) in central-eastern France (Bresse). An analysis of isolation-by-resistance using a causal modeling approach showed an influence of landscape cover and/or trapping pressure on gene flow according to age and sex class. Overall, the connectivity in the study area is provided mainly by vegetation cover, while roads and open areas partially impede it. Unexpectedly for this “urban adapter” species, buildings could reduce gene flow. We also emphasized the sex-dependent effect of trapping on gene flow. Genetic differentiation in males was influenced by trapping pressure and landscape structure while only the latter influenced genetic differentiation in females. A stronger isolation by distance in males than in females suggested that at the scale of the study area, males are more exposed to trapping pressure, which reduces effective dispersal. Overall, the combination of both landscape and trapping costs might create an ‘ecological trap’ that could disrupt gene flow, leading to a north–south division in the study area.     

Phylogeny and physiology of candidate phylum ‘Atribacteria' (OP9/JS1) inferred from cultivation-independent genomics

The ‘Atribacteria'' is a candidate phylum in the Bacteria recently proposed to include members of the OP9 and JS1 lineages. OP9 and JS1 are globally distributed, and in some cases abundant, in anaerobic marine sediments, geothermal environments, anaerobic digesters and reactors and petroleum reservoirs. However, the monophyly of OP9 and JS1 has been questioned and their physiology and ecology remain largely enigmatic due to a lack of cultivated representatives. Here cultivation-independent genomic approaches were used to provide a first comprehensive view of the phylogeny, conserved genomic features and metabolic potential of members of this ubiquitous candidate phylum. Previously available and heretofore unpublished OP9 and JS1 single-cell genomic data sets were used as recruitment platforms for the reconstruction of atribacterial metagenome bins from a terephthalate-degrading reactor biofilm and from the monimolimnion of meromictic Sakinaw Lake. The single-cell genomes and metagenome bins together comprise six species- to genus-level groups that represent most major lineages within OP9 and JS1. Phylogenomic analyses of these combined data sets confirmed the monophyly of the ‘Atribacteria'' inclusive of OP9 and JS1. Additional conserved features within the ‘Atribacteria'' were identified, including a gene cluster encoding putative bacterial microcompartments that may be involved in aldehyde and sugar metabolism, energy conservation and carbon storage. Comparative analysis of the metabolic potential inferred from these data sets revealed that members of the ‘Atribacteria'' are likely to be heterotrophic anaerobes that lack respiratory capacity, with some lineages predicted to specialize in either primary fermentation of carbohydrates or secondary fermentation of organic acids, such as propionate.