Noncoding RNAs and Duchenne muscular dystrophy

Noncoding RNAs (ncRNAs) such as miRNAs and long noncoding RNAs modulate gene transcription in response to environmental stressors and other stimuli. A role for ncRNAs in muscle pathologies has been demonstrated and further evidence suggests that ncRNAs also play a role in Duchenne muscular dystrophy (DMD). Studies investigating the differential expression of miRNAs in biological fluids between DMD patients and models of dystrophin deficiency (the MDX mouse model, canine models of DMD) and controls have been published, as these have a role in fibrosis. Long noncoding RNAs are differentially expressed in DMD patients and may, in part, have a mechanism of action via targeting of miRNAs. Although many of these recent findings need to be confirmed, ncRNAs may prove to be useful as potential biomarkers of disease. However, their use as therapeutic targets in DMD remains unclear

Extending genome-wide association study (GWAS) results to test classic anthropological hypotheses: Human third molar agenesis and the ‘probable mutation effect’

A genome-wide association study (GWAS) identifies regions of the genome that likely affect the variable state of a phenotype of interest. These regions can then be studied with population genetic methods to make inferences about the evolutionary history of the trait. There are increasing opportunities to use GWAS results – even from clinically-motivated studies – for tests of classic anthropological hypotheses. One such example, presented here as a case study for this approach, involves tooth development variation related to dental crowding. Specifically, more than 10% of humans fail to develop one or more permanent third molars (M3 agenesis). M3 presence/absence variation within human populations has a significant genetic component (heritability estimate h2 = 0.47). The evolutionary significance of M3 agenesis has a long history of anthropological speculation. First, the modern frequency of M3 agenesis could reflect a relaxation of selection pressure to retain larger and more teeth following the origins of cooking and other food-softening behaviors (i.e., the genetic drift hypothesis, or classically, the “probable mutation effect”). Alternatively, commensurate with increasing hominin brain size and facial shortening, M3 agenesis may have conferred an adaptive fitness advantage if the risk of M3 impaction and potential health complications was reduced (i.e., the positive selection hypothesis). A recent GWAS identified 70 genetic loci that may play a role in human M3 presence/absence variation. To begin evaluating the contrasting evolutionary scenarios for M3 agenesis, we used the integrated haplotype score (iHS) statistic to test whether those 70 genetic regions are enriched for genomic signatures of recent positive selection. None of our findings are inconsistent with the null hypothesis of genetic drift to explain the high prevalence of human M3 agenesis. This result might suggest that M3 impaction rates for modern humans don’t accurately retrodict those of the pre-agricultural past. Alternatively, the absence of support for the positive selection hypothesis could reflect a lack of power; this analysis should be repeated following the completion of more comprehensive GWAS analyses for human M3 agenesis

Is paromomycin the drug of choice for eradication of Dientamoeba fragilis in adults?

Dientamoeba fragilis is a debated protozoan parasite that is often detected in stools of patients with chronic gastro-intestinal complaints. A retrospective follow-up study of a large cohort of patients was performed to better understand the natural course of the infection and possible treatment options. D. fragilis was spontaneously cleared in 41% of untreated cases. With an eradication rate of 98%, treatment with paromomycin appeared more effective than treatment with clioquinol (83%) or metronidazole (57%)

The Vacuum in Light-Cone Field Theory

This is an overview of the problem of the vacuum in light-cone field theory, stressing its close connection to other puzzles regarding light-cone quantization. I explain the sense in which the light-cone vacuum is ``trivial,'' and describe a way of setting up a quantum field theory on null planes so that it is equivalent to the usual equal-time formulation. This construction is quite helpful in resolving the puzzling aspects of the light-cone formalism. It furthermore allows the extraction of effective Hamiltonians that incorporate vacuum physics, but that act in a Hilbert space in which the vacuum state is simple. The discussion is fairly informal, and focuses mainly on the conceptual issues. [Talk presented at {\sc Orbis Scientiae 1996}, Miami Beach, FL, January 25--28, 1996. To appear in the proceedings.]Comment: 20 pages, RevTeX, 4 Postscript figures. Minor typos correcte

Optical Space Switches in Data Centers: Issues with Transport Protocols

A number of new architectures for data centre networks employing reconfigurable, SDN controlled, all-optical networks have been reported in recent years. In most cases, additional capacity was added to the system which unsurprisingly improved performance. In this study, a generalised network model that emulates the behaviour of these types of network was developed but where the total capacity is maintained constant so that system behaviour can be understood. An extensive emulated study is presented which indicates that the reconfiguration of such a network can have a detrimental impact on Transmission Control Protocol (TCP) congestion control mechanisms that can degrade the performance of the system. A number of simple scheduling mechanisms were investigated and the results show that an on-demand scheduling mechanism could deliver a throughput increase of more than ∼50% without any increase in total installed network capacity. These results, therefore, indicate the need to link the network resource management with new datacentre network architectures

Bronchiectasis: a model for chronic bacterial infection inducing autoimmunity in rheumatoid arthritis.

ArticleCopyright © 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.Objective: Bronchiectasis (BR) is a risk factor for rheumatoid arthritis (RA). Here we examine the potential of BR in generating rheumatoid factors (RFs) and anti-citrullinated peptide antibodies (ACPA) in patients with BR alone and in patients with BR and RA (BRRA). Methods: We studied 122 patients with BR alone, 50 BRRA, 50 RA without lung disease, with 87 asthma and 79 healthy subjects as controls. RFs were measured by an automated analyzer, and ACPA using CCP2. Fine specificities to citrullinated α-enolase (CEP-1), citrullinated vimentin (cVim) and fibrinogen (cFib) with their arginine control peptides (REP-1, Vim and Fib) measured by ELISA. Results: In the BR patients 39% were ever smokers compared to 42% of the controls. Serum samples from BR patients had an increased frequency of RF (25%; p< 0.05) and 5% to CCP2, 7% to CEP-1, 7% to cVIM (all p=ns) and 12% cFib (p <0.05). There was also a corresponding increase in antibodies to the arginine-containing control peptides in the BR patients; REP-1, 19% (p< 0.01) and Vim, 16% (p<0.05), demonstrating that the ACPA response in BR is not citrulline-specific. Lack of citrulline specificity was further confirmed by absorption studies. In BRRA all ACPA specificities were highly citrulline-specific. Conclusion: Bronchiectasis is an unusual but potent model for the induction of autoimmunity in RA by bacterial infection in the lung. Our study suggests that in the early stages of tolerance breakdown, the ACPA response is not citrulline-specific, but becomes more so in those patients with BR that develop BRRA.Arthritis Research UKEuropean UnionIMI project BTCure7th Framework Programme project Gums and Joint

Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in bihar, India:a retrospective cohort study

Funding: This work was supported by a Clinical PhD Fellowship to MRP (090665) and a Principal Research Fellowship to AHF (079838) from the Wellcome Trust (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

The potential role of cost-utility analysis in the decision to implement major system change in acute stroke services in metropolitan areas in England

BACKGROUND: The economic implications of major system change are an important component of the decision to implement health service reconfigurations. Little is known about how best to report the results of economic evaluations of major system change to inform decision-makers. Reconfiguration of acute stroke care in two metropolitan areas in England, namely London and Greater Manchester (GM), was used to analyse the economic implications of two different implementation strategies for major system change. METHODS: A decision analytic model was used to calculate difference-in-differences in costs and outcomes before and after the implementation of two major system change strategies in stroke care in London and GM. Values in the model were based on patient level data from Hospital Episode Statistics, linked mortality data from the Office of National Statistics and data from two national stroke audits. Results were presented as net monetary benefit (NMB) and using Programme Budgeting and Marginal Analysis (PBMA) to assess the costs and benefits of a hypothetical typical region in England with approximately 4000 strokes a year. RESULTS: In London, after 90 days, there were nine fewer deaths per 1000 patients compared to the rest of England (95% CI -24 to 6) at an additional cost of £770,027 per 1000 stroke patients admitted. There were two additional deaths (95% CI -19 to 23) in GM, with a total costs saving of £156,118 per 1000 patients compared to the rest of England. At a £30,000 willingness to pay the NMB was higher in London and GM than the rest of England over the same time period. The results of the PBMA suggest that a GM style reconfiguration could result in a total greater health benefit to a region. Implementation costs were £136 per patient in London and £75 in GM. CONCLUSIONS: The implementation of major system change in acute stroke care may result in a net health benefit to a region, even one functioning within a fixed budget. The choice of what model of stroke reconfiguration to implement may depend on the relative importance of clinical versus cost outcomes

Conformism in the food processing techniques of white-faced capuchin monkeys (Cebus capucinus)

Researchers of “culture” have long been interested in the role of social learning in establishing patterns of behavioral variation in wild animals, but very few studies examine this issue using a developmental approach. This 7-year study examines the acquisition of techniques used to process Luehea candida fruits in a wild population of white-faced capuchin monkeys, Cebus capucinus, residing in and near Lomas Barbudal Biological Reserve, Costa Rica. The two techniques for extracting seeds (pounding or scrubbing) were approximately equal in efficiency, and subjects experimented with both techniques before settling on one technique—typically the one they most frequently observed. In a sample of 106 subjects that had already settled on a preferred technique, the females adopted the maternal technique significantly more often than expected by chance, but the males did not. Using a longitudinal approach, I examined the acquisition of Luehea processing techniques during the first 5 years of life. Regression analysis revealed that the technique most frequently observed (measured as proportion of Luehea processing bouts observed that used pounding as opposed to scrubbing) significantly predicted the technique adopted by female observers, particularly in the second year of life; the amount of impact of the observed technique on the practiced technique was somewhat less significant for male observers. These results held true for (a) observations of maternal technique only, (b) observations of technique used by all individuals other than the mother, and (c) observations of maternal and non-maternal techniques combined

Comparison of governance approaches for the control of antimicrobial resistance: Analysis of three European countries

Policy makers and governments are calling for coordination to address the crisis emerging from the ineffectiveness of current antibiotics and stagnated pipe-line of new ones – antimicrobial resistance (AMR). Wider contextual drivers and mechanisms are contributing to shifts in governance strategies in health care, but are national health system approaches aligned with strategies required to tackle antimicrobial resistance? This article provides an analysis of governance approaches within healthcare systems including: priority setting, performance monitoring and accountability for AMR prevention in three European countries: England, France and Germany. Advantages and unresolved issues from these different experiences are reported, concluding that mechanisms are needed to support partnerships between healthcare professionals and patients with democratized decision-making and accountability via collaboration. But along with this multi-stakeholder approach to governance, a balance between regulation and persuasion is needed