Hyaluronidase recruits mesenchymal-like cells to the lung and ameliorates fibrosis

Hyaluronidases (HYALs) comprise a group of enzymes that degrade hyaluronic acid (HA). In this report, we reveal that a single intranasal inoculation of HYAL induces an increase in mononuclear cells within the bronchoalveolar space demonstrating a mesenchymal-like phenotype, expressing stem cell antigen-1 (SCA-1), CD44 and CD73 but not CD34, CD45, CD3, CD4, CD8 or CD19. This influx of mesenchymal stem cell (MSC)-like cells was dependent on leukotriene production within the lung parenchyma. These findings prompted experiments demonstrating that HYAL treatment potently blocked bleomycin-induced lung injury and fibrosis while decreasing transforming growth factor (TGF)-β production and collagen deposition. These data suggest that HYAL is a novel and promising tool to use autologous MSC-like cells in the treatment of pulmonary fibrosis

Variation at the NFATC2 Locus Increases the Risk of Thiazolidinedione-Induced Edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) Study

Objective: Thiazolidinediones are used to treat type 2 diabetes. Their use has been associated with peripheral edema and congestive heart failure - outcomes that may have a genetic etiology. Research Design and Methods: We genotyped 4,197 participants of the multiethnic DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) trial with a 50k single nucleotide polymorphisms (SNP) array, which captures ∼2000 cardiovascular, inflammatory, and metabolic genes. We tested 32,088 SNPs for an association with edema among Europeans who received rosiglitazone (n = 965). Results: One SNP, rs6123045, in NFATC2 was significantly associated with edema (odds ratio 1.89 [95% CI 1.47-2.42]; P = 5.32 × 10-7, corrected P = 0.017). Homozygous individuals had the highest edema rate (hazard ratio 2.89, P = 4.22 × 10-4) when compared with individuals homozygous for the protective allele, with heterozygous individuals having an intermediate risk. The interaction between the SNP and rosiglitazone for edema was significant (P = 7.68 × 10-3). Six SNPs in NFATC2 were significant in both Europeans and Latin Americans (P < 0.05). Conclusions: Genetic variation at the NFATC2 locus contributes to edema among individuals who receive rosiglitazone

A prospective observational study of bacteraemia in adults admitted to an urban Mozambican hospital

Background. Bacteraemia is a common cause of fever among patients presenting to hospitals in  sub-Saharan Africa. The worldwide rise of antibiotic resistance makes empirical therapy increasingly  difficult, especially in resource-limited settings.Objectives. To describe the incidence of bacteraemia in febrile adults presenting to Maputo Central Hospital (MCH), an urban referral hospital in the capital of Mozambique, and characterise the causative  organisms and antibiotic susceptibilities. We aimed to describe the antibiotic prescribing habits of local doctors, to identify areas for quality improvement.Methods. Inclusion criteria were: (i) .18 years of age; (ii) axillary temperature .38‹C or .35‹C; (iii) admission to MCH medical wards in the past 24 hours; and (iv) no receipt of antibiotics as an inpatient. Blood cultures were drawn from enrolled patients and incubated using the BacT/Alert automated system (bioMerieux, France). Antibiotic susceptibilities were tested using the Kirby-Bauer disc diffusion method.Results. Of the 841 patients enrolled, 63 (7.5%) had a bloodstream infection. The most common isolates were Staphylococcus aureus, Escherichia coli, and non-typhoidal Salmonella. Antibiotic resistance was common, with 20/59 (33.9%) of all bacterial isolates showing resistance to ceftriaxone, the broadest-spectrum antibiotic commonly available at MCH. Receipt of insufficiently broad empirical antibiotics was associated with poor in-hospital outcomes (odds ratio 8.05; 95% confidence interval 1.62 - 39.91;  p=0.04).Conclusion. This study highlights several opportunities for quality improvement, including educating doctors to have a higher index of suspicion for bacteraemia, improving local antibiotic guidelines,  improving communication between laboratory and doctors, and increasing the supply of some key antibiotics

The algebra of lexical semantics

Abstract. The current generative theory of the lexicon relies primar-ily on tools from formal language theory and mathematical logic. Here we describe how a different formal apparatus, taken from algebra and automata theory, resolves many of the known problems with the gener-ative lexicon. We develop a finite state theory of word meaning based on machines in the sense of Eilenberg [11], a formalism capable of de-scribing discrepancies between syntactic type (lexical category) and se-mantic type (number of arguments). This mechanism is compared both to the standard linguistic approaches and to the formalisms developed in AI/KR. 1 Problem Statement In developing a formal theory of lexicography our starting point will be the informal practice of lexicography, rather than the more immediately related for-mal theories of Artificial Intelligence (AI) and Knowledge Representation (KR). Lexicography is a relatively mature field, with centuries of work experience an

Comparative effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors and human glucagon-like peptide-1 (GLP-1) analogue as add-on therapies to sulphonylurea among diabetes patients in the Asia-Pacific region: a systematic review

The prevalence of diabetes mellitus is rising globally, and it induces a substantial public health burden to the healthcare systems. Its optimal control is one of the most significant challenges faced by physicians and policy-makers. Whereas some of the established oral hypoglycaemic drug classes like biguanide, sulphonylureas, thiazolidinediones have been extensively used, the newer agents like dipeptidyl peptidase-4 (DPP-4) inhibitors and the human glucagon-like peptide-1 (GLP-1) analogues have recently emerged as suitable options due to their similar efficacy and favorable side effect profiles. These agents are widely recognized alternatives to the traditional oral hypoglycaemic agents or insulin, especially in conditions where they are contraindicated or unacceptable to patients. Many studies which evaluated their clinical effects, either alone or as add-on agents, were conducted in Western countries. There exist few reviews on their effectiveness in the Asia-Pacific region. The purpose of this systematic review is to address the comparative effectiveness of these new classes of medications as add-on therapies to sulphonylurea drugs among diabetic patients in the Asia-Pacific countries. We conducted a thorough literature search of the MEDLINE and EMBASE from the inception of these databases to August 2013, supplemented by an additional manual search using reference lists from research studies, meta-analyses and review articles as retrieved by the electronic databases. A total of nine randomized controlled trials were identified and described in this article. It was found that DPP-4 inhibitors and GLP-1 analogues were in general effective as add-on therapies to existing sulphonylurea therapies, achieving HbA1c reductions by a magnitude of 0.59–0.90% and 0.77–1.62%, respectively. Few adverse events including hypoglycaemic attacks were reported. Therefore, these two new drug classes represent novel therapies with great potential to be major therapeutic options. Future larger-scale research should be conducted among other Asia-Pacific region to evaluate their efficacy in other ethnic groups

Calorimetric Investigation of Copper Binding in the N-Terminal Region of the Prion Protein at Low Copper Loading: Evidence for an Entropically Favorable First Binding Event

Although the Cu²⁺-binding sites of the prion protein have been well studied when the protein is fully saturated by Cu²⁺, the Cu²⁺-loading mechanism is just beginning to come into view. Because the Cu²⁺-binding modes at low and intermediate Cu²⁺ occupancy necessarily represent the highest-affinity binding modes, these are very likely populated under physiological conditions, and it is thus essential to characterize them in order to understand better the biological function of copper–prion interactions. Besides binding-affinity data, almost no other thermodynamic parameters (e.g., Δ<i>H</i> and Δ<i>S</i>) have been measured, thus leaving undetermined the enthalpic and entropic factors that govern the free energy of Cu²⁺ binding to the prion protein. In this study, isothermal titration calorimetry (ITC) was used to quantify the thermodynamic parameters (<i>K</i>, Δ<i>G</i>, Δ<i>H</i>, and <i>T</i>Δ<i>S</i>) of Cu²⁺ binding to a peptide, PrP­(23–28, 57–98), that encompasses the majority of the residues implicated in Cu²⁺ binding by full-length PrP. Use of the buffer <i>N</i>-(2-acetomido)-aminoethanesulfonic acid (ACES), which is also a well-characterized Cu²⁺ chelator, allowed for the isolation of the two highest affinity binding events. Circular dichroism spectroscopy was used to characterize the different binding modes as a function of added Cu²⁺. The <i>K</i>_d values determined by ITC, 7 and 380 nM, are well in line with those reported by others. The first binding event benefits significantly from a positive entropy, whereas the second binding event is enthalpically driven. The thermodynamic values associated with Cu²⁺ binding by the Aβ peptide, which is implicated in Alzheimer’s disease, bear striking parallels to those found here for the prion protein

State of the field: What can political ethnography tell us about anti-politics and democratic disaffection?

This article adopts and reinvents the ethnographic approach to uncover what governing elites do, and how they respond to public disaffection. Although there is significant work on the citizens’ attitudes to the governing elite (the demand side) there is little work on how elites interpret and respond to public disaffection (the supply side). We argue that ethnography is the best available research method for collecting data on the supply side. In doing so, we tackle long-standing stereotypes in political science about the ethnographic method and what it is good for. We highlight how the innovative and varied practices of contemporary ethnography are ideally suited to shedding light into the ‘black box’ of elite politics. We demonstrate the potential pay-off with reference to important examples of elite ethnography from the margins of political science scholarship. The implications from these rich studies, we argue, suggest a reorientation of how we understand the drivers of public disaffection and the role that political elites play in exacerbating cynicism and disappointment. We conclude by pointing to the benefits to the discipline in embracing elite ethnography both to diversify the methodological toolkit in explaining the complex dynamics of disaffection,and to better enable engagement in renewed public debate about the political establishment