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Background: Myocardial infarction (MI) is a major cause of heart failure. The carboxypeptidase cathepsin A is a novel target in the treatment of cardiac failure. We aim to show that recently developed inhibitors of the protease cathepsin A attenuate post-MI heart failure.Methods: Mice were subjected to permanent left anterior descending artery (LAD) ligation or sham operation. 24 h post-surgery, LAD-ligated animals were treated with daily doses of the cathepsin A inhibitor SAR1 or placebo. After 4 weeks, the three groups (sham, MI-placebo, MI-SAR1) were evaluated.Results: Compared to sham-operated animals, placebo-treated mice showed significantly impaired cardiac function and increased plasma BNP levels. Cathepsin A inhibition prevented the increase of plasma BNP levels and displayed a trend towards improved cardiac functionality. Proteomic profiling was performed for the three groups (sham, MI-placebo, MI-SAR1). More than 100 proteins were significantly altered in placebo-treated LAD ligation compared to the sham operation, including known markers of cardiac failure as well as extracellular/matricellular proteins. This ensemble constitutes a proteome fingerprint of myocardial infarction induced by LAD ligation in mice. Cathepsin A inhibitor treatment normalized the marked increase of the muscle stress marker CA3 as well as of Igγ 2b and fatty acid synthase. For numerous further proteins, cathepsin A inhibition partially dampened the LAD ligation-induced proteome alterations.Conclusions: Our proteomic and functional data suggest that cathepsin A inhibition has cardioprotective properties and support a beneficial effect of cathepsin A inhibition in the treatment of heart failure after myocardial infarction. [ABSTRACT FROM AUTHOR]

Background: The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) was established in 2008 to answer strategic questions about schistosomiasis control. For programme managers, a high-priority question is: what are the most cost-effective strategies for delivering preventive chemotherapy (PCT) with praziquantel (PZQ)? This paper describes the process SCORE used to transform this question into a harmonized research protocol, the study design for answering this question, the village eligibility assessments and data resulting from the first year of the study.Methods: Beginning in 2009, SCORE held a series of meetings to specify empirical questions and design studies related to different schedules of PCT for schistosomiasis control in communities with high (gaining control studies) and moderate (sustaining control studies) prevalence of Schistosoma infection among school-aged children. Seven studies are currently being implemented in five African countries. During the first year, villages were screened for eligibility, and data were collected on prevalence and intensity of infection prior to randomisation and the implementation of different schemes of PZQ intervention strategies.Results: These studies of different treatment schedules with PZQ will provide the most comprehensive data thus far on the optimal frequency and continuity of PCT for schistosomiasis infection and morbidity control.Conclusions: We expect that the study outcomes will provide data for decision-making for country programme managers and a rich resource of information to the schistosomiasis research community.Trial Registration: The trials are registered at International Standard Randomised Controlled Trial registry (identifiers: ISRCTN99401114 , ISRCTN14849830 , ISRCTN16755535 , ISRCTN14117624 , ISRCTN95819193 and ISRCTN32045736 ). [ABSTRACT FROM AUTHOR]

Background: Teriparatide (TPTD) is a drug for osteoporosis that promotes bone formation and improves bone quality. However, the effects of TPTD on cortical bone are not well understood. Sweep imaging with Fourier transform (SWIFT) has been reported as a useful tool for evaluating bound water of cortical bone, but it has yet to be used to investigate the effects of TPTD on cortical bone. This study aimed to evaluate the consequences of the effect of TPTD on cortical bone formation using SWIFT.Methods: Twelve-week-old female Sprague-Dawley rats (n = 36) were reared after ovariectomy to create a postmenopausal osteoporosis model. They were divided into two groups: the TPTD and non-TPTD groups. Rats were euthanized at 4, 12, and 24 weeks after initiating TPTD treatment. Tibial bones were evaluated using magnetic resonance imaging (MRI) and bone histomorphometry. In MRI, proton density-weighted imaging (PDWI) and SWIFT imaging were performed. The signal-to-noise ratio (SNR) was calculated for each method. The same area evaluated by MRI was then used to calculate the bone formation rate by bone histomorphometry. Measurements were compared using the Mann-Whitney U-test, and a P-value of < 0.05 was considered significant.Results: PDWI-SNR was not significantly different between the two groups at any time point (P = 0.589, 0.394, and 0.394 at 4, 12, and 24 weeks, respectively). Contrarily, SWIFT-SNR was significantly higher in the TPTD group than in the non-TPTD group at 4 weeks after initiating treatment, but it was not significantly different at 12 and 24 weeks (P = 0.009, 0.937, and 0.818 at 4, 12, and 24 weeks, respectively). The bone formation rate assessed by histomorphometry was significantly higher in the TPTD group than in the non-TPTD group at all timepoints (P < 0.05, all weeks). In particular, at 4 weeks, the bone formation rate was markedly higher in the TPTD group than in the non-TPTD group (P = 0.028, 1.98 ± 0.33 vs. 0.09 ± 0.05 μm3/μm2/day).Conclusions: SWIFT could detect increased signals of bound water, reflecting the effect of TPTD on the cortical bone. The signal detected by SWIFT reflects a marked increase in the cortical bone formation rate. [ABSTRACT FROM AUTHOR]

Chronic subdural haematoma (CSDH) is an encapsulated collection of blood and fluid on the surface of the brain. Historically considered a result of head trauma, recent evidence suggests there are more complex processes involved. Trauma may be absent or very minor and does not explain the progressive, chronic course of the condition. This review focuses on several key processes involved in CSDH development: angiogenesis, fibrinolysis and inflammation. The characteristic membrane surrounding the CSDH has been identified as a source of fluid exudation and haemorrhage. Angiogenic stimuli lead to the creation of fragile blood vessels within membrane walls, whilst fibrinolytic processes prevent clot formation resulting in continued haemorrhage. An abundance of inflammatory cells and markers have been identified within the membranes and subdural fluid and are likely to contribute to propagating an inflammatory response which stimulates ongoing membrane growth and fluid accumulation. Currently, the mainstay of treatment for CSDH is surgical drainage, which has associated risks of recurrence requiring repeat surgery. Understanding of the underlying pathophysiological processes has been applied to developing potential drug treatments. Ongoing research is needed to identify if these therapies are successful in controlling the inflammatory and angiogenic disease processes leading to control and resolution of CSDH. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial resistance is driven by multiple factors. Resolving the threat to human and animal health presented by drug-resistant infections remains a societal challenge that demands close collaboration between scientists and citizens. We compared current public views about key contributing factors to antimicrobial resistance with those expressed by experts.Methods: Overarching factors contributing to antimicrobial resistance were identified following a review of literature. The factors were then described in plain language and attached to ballot boxes at a public engagement event organised by a university. Responses to each factor were counted at the end of the event.Results: Four hundred five responses were received from 3750 visitors (11 % response rate). Nearly half of responses (192/405, 47 · 4 %) considered the misuse/overuse of antibiotics in humans as the main determinant of antimicrobial resistance. The misuse of antibiotics in animal health obtained 16 · 3 % (66/405) responses. However, the lack of quick tests to diagnose infections received 10/405 votes (2 · 47 %), and the lack of effective vaccines received one vote (0 · 25 %).Conclusions: The majority of responses ascribed the emergence of drug-resistant infections to the misuse of antibiotics in human and animals. Suboptimal dosing, availability of diagnostics and environmental contamination were considered less influential on the development of antimicrobial resistance. The growing recognition of broader multifaceted drivers of drug resistance by experts is not yet echoed in the public mind. [ABSTRACT FROM AUTHOR]

Background: Bacterial meningitis is still a cause of severe neurological disability. The brain is protected from penetrating pathogens by the blood-brain barrier and the innate immune system. The invading pathogens are recognized by pattern recognition receptors including the G-protein-coupled formyl peptide receptors (FPRs), which are expressed by immune cells of the central nervous system. FPRs show a broad spectrum of ligands, including pro- and anti-inflammatory ones. Here, we investigated the effects of the annexin A1 mimetic peptide Ac2-26 in a mouse model of pneumococcal meningitis.Methods: Wildtype (WT) and Fpr1- and Fpr2-deficient mice were intrathecally infected with Streptococcus pneumoniae D39 (type 2). Subsequently, the different mice groups were treated by intraperitoneal injections of Ac2-26 (1 mg/kg body weight) 2, 8, and 24 h post-infection. The extent of inflammation was analyzed in various brain regions by means of immunohistochemistry and real-time reverse transcription polymerase chain reaction (RT-PCR) 30 h post-infection.Results: Ac2-26-treated WT mice showed less severe neutrophil infiltration, paralleled by a reduced induction of pro-inflammatory glial cell responses in the hippocampal formation and cortex. While meningitis was ameliorated in Ac2-26-treated Fpr1-deficient mice, this protective effect was not observed in Fpr2-deficient mice. Irrespective of Ac2-26 treatment, inflammation was more severe in Fpr2-deficient compared to Fpr1-deficient mice.Conclusions: In summary, this study demonstrates anti-inflammatory properties of Ac2-26 in a model of bacterial meningitis, which are mediated via FPR2, but not FPR1. Ac2-26 and other FPR2 modulators might be promising targets for the development of novel therapies for Streptococcus pneumoniae-induced meningitis. [ABSTRACT FROM AUTHOR]

Background: Gastroparesis, a condition of abnormal gastric emptying, is most commonly observed in diabetic women. To date, the role of ovarian hormones and/or gastric hormone receptors on regulating nitrergic-mediated gastric motility remains inconclusive.Aim: The purpose of this study is to investigate whether sex hormones/their receptors can attenuate altered Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), neuronal Nitric Oxide Synthase (nNOS) expression and nitrergic relaxation in gastric neuromuscular tissues exposed to in-vitro hyperglycemia (HG).Methods: Gastric neuromuscular sections from adult female C57BL/6 J mice were incubated in normoglycemic (NG, 5 mM) or hyperglycemic (30 mM or 50 mM) conditions in the presence or absence of selective estrogen receptor (ER) agonists (ERα /PPT or ERβ: DPN); or non-selective sex hormone receptor antagonists (ER/ICI 182,780, or progesterone receptor (PR)/ RU486) for 48 h. mRNA, protein expression and nitrergic relaxation of circular gastric neuromuscular strips were assessed.Results: Our findings in HG, compared to NG, demonstrate a significant reduction in ER, Nrf2, and nNOS expression in gastric specimens. In addition, in-vitro treatment with sex hormones and/or their agonists significantly (*p < 0.05) restored Nrf2/nNOSα expression and total nitrite production. Conversely, ER, but not PR, antagonist significantly reduced Nrf2/nNOSα expression and nitrergic relaxation.Conclusions: Our data suggest that ER's can regulate nitrergic function by improving Nrf2/nNOS expression in experimental hyperglycemia. [ABSTRACT FROM AUTHOR]