Loss of DNA repair mechanisms in cardiac myocytes induce dilated cardiomyopathy

Cardiomyopathy is a progressive disease of the myocardium leading to impaired contractility. Genotoxic cancer therapies are known to be potent drivers of cardiomyopathy, whereas causes of spontaneous disease remain unclear. To test the hypothesis that endogenous genotoxic stress contributes to cardiomyopathy, we deleted the DNA repair gene Ercc1 specifically in striated muscle using a floxed allele of Ercc1 and mice expressing Cre under control of the muscle-specific creatinine kinase (Ckmm) promoter or depleted systemically (Ercc1^−/D mice). Ckmm-Cre^+/−;Ercc1^−/fl mice expired suddenly of heart disease by 7 months of age. As young adults, the hearts of Ckmm-Cre^+/−;Ercc1^−/fl mice were structurally and functionally normal, but by 6-months-of-age, there was significant ventricular dilation, wall thinning, interstitial fibrosis, and systolic dysfunction indicative of dilated cardiomyopathy. Cardiac tissue from the tissue-specific or systemic model showed increased apoptosis and cardiac myocytes from Ckmm-Cre^+/-;Ercc1^−/fl mice were hypersensitive to genotoxins, resulting in apoptosis. p53 levels and target gene expression, including several antioxidants, were increased in cardiac tissue from Ckmm-Cre^+/−;Ercc1^−/fl and Ercc1^−/D mice. Despite this, cardiac tissue from older mutant mice showed evidence of increased oxidative stress. Genetic or pharmacologic inhibition of p53 attenuated apoptosis and improved disease markers. Similarly, overexpression of mitochondrial-targeted catalase improved disease markers. Together, these data support the conclusion that DNA damage produced endogenously can drive cardiac disease and does so mechanistically via chronic activation of p53 and increased oxidative stress, driving cardiac myocyte apoptosis, dilated cardiomyopathy, and sudden death.     

Self referral to an accident and emergency department for another opinion.

OBJECTIVE--To determine whether patients referring themselves to an accident and emergency department for another opinion after consulting their general practitioner present with serious illness, show any risk factors for being admitted, or are more likely to be patients of particular practitioners. DESIGN--Six month prospective survey. SETTING--District general hospital''s accident and emergency department, receiving 42,000 new patients a year. PATIENTS--180 Patients identified as attending for another opinion having already consulted a general practitioner. INTERVENTIONS--Classified as admission, referral to specialist clinic, follow up in accident and emergency department, or referral back to general practitioner. END POINT--Admission, with an analysis of admitted patients. MEASUREMENTS AND MAIN RESULTS--General outcome, diagnostic category, age, time of attendance, time since seen by general practitioner, and name of general practitioner were recorded. Forty seven patients were admitted, 99 were discharged back to the general practitioner (62 without a letter), and two died. Patients were most likely to be admitted if they attended within 24 hours after seeing a general practitioner, were aged under 5, or presented with respiratory or gastrointestinal complaints. Some general practitioners were overrepresented. CONCLUSIONS--Important disorders present in this way, and therefore these patients should be seen by a doctor. Information about these attendances could be useful to general practitioners in reviewing their performance.     

Discovery of a novel class of biphenyl pyrazole sodium channel blockers for treatment of neuropathic pain

A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain.     

Effects of urbanisation on disease prevalence and age structure in blackbird Turdus merula populations

Despite increasing interest in urban ecology most attention has focussed on describing changes in assemblage composition and structure along urbanisation gradients, whilst relatively little research has focussed on the mechanisms behind these changes. Ecological theory predicts that alterations in biotic interactions are particularly likely to arise, especially with regard to disease risk. Here, we report on differences in prevalence of avian malaria and tick infection and intensity in 11 paired urban and rural blackbird Turdus merula populations from across the western Palearctic. We find large and consistent reductions in tick prevalence and intensity in urban areas. There are also large reductions in the prevalence of avian malaria in many, but not all, urban areas. The proportion of first year birds in urban populations is significantly lower than that in rural ones, and across the more natural rural sites southerly populations contain fewer first years than northern ones. These patterns are expected to arise if survival rates are higher in urban areas, and are negatively correlated with latitude.     

DNA accelerates the inhibition of human cathepsin V by serpins

A balance between proteolytic activity and protease inhibition is crucial to the appropriate function of many biological processes. There is mounting evidence for the presence of both papain-like cysteine proteases and serpins with a corresponding inhibitory activity in the nucleus. Well characterized examples of cofactors fine tuning serpin activity in the extracellular milieu are known, but such modulation has not been studied for protease-serpin interactions within the cell. Accordingly, we present an investigation into the effect of a DNA-rich environment on the interaction between model serpins (MENT and SCCA-1), cysteine proteases (human cathepsin V and human cathepsin L), and cystatin A. DNA was indeed found to accelerate the rate at which MENT inhibited cathepsin V, a human orthologue of mammalian cathepsin L, up to 50-fold, but unexpectedly this effect was primarily effected via the protease and secondarily by the recruitment of the DNA as a "template" onto which cathepsin V and MENT are bound. Notably, the protease-mediated effect was found to correspond both with an altered substrate turnover and a conformational change within the protease. Consistent with this, cystatin inhibition, which relies on occlusion of the active site rather than the substrate-like behavior of serpins, was unaltered by DNA. This represents the first example of modulation of serpin inhibition of cysteine proteases by a co-factor and reveals a mechanism for differential regulation of cathepsin proteolytic activity in a DNA-rich environment.     

Discovery of novel 2,3-diarylfuro[2,3-b]pyridin-4-amines as potent and selective inhibitors of Lck: synthesis, SAR, and pharmacokinetic properties

2,3-Diarylfuro[2,3-b]pyridine-4-amines are a novel class of potent and selective inhibitors of Lck. The discovery, synthesis, and structure activity relationships of this series of inhibitors are reported. The most promising compounds were also profiled to deduce their pharmacokinetic properties.