Neurodegeneration: a failure of neuroregeneration?

Evidence suggests that the brain, like many other tissues, is in a state of dynamic equilibrium. It has an endogenous population of stem cells that proliferate in response to environmental and pharmacological manipulations and that can replace cells lost in some experimental lesions. However, the fact remains that neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are characterised by continuous loss of neurons that are not replaced. In this hypothesis, we postulate that a primary deficit in neural stem-cell proliferation; migration, or differentiation, or both, might contribute to net cell loss and neuronal circuit disruption in these disorders. Experimental validation of this hypothesis would not only substantially advance understanding of the pathogenesis of these diseases, but could also have profound implications for future treatment of these incurable disorders.     

Drugs for neglected diseases: a failure of the market and a public health failure?

Infectious diseases cause the suffering of hundreds of millions of people, especially in tropical and subtropical areas. Effective, affordable and easy‐to‐use medicines to fight these diseases are nearly absent. Although science and technology are sufficiently advanced to provide the necessary medicines, very few new drugs are being developed. However, drug discovery is not the major bottleneck. Today’s R&D‐based pharmaceutical industry is reluctant to invest in the development of drugs to treat the major diseases of the poor, because return on investment cannot be guaranteed. With national and international politics supporting a free market‐based world order, financial opportunities rather than global health needs guide the direction of new drug development. Can we accept that the dearth of effective drugs for diseases that mainly affect the poor is simply the sad but inevitable consequence of a global market economy? Or is it a massive public health failure, and a failure to direct economic development for the benefit of society? An urgent reorientation of priorities in drug development and health policy is needed. The pharmaceutical industry must contribute to this effort, but national and international policies need to direct the global economy to address the true health needs of society. This requires political will, a strong commitment to prioritize health considerations over economic interests, and the enforcement of regulations and other mechanisms to stimulate essential drug development. New and creative strategies involving both the public and the private sector are needed to ensure that affordable medicines for today’s neglected diseases are developed. Priority action areas include advocating an essential medicines R&D agenda, capacity‐building in and technology transfer to developing countries, elaborating an adapted legal and regulatory framework, prioritizing funding for essential drug development and securing availability, accessibility, distribution and rational use of these drugs.     

Acute pyelonephritis: a cause of acute renal failure?

Two patients with acute renal failure due to acute pyelonephritis are described. Examination of the renal biopsy showed normal glomeruli, severe interstitial neutrophilic infiltration and edema with no signs of acute tubular necrosis. Until now, only twelve biopsy-proven proven cases have been reported. A review of the literature on acute renal failure due to acute pyelonephritis is presented.     

β-blockers in stage B: a precursor of heart failure

β-blockers are an important treatment of heart failure (HF) and are useful in reducing the progression of the syndrome. They should be considered for patients with asymptomatic left ventricular (LV) dysfunction. Evidence-based β-blocker therapy (bisoprolol, carvedilol, or metoprolol succinate) in combination with standard therapy is a mainstay of treatment of all symptomatic patients with LV systolic dysfunction. Patients in stage B also benefit from the early introduction of β-blockers, but there are no large randomized clinical trials to support this strategy. Whether there is a role for ivabradine in the treatment of HF is not clear.     

Is coeliac disease a potentially treatable cause of liver failure?

Hypertransaminasaemia is a common abnormality found in up to 40% of untreated coeliac patients, which resolves with the institution of a gluten-free diet. A much rarer occurrence is the association of chronic liver disease with coeliac disease. Primary biliary cirrhosis, primary sclerosing cholangitis, and chronic autoimmune hepatitis have all been recognized in coeliac patients. More recently, the occurrence of coeliac disease in patients with chronic liver disease is found to be 10 times greater than that in the general population. Of particular note are the 13 patients reported to date with liver failure and coeliac disease. Among those patients commenced on a gluten-free diet an improvement in liver function was observed. The relationship between coeliac disease, a gluten-free diet, and the course of chronic liver disease needs to be clarified.     

Testosterone modulation of cardiac β-adrenergic signals in a rat model of heart failure

In this study, we examined the effects of castration and testosterone replacement on β-adrenoceptor and G protein expression in rats subjected to doxorubicin-induced heart failure. Five groups were included in this report: control, sham-castration with heart failure, castration with heart failure, castration + testosterone replacement with heart failure and castration + testosterone replacement and flutamide with heart failure. At 4 weeks post-treatment, echocardiography, hemodynamics and histopathology were assessed. Castration led to a further deterioration in myocardial performance, apoptosis and fibrosis, while testosterone replacement ameliorated these effects. Data obtained from Western blots revealed that testosterone upregulated the expression of β₂-adrenoceptor, Gs, Gi₂ and bcl2 levels, downregulated the expression of β₃-adrenoceptor, Gi₃ and GRK2 levels, and did not modify the expression of β₁-adrenoceptor levels in the hearts of castrated rats subjected to doxorubicin-induced heart failure. Analyses of serum 17β-estradiol concentrations test confirmed that these effects of testosterone were exerted through the androgen pathway. Thus our findings suggest that testosterone may have beneficial effects for male heart failure patients with androgen deficiency and this protection involves modulation of the cardiac β-adrenergic system.     

The role of mechanotransduction in heart failure pathobiology—a concise review

Heart Failure Reviews - This review evaluates the role of mechanotransduction (MT) in heart failure (HF) pathobiology. Cardiac functional and structural modifications are regulated by biomechanical...