Clinical science
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Familial hypercholesterolaemia (FH) is an autosomal co-dominant disorder that markedly raises plasma low-density lipoprotein-cholesterol (LDL-C) concentration, causing premature atherosclerotic coronary artery disease (CAD). FH has recently come under intense focus and, although there is general consensus in recent international guidelines regarding diagnosis and treatment, there is debate about the value of genetic studies. Genetic testing can be cost-effective as part of cascade screening in dedicated centres, but the full mutation spectrum responsible for FH has not been established in many populations, and its use in primary care is not at present logistically feasible. ⋯ Lipoprotein apheresis remains an effective treatment for severe FH and, although expensive, it costs less than the two recently introduced orphan drugs (lomitapide and mipomersen) for homozygous FH. Recent advances in understanding of the biology of proprotein convertase subtilisin/kexin type 9 (PCSK9) have further elucidated the regulation of lipoprotein metabolism and led to new drugs for effectively treating hypercholesterolaemia in FH and related conditions, as well as for treating many patients with statin intolerance. The mechanisms of action of PCSK9 inhibitors on lipoprotein metabolism and atherosclerosis, as well as their impact on cardiovascular outcomes and cost-effectiveness, remain to be established.
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Septic shock results from the dysregulation of the innate immune response following infection. Despite major advances in fundamental and clinical research, patients diagnosed with septic shock still have a poor prognostic outcome, with a mortality rate of up to 50%. Indeed, the reasons leading to septic shock are still poorly understood. ⋯ In addition, novel experimental approaches, using more clinically relevant animal models, to standardize and stratify research outcomes are now being argued for. In the present review, we discuss the most recent findings in relation to our understanding of the underlying mechanisms involved in septic shock, and highlight the attempts made to improve animal experimental models. We also review recent studies reporting promising results with two vastly different therapeutic approaches influencing the renin-angiotensin system and applying mesenchymal stem cells for clinical intervention.
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Membrane microparticles are submicron fragments of membrane shed into extracellular space from cells under conditions of stress/injury. They may be distinguished from other classes of extracellular vesicles (i.e. exosomes) on the basis of size, content and mechanism of formation. Microparticles are found in plasma and other biological fluids from healthy individuals and their levels are altered in various diseases, including diabetes, chronic kidney disease, pre-eclampsia and hypertension among others. ⋯ Thus microparticles appear to serve as both markers and mediators of pathology. The present review examines the evidence for microparticles as both biomarkers of, and contributors to, the progression of disease. Approaches for the detection of microparticles are summarized and novel concepts relating to the formation of microparticles and their biological effects are examined.
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ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin II receptor blockers) are already widely used for the treatment and prevention of cardiovascular disease and their potential role in other disease states has become increasingly recognized. COPD (chronic obstructive pulmonary disease) is characterized by pathological inflammatory processes involving the lung parenchyma, airways and vascular bed. ⋯ The review will, in particular, address the emerging evidence that ACE inhibition could have a beneficial effect on skeletal muscle function and cardiovascular co-morbidity in COPD patients. The evidence to support the effect of RAS blockade as a novel therapeutic approach in COPD will be discussed.
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Review
Selecting exercise regimens and strains to modify obesity and diabetes in rodents: an overview.
Exercise is part of a healthy lifestyle and frequently is an important component in combating chronic diseases, such as obesity and diabetes. Understanding the molecular events initiated by regular exercise is best studied in laboratory animals, with mice and rats being favoured for a number of reasons. However, the wide variety of rodent strains available for biomedical research often makes it challenging to select an animal strain suitable for studying specific disease outcomes. In the present review we focus on exercise as a management strategy for obesity and diabetes and we discuss: (i) exercise paradigms in humans shown to ameliorate signs and symptoms of obesity and diabetes; (ii) different rodent strains in terms of their advantages, disadvantages and limitations when using specific forms of exercise; (iii) the strengths and weaknesses of commonly used laboratory methods for rodent exercise; and (iv) the unintended consequences of exercise that are often manifested by increased hormonal and oxidative stress responses.