Annals of medicine
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The thrombin-catalysed conversion of plasma fibrinogen into fibrin and the development of an insoluble fibrin clot are the final steps of the coagulation cascade during haemostasis. A delicate balance between coagulation and fibrinolysis determines the stability of the fibrin clot. Thrombin plays a central role in this process, it not only forms the clot but it is also involved in stabilizing the clot by activating thrombin activatable fibrinolysis inhibitor (TAFI). ⋯ Vice versa an increased activation of TAFI due to an increased rate of thrombin generation might lead to thrombotic disorders. Specific inhibitors of activated TAFI or inhibitors that interfere with the generation of thrombin might provide novel therapeutic strategies for thrombolytic therapy. Besides having a role in the regulation of fibrinolysis, TAFI may also have an important function in the regulation of inflammation, wound healing and blood pressure.
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Review
Recent advance in antiplatelet therapy: the mechanisms, evidence and approach to the problems.
Antiplatelet therapy has been established as a preventive medicine for ischemic cardiovascular diseases both at acute and chronic phases. This therapy is also crucial for the prevention of thrombotic events after coronary stent implantation. So far, many lines of clinical evidence have demonstrated the beneficial effects of aspirin (an irreversible cyclooxygenase inhibitor) and thienopyridine derivatives (adenosine diphosphate (ADP)-receptor P2Y12 inhibitors). ⋯ In addition to aspirin and thienopyridines, several types of drugs with antiplatelet effects are currently available in clinical practice. Clinical evidence has recently been accumulating for these drugs that can be potential alternatives in patients with aspirin or thienopyridine resistance. In this review, the mechanisms, evidence and approach to the present problems of drugs with antiplatelet effects are discussed.
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Today, the average life expectancy in developed nations is over 80 years and climbing. And yet, the quality of life during those additional years is often significantly diminished by the effects of age-related, degenerative diseases, including age-related macular degeneration (AMD), the leading cause of blindness in the elderly worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a highly specialized region of the ocular retina responsible for fine visual acuity. ⋯ Recently, compelling evidence has emerged that the innate immune system and, more specifically, uncontrolled regulation of the complement alternative pathway plays a central role in the pathobiology of AMD. The complement Factor H gene--which encodes the major inhibitor of the complement alternative pathway--is the first gene identified in multiple independent studies that confers a significant genetic risk for the development of AMD. The emergence of this new paradigm of AMD pathogenesis should hasten the development of novel diagnostic and therapeutic approaches for this disease that will dramatically improve the quality of our prolonged lifespan.
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The RET proto-oncogene is the major gene involved in the pathogenesis of Hirschsprung (HSCR), a complex genetic disease characterized by lack of ganglia along variable lengths of the gut. Here we present a survey of the different molecular mechanisms through which RET mutations lead to the disease development. Among these, loss of function, gain of function, apoptosis, aberrant splicing and decreased gene expression are exemplified and considered with respect to their pathogenetic impact. ⋯ Notably, gene expression impairment seems to be at the basis of the association of HSCR disease with several RET polymorphisms, allowing us to define a predisposing haplotype spanning from the promoter to exon 2. Putative functional variants, in the promoter and in intron 1, and proposed as low penetrant predisposing alleles, are presented and discussed. Finally, based on the RET mutation effects thus summarized, we attempt to derive conclusions which may be useful for HSCR risk prediction and genetic counselling.
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NPAS3 is a member of the basic helix-loop-helix PAS domain class of transcription factors expressed in the brain. Evidence from a human chromosomal rearrangement and a mouse knock-out strain suggest that it may play a part in the aetiology of psychiatric illness. In this review, we describe evolutionary constraints on the NPAS3 gene, relevant functional studies from a related gene and the behavioural and hippocampal neurogenesis deficit observed in the mutant mouse. In addition, we speculate on the physiological regulation of NPAS3 and whether NPAS3 gene variation contributes to psychiatric illness at the population level.