Annals of medicine
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Recent data demonstrate the fundamental role of endothelin in the pathogenesis of fibrosis, and the anti-fibrotic potential of dual endothelin receptor antagonists such as bosentan. Although transforming growth factor-beta, aldosterone and connective tissue growth factor, have already been established as contributors to the process of fibrosis, endothelin now emerges as a key player, which may have a role both in the initiation and in maintenance of fibrosis, and may mediate the pro-fibrotic effects of the other agents. ⋯ Bosentan even reverses existing fibrosis, possibly by its effect of stimulating matrix metalloproteinase type 1 (collagenase) expression. The anti-fibrotic effects of bosentan extend to fibrosis induced by mediators other than endothelin such as transforming growth factor-beta, angiotensin II and aldosterone, indicating a central role of endothelin and endothelin receptors in fibrotic processes.
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Twenty years ago Parkinson's disease (PD) was thought of as an environmentally determined neurodegenerative disease. It is now known that there are two autosomal dominant disease genes, alpha-synuclein and dardarin, and three genes responsible for autosomal recessive PD, parkin, DJ-1 and PINK-1. Although these gene mutations are not common, their identification has led to a new understanding of the pathogenesis of PD, and to a development in the understanding of the clinical and pathological definitions of PD and Lewy body disease. Ultimately, these advances may lead to the development of new disease-modifying therapies, but more immediately these discoveries have led to a more coherent view of the spectrum of PD and Lewy body diseases and to accurate genetic diagnosis and counselling for some families.
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Within the past decade it has been possible to identify susceptibility gene loci that predispose to migraine using genetic markers distributed across the human genome. Five new loci with significant linkage to common types of migraine--migraine with or without aura--have been identified on four different chromosomes using a genome-wide screen approach. So far, only the locus on 4q has been replicated but no specific, disease-causing mutations have been described in these common forms of migraine. ⋯ In 50%-70% of FHM families, mutations in the calcium channel gene CACNA1A in chromosome 19p13 have been identified. In some families, mutations in the ATP1A2 gene encoding the alpha2 subunit of the Na+, K+-ATPase are associated with FHM, linked to 1q23. Here we discuss the current knowledge of the heritability of migraine and rare migraine variants as models for understanding the pathophysiology of common migraine and animal models that might contribute to understanding common forms of migraine.
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A variety of clinical conditions may cause systemic activation of coagulation, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation (DIC). DIC consists of a widespread systemic activation of coagulation, resulting in diffuse fibrin deposition in small and midsize vessels. There is compelling evidence from clinical and experimental studies that DIC is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. ⋯ Interestingly, an extensive cross-talk between activation of inflammation and coagulation exists, where inflammatory mediators (such as cytokines) not only activate the coagulation system, but vice versa activated coagulation proteases and protease inhibitors may modulate inflammation through specific cell receptors. Supportive strategies aimed at the inhibition of coagulation activation may theoretically be justified and have been found beneficial in experimental and initial clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways, for example by means of the administration of recombinant human activated protein C.
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We discuss in this review the role of the neuregulin (NRG1) gene in schizophrenia. NRG1 contributes to the genetics of schizophrenia in both Icelandic and Scottish schizophrenia patients. ⋯ NRG1 plays a central role in neural development and is most likely involved in regulating synaptic plasticity, or how the brain responds or adapts to the environment. The discovery that defects in NRG1 signaling may be involved in some cases of schizophrenia, not only implicates NRG1, but suggests that its biological pathway, active both at developing and mature synapses, is worth inspecting further in a search for other schizophrenia genes possibly in epistasis with NRG1.