The pathogenesis of CADASIL: an update.
ABSTRACT Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) appears to be the most common form of hereditary stroke disorder. CADASIL is associated with arterial smooth muscle degeneration linked to mutations in the Notch3 gene, whose product is a transmembrane receptor that functions in cell-cell communication. The pathogenesis of CADASIL remains unclear. Current research efforts are directed towards the elucidation of various features of the disorder including investigations on CADASIL-like disorders, early cognitive changes, specificity of neuroimaging for diagnosis, discovery of de novo mutations, the development of Notch3 transgenic mouse models and molecular cellular studies in Notch3 signaling. The genetics of cerebrovascular disorders (CVD) was virtually unknown until recently. Genetic associations may have been evaded because of widely variable phenotypes, even within monogenic disorders such as CADASIL. Several investigators have attempted genotype-phenotype correlation in CADASIL cases but the relationship between genetic alterations and overt manifestation of phenotype remains elusive. However, the elucidation of the genetics and pathogenesis of CADASIL have been important in further understanding of the primary vascular mechanisms that lead to ischemic blood flow and its consequences on neuronal survival. This report summarizes some of the highlights of the satellite symposium on CADASIL at Vas-Cog 2003.
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ABSTRACT: Recent Surface Forces Apparatus (SFA) experiments have shed new light on the roles of surface roughness and surface deformations, both at the molecular and microscopic scales, in determing adhesion and friction. Depending on the roughness, but also on other factors such as the stiffness and viscoelasticity of surfaces, these effects can cause the effective adhesion force to be orders of magnitude lower or higher than the thermodynamic (equilibrium) value, which in turn determines the frictional behaviour.The interactions of ‘ideal’, i.e., molecularly smooth, undamaged, surfaces are now quite wellunderstood, both theoretically and experimentally. However, this is not the case for rough surfaces, which are difficult to define and characterize, and for which rigorous theories and reliable experimental data are lacking. Yet, most real or ‘engineering’ surfaces are rough on the nanometer to micrometer scale. This significantly affects their short-range interactions, their tribological behavior (adhesion, friction and lubrication) and their failure mechanisms (fracture and wear). Even when great care is taken to ensure smoothness, it is generally very difficult to produce a surface with a roughness of less than 25 except over small areas (usually for research purposes) and it is known that even a few nm of roughness can reduce the adhesion force between hard surfaces by more than an order of magnitude, and totally change their tribological behavior.To date there is no general theory for the interactions of rough surfaces nor any systematic experiments that identify the main trends; for example, how does the adhesion force or friction coefficient of a particular surface depend on its roughness? Indeed, one of the major problems is that roughness itself is not well defined. Simply quoting the RMS roughness of a surface is too simplistic, whereas describing it rigorously in terms of its Fourier components is too impractical. This whole issue has recently come to be appreciated as central to many tribological questions.We have recently performed measurements, using the SFA and scanning lateral probe techniques, on various surfaces having different roughness in an attempt to uncover some general trends and principles that describe the dependence of adhesion, friction and wear on roughness. We find, for example, that there is a generic, approximately exponential, relationship for the repulsive force between two rough surfaces, and that for non-adhering surfaces the friction force is proportional to the load (not the real contact area) at the molecular level. These and other, such as the dynamic, aspects of the tribological interactions between rough surfaces are described and discussed.Tribology and Interface Engineering Series 01/2000; 38:3-12.
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ABSTRACT: Clinical presentation of CADASIL patients is variable due to the impact of other vascular risk factors and the type of a NOTCH3 mutation. This variability may impede the diagnosis of the disease. We report a comprehensive evaluation of several individuals in the CADASIL family whose member was identified to have the new mutation of NOTCH3 receptor on exon 6 (p. G296C). We performed genetic testing, clinical and neuropsychological examination, cerebral MRI, Doppler sonography of cerebral arteries, fundoscopic examination and fluorescent angiography in six family members to determine the corresponding clinical spectrum associated with the new mutation. Results and Conclusion. The CADASIL mutation was detected in four individuals. Three of them were symptomatic, two having a history of stroke and one suffering from migraine. Although individuals had heterogeneous findings, the common feature included vascular changes that were present on cerebral and/or retinal arteries in all the mutation carriers even in one subject without clinical manifestation of the disease.Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia 09/2013; · 1.66 Impact Factor