RESUMO
Advances in molecular genetics have enabled identification of several monogenic conditions involving small vessels predisposing to ischaemic and haemorrhagic strokes and diffuse white matter disease. With emphasis on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we review the molecular pathogenesis of recently characterized disorders including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and the Collagen type IV, alpha 1 (COL4A1)-related disorders. CADASIL remains the most common hereditary small vessel disease (SVD) caused by >190 different mutations in the NOTCH3 gene, which encodes a cell-signalling receptor. Mutant NOTCH3 instigates degeneration of vascular smooth muscle cells in small arteries and arterioles leading to recurrent lacunar infarcts. Mutations in the serine protease HTRA1 gene are associated with CARASIL. Aberrant HTRA1 activity results in increased transforming growth factor-ß signalling provoking multiple actions including vascular fibrosis and extracellular matrix synthesis. The RVCL disorders characterized by profound retinopathy are associated with mutations in TREX1, which encodes an abundant 3'-5' DNA-specific exonuclease. TREX1 mutations lead to detrimental gain-of-function or insufficient quantities of enzyme. The COL4A1-related disorders are highly variable comprising four major phenotypes with overlapping systemic and central nervous system features including SVD with cerebral haemorrhages in children and adults. Mutant COL4A1 likely disrupts the extracellular matrix resulting in fragile vessel walls. The hereditary SVDs albeit with variable phenotypes demonstrate how effects of different defective genes converge to produce the characteristic arteriopathy and microvascular disintegration leading to vascular cognitive impairment.
Assuntos
Encéfalo/patologia , Capilares/patologia , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/patologia , Biologia Molecular , Animais , CADASIL/genética , CADASIL/patologia , Doenças Arteriais Cerebrais/genética , Doenças Arteriais Cerebrais/patologia , Infarto Cerebral/genética , Infarto Cerebral/patologia , Colágeno Tipo IV/genética , Humanos , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Mutação/genética , Mutação/fisiologia , Receptor Notch3 , Receptores Notch/genética , Receptores Notch/fisiologia , Vasos Retinianos/patologia , Transdução de Sinais/genéticaRESUMO
Bovine soles and shavings from the heel were used in laboratory tests that examined the softening and swelling effects of rainwater, cow slurry (faeces plus urine), urine, silage effluent, and washings from recently laid concrete. Formalin, glutaraldehyde and butyraldehyde were compared for their ability to prevent softening induced by water, urine or urea plus 2-mercaptoethanol. Exposure to rainwater, slurry or urine for 72 h softened the soles on average by 16, 13 and 14 Shore Durometer Units. Silage effluent had less softening effect on soles (7 Shore Durometer Units), and pre-treating heel shavings with silage effluent reversed the swelling effect of water. Washings and scrapings taken from 3- and 7-d-old concrete surfaces prepared from Portland cement, caused swelling in heel shavings by a factor of 1.5 and 1.3. Formaldehyde, glutaraldehyde and butyraldehyde pre-treatment reduced the sole softening effect of urea plus 2-mercaptoethanol in cow soles. Formaldehyde and glutaraldehyde pre-treatment reduced the sole softening effect of urine, and formaldehyde was effective at reducing concrete washings-induced swelling. The findings are relevant to solar bruising and ulceration in cattle.