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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) often begins with migraine with aura. Recurrent strokes usually appear between 30 and 50 years of age. The arteriopathy develops slowly, resulting in destruction of smooth muscle cells and thickening and fibrosis of the walls of small and medium-sized penetrating arteries with consequent narrowing of the lumen. This impairs cerebral blood flow, visible in PET, and produces characteristic white-matter hyperintensities in T2-weighted MRI on the basis of which CADASIL may be diagnosed well before the first stroke. Multiple lacunar infarcts, mainly in the frontal white matter and basal ganglia, lead to progressive permanent brain damage manifested as cognitive decline and finally as dementia. At present, no specific therapy is available. Infarcts result from thickening and fibrosis of the walls of small and medium-sized penetrating arteries with consequent obliteration and/or thrombosis. Although the symptoms are almost exclusively neurological, the arteriopathy is generalized and diagnosis can be made on the basis of accumulation of pathognomonic basophilic, PAS-positive and in electron microscopy osmiophilic material between degenerating smooth muscle cells in dermal arteries. CADASIL is caused by missense point mutations in the Notch3 gene, which encodes a transmembrane receptor protein with an important signaling function during development. The gene defects lead to either a gain or loss of a cysteine residue in the extracellular N-terminal part of the molecule, most probably causing a conformational and functional alteration. The function of Notch3 in adults and the definite pathogenesis of CADASIL are still unknown, but interestingly its intramembranous proteolytic cleavage may be regulated or implemented by presenilin similarly as cleavage of amyloid precursor protein in Alzheimer's disease.
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PMID:CADASIL: hereditary arteriopathy leading to multiple brain infarcts and dementia. 1081 16

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary microangiopathic condition causing stroke in young adults. The responsible gene has recently been identified as the Notch3 gene. Notch3 encodes a large transmembrane receptor with 34 extracellularly localised epidermal growth factor-like (EGF) repeat domains. We screened 71 unrelated CADASIL families for mutations in two exons coding for the first five EGF-like repeats and found mutations in 70% of the families (n = 50). Two types of mutations were identified: 48 families (96%) had missense mutations and two families (4%) had small in-frame deletions. Seven mutations occurred multiple times. All of them are C to T transitions that affect CpG dinucleotides, suggesting that their multiple occurrence is due to the hypermutability of this sequence. All mutations, including the two deletions, result in the gain or loss of a cysteine residue, thus substantiating the pivotal role of an uneven number of cysteine residues within EGF-like repeat domains of Notch3 in the pathogenesis of CADASIL. To study the potential effects of these mutations 3D homology models of the first six EGF domains were generated on the basis of NMR data from human fibrillin-1. These models predict domain misfolding for a subset of mutations.
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PMID:Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. 1085 11

Despite the growing evidence that plasma homocysteine is a cardiovascular risk factor, the mechanism behind the vascular injuries is still unknown. Studies are difficult as a result of the fact that little is known about the formation of different homocysteine species in vivo. Since extracellular glutathione and cysteine may influence the formation of different homocysteine species, we have in the present study investigated the different fractions of homocysteine and their relation to the different fractions of glutathione and cysteine in stroke patients and control subjects. We found a ratio of about 32-33% between reduced and total plasma glutathione concentrations and 2.6 3.0% between reduced and total plasma cysteine concentrations both in patients and in healthy control subjects. We noted an elevated concentration of total plasma homocysteine in stroke patients, but no difference in the ratio between reduced and total plasma homocysteine concentrations in patients and control subjects (mean value 1.20 and 1.10%, respectively). However, in a subgroup of patients with higher concentrations of total plasma homocysteine, we observed a significantly lower ratio of reduced to total plasma homocysteine compared to a subgroup of patients with lower concentration of total plasma homocysteine. A low reduced/total ratio of plasma homocysteine in combination with elevated plasma homocysteine concentrations might reflect an increased pro-oxidant activity in plasma from these patients. Thus, increased pro-oxidant activity in plasma might be one factor, besides genetic and nutritional factors, that could explain hyperhomocysteinemia. Since substantial evidence indicates that progression of atherosclerosis is related to enhanced pro-oxidant activity, the premature vascular disease associated with increased plasma homocysteine concentration might be as a result of increased pro-oxidant activity and the elevated plasma homocysteine concentration may only reflect the increased oxidative stress.
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PMID:Redox status of plasma homocysteine and other plasma thiols in stroke patients. 1092 31

Apoptosis is a form of programmed cell death that occurs in neurons during development of the nervous system and may also be a prominent form of neuronal death in chronic neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Recent findings also implicate apoptosis in neuronal degeneration after ischemic brain injury in animal models of stroke. Activation of both apoptotic and antiapoptotic signaling cascades occurs in neurons in animal and cell culture models of stroke. Apoptotic cascades involve: increased levels of intracellular oxyradicals and calcium; induction of expression of proteins such as Par-4 (prostate apoptosis response-4), which act by promoting mitochondrial dysfunction and suppressing antiapoptotic mechanisms; mitochondrial membrane depolarization, calcium uptake, and release of factors (e.g., cytochrome c) that ultimately induce nuclear DNA condensation and fragmentation; activation of cysteine proteases of the caspase family; activation of transcription factors such as AP-1 that may induce expression of "killer genes." Antiapoptotic signaling pathways are activated by neurotrophic factors, certain cytokines, and increases in oxidative and metabolic stress. Such protective pathways include: activation of the transcription factors (e.g., nuclear factor-kappa B, NF-kappa B) that induce expression of stress proteins, antioxidant enzymes, and calcium-regulating proteins; phosphorylation-mediated modulation of ion channels and membrane transporters; cytoskeletal alterations that modulate calcium homeostasis; and modulation of proteins that stabilize mitochondrial function (e.g., Bcl-2). Intervention studies in experimental stroke models have identified a battery of approaches of potential benefit in reducing neuronal death in stroke patients, including administration of antioxidants, calcium-stabilizing agents, caspase inhibitors, and agents that activate NF-kappa B. Interestingly, recent studies suggest novel dietary approaches (e.g., food restriction and supplementation with antioxidants) that may reduce brain damage following stroke.
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PMID:Apoptotic and antiapoptotic mechanisms in stroke. 1092 90

Brain aging, Alzheimer disease and stroke share common elements of deficits in calcium regulation, declines in mitochondrial function, increases in generation of reactive oxygen species (ROS), accumulated damage from ROS and immune system dysfunction. The problem is to distinguish less significant side reactions, such as gray hair, from aspects of aging that contribute to disease. Toward establishing cause and effect relationships, a neuron cell culture system is described that allows comparisons with age under uniform environmental conditions. This neuron culture model indicates that susceptibility to death by apoptosis and consequences of the inflammatory response from beta-amyloid are age-related and an inherent characteristic of the neurons. Further mechanistic investigations are possible. New therapeutic approaches are suggested that combine inhibition of calcium overloads (calcium channel blockers), reduced ROS damage (melatonin, N-acetyl-cysteine), and bolstered mitochondrial function and energy generation (creatine). Together with newly demonstrated capabilities for adult and aged neuron regeneration and multiplication, i.e. plasticity, these approaches offer new hope toward reversing age-related decrements and damage from neurodegenerative disease.
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PMID:Neuronal plasticity and stressor toxicity during aging. 1111

Neuronal death underlies the symptoms of many human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, stroke, and amyotrophic lateral sclerosis. The identification of specific genetic and environmental factors responsible for these diseases has bolstered evidence for a shared pathway of neuronal death--apoptosis--involving oxidative stress, perturbed calcium homeostasis, mitochondrial dysfunction and activation of cysteine proteases called caspases. These death cascades are counteracted by survival signals, which suppress oxyradicals and stabilize calcium homeostasis and mitochondrial function. With the identification of mechanisms that either promote or prevent neuronal apoptosis come new approaches for preventing and treating neurodegenerative disorders.
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PMID:Apoptosis in neurodegenerative disorders. 1125 64

Binding of ATP to the catalytic domain of myosin induces a local conformational change which is believed to cause a major rotation of an 8.5 nm alpha-helix that is stabilized by the regulatory and essential light chains. Here we attempt to follow this rotation by measuring the mobility and orientation of a fluorescent probe attached near the C- or N-terminus of essential light chain 1 (LC1). Cysteine 178 of wild-type LC1, or Cys engineered near the N-terminus of mutant LC1, was labeled with tetramethylrhodamine and exchanged into skeletal subfragment-1 (S1) or into striated muscle fibers. In the absence of ATP, the fluorescence anisotropy (r) and the rotational correlation time (rho) of S1 reconstituted with LC1 labeled near the C-terminus were 0.195 and 66.6 ns, respectively. In the presence of ATP, r and rho increased to 0.233 and 233 ns, indicating considerable immobilization of the probe. A related parameter indicating the degree of order of cross-bridges in muscle fibers, Deltar, was small in rigor fibers (-0.009) and increased in relaxed fibers (0.030). For S1 reconstituted with LC1 labeled near the N-terminus, the steady-state anisotropy was 0.168 in rigor, and increased to 0.223 in relaxed state. In fibers, the difference in rigor was large (Deltar = 0.080), because of binding to the thin filaments, and decreased to 0.037 in relaxed fibers. These results suggest that before the power stroke, in the presence of ATP or its products of hydrolysis, the termini of LC1 are immobilized and ordered, and after the stroke, they become more mobile and partially disordered. The results are consistent with crystallographic structures that show that the level of putative stabilizing interactions of LC1 with the heavy chain of S1 in the transition state is reduced as the regulatory domain rotates to its post-power stroke position.
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PMID:The power stroke causes changes in the orientation and mobility of the termini of essential light chain 1 of myosin. 1130 Jul 59

Despite the immediate event, such as cerebral trauma, cardiac arrest, or stroke that may result in neuronal or vascular injury, specific cellular signal transduction pathways in the central nervous system ultimately influence the extent of cellular injury. Yet, it is a cascade of mechanisms, rather than a single cellular pathway, which determine cellular survival during toxic insults. Although neuronal injury associated with several disease entities, such as Alzheimer's disease, Parkinson's disease, and cerebrovascular disease was initially believed to be irreversible, it has become increasingly evident that either acute or chronic modulation of the cellular and molecular environment within the brain can prevent or even reverse cellular injury. In order to develop rational, efficacious, and safe therapy against neurodegenerative disorders, it becomes vital to elucidate the cellular and molecular mechanisms that control neuronal and vascular injury. These include the pathways of free radical injury, the independent mechanisms of programmed cell death, and the downstream signal transduction pathways of endonuclease activation, intracellular pH, cysteine proteases, the cell cycle, and tyrosine phosphatase activity. Employing the knowledge gained from investigations into these pathways will hopefully further efforts to successfully develop effective treatments against central nervous system disorders.
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PMID:The dynamics of cellular injury: transformation into neuronal and vascular protection. 1133 19

Mutations in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary angiopathy causing stroke and vascular dementia. All CADASIL mutations identified so far result in the loss or gain of one cysteine residue within epidermal growth factor (EGF)-like repeat domains. Here an in-frame deletion causing a loss of three cysteine residues within EGF repeat 6 is reported. These data are consistent with the hypothesis that the change toward an odd number of cysteine residues within a given EGF repeat and therefore an unpaired, reactive cysteine residue is the common and critical molecular event in CADASIL.
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PMID:NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL. 1170 20

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a type of hereditary stroke and dementia. More than 90% of patients with CADASIL have mutations in the Notch3 gene. All mutations either create or destroy a cysteine residue in the epidermal growth factor-like repeats. In addition, five polymorphisms, which lead to amino acid substitutions, have been identified within the Notch3 coding sequence. However, whether these polymorphisms affect Notch signalling or are involved in cerebrovascular diseases is unknown. In the present study, we investigated a possible association between a T6746C polymorphism in the Notch3 coding region and the occurrence of symptomatic ischaemic cerebrovascular disease (CVD) was investigated. Two hundred and thirty five patients with CVD, as confirmed by brain CT or MRI, and 315 age and sex matched control subjects were analyzed for genotype frequencies of the T6746C polymorphism in Notch3. The genotype distributions were: patients with CVD, C/C 14.0%, C/T 45.5%, and T/T 40.4%; controls, C/C, 14.3%; C/T, 47.9%; T/T, 37.8%. The Japanese population has a higher C allele frequency of the T6746C polymorphism than European populations. There was no significant difference between the T6746C polymorphism in patients with CVD and controls (chi(2)=0.414, p=0.813). This was confirmed by the results of multiple logistic regression analysis including established risk factors (chi(2) =4.65, p=0.311). In conclusion, the results indicate that T6746C polymorphism in the intracellular domain of the Notch3 gene is not associated with an increased risk for CVD.
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PMID:Notch3 gene polymorphism and ischaemic cerebrovascular disease. 1186 1


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