Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The blood-brain barrier (BBB) serves as a critical regulator of brain homeostasis. Following hypoxia (i.e. 6% oxygen/1 h) and reoxygenation (H/R), the BBB tight junctional complex is disrupted, resulting in increased BBB permeability and the development of vasogenic brain edema. In this study, we examined the effect of H/R on the in vivo rat BBB over a 36 h time course in conjunction with paracellular permeability, gray matter edema, and systemic inflammatory activity. A biphasic increase was observed in the brain uptake of (14)C-sucrose, a paracellular permeability marker; with the first increase at the 10 min reoxygenation time point, and the second increase at the 6-18 h time points. Increased brain water weight gain (edema) also showed a biphasic response with the first increase at the 10 min-1 h reoxygenation time points; and the second increase at only the 24 h time point. Analysis of serum derived cytokines (IL-1beta, TNFalpha, IL-6, IL-10, and IFNgamma) demonstrated that only IL-1beta and IL-6 were at detectable levels, but these levels were similar to controls. White blood cell counts showed significant decreases in lymphocytes (10 min-3 h), increases in monocytes (10 min-3 h and 12 h), and increases in polymorphonuclear cells (1 h and 3 h). We have shown that H/R elicits a biphasic increase in paracellular permeability and edema, which parallel to post-stroke sequelae, despite the lack of occlusion or complete depletion of oxygen.
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PMID:Reoxygenation stress on blood-brain barrier paracellular permeability and edema in the rat. 1765 65

There have been difficulties to demonstrate a relationship between endotoxin concentration and clinical response. One hypothesis for this difficulty might be that a fast increase in endotoxin concentration elicits a stronger biological response than a more gradual one of the same dose. The aim of the present study was to investigate the existence of such a response. Eighteen randomized pigs were given the same amount of endotoxin either with an initial infusion rate of 4 microg kg(-1) h(-1), which after 1 h was tapered to 0.5 microg kg(-1) h(-1), and after 2 h to 0.063 microg kg(-1) h(-1) (group I), or with a reverse escalating order with the lowest infusion rate given first (group II). After 3 h, the endotoxin infusion was stopped, and the pigs were observed for another 3 h. The responses in TNF-alpha, core temperature, leukocytes, platelets, MAP, left ventricular stroke work index, mixed venous saturation, base excess, pH, and pulmonary compliance were greater in group I than in group II, whereas the IL-6 response did not differ between groups. The biological responses of inflammation, hypotension, hypoperfusion, and organ dysfunction are increased if the organism is exposed to a fixed amount of endotoxin more quickly.
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PMID:Effect of the administration rate on the biological responses to a fixed dose of endotoxin in the anesthetized pig. 1766 61

Inflammation is associated with both acute and chronic neurological disorders, including stroke and Alzheimer's disease (AD). Cytokines such as interleukin (IL)-1 have several activities in the brain both under physiological and pathophysiological conditions. The objective of this study was to evaluate consequences of the central blockade of IL-1 transmission in a previously developed transgenic mouse strain with brain-directed overexpression of human soluble IL-1 receptor antagonist (Tg hsIL-1ra). Effects on brain morphology and brain levels of the AD-related proteins beta-amyloid precursor protein (APP) and presenilin 1(PS1), as well as the levels of IL-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha) were analysed in homozygotic and heterozygotic mice and wild type (WT) controls, of both genders and of young (30-40 days) and adult (13-14 months) age. A marked reduction in brain volume was observed in transgenic mice as determined by volumetry. Western blot analysis showed higher levels of APP, but lower levels of PS1, in adult animals than in young ones. In the cerebellum, heterozygotic (Tg hsIL-1ra(+/-)) mice had lower levels of APP and PS1 than WT mice. With one exception, there were no genotypic differences in the levels of IL-1beta, IL-6 and TNF-alpha. The cytokine levels were generally higher in adult than in young mice. In conclusion, the chronic blockade of IL-1 signalling in the brain was associated with an atrophic phenotype of the brain, and with modified levels of APP and PS1. Brain-directed overexpression of hsIL-1ra was not followed by major compensatory changes in the levels of pro-inflammatory cytokines.
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PMID:Studies on brain volume, Alzheimer-related proteins and cytokines in mice with chronic overexpression of IL-1 receptor antagonist. 1776 Aug 42

Fatigue without coincident depression may accompany many neurological disorders, including multiple sclerosis, Parkinson's disease, motor neuron disease, stroke and post-polio syndrome, and is frequently reported by patients as a predominant complaint. The pathophysiology of fatigue is unknown. The role of various mechanisms has been suggested, including the effect of proinflammatory cytokines (TNF-alpha, IL-1beta and IL-6) on glutaminergic transmission, hypothalamo-pituitary-adrenal (HPA) axis dysfunction, disturbances of astroglia metabolism and decreased levels of the neurotransmitters noradrenaline and serotonin. The diagnosis of fatigue syndrome is based on exclusion of depression and additional organic conditions (anaemia, cardiovascular disorders, kidney diseases or hypothyroidism). The treatment of fatigue syndrome is complex. Physical activity, rehabilitation, psychotherapy and avoidance of factors which may increase fatigue, such as fever, anxiety, depression, pain, sleep disturbances, as well as some drugs like opioids and benzodiazepines, are important. Pharmacological treatment leads to slight improvement. Amantadine, modafinil and pemoline are administered to such patients.
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PMID:[Fatigue syndrome in chronic neurological disorders]. 1787 43

In January 2004, the normally picturesque Cache Valley in northern Utah made national headlines with the highest PM2.5 levels in the nation. Epidemiological studies linked exposure to particulate air pollution in other locations with stroke and Alzheimer's disease and to early mortality from all causes, cancer, and cardiopulmonary diseases. To determine potential effects of these particles on human health, human bronchial epithelial cells (BEAS-2B) were cultured with PM2.5 collected from various locations in the Cache Valley. These particles were slightly cytotoxic, but more potent than NH4NO3, the major chemical component of Cache Valley PM2.5. Gene expression analysis of PM2.5-exposed cells was performed using microarray and quantitative reverse-transcription polymerase chain reaction (RT-PCR). Among other genes, PM2.5 exposure induced genes and proteins involved in the inflammatory response. Most notably, PM2.5-exposed cells showed significant gene level upregulation of activating receptors to interleukins 1 and 6 (IL-1R1 and IL-6R), as well as concomitant increases in protein. Increases in IL-1 receptor associated kinase-1 (IRAK) protein were observed. PM2.5 exposure resulted in release of IL-6, as well phosphorylated STAT3 protein, providing evidence that PM activates the IL-6/gp130/STAT3 signaling pathway in BEAS-2B cells. IL-20 and major histocompatibility complex peptide class-1 (MICA) were upregulated and cleavage of caspase-12 was detected. In total, our results indicate that Cache Valley PM2.5 produces the upregulation of important cytokine receptors and is able to activate both IL-1R- and IL-6R-mediated signaling pathways in human lung cells. These observations are generally consistent with the adverse effects associated with inhalation of fine particulate matter like PM2.5.
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PMID:Effects of PM2.5 collected from Cache Valley Utah on genes associated with the inflammatory response in human lung cells. 1788 30

Cytokines regulate the innate and adaptive immune responses and are pleiotropic, redundant and multifunctional. Expression of most cytokines, including TNF-alpha and IL-1alpha/beta, is very low in normal brain. Metabolism of lipids is of particular interest due to their high concentration in the brain. Inflammatory response after stroke suggests that cytokines (TNF-alpha, IL-1alpha/beta, IL-6), affect the phospholipid metabolism and subsequent production of eicosanoids, ceramide, and ROS that may potentiate brain injury. Phosphatidylcholine and sphingomyelin are source for lipid messengers. Sphingomyelin synthase serves as a bridge between metabolism of glycerolipids and sphingolipids. TNF-alpha and IL-1alpha/beta can induce phospholipases (A2, C, and D) and sphingomyelinases, and concomitantly proteolyse phosphatidylcholine and sphingomyelin synthesizing enzymes. Together, these alterations contribute to loss of phosphatidylcholine and sphingomyelin after stroke that can be attenuated by inhibiting TNF-alpha or IL-1alpha/beta signaling. Inflammatory responses are instrumental in the formation and destabilization of atherosclerotic plaques. Secretory PLA2 IIA is found in human atherosclerotic lesions and is implicated in initiation, progression and maturation of atherosclerosis, a risk factor for stroke. Lipoprotein-PLA2, part of apolipoprotein B-100 of LDL, plays a role in vascular inflammation and coronary endothelial dysfunction. Cytokine antagonism attenuated secretory PLA2 IIA actions, suggesting cytokine-lipid integration studies will lead to new concepts contributing to bench-to-bedside transition for stroke therapy.
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PMID:Integration of cytokine biology and lipid metabolism in stroke. 1798 27

1. Aetiological studies have shown that sodium loading increases both blood pressure and death from stroke. The present study was designed to investigate the pressor and non-pressor effects of sodium loading on stroke in stroke-prone spontaneously hypertensive rats (SHRSP). 2. Eighty-five female SHRSP were used. Forty-nine SHRSP, aged 5 months, were randomly divided into two groups with or without sodium loading and their survival times were recorded. Thirty-six SHRSP, aged 3 months, were randomly divided into two groups and were instrumented to determine blood pressure, heart period and baroreflex sensitivity (BRS) after 4 months of sodium loading or normal rat chow. After determination of BRS, blood samples were collected for the measurement of tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6 and angiotensin (Ang) II and brains were dissected for light microscopic examination. 3. Over the 15 month period, the mortality of control SHRSP was 37.5%, which reached 80.0% in the sodium loading group. Compared with the control group, blood pressure was increased but BRS was significantly decreased (P < 0.001) in sodium-loaded rats. Levels of IL-1beta, IL-6 and AngII were all significantly increased (P < 0.05) in the sodium-loaded rats. Sodium loading also markedly increased the number of cerebral aneurysms. Multivariate regression analysis showed that IL-6 was the most significant factor related to aneurysm formation. 4. Sodium loading increases death from stroke in SHRSP. The increased blood pressure, impaired BRS, inflammatory reaction and the formation of cerebral aneurysms may contribute to the development of stroke.
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PMID:Pressor and non-pressor effects of sodium loading on stroke in stroke-prone spontaneously hypertensive rats. 1804 33

Sequence variations in genes involved in inflammation system are known to contribute to the risk of cardiovascular diseases (CVD) including stroke. In this study, we performed a genetic association study on the single nucleotide polymorphisms (SNPs) present in the genes CD14 (-159 C/T), TNFalpha (-308 G/A), IL-1alpha (-889 C/T), IL-6 (-174 G/C), PSMA6 (-8 C/G), and PDE4D (SNP83 T/C, respectively) in order to discern their possible role in the susceptibility to stroke in a North Indian population. These SNPs were previously found to be associated with CVD through their contribution to inflammation. A case-control design was used to examine 176 stroke patients (112 ischemic and 64 hemorrhagic stroke patients) and 212 unrelated healthy control individuals. After adjustment for the confounding risk factors, the IL-1alpha -889 T allele carriers (TT+CT) were found to be strongly associated with both forms of stroke (OR=2.56; 95% CI=1.53-4.29; P=0.0004). The CC genotype of PDE4D was found to be associated only with ischemic stroke (OR=2.02; 95% CI=1.08-3.76; P=0.03). None of the variants tested for the CD14, TNFalpha, IL-6, and PSMA6 genes found to confer risk for stroke in the study population. In conclusion, the -889 C/T and SNP83 T/C SNPs of the IL-1alpha and PDE4D genes, respectively, appear to be genetic risk factors for stroke in our study population.
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PMID:Inflammatory system gene polymorphism and the risk of stroke: a case-control study in an Indian population. 1815 10

Stroke triggers a local and systemic inflammatory response leading to the production of cytokines that can influence blood vessel reactivity. In this study, we aimed to assess whether cerebral ischemia/reperfusion could affect vasoconstriction and vasodilatation on mesenteric resistance arteries (MRA) from Wistar Kyoto rats. The right middle cerebral artery was occluded (90 min) and reperfused (24 h). Sham-operated animals were used as controls. Plasma levels of interleukin (IL)-6 and IL-1beta were measured at 24 h. Vasoconstrictor and vasodilator responses were recorded in a wire myograph. Protein expression was determined by Western blot and immunofluorescence, and superoxide anion (O(2)(.)) production was evaluated by ethidium fluorescence. In MRA, ischemia/reperfusion increased plasma levels of IL-6, O2. production, protein expression of cyclooxygenase-2, and protein tyrosine nitrosylation, but it impaired acetylcholine (ACh) vasodilatation without modifying the vasodilatations to sodium nitroprusside or the contractions to phenylephrine and KCl. Superoxide dismutase (SOD) and indomethacin reversed the impairment of ACh relaxation induced by ischemia/reperfusion. However, N(omega)-nitro-l-arginine methyl ester affected similarly ACh-induced vasodilatations in MRA of ischemic and sham-operated rats. Protein expression of endothelial and inducible nitric-oxide synthase, copper/zinc SOD, manganese SOD, and extracellular SOD was similar in both groups of rats. Our results show MRA endothelial dysfunction 24 h after brain ischemia/reperfusion. Excessive production of O2. in MRA mediates endothelial dysfunction, and the increase in plasma cytokine levels after brain ischemia/reperfusion might be involved in this effect.
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PMID:Endothelial dysfunction in rat mesenteric resistance artery after transient middle cerebral artery occlusion. 1825 83

Early non-invasive diagnostic information would be useful in identifying patients at risk of progressive carotid atherosclerosis, despite an apparently harmless plaque on ultrasound imaging. In this study, we assessed the possible association of intracellular cytokines in peripheral blood with the ultrasound (stenosis > or = 70%) and clinical indications (transient ischaemic attack, amaurosis fugax or stroke) for carotid endarterectomy (CEA) in patients. Intracellular cytokine expression was determined in 106 patients (67 undergoing and 39 not undergoing CEA). Cells primed for the proinflammatory cytokines tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-6, IL-8 and the anti-inflammatory cytokines IL-4 and IL-10 were found in significantly higher percentages in patients undergoing CEA than in patients who were not (P < 0.05). Intracellular cytokine expression was significantly higher in patients undergoing CEA who had stenosis > or = 70% (TNF-alpha, IFN-gamma, IL-1beta, IL-6, IL-4 and IL-10), with previous stroke (IFN-gamma, IL-1beta, IL-6, IL-8, IL-4 and IL-10) and with amaurosis fugax (IFN-gamma, IL-6, IL-4 and IL-10) than in patients not undergoing CEA. Increased intracellular cytokines in patients' peripheral blood might be a warning signal indicating progressive atherosclerosis. If so, intracellular cytokine monitoring could help in selecting patients at high risk of future clinical cardiovascular events and therefore most likely to benefit from CEA or adjustment of pharmacological therapy.
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PMID:Association of intracellular pro- and anti-inflammatory cytokines in peripheral blood with the clinical or ultrasound indications for carotid endarterectomy in patients with carotid atherosclerosis. 1830 18


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