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)

Myoplasmic calcium homeostasis is an essential feature of skeletal muscle contraction. The calcium mobilisation complex (CMC) located at the level of the triadic junction plays a major role for the regulation of calcium fluxes between extra-cellular, cytoplasmic and intra-cellular compartments. The ryanodine receptor type I (RYR1), which is located at the level of the terminal cisternae of the sarcoplasmic reticulum is a key component of the CMC. RYR1 allow the release into the myoplasm of the intralumenal stores of calcium. RYR1 interacts with other proteins: DiHydroPyridine Receptor, triadin, calsequestrin, FKBP12, calmodulin. Malignant hyperthermia (MHS) and congenital core myopathies have been associated with a dysfunction of the CMC. MHS is an autosomic dominant pharmacogenetic disease. The MH crisis is induced by exposure of the predisposed patients to halogenated volatile anaesthetics. MHS is characterised by a genetic heterogeneity and two genes, RYR1 and CACNA1S, have been associated so far with the disease. Mutations in the RYR1 gene have been recently associated with heat stroke, a related syndrome. Central Core Disease (CCD) and Multi minicore Disease (MmD) are congenital myopathies presenting with clinical variability and characterized by the presence of specific although heterogeneous muscle histological features: the cores. Clinical boundaries between the two diseases may overlap and the specific diagnosis is often based on the nature of the cores. These diseases show genetic heterogeneity with both autosomic dominant and recessive mode of inheritance and mutations in the SEPN1, RYR1, ACTA1, TPM3 genes have been reported. Mutations associated with MHS were mainly identified into 2 regions of the N-terminal part of RYR1. Functional role of these two domains is still unclear. Mutations responsible for congenital myopathies mainly mapped to the C terminal region of RYR1 that form the transmembrane calcium channel. Functional studies of the RYR1 mutations have shown that MHS mutations were mainly associated with an alteration of the calcium fluxes in response to caffeine or halothane while CCD mutations would result in a leaky RYR1 channel or would alter the Excitation-Contraction coupling at the level of the CMC.
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PMID:[Genetic of diseases by abnormal functioning of the skeletal muscle-calcium releasing complex]. 1526 63

Because of possible side effects of herbal medicines containing ephedrine and guarana-derived caffeine, including increased risk of stroke, myocardial infarction, and sudden death, the Food and Drug Administration recently banned the sale of ephedra-containing products, specifically over-the-counter dietary supplements. We report cardiac in 7- and 14-week-old male F344 rats exposed by gavage to ephedrine(25 mg/kg) and caffeine (30 mg/kg) administered in combination for one or two days. The ephedrine-caffeine dosage was approximately 12- and 1.4-fold, respectively, above average human exposure, based on a mg/m2 body surface-area comparison. Several (5/7) of the exposed 14-week-old rats died or were sacrificed in extremis 4-5 h after the first dosing. In these hearts, changes were observed chiefly in the interventricular septum but also left and right ventricular walls. Massive interstitial hemorrhage, with degeneration of myofibers, occurred at the subendocardial myocardium of the left ventricle and interventricular septum. Immunostaining for cleaved caspase-3 and hyperphosphorylated H2A.X, a histone variant that becomes hyperphosphorylated during apoptosis, indicated multifocal generalized positive staining of degenerating myofibers and fragmenting nuclei, respectively. The Barbeito-Lopez trichrome stain revealed generalized patchy yellow myofibers consistent with degeneration and/or coagulative necrosis. In ephedrine-caffeine-treated animals terminated after the second dosing, foci of myocardial degeneration and necrosis were already infiltrated by mixed inflammatory cells. The myocardial necrosis may occur secondarily to intense diffuse vasoconstriction of the coronary arterial system with decreased myocardial perfusion. Our work shows the direct relationship between combined ephedrine and caffeine exposure and cardiac pathology.
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PMID:Acute hemorrhagic myocardial necrosis and sudden death of rats exposed to a combination of ephedrine and caffeine. 1553 44

In response to concerns regarding the safety of ephedra-containing dietary supplements, manufacturers have marketed "ephedra-free" products. Many of these contain synephrine, a sympathomimetic amine from the plant Citrus aurantium. Synephrine is structurally similar to ephedrine and has vasoconstrictor properties. We describe a 38-year-old patient with ischemic stroke associated with an ephedra-free dietary supplement containing synephrine and caffeine. The patient presented with memory loss and unsteady gait after taking 1 or 2 capsules per day of a dietary supplement (Stacker 2 Ephedra-Free) for 1 week. He had no notable medical history or major atherosclerotic risk factors and took no other medications. Physical examination showed a mildly ataxic gait and substantial Impairment of both concentration and memory. Computed tomography and magnetic resonance Imaging of the brain showed subacute infarctions in the left thalamus and left cerebellum in the distribution of the vertebrobasilar circulation. Other causes of ischemic stroke were evaluated, and findings were unremarkable; a vasospastic origin was considered most likely. The patient was discharged with nearly complete resolution of symptoms. Synephrine, a sympathomimetic amine related to ephedrine, may be associated with Ischemic stroke. Consumers and clinicians need to be Informed about the potential risks of ephedra-free products.
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PMID:Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine. 1581 93

Vascular biology assumes a pivotal role in the initiation and perpetuation of hypertension and target organ damage sequelae. Endothelial activation, oxidative stress, and vascular smooth muscle dysfunction (hypertrophy, hyperplasia, remodeling) are initial events that start hypertension. Nutrient-gene interactions determine a broad array of phenotypic consequences such as vascular problems and hypertension. Optimal nutrition, nutraceuticals, vitamins, antioxidants, minerals, weight loss, exercise, smoking cessation, and moderate restriction of alcohol and caffeine in addition to other lifestyle modifications can prevent, delay the onset, reduce the severity, treat, and control hypertension in many patients. An integrative approach combining these lifestyle suggestions with the correct pharmacological treatment will best achieve new goal blood pressure levels, reduce cardiovascular risk factors, improve vascular biology and vascular health, and reduce target organ damage including coronary heart disease, stroke, congestive heart failure, and renal disease. The expanded scientific roles for nutraceutical supplements will be discussed in relation to the prevention and treatment of essential hypertension with emphasis on mechanisms of action and clinical integration with drug therapy as indicated based, in part, on the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, the European Society of Hypertension, the European Society of Cardiology, the International Society of Hypertension, the Canadian Society of Hypertension, and other hypertension guidelines.
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PMID:Nutraceuticals, vitamins, antioxidants, and minerals in the prevention and treatment of hypertension. 1611 19

Rizatriptan and zolmitriptan are both used to relieve acute migraine and cluster headaches. The mechanism of action is similar to the other triptans, in that they reverse abnormal cerebral vasodilation through their activity as 5-HT1B receptor agonists. Triptan-induced vasoconstriction is attributed to its activity on peripheral 5-HT1B receptors and has rarely been reported to result in stroke, myocardial infarction and ischemic colitis. We present two cases of renal infarction associated with therapeutic triptan use. The first patient is a 57-year-old man with a history of hypertension that was well controlled on valsartan and hydrochlorothiazide. He was recently diagnosed with cluster headaches and was treated with indomethacin, prednisone, butalbital-acetaminophen-caffeine and hydrocodone without relief. He then received two therapeutic doses of rizatriptan on each of the two days prior to presentation. Subsequently, he presented to the emergency department complaining of nausea, vomiting and right-sided abdominal pain. A computerized tomography (CT) scan of the abdomen and pelvis with intravenous contrast revealed a very large wedge shaped infarction of the right kidney. The second patient is a 34-year-old man with a past medical history significant only for life-long migraine headaches successfully treated for the past six years with zolmitriptan. Shortly after taking one therapeutic dose of zolmitriptan, he presented to the emergency department complaining of nausea and left-sided abdominal pain. A CT scan of the abdomen and pelvis with intravenous contrast revealed multiple wedge-shaped infarctions of the left kidney. Renal infarction was confirmed in both patients by arteriogram of the renal arteries. Although both rizatriptan and zolmitriptan are effective in the treatment of migraine and cluster headaches, they may induce peripheral vasospasm leading to renal infarction.
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PMID:Renal infarction during the use of rizatriptan and zolmitriptan: two case reports. 1661 76

The adenosine A(2A) receptor has recently emerged as a leading non-dopaminergic therapeutic target for Parkinson's disease, largely due to the restricted distribution of the receptor in the striatum and the profound interaction between adenosine and dopamine receptors in brain. Two lines of research in particular have demonstrated the promise of the A(2A) receptor antagonists as novel anti-parkinsonian drugs. First, building on extensive preclinical animal studies, the A(2A) receptor antagonist KW6002 has demonstrated its potential to increase motor activity in PD patients of the advanced stage in a recent clinical phase IIB trial. Second, recently two prospective epidemiological studies of large cohorts have firmly established the inverse relationship between the consumption of caffeine (a non-specific adenosine antagonist) and the risk of developing PD. The potential neuroprotective effect of caffeine and A(2A) receptor antagonists in PD is further substantiated by the demonstration that pharmacological blockade (by caffeine or specific A(2A) antagonists) or genetic depletion of the A(2A) receptor attenuated dopaminergic neurotoxicity and neurodegeneration in animal models of PD. Moreover, A(2A) receptor antagonism-mediated neuroprotection goes beyond PD models and can be extended to a variety of other brain injuries induced by stroke, excitotoxicity and mitochondrial toxins. Intensive investigations are under way to dissect out common cellular mechanisms (such as A(2A) receptor modulation of neuroinflammation) which may underlie the broad spectrum of neuroprotection by A(2A) receptor inactivation in brain.
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PMID:Novel neuroprotection by caffeine and adenosine A(2A) receptor antagonists in animal models of Parkinson's disease. 1680 72

The nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 has an important role in regulating cell death and cellular responses to DNA repair. Pharmacological inhibitors of PARP have entered clinical testing as cytoprotective agents in cardiovascular diseases and as adjunct antitumor therapeutics. Initially, it was assumed that the regulation of PARP occurs primarily at the level of DNA breakage: recognition of DNA breaks was considered to be the primary regulator (activator) or the catalytic activity of PARP. Recent studies have provided evidence that PARP-1 activity can also be modulated by several endogenous factors, including various kinases, purines and caffeine metabolites. There is a gender difference in the contribution of PARP-1 to stroke and inflammatory responses, which is due, at least in part, to endogenous estrogen levels. Several tetracycline antibiotics are also potent PARP-1 inhibitors. In this article, we present an overview of novel PARP-1 modulators.
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PMID:Novel modulators of poly(ADP-ribose) polymerase. 1705 69

This article reviews research sourced through sport science and medical journal databases (SportDiscus and PubMed) that has attempted to quantify the effects of fatigue on tennis performance. Specific physiological perturbations and their effects on common performance measures, such as stroke velocity and accuracy, are discussed. Current literature does not convincingly support anecdotal assertions of overt performance decrements during prolonged matches or matches played during unfavourable (e.g. hot and humid) environmental conditions. The constraints of field-based research have presented, and continue to present, a methological challenge to investigators within this domain. Limitations of previous investigations have included the following: (i) a restricted measurement approach to the multifaceted skills that form the basis of match performance; (ii) a lack of sensitivity and large variability in skill or performance measures; (iii) usage of non tennis-specific methods to induce fatigue; and (iv) fatigue levels failing to reflect those recorded in match play. Hyperthermia, dehydration and hypoglycaemia have all been identified as common challenges to sustained performance proficiency in tennis, with emerging evidence suggesting central fatigue may also be a key stressor. Mixed results underpin attempts to mitigate physiological compromise and in situ performance deterioration through application of potential ergogenetic strategies (e.g. carbohydrate and caffeine supplementation, and hyperhydration). Methodological limitations are again a likely explanation, but positive findings from other skill-based sports should encourage further research in tennis. To date, tennis has largely relied on traditional methods to measure performance and has not yet realised the benefits of new sports science methods. Future research is encouraged to adopt methodological approaches that capture the multi-dimensional nature of tennis. This can be achieved through the incorporation of multifaceted performance assessment (i.e. perceptual-cognitive and biomechanical measurement approaches), the improvement of measurement sensitivity in the field setting and through the use of experimental settings that accurately simulate the energetic demands of match play.
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PMID:Fatigue in tennis: mechanisms of fatigue and effect on performance. 1732 96

We examined the tension responses to ramp shortening and lengthening over a range of velocities (0.1-5 L(0)/s) and at 20 degrees C and 30 degrees C in tetanized intact fibre bundles from a rat fast (flexor hallucis brevis) muscle; fibre length (L(0)) was 2.2 mm and sarcomere length approximately 2.5 microm. The tension change during ramp releases as well as ramp stretches showed an early transition (often appearing as an inflection) at 1-4 ms; the tension change at this transition and the length change at which it occurred increased with velocity. A second transition, indicated by a more gradual reduction in slope, occurred when the length had changed by 14-28 nm per half-sarcomere; the tension at this transition increased with lengthening velocity towards a plateau and it decreased with shortening velocity towards zero tension. The velocity dependence of the time to the transitions and the length change at the transitions showed some asymmetries between shortening and lengthening. Based on analyses of the velocity dependence of the tension and modelling, we propose that the first transition reflects the tension change associated with the crossbridge power stroke in shortening, or with the reversal of the power stroke in lengthening. Modelling shows that the reduction in slope at the second transition occurs when most of the crossbridges (myosin heads) that were attached at the start of the ramp become detached. After the second transition, the tension reaches a steady level in the model whereas the tension continues to increase during lengthening and continues to decrease during shortening in the experiments; this continuous tension change is seen at a wide range of initial sarcomere lengths and when active force is reduced by the myosin inhibitor, BTS. The continuous tension decline during shortening is not abolished by caffeine, but the rate of decline is reduced when the active force is depressed by BTS. We propose that stiffening of non-crossbridge visco-elastic elements upon activation contributes to the continuous tension rise during lengthening and the release of such tension and Ca-insensitive deactivation contribute to the tension decline during shortening in muscle fibres.
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PMID:Comparison of the tension responses to ramp shortening and lengthening in intact mammalian muscle fibres: crossbridge and non-crossbridge contributions. 1761 Jan 36

Caffeine, the most consumed psychoactive drug and non-specific adenosine receptor antagonist, has recently been shown to exert a neuroprotective effect against brain injury in animal models of Parkinson's disease (PD) and stroke. However, the effects of caffeine on traumatic brain injury (TBI) are not known. In this study, we investigated the effects of acute and chronic caffeine treatment on brain injury in a cortical-impact model of TBI in mice. Following TBI, neurological deficits, cerebral edema, as well as inflammatory cell infiltration were all significantly attenuated in mice pretreated chronically (for 3 weeks) with caffeine in drinking water compared with the mice pretreated with saline. Furthermore, we found that chronic caffeine treatment attenuated glutamate release and inflammatory cytokine production, effects that were correlated with an upregulation of brain A1 receptor mRNA. By contrast, acute treatment with caffeine (i.p. injection, 30 min before TBI) was not effective in protecting against TBI-induced brain injury. These results suggest that chronic (but not acute) caffeine treatment attenuates brain injury, possibly by A1 receptor-mediated suppression of glutamate release and inhibition of excessive inflammatory cytokine production. These results highlight the potential benefit of chronic caffeine intake for preventing TBI and provide a rationale for the epidemiological investigation of the potential association between TBI and human caffeine intake.
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PMID:Chronic but not acute treatment with caffeine attenuates traumatic brain injury in the mouse cortical impact model. 1820 47


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