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)

Twenty-four patients who underwent transvenous catheter ablation of the atrioventricular (A-V) junction between November 1982 and February 1987 were followed from 18-72 months (mean 47.9) to assess the long term efficacy and safety of the procedure. All had severely symptomatic supraventricular tachyarrhythmias refractory to standard treatment. Atrioventricular conduction was abolished in 23 patients, 22 having permanent pacemakers implanted. Conduction has recovered, though it is modified, in one patient who is asymptomatic on digoxin. Four patients have died; one suddenly 20 months following the procedure, one of progressive heart and liver failure due to hemochromatosis, and two of a stroke. Four patients have had complications related to permanent pacing; one patient has required generator replacement and one patient ventricular lead replacement, one patient had asystole and one patient had a pacemaker-related tachycardia. Two patients remain symptomatic but improved by the procedure. Seventeen patients are free of their original symptoms, 11 having no intervening morbid events. These results demonstrate that patients with severely symptomatic supraventricular tachyarrhythmias may gain long term symptomatic relief from the procedure, but permanent pacing is a cause of significant morbidity and there is a small incidence of late sudden cardiac death.
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PMID:Long term efficacy of transvenous catheter ablation of the atrioventricular junction for refractory supraventricular tachycardia. 259 91

Therapeutic erythrocytapheresis (TEA) has been used in different diseases such as polycythemia vera (PV), secondary erythrocytosis or hemochromatosis as a process of the less cumbersome but more expensive phlebotomy. TEA is preferred in emergency conditions such as thrombocytosis or in conditions such as porphyria cutanea tarda (PCT) or erythropoietic porphyria when plasma exchange (PEX) is often combined with TEA to reduce extracellular levels of uroporphyrin which contribute to plasma hyperviscosity. TEA is often combined with drug therapy that varies from etoposide in PV to EPO and desferoxamine which are used to mobilize and reduce iron stores in hemochromatosis. Benefits from this combination may be more long lasting than expected. Nonetheless for TEA, there is no standard protocol and, clinical experience with this therapy remains highly anecdotal. Therapeutic red cell-exchange (TREX) has been used with much interest over the years, starting with the management of hemolytic disease of the newborn and later used to correct severe anemia in thalassemia patients thereby preventing iron overload. It has also been used for the management of complications of sickle cell disease such as priapism, chest syndrome, stroke, retinal, bone, splenic and hepatic infarction or in preparation for surgery by reducing HbS to less than 30%. Automated apheresis has also favored the use of TREX in conditions such as paroxysmal nocturnal hemoglobinuria and aniline poisoning, arsenic poisoning, Na chlorate intoxications and CO intoxications, hemoglobinopathies, autoimmune hemolytic anemia, reactions due to ABO incompatibility, in preparation for ABO incompatible bone marrow transplantation or for preventing anti-D immunization after the transfusion of D(+) cells to D(-) recipients. Another field of application has been in the emergency management of intraerythrocytic parasite infections such as malaria and babesiosis. Application of TREX may be wide but its real use remains limited. In our personal experience, in 16 years, only 167 TREX procedures have been carried out in a total of 13,747 therapeutic procedures. This represents only 1.21% of the total.
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PMID:Clinical application of therapeutic erythrocytapheresis (TEA). 1083 21

Of the three major functional categories of cardiomyopathies (dilated, hypertrophic, and restrictive), the restrictive cardiomyopathies (RCMs) are the least common in the Western world, but unfortunately often are associated with the greatest morbidity and mortality. Infiltrative disease of the myocardium (often caused by amyloidosis) is a common cause of RCMs and has a significantly lower long-term survival rate when compared to cardiomyopathies of various other causes. Treatment of the RCM is, in general, difficult and often ineffective. Because of the abnormalities of diastolic filling that are characteristic of this condition, general measures to reduce venous and systemic congestion such as with the use of diuretics, are desirable but often result in an attendant reduction in stroke volume and cardiac output. Digoxin, calcium channel blocking drugs, and beta-adrenergic blocking agents are of limited value, although they may be used with benefit to control the heart rate response in the subgroup of patients with atrial fibrillation. Angiotensin-converting enzyme inhibitors are generally ineffective in RCM. Targeted therapy directed against specific causal entities (such as the use of somatostatin analogues in carcinoid syndrome or iron chelation with desferrioxamine in hemochromatosis) may be more effective than simple symptomatic therapy. Differentiation of RCM from constrictive pericarditis is crucial, since constriction may be treated effectively by surgical removal of the thickened pericardium. A limited number of patients appear to have benefited from novel treatment strategies, such as autologous stem cell transplant in amyloidosis, balloon valvuloplasty of stenotic tricuspid or pulmonary valves in cardiac carcinoid syndrome, and cardiac transplantation. Truly effective therapy for RCM is generally lacking, and the best chance for optimizing the clinical outcome is early detection and aggressive medical treatment in an attempt to maintain the highest possible level of patient function for as long as possible.
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PMID:Restrictive Cardiomyopathy. 1109 47

This study assessed psychological adjustment and quality of life relative to population-based norms and knowledge about hereditary hemochromatosis in a sample of 101 patients who attended a hemochromatosis clinic. Participants were assessed prior to their clinic visit, and two weeks and 12 months after attendance, using self-administered questionnaires. Mean Mental Health Component Scores from the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) (45.3, 95% CI 43.2, 47.4) were as compromised as those found amongst stroke victims (45.9, 95% CI 42.8, 49.0) who had participated in a national health survey. Recall of the genetic testing result was less than optimal, in that only 69.3% of those with genetic testing results knew whether they carried one or two mutations. This study demonstrates that patients would benefit from routine assessment of psychological distress and referral to mental health professionals of those whose levels of distress suggest a need for clinical intervention. Results also show that patients may benefit from strategies aimed at improving recall of genetic testing results.
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PMID:Psychological adjustment and knowledge about hereditary hemochromatosis in a clinic-based sample: a prospective study. 1638 26

More than 25 years ago, the iron hypothesis proposed that a state of sustained iron depletion or mild iron deficiency exerts a primary protective action against ischemic heart disease. Iron depletion leads to a decreased availability of redox-active iron in vivo. The amount of free iron available at sites of oxidative or inflammatory injury appears to be a function of the stored iron level. Depletion of iron levels by phlebotomy, systemic iron chelation treatment or dietary iron restriction reduce atherosclerotic lesion size and increase plaque stability. In homozygous hemochromatosis there is commonly a defect that inhibits iron retention in macrophages. This defect may explain why atherosclerotic lesions appear to be less prevalent in this disorder. Findings of the "FeAST" trial have been recently reported. The trial assessed the potential benefit of mild iron reduction therapy in secondary prevention of cardiovascular disease. It was therefore not a fully valid test of primary prevention as postulated by the iron hypothesis. However, although no overall statistically significant cardiovascular benefit was found, in the youngest quartile at entry there were highly significant reductions in all cause mortality and in combined death plus non-fatal myocardial infarction and stroke in association with iron reduction therapy. The FeAST trial adds urgency to the initiation of new studies to assess the impact of maintenance of complete iron depletion in the primary prevention of cardiovascular diseases.
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PMID:[Current status of the iron hypothesis of cardiovascular diseases]. 1768 84

A major challenge for neurological therapeutics is the development of small molecule drugs that can activate a panoply of downstream pathways without toxicity. Over the past decade our group has shown that a family of enzymes that regulate posttranscriptional and transcriptional adaptive responses to hypoxia are viable targets for neuronal protection and repair. The family is a group of iron, oxygen, and 2-oxoglutarate-dependent dioxygenases, known as the HIF prolyl 4-hydroxylases (HIF PHDs). We have previously shown that pluripotent protection offered by iron chelators is mediated, in part, via the ability of these agents to inhibit the HIF PHDs. Our group and others have implicated the transcriptional activator HIF-1 in some of the salutary effects of iron chelation-induced PHD inhibition. While some iron chelators are currently employed in humans for conditions such as hemochromatosis, the diverse utilization of iron in physiological processes in the brain makes the development of HIF activators that do not bind iron a high priority. Here we report the development of a high throughput screen to develop novel HIF activators and/or PHD inhibitors for therapeutic use in the central nervous system (CNS). We show that tilorone, a low-molecular weight, antiviral, immunomodulatory agent is the most effective activator of the HIF pathway in a neuronal line. We also show that tilorone enhances HIF protein levels and increases the expression of downstream target genes independent of iron chelation and HIF PHD inhibition in vitro. We further demonstrate that tilorone can activate an HIF-regulated reporter gene in the CNS. These studies confirm that tilorone can penetrate the blood-brain barrier to activate HIF in the CNS. As expected from these findings, we show that tilorone provides effective prophylaxis against permanent ischemic stroke and traumatic spinal cord injury in male rodents. Altogether these findings identify tilorone as a novel and potent modulator of HIF-mediated gene expression in neurons with neuroprotective properties.
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PMID:Small molecule activation of adaptive gene expression: tilorone or its analogs are novel potent activators of hypoxia inducible factor-1 that provide prophylaxis against stroke and spinal cord injury. 1907 58

Ephedra is an amphetamine-like compound with a potent sympathomimetic effect. Ephedrine, its active component, is widely used for weight loss, to enhance athletic performance or as component of some drugs. Its cardiovascular effects include tachycardia, increased inotropy, arterial vasoconstriction and hypertension, and these are the effects for which it is used therapeutically. However, it can also cause adverse effects, such as neuropathy, myopathy, psychosis, addiction, stroke, insomnia, myocarditis, arrhythmias, myocardial infarction or sudden death. We present the case of a patient, with pre-existing psychiatric conditions, who developed congestive heart failure and pulmonary oedema in the context of severe biventricular dysfunction and myocardial necrosis secondary to longstanding ephedrine abuse. Secondary causes of dilated myocardiopathy such as alcohol abuse, autoimmunity, hemochromatosis, thyroid alterations, viral or bacterial myocarditis and coronary heart disease, were ruled out. Five years after total cessation of use of the drug containing ephedrine, the patient is symptom-free, with partial recovery of left ventricular ejection fraction.
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PMID:[Myocardial necrosis and severe biventricular dysfunction in the context of chronic ephedrine abuse]. 2030 Jul 11

Iron accumulation in the brain and increased oxidative stress are consistent observations in many neurodegenerative diseases. Thus, we have begun examination into gene mutations or allelic variants that could be associated with loss of iron homeostasis. One of the mechanisms leading to iron overload is a mutation in the HFE gene, which is involved in iron metabolism. The 2 most common HFE gene variants are C282Y (1.9%) and H63D (8.9%). The C282Y HFE variant is more commonly associated with hereditary hemochromatosis, which is an autosomal recessive disorder, characterized by iron overload in a number of systemic organs. The H63D HFE variant appears less frequently associated with hemochromatosis, but its role in the neurodegenerative diseases has received more attention. At the cellular level, the HFE mutant protein resulting from the H63D HFE gene variant is associated with iron dyshomeostasis, increased oxidative stress, glutamate release, tau phosphorylation, and alteration in inflammatory response, each of which is under investigation as a contributing factor to neurodegenerative diseases. Therefore, the HFE gene variants are proposed to be genetic modifiers or a risk factor for neurodegenerative diseases by establishing an enabling milieu for pathogenic agents. This review will discuss the current knowledge of the association of the HFE gene variants with neurodegenerative diseases: amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and ischemic stroke. Importantly, the data herein also begin to dispel the long-held view that the brain is protected from iron accumulation associated with the HFE mutations.
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PMID:HFE gene variants affect iron in the brain. 2134 98

Iron is a redox active metal involved in the oxidation-reduction reactions and regulation of cell growth and differentiation. Iron is an integral part of many proteins and enzymes that maintains various physiological functions. Most of the human body's iron is contained in red blood cells. Despite iron being an abundant trace metal in food, millions of people worldwide suffer from anemia. Iron deficiency results in impaired production of iron-containing proteins and inhibition of cell growth. In contrast, abnormal iron uptake has been related to the most common hereditary disease hemochromatosis, leading to tissue damage derived from free radical toxicity. In addition, disruption of iron regulation plays a key role in the etiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedreich's ataxia and other neurological disorders, cancer (lung cancer, breast cancer, colon cancer), Fanconi anemia, stroke and ageing. Thus the control of this necessary but potentially toxic substance is an important part of many aspects of human health and disease. The most frequent is the toxic role of iron linked with the catalytic decomposition of hydrogen peroxide (Fenton reaction) leading to the formation of reactive oxygen species (ROS) causing damage to biomolecules, including lipids, proteins and DNA. The binding of iron-designed chelators via nitrogen, oxygen or sulphur donor atoms blocks iron s ability to catalyze the formation of free radicals. Thus the design of various metal chelators to prevent free radical reactions is an important approach in the treatment of many iron-related diseases. The development of effective dual functioning antioxidants, possessing both metal-chelating and free radical-scavenging properties is awaited. The aim of this review is to discuss the role of iron and importance of iron-chelation in human disease and ageing.
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PMID:Importance of iron chelation in free radical-induced oxidative stress and human disease. 2190 63

Beta-thalassemia major (beta-TM) is a rare genetic disorder that benefits from regular blood transfusions. Nevertheless some major complications arise from this life long treatment: hemolysis, hemochromatosis and a hypercoagulability state. Ischemic stroke may be another major complication. We present a patient with severe beta-TM diagnosed in early childhood who encountered all the first three complications and suffered a cerebellar ischemic stroke. In this case report we look over the possible physiopathological mechanisms that may have interfered in the onset and deployment of the ischemic event. We specify the neuroimagistic approaches that may be used in monitoring of these patients. In conclusion, we point out that there are many prothrombotic risk factors contributors to the hypercoagulable state that concurs to a cerebral infarct in a beta-TM patient. Careful monitoring and imagistic examination may select the patients at risk for a stroke event.
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PMID:Acute cerebellar infarcts in a young woman with beta-thalassemia major. 2230 6


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