Search

PRKAG2 Gene in Sporadic WPW Syndrome. Introduction: Mutations in the PRKAG2 gene that encodes the gamma2 regulatory subunit of AMP-activated protein kinase have been shown to cause autosomal dominant Wolff-Parkinson-White (WPW) syndrome associated with hypertrophic cardiomyopathy. Prior studies focused on familial WPW syndrome associated with other heart disease such as hypertrophic cardiomyopathy. However, such disease accounts for only a small fraction of WPW cases, and the contribution of PRKAG2 mutations to sporadic isolated WPW syndrome is unknown. Methods and Results: Subjects presented for clinical electrophysiologic evaluation of suspected WPW syndrome. WPW syndrome was diagnosed by ECG findings and/or by clinically indicated electrophysiologic study prior to enrollment. Echocardiography excluded hypertrophic cardiomyopathy. Denaturing high-performance liquid chromatography and automated sequencing were used to search for PRKAG2 mutations. Twenty-six patients without a family history of WPW syndrome were studied. No subject had cardiac hypertrophy, and only one patient had associated congenital heart disease. Accessory pathways were detected at diverse locations within the heart. Two polymorphisms in PRKAG2 were detected. [inv6+36insA] occurred in intron 6 in 4 WPW patients and [inv10+10delT] in intron 10 in 1 WPW patient. Both occurred in normal unrelated chromosomes. No PRKAG2 mutations were detected. Conclusion: This study shows that, unlike familial WPW syndrome, constitutional mutation of PRKAG2 is not commonly associated with sporadic WPW syndrome. Although polymorphisms within the PRKAG2 introns were identified, there is no evidence that these polymorphisms predispose to accessory pathway formation because their frequency is similarly high in both WPW patients and normal individuals. Further studies are warranted to identify the molecular basis of common sporadic WPW syndrome.(J Cardiovasc Electrophysiol, Vol. 14, pp. 263-268, March 2003). [ABSTRACT FROM AUTHOR]

Presents information on a study which identified the dopamine receptor in the gut regions of rats. Background of the actions of dopamine; Methodology used in the study; Results and its implications.

Determines the regional distribution of the D[sub 1A] receptor throughout the rat gastrointestinal tract (GIT). Light microscopic immunohistochemistry; In situ amplification and hybridization histochemistry.

Describes hypertensive emergencies and hypertensive urgencies. Epidemiology of hypertension; Pathophysiology of the condition; Approaches to therapy, including parenteral therapy with beta-blockers; Development of other therapies, including the peripheral dopamine-receptor agonist fenoldapam.

Presents an overview of seizures. Definition; Pathophysiology of seizures in systemic illness; Aetiology; Various illnesses in which seizures are associated; Treatments. INSETS: Potential causes of seizures;Principles of seizure management in patients with medical....

Discusses statins. Use of simvastatin and pravastatin to lower plasma cholesterol concentration in coronary artery disease patients; The findings of the Multicenter Anti-Antheroma Study (MAAS); Changes in the heart vessel wall; Blood flow, vasomotor tone, and endothelial function; Changes in the constituents of blood; Other details.

Stroke is a major cause of mortality and morbidity. The epidemiologic association between elevated serum cholesterol and stroke risk is controversial. However, recent secondary prevention studies with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have demonstrated a significant reduction in ischemic stroke without an increase in hemorrhagic stroke. Statins probably reduce stroke by a variety of mechanisms, including modulation of precerebral atherothrombosis in the aorta and the carotid artery, thus preventing plaque disruption and artery-to-artery thromboembolism. Statins also improve endothelial homeostasis by increasing the bioavailability of nitric oxide, which orchestrates the paracrine antiatherosclerotic functions of the endothelium. Studies in experimental models of ischemic stroke show that statin therapy reduces brain infarct size and improves neurologic outcome by directly upregulating brain endothelial nitric oxide synthase. Putative anti-inflammatory actions of statins may also contribute to neuroprotection and stroke prevention. Although the clinical benefit of statins largely depends on lowering low-density lipoprotein cholesterol, accumulating data indicate that many of the pleiotropic effects of statins are attributable to the cellular consequences of depletion of intermediates in the cholesterol biosynthetic pathway (isoprenoids). These molecules play fundamental roles in cell growth, signal transduction, and mitogenesis. In addition to reducing stroke risk, emerging data suggest that statins may reduce dementia. Further studies are needed to fully address the role of statins in the prevention of stroke in patients without established vascular disease and the role of cholesterol modulation in the treatment of dementia. [ABSTRACT FROM AUTHOR]

Reports on a study of the beneficial effect of nicotine on symptoms of spastic dystonia. Brief patient history; Treatment with transdermal nicotine; Results.

Presents several letters to the editors of "Lancet" and responses. Findings of the Heart Protection Study (HPS) which found that therapy with simvastatin reduced the composite primary endpoint of coronary heart disease (CHD) death; Discovery that tamoxifen may not significantly reduce the rate of breast cancer in women who have had hysterectomies; Effect of diet on blood pressure; Concerns over the high rate of HIV/AIDS in Africa; Focus on HIV-1 incidence and prevalence in Uganda; Efforts to control HIV/AIDS in India; Update from Mbarara University Teaching Hospital in Uganda; The connection between human pituitary growth hormone and risk of developing cancer; Method of relieving benign paroxysmal positional vertigo which developed following a trip on a roller coaster.

Multiple randomized controlled trials (RCTs) have established the efficacy of statins for the prevention of cardiovascular disease. The benefits observed are often framed in terms of percentage reductions in low-density lipoprotein (LDL) cholesterol from baseline or percentage reductions between control and treatment groups, although epidemiologic data suggest that the absolute intergroup difference in LDL cholesterol (ΔLDLControl-Rx) is the more informative measure. A systematic review of large-scale trials of statins versus placebo, usual care, or active (lower dose statin) control was conducted to calculate updated summary estimates of risk reduction in coronary artery disease and all-cause mortality. Meta–regression analysis was used to ascertain the relations of different LDL cholesterol metrics to outcomes. In 20 eligible RCTs, there were significant overall reductions for coronary artery disease (odds ratio 0.72, 95% confidence interval 0.67 to 0.78) and mortality (odds ratio 0.89, 95% confidence interval 0.84 to 0.94), but with substantial variability in trial results. ΔLDLControl-Rx was the strongest determinant of coronary artery disease risk reduction, particularly after excluding active-comparator studies, and was independent of baseline LDL cholesterol. In contrast, baseline LDL cholesterol edged out ΔLDLControl-Rx as the strongest determinant of mortality, but neither was significant after the exclusion of active-comparator studies. The exclusion of 3 RCTs involving distinct populations, however, rendered ΔLDLControl-Rx the predominant determinant of mortality reduction. In conclusion, these findings underscore the primacy of absolute reductions in LDL cholesterol in the design and interpretation of RCTs of lipid-lowering therapies and in framing treatment recommendations on the basis of the proved coronary benefits of these drugs. [Copyright &y& Elsevier]

Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by cardiac and extracardiac myxomas in the setting of spotty skin pigmentation and endocrinopathy. We previously identified PRKAR1A (regulatory subunit 1α of protein kinase A) mutations in CNC. Mutational analyses of the PRKAR1A gene in 51 unrelated CNC probands now detect mutations in 65%. All mutations, except for one unique missense mutation, lead to PRKAR1A haploinsufficiency. Therefore, we studied the consequences of prkar1a haploinsufficiency in mice. Although we did not observe cardiac myxomas or altered pigmentation in prkar1a+/- mice, we did observe some phenotypes similar to CNC, including altered heart rate variability. Moreover, prkar1a+/- mice exhibited a marked propensity for extracardiac tumorigenesis. They developed sarcomas and hepatocellular carcinomas. Sarcomas were frequently associated with myxomatous differentiation. Tumors from prkar1a+/- mice did not exhibit prkar1a loss of heterozygosity. Thus, we conclude that although PRKAR1A haploinsufficiency does predispose to tumorigenesis, distinct secondary genetic events are required for tumor formation. [ABSTRACT FROM AUTHOR]