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Different forms of ventricular arrhythmias have been linked to mutations in the cardiac ryanodine receptor (RyR)2, but the molecular basis for this phenotypic heterogeneity is unknown. We have recently demonstrated that an enhanced sensitivity to luminal Ca2+ and an increased propensity for spontaneous Ca2+ release or store-overload-induced Ca2+ release (SOICR) are common defects of RyR2 mutations associated with catecholaminergic polymorphic or bidirectional ventricular tachycardia. Here, we investigated the properties of a unique RyR2 mutation associated with catecholaminergic idiopathic ventricular fibrillation, A4860G. Single-channel analyses revealed that, unlike all other disease-linked RyR2 mutations characterized previously, the A4860G mutation diminished the response of RyR2 to activation by luminal Ca2+, but had little effect on the sensitivity of the channel to activation by cytosolic Ca2+. This specific impact of the A4860G mutation indicates that the luminal Ca2+ activation of RyR2 is distinct from its cytosolic Ca2+ activation. Stable, inducible HEK293 cells expressing the A4860G mutant showed caffeine-induced Ca2+ release but exhibited no SOICR. Importantly, HL-1 cardiac cells transfected with the A4860G mutant displayed attenuated SOICR activity compared with cells transfected with RyR2 WT. These observations provide the first evidence that a loss of luminal Ca2+ activation and SOICR activity can cause ventricular fibrillation and sudden death. These findings also indicate that although suppressing enhanced SOICR is a promising antiarrhythmic strategy, its oversuppression can also lead to arrhythmias.
spontaneous Ca2+ release, sudden cardiac death, ventricular arrhythmia
Loss of luminal Ca2+ activation in the cardiac ryanodine receptor is associated with ventricular fibrillation and sudden death
Dawei Jiang, Wenqian Chen, Ruiwu Wang, Lin Zhang, and S. R. Wayne Chen*
2007 Nov 13;
When profiling hospital performance, quality inicators are commonly evaluated through hospital-specific adjusted means with confidence intervals. When identifying deviations from a norm, large hospitals can have statistically significant results even for clinically irrelevant deviations while important deviations in small hospitals can remain undiscovered. We have used data from the Swedish Stroke Register (Riksstroke) to illustrate the properties of a benchmarking method that integrates considerations of both clinical relevance and level of statistical significance.
The performance measure used was case-mix adjusted risk of death or dependency in activities of daily living within 3 months after stroke. A hospital was labeled as having outlying performance if its case-mix adjusted risk exceeded a benchmark value with a specified statistical confidence level. The benchmark was expressed relative to the population risk and should reflect the clinically relevant deviation that is to be detected. A simulation study based on Riksstroke patient data from 2008-2009 was performed to investigate the effect of the choice of the statistical confidence level and benchmark value on the diagnostic properties of the method.
Simulations were based on 18,309 patients in 76 hospitals. The widely used setting, comparing 95% confidence intervals to the national average, resulted in low sensitivity (0.252) and high specificity (0.991). There were large variations in sensitivity and specificity for different requirements of statistical confidence. Lowering statistical confidence improved sensitivity with a relatively smaller loss of specificity. Variations due to different benchmark values were smaller, especially for sensitivity. This allows the choice of a clinically relevant benchmark to be driven by clinical factors without major concerns about sufficiently reliable evidence.
The study emphasizes the importance of combining clinical relevance and level of statistical confidence when profiling hospital performance. To guide the decision process a web-based tool that gives ROC-curves for different scenarios is provided.
The Importance of Integrating Clinical Relevance and Statistical Significance in the Assessment of Quality of Care -Illustrated Using the Swedish Stroke Register
Anita Lindmark,1,* Bart van Rompaye,1,2 Els Goetghebeur,2 Eva-Lotta Glader,3 and Marie Eriksson1
Ribonucleases represent a new class of antitumor RNA-damaging drugs. However, many wild-type members of the vertebrate secreted ribonuclease family are not cytotoxic because they are not able to evade the cytosolic ribonuclease inhibitor. We previously engineered the human pancreatic ribonuclease to direct it to the cell nucleus where the inhibitor is not present. The best characterized variant is PE5 that kills cancer cells through apoptosis mediated by the p21WAF1/CIP1 induction and the inactivation of JNK. Here, we have used microarray-derived transcriptional profiling to identify PE5 regulated genes on the NCI/ADR-RES ovarian cancer cell line. RT-qPCR analyses have confirmed the expression microarray findings. The results show that PE5 cause pleiotropic effects. Among them, it is remarkable the down-regulation of multiple genes that code for enzymes involved in deregulated metabolic pathways in cancer cells.
antitumor drug, human pancreatic ribonuclease, metabolism of cancer cells, microarray profiling, tumor cell death
A nuclear-directed human pancreatic ribonuclease (PE5) targets the metabolic phenotype of cancer cells
Anna Vert,1,2 Jessica Castro,1,2 Marc Ribo,1,2 Antoni Benito,1,2 and Maria Vilanova1,2
2016 Apr 5;