AIMS: Mutations in cardiac ryanodine receptors (RyR2s) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), characterized by risk of polymorphic ventricular tachyarrhythmias and sudden death during exercise. Arrhythmias are caused by gain-of-function defects in RyR2, but cellular arrhythmogenesis remains elusive. METHODS AND RESULTS: We recorded endocardial monophasic action potentials (MAPs) at right ventricular septum in 15 CPVT patients with a RyR2 mutation (P2,328S, Q4,201R, and V4,653F) and in 12 control subjects both at baseline and during epinephrine infusion (0.05 microg/kg/min). At baseline 3 and during epinephrine infusion, four CPVT patients, but none of the control subjects, showed delayed afterdepolarizations (DADs) occasionally coinciding with ventricular premature complexes. In order to study the underlying mechanisms, we expressed two types of mutant RyR2 (P2,328S and V4,653F) causing CPVT as well as wild-type RyR2 in HEK 293 cells. Confocal microscopy of Fluo-3 loaded cells transfected with any of the three RyR2s showed no spontaneous subcellular Ca(2+) release events at baseline. Membrane permeable cAMP analogue (Dioctanoyl-cAMP) triggered subcellular Ca(2+) release events as Ca(2+) sparks and waves. Cells expressing mutant RyR2s showed spontaneous Ca(2+) release events at lower concentrations of cAMP than cells transfected with wild-type RyR2. CONCLUSION: CPVT patients show DADs coinciding with premature action potentials in MAP recordings. Expression studies suggest that DADs are caused by increased propensity of abnormal RyR2s to generate spontaneous Ca(2+) waves in response to cAMP stimulation. Increased sensitivity of mutant RyR2s to cAMP may explain the occurrence of arrhythmias during exercise or emotional stress in CPVT. 相似文献
We describe results from the first year of a three year economic evaluation of genetic services in the context of DNA probes provided at three genetic centres in Great Britain. The analysis so far has concentrated on the costs of providing DNA diagnostic services. Estimates are given of the total costs of providing DNA probe services at each of the three centres, together with information for assessing the cost implications of future developments in these services. DNA probe services are likely to be funded as a Regional specialty. This paper concludes that relative to other developing medical technologies and as an investment by Regions, DNA probe services are inexpensive. An appraisal of the benefits to be derived from DNA probe services is still to be undertaken. 相似文献
AIMS: To explore effects of epinephrine and phenylephrine on the behavior of right ventricular monophasic action potentials (MAPs) in symptomatic LQT1 and LQT2 patients. METHODS AND RESULTS: We recorded endocardial MAPs from right interventricular septum at baseline and during epinephrine and phenylephrine infusions in six symptomatic DNA-verified LQT1 (QTc 528 +/- 83) and five LQT2 patients (QTc 527 +/- 72) and in five control patients (QTc 381 +/- 22). We measured MAP durations at 90% and at 50% levels of repolarization and their difference (MAP50 to MAP90, a measure of MAP morphologic "triangulation"), during atrial pacing to characterize rate dependence of MAPs and repolarization phase 3 durations, respectively. Restitution kinetics were determined during atrioventricular sequential pacing, using the approach of empirical restitution rate. Epinephrine prolonged MAP50-to-MAP90 duration and increased the rate dependence of MAP90 duration and increased restitution rate in type LQT1, but not in LQT2 patients nor in control subjects. Phenylephrine did not change MAP behavior. During epinephrine administration, both LQT1 and LQT2 patients had a ratio of the restitution rate of MAP to diastolic interval >1.0 at short diastolic intervals. CONCLUSION: Symptomatic LQT1 patients with prolonged baseline QTc intervals showed beta-adrenergic-induced changes in MAPs (triangulation) known to be arrhythmogenic, thus giving insight to the difference in clinical triggers of life-threatening arrhythmias between LQT1- and LQT2-affected individuals. 相似文献
Objective: To evaluate the performance of first trimester biochemical markers, pregnancy-associated plasma protein-A (PAPP-A), free beta human chorionic gonadotropin (fβ-hCG), and nuchal translucency (NT) in detection of severe congenital heart defects (CHDs).
Methods: During the study period from 1 January 2008 to 31 December 2011, biochemical markers and NT were measured in 31,144 women as part of voluntary first trimester screening program for Down’s syndrome in Northern Finland. Data for 71 severe CHD cases and 762 controls were obtained from the hospital records and from the National Medical Birth Register, which records the birth of all liveborn and stillborn infants, and from the National Register of Congenital Malformations that receives information about all the CHD cases diagnosed in Finland.
Results: Both PAPP-A and fβ-hCG multiple of median (MoM) values were decreased in all severe CHDs: 0.71 and 0.69 in ventricular septal defects (VSDs), 0.58 and 0.88 in tetralogy of Fallot cases (TOFs), 0.82 and 0.89 in hypoplastic left heart syndromes (HLHSs), and 0.88 and 0.96 in multiple defects, respectively. NT was increased in all study groups except of VSD group. ROC AUC was 0.72 for VSD when combining prior risk with PAPP-A and fβ-hCG. Adding NT did not improve the detection rate. With normal NT but decreased (<0.5 MoM) PAPP-A and fβ-hCG odds ratios for VSD and HLHS were 19.5 and 25.6, respectively.
Conclusions: Maternal serum biochemistry improves the detection of CHDs compared to NT measurement only. In cases with normal NT measurement but low concentrations of both PAPP-A and fβ-hCG, an alert for possible CHD, especially VSD, could be given with thorough examination of fetal heart in later ultrasound scans. 相似文献
We recently concluded that exposure to solvent-contaminated drinking water was an unlikely explanation for observed excesses of adverse pregnancy outcomes during 1980–1981 in the Los Paseos neighborhood of Santa Clara County, California, because these excesses were not observed in an adjacent exposed area. The validity of this conclusion depends on the assumption that the two areas had comparable exposure. Using quantitative methods to model movement of the solvent leak plume and water flow within the distribution system, we estimated that women with adverse outcomes were no more likely to have received contaminated water than women with normal live births. These results strengthen the conclusion that exposures to water from the contaminated well were not responsible for the excess of adverse outcomes observed in the Los Paseos area. 相似文献
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that is effective and generally well tolerated when administered as a single agent to treat advanced breast cancer. Efficacy has now been demonstrated in randomized trials as first line, second line, and later than the second line treatment of advanced breast cancer. T-DM1 is currently being evaluated as adjuvant treatment for early breast cancer. It has several mechanisms of action consisting of the anti-tumor effects of trastuzumab and those of DM1, a cytotoxic anti-microtubule agent released within the target cells upon degradation of the human epidermal growth factor receptor-2 (HER2)-T-DM1 complex in lysosomes. The cytotoxic effect of T-DM1 likely varies depending on the intracellular concentration of DM1 accumulated in cancer cells, high intracellular levels resulting in rapid apoptosis, somewhat lower levels in impaired cellular trafficking and mitotic catastrophe, while the lowest levels lead to poor response to T-DM1. Primary resistance of HER2-positive metastatic breast cancer to T-DM1 appears to be relatively infrequent, but most patients treated with T-DM1 develop acquired drug resistance. The mechanisms of resistance are incompletely understood, but mechanisms limiting the binding of trastuzumab to cancer cells may be involved. The cytotoxic effect of T-DM1 may be impaired by inefficient internalization or enhanced recycling of the HER2-T-DM1 complex in cancer cells, or impaired lysosomal degradation of trastuzumab or intracellular trafficking of HER2. The effect of T-DM1 may also be compromised by multidrug resistance proteins that pump DM1 out of cancer cells. In this review we discuss the mechanism of action of T-DM1 and the key clinical results obtained with it, the combinations of T-DM1 with other cytotoxic agents and anti-HER drugs, and the potential resistance mechanisms and the strategies to overcome resistance to T-DM1. 相似文献
Aim To examine whether Rasch modeling would yield a unidimensional withdrawal sensitivity measure correlating with factors associated with successful smoking cessation. Design The psychometric Rasch modeling approach was applied to estimate an underlying latent construct (withdrawal sensitivity) in retrospective responses from 1644 smokers who reported quitting for 3 or more months at least once. Setting Web-based, passcode-controlled self-administered computerized questionnaire. Participants Randomly selected convenience sample of 1644 adult members of an e-mail invitation-only web panel drawn from consumer databases. Measurements Lifetime Tobacco Use Questionnaire, assessing tobacco use across the life-span, including demographics and respondent ratings of the severity of withdrawal symptoms experienced in respondents' first and most recent quit attempts lasting 3 or more months. Findings Rasch-modeled withdrawal sensitivity was generally unidimensional and was associated with longer periods of smoking cessation. One latent variable accounted for 74% of the variability in symptom scores. Rasch modeling with a single latent factor fitted withdrawal symptoms well, except for increased appetite, for which the fit was marginal. Demographic variables of education, gender and ethnicity were not related to changes in sensitivity. Correlates of greater withdrawal sensitivity in cessation attempts of at least 3 months included younger age at first quit attempt and indicators of tobacco dependence. Conclusion The relationship between tobacco dependence symptoms and Rasch-model withdrawal sensitivity defines further the relationship between sensitivity and dependence. The findings demonstrate the utility of modeling to create an individual-specific sensitivity measure as a tool for exploring the relationships among sensitivity, dependence and cessation. 相似文献
Introduction: We screened the candidate genes from a Finnish family in which the mother was resuscitated from ventricular fibrillation and the daughter died suddenly without any prior cardiac symptoms. Methods and Results: In addition to screening of potential structural gene mutations, phenotyping of the proband and medico-legal autopsy of the victim of the sudden death, including histopathological examinations, were performed. Genetic screening revealed an R541C mutation in the lamin A/C gene both in the proband and her daughter. None of the 16 first- or second-degree relatives, or 96 unrelated healthy subjects, carried the same mutation. In the proband, the size and the global function of the left ventricle (LV) were normal, but a local hypokinesia and thinning of inferoposterior area of the LV were seen in 2D echocardiography and magnetic resonance imaging. Coronary angiogram and the results of the electrophysiological study were normal. Autopsy of the victim of sudden death showed localized thinning and fibrosis in the inferoposterior area of the LV, with only minimal fibrosis in the right ventricle and no abnormalities in the interventricular septum. Conclusion: These observations indicate that a fatal or near-fatal cardiac arrhythmia can be the first clinical manifestation of a "de novo" mutation R541C of the lamin A/C gene. Replacement of cardiac myocytes by fibrosis seems to be the predominant pathologic-anatomic finding. 相似文献
Background: Delayed electrical activity necessary for re‐entrant ventricular tachycardia (VT) is detectable noninvasively with high resolution techniques. We compared high resolution signalaveraged analysis of magnetocardiography (MCG), body surface potential mapping (BSPM), and orthogonal three‐lead ECG (SA‐ECG) in the identification of patients prone to VT after myocardial infarction (Ml). Methods: Patients with remote myocardial infarction and cardiac dysfunction were studied, 22 with (VT group) and 22 without VT (control group). MCG with seven channels and BSPM with 63 and SA‐ECG with three orthogonal leads were registered. After signal‐averaging and highpass filtering, three time domain analysis (TDA) parameters describing late electrical activity were computed: QRS duration (QRSd), root mean square amplitude (RMS) of the last 40 ms of QRS, and the duration of the low‐amplitude QRS end (LAS). Results: All parameters by each method were significantly different between the patients’groups. For example, LAS parameter in MCG was 59 (SD 22) ms in the VT group vs. 37 (SD 13) ms in controls (P < 0.001), 77 (SD 22) ms vs. 56 (SD 19) ms in BSPM (P = 0.002), and 60 (SD 24) ms vs. 39 (SD 22) ms in SA‐ECG (P = 0.005). The combination of LAS parameter in MCG and SA‐ECG resulted in improved performance in comparison to any single parameter with 95% sensitivity and 68% specificity. Conclusions: All three high resolution methods identified VT propensity among post‐Mi patients with cardiac dysfunction and between‐method differences were small. Information in MCG and SA‐ECG may be complementary and their combination could be of value in postinfarction arrhythmia risk assessment. A.N.E. 2002;7(4):389–398 相似文献