Regulatory activity revealed by dynamic correlations in gene expression noise.

Gene regulatory interactions are context dependent, active in some cellular states but not in others. Stochastic fluctuations, or 'noise', in gene expression propagate through active, but not inactive, regulatory links. Thus, correlations in gene expression noise could provide a noninvasive means to probe the activity states of regulatory links. However, global, 'extrinsic', noise sources generate correlations even without direct regulatory links. Here we show that single-cell time-lapse microscopy, by revealing time lags due to regulation, can discriminate between active regulatory connections and extrinsic noise. We demonstrate this principle mathematically, using stochastic modeling, and experimentally, using simple synthetic gene circuits. We then use this approach to analyze dynamic noise correlations in the galactose metabolism genes of Escherichia coli. We find that the CRPGalS-GalE feed-forward loop is inactive in standard conditions but can become active in a GalR mutant. These results show how noise can help analyze the context dependence of regulatory interactions in endogenous gene circuits.

Prognostic value and temporal behavior of the planar QRS-T angle in patients with nonischemic cardiomyopathy.

BACKGROUND: The planar QRS-T angle can be easily obtained from standard 12-lead ECGs, but its predictive ability is not established. We sought to determine the predictive ability of the planar QRS-T angle in patients with nonischemic cardiomyopathy and to assess QRS-T angle behavior over time. METHODS AND RESULTS: Baseline QRS-T angles from 455 patients in the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial were measured. All patients had nonischemic cardiomyopathy, New York Heart Association class I to III heart failure, and nonsustained ventricular tachycardia or frequent ventricular ectopy. The primary end point (a composite of total mortality, appropriate implantable cardioverter-defibrillator shock, or resuscitated cardiac arrest) occurred in 25 of 172 patients (14.5%) with a QRS-T angle < or =90 degrees and in 72 of 283 patients (25.4%) with a QRS-T angle >90 degrees (hazard ratio, 1.93; 95% confidence interval, 1.23 to 3.05; P=0.002). A QRS-T angle >90 degrees remained a significant predictor of the primary end point (P=0.039) after adjustment for treatment group, age, gender, QRS duration, left bundle-branch block, left ventricular ejection fraction, New York Heart Association class III, atrial fibrillation, and diabetes mellitus. The secondary end point (total mortality) occurred in 17 of the 172 patients (9.9%) with a QRS-T angle < or =90 degrees and in 49 of the 283 patients (17.3%) with a QRS-T angle >90 degrees (hazard ratio, 1.79; 95% confidence interval, 1.03 to 3.10; P=0.016). A sample of 152 patients with multiple follow-up ECGs was analyzed to assess temporal QRS-T angle behavior. Changes in the QRS-T angle correlated with changes in left ventricular ejection fraction and QRS duration over time (P<0.001). CONCLUSIONS: A planar QRS-T angle >90 degrees is a significant predictor of a composite end point of death, appropriate implantable cardioverter-defibrillator shock, or resuscitated cardiac arrest in nonpaced, mild to moderately symptomatic patients with nonischemic cardiomyopathy with frequent or complex ventricular ectopy. QRS-T angles changed predictably with left ventricular ejection fraction and QRS duration.

Are implantable cardioverter defibrillator shocks a surrogate for sudden cardiac death in patients with nonischemic cardiomyopathy?

BACKGROUND: Ventricular tachyarrhythmias long enough to cause implantable cardioverter defibrillator (ICD) shocks are generally thought to progress to cardiac arrest. In previous ICD trials, shocks have been considered an appropriate surrogate for sudden cardiac death (SCD) because the number of shocks has been thought to be equivalent to the mortality excess in patients without ICDs. The practice of equating ICD shocks with mortality is controversial and has not been validated critically. METHODS AND RESULTS: The Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial was a prospective, randomized, multicenter trial of ICD therapy in 458 patients with nonischemic cardiomyopathy. Patients were randomized to receive standard medical therapy (STD) or STD plus an ICD. Shock electrograms were reviewed, and the cause of death was evaluated by a separate blinded events committee. There were 15 SCD or cardiac arrests in the STD group and only 3 in the ICD arm. In contrast, of the 229 patients randomized to an ICD, 33 received 70 appropriate ICD shocks. Patients in the ICD arm were more likely to have an arrhythmic event (ICD shock plus SCD) than patients in the STD arm (hazard ratio 2.12, 95% CI 1.153 to 3.893, P=0.013). The number of arrhythmic events when one includes syncope as a potential arrhythmic event was similar in both groups (hazard ratio 1.20, 95% CI 0.774 to 1.865, P=0.414). Approximately the same number of total events was noted in each arm when we compared syncope plus SCD/cardiac arrest in the STD arm with SCD plus ICD shocks plus syncope in the ICD arm. CONCLUSIONS: Appropriate ICD shocks occur more frequently than SCD in patients with nonischemic cardiomyopathy. This suggests that episodes of nonsustained ventricular tachycardia frequently terminate spontaneously in such patients.

Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.

BACKGROUND: Patients with nonischemic dilated cardiomyopathy are at substantial risk for sudden death from cardiac causes. However, the value of prophylactic implantation of an implantable cardioverter-defibrillator (ICD) to prevent sudden death in such patients is unknown. METHODS: We enrolled 458 patients with nonischemic dilated cardiomyopathy, a left ventricular ejection fraction of less than 36 percent, and premature ventricular complexes or nonsustained ventricular tachycardia. A total of 229 patients were randomly assigned to receive standard medical therapy, and 229 to receive standard medical therapy plus a single-chamber ICD. RESULTS: Patients were followed for a mean (+/-SD) of 29.0+/-14.4 months. The mean left ventricular ejection fraction was 21 percent. The vast majority of patients were treated with angiotensin-converting-enzyme (ACE) inhibitors (86 percent) and beta-blockers (85 percent). There were 68 deaths: 28 in the ICD group, as compared with 40 in the standard-therapy group (hazard ratio, 0.65; 95 percent confidence interval, 0.40 to 1.06; P=0.08). The mortality rate at two years was 14.1 percent in the standard-therapy group (annual mortality rate, 7 percent) and 7.9 percent in the ICD group. There were 17 sudden deaths from arrhythmia: 3 in the ICD group, as compared with 14 in the standard-therapy group (hazard ratio, 0.20; 95 percent confidence interval, 0.06 to 0.71; P=0.006). CONCLUSIONS: In patients with severe, nonischemic dilated cardiomyopathy who were treated with ACE inhibitors and beta-blockers, the implantation of a cardioverter-defibrillator significantly reduced the risk of sudden death from arrhythmia and was associated with a nonsignificant reduction in the risk of death from any cause.

Robust persistent neural activity in a model integrator with multiple hysteretic dendrites per neuron.

Short-term memory is often correlated with persistent changes in neuronal firing rates in response to transient inputs. We model the persistent maintenance of an analog eye position signal by an oculomotor neural integrator receiving transient eye movement commands. Previous models of this network rely on precisely tuned positive feedback with <1% tolerance to mistuning, or use neurons that exhibit large discontinuities in firing rate with small changes in eye position. We show analytically how using neurons with multiple bistable dendritic compartments can enhance the robustness of eye fixations to mistuning while reproducing the approximately linear and continuous relationship between neuronal firing rates and eye position, and the dependence of neuron pair firing rate relationships on the direction of the previous saccade. The response of the model to continuously varying inputs makes testable predictions for the performance of the vestibuloocular reflex. Our results suggest that dendritic bistability could stabilize the persistent neural activity observed in working memory systems.