TASK DEFINITION: Given a passage, construct a question on the basis of the information present in the passage. Construct the question in such a way that (i) it is unambiguous, (ii) it is answerable from the passage, (iii) its answer is unique (iv) it answer uses text phrases from the passage. Avoid creating questions that (i) can't be answered correctly without actually understanding the passage and (ii) uses the same words or phrases given in the passage.
PROBLEM: Class III antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD). In spite of the several theories developed so far to explain this reverse rate dependency (RRD), its mechanism has not yet been clarified. The aim of the present work was to further elucidate the mechanisms responsible for reverse rate-dependent drug effects.', 'Action potentials were recorded from multicellular canine ventricular preparations and isolated cardiomyocytes, at cycle lengths (CLs) varying from 0.3 to 5 s, using conventional sharp microelectrodes. APD was either modified by applying inward and outward current pulses, or by superfusion of agents known to lengthen and shorten APD. Net membrane current (I(m)) was calculated from action potential waveforms. The hypothesis that RRD may be implicit in the relationship between I(m) and APD was tested by numerical modelling. Both drug-induced lengthening (by veratrine, BAY-K 8644, dofetilide, and BaCl(2)) and shortening (by lidocaine and nicorandil) of action potentials displayed RRD, i.e. changes in APD were greater at longer than at shorter CL. A similar dependency of effect on CL was found when repolarization was modified by injection of inward or outward current pulses. I(m) measured at various points during repolarization was inversely proportional to APD and to CL. Model simulations showed that RRD is expected as a consequence of the non-linearity of the relationship between I(m) and APD.

SOLUTION: Is reverse rate dependency an intrinsic property of canine cardiac preparations?

PROBLEM: Hepatocyte nuclear factor 4 (HNF4) is a liver enriched transcription factor and is indispensable for liver development. However, the role of HNF4 in hepatocellular carcinoma (HCC) progression remains to be elucidated. We report that reduced HNF4 expression correlated well with the aggressive clinicopathological characteristics of HCC and predicted poor prognosis of patients. HNF4 levels were even lower in metastatic HCCs, and ectopic HNF4 expression suppressed the metastasis of hepatoma cells both in vitro and in vivo. Forced HNF4 expression attenuated the expression and nuclear translocation of RelA (p65) and impaired NF-B activation through an IKK-independent mechanism. Blockage of RelA robustly attenuated the suppressive effect of HNF4 on hepatoma cell metastasis. MicroRNA (miR)-7 and miR-124 were transcriptionally up-regulated by HNF4, which repressed RelA expression by way of interaction with RelA-3' untranslated region (UTR). In addition, nuclear factor kappa B (NF-B) up-regulated the expression of miR-21 in hepatoma cells, resulting in decreased HNF4 levels through down-regulating HNF4-3'UTR activity.

SOLUTION: Does hepatocyte nuclear factor 4-nuclear factor-B feedback circuit modulate liver cancer progression?

PROBLEM: Data on combined permanent atrial fibrillation (pAF) surgery and coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR) are scarce, and the mid- and long-term effects on survival and cardiac rhythm are unknown.', 'In a prospective analysis 125 patients (Group I: CABG and/or AVR, n = 50; Group II: mitral valve [MV] surgery, n = 75) with pAF (> or = 6 months) underwent either concomitant monopolar (Group I: n = 20; Group II: n = 75) or bipolar (Group I: n = 30) radiofrequency (RF) ablation procedures. Group I patients had a significantly smaller left atrial (LA) size than Group II patients (LA-diameter: 47.7 +/- 4.6 vs. 58.2 +/- 6.1 mm; p < 0.01). Regular follow-up was performed from 3 to 36 months after surgery to assess survival, NYHA-class, and conversion rate to stable sinus rhythm (SR).', 'Early mortality (< 30 days) of Group I patients was 0% (Group II: 2.7%), cumulative survival at long-term follow-up was 0.95 vs. 0.82 (p = 0.31) and NYHA-class improved significantly in both groups, particularly in cases with stable SR. At follow-up 80% of Group I patients had SR (Group II: 70%). In Group I patients the bipolar approach was associated with significantly shorter ablation procedure times compared to the monopolar procedure (12.1 +/- 3.4 vs. 18.9 +/- 1.6 min; p < 0.05).

SOLUTION:
Is permanent atrial fibrillation ablation surgery in CABG and aortic valve patients at least as effective as in mitral valve disease?