Facilitation of I Kr current by some hERG channel blockers suppresses early afterdepolarizations.

Drug-induced block of the cardiac rapid delayed rectifying potassium current (I Kr), carried by the human ether-a-go-go-related gene (hERG) channel, is the most common cause of acquired long QT syndrome. Indeed, some, but not all, drugs that block hERG channels cause fatal cardiac arrhythmias. However, there is no clear method to distinguish between drugs that cause deadly arrhythmias and those that are clinically safe. Here we propose a mechanism that could explain why certain clinically used hERG blockers are less proarrhythmic than others. We demonstrate that several drugs that block hERG channels, but have favorable cardiac safety profiles, also evoke another effect; they facilitate the hERG current amplitude in response to low-voltage depolarization. To investigate how hERG facilitation impacts cardiac safety, we develop computational models of I Kr block with and without this facilitation. We constrain the models using data from voltage clamp recordings of hERG block and facilitation by nifekalant, a safe class III antiarrhythmic agent. Human ventricular action potential simulations demonstrate the ability of nifekalant to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive I Kr block evokes early afterdepolarizations, which cause lethal arrhythmias. When facilitation is introduced, early afterdepolarizations are prevented at the same degree of block. Facilitation appears to prevent early afterdepolarizations by increasing I Kr during the repolarization phase of action potentials. We empirically test this prediction in isolated rabbit ventricular myocytes and find that action potential prolongation with nifekalant is less likely to induce early afterdepolarization than action potential prolongation with dofetilide, a hERG channel blocker that does not induce facilitation. Our data suggest that hERG channel blockers that induce facilitation increase the repolarization reserve of cardiac myocytes, rendering them less likely to trigger lethal ventricular arrhythmias

Integrating Cancer Patients’ Satisfaction with Rescue Medication in Pain Assessments

A patient’s pain intensity rating alone is insufficient grounds for determining the pain medication and dosage to administer daily. This study aimed to investigate whether a convenient assessment method could be developed that would reflect the effectiveness of an opioid analgesic on cancer patients’ pain management. We investigated pain intensity （worst, least, average, current） and the effectiveness of the opioid rescue medication in terms of patient satisfaction. This study used Spearman’s rank correlation coefficients to evaluate the relationships between patient satisfaction with rescue medication and both pain intensity and the medication’s perceived effectiveness. Data from 60 participants with a mean age of 60.5±11.4 years （range: 31-79 years） were analyzed. Thirty-eight （63.3%） participants were male, and 22 （36.7%） were female. The correlations found between rescue medication satisfaction and both the worst numerical rating scale （NRS） rating （r＝−0.15, P＝0.16） and the average NRS rating （r＝−0.13, P＝0.13） were not statistically significant. A significant positive correlation was observed between rescue medication satisfaction and the medication’s perceived effectiveness （r＝0.79, P＜0.0001）. Patient satisfaction with their rescue medication can be routinely assessed without imposing a significant burden on the patient. A new assessment method incorporating rescue medication satisfaction and pain intensity measures could allow routine pain assessments to reflect both pain intensity and the effectiveness of opioid analgesics. This new assessment method is potentially preferable to self-reported pain intensity and can identify patients for whom treatment is a priority. It also facilitates rapid dose adjustments and reduces the side effects of overdose due to unnecessary increases in opioid analgesics

Small cholangiolocellular carcinoma that was difficult to distinguish from cholangiocellular carcinoma: a case report

Abstract Background Cholangiolocellular carcinoma (CoCC) is thought to be derived from hepatic progenitor cells. Because of its origin, CoCC has diverse clinicopathological and imaging findings. Here, we report a case of small CoCC that was difficult to diagnose preoperatively. Case presentation A 62-year-old woman was confirmed with a small liver nodule in the left lobe 2 years after a sustained virological response of hepatitis C virus. The size of the nodule was 11.9 × 6.1 mm, and 6 months later, the size increased to 12.5 × 7.8 mm. The doubling time of this tumor was 285 days. The tumor revealed peripheral early enhancement and delayed internal staining in dynamic computed tomography images and marked high intensity in diffusion-weighted magnetic resonance imaging scans. These imaging findings resembled those of cholangiocellular carcinoma (CCC). The tumor was removed by laparoscopic lateral sectionectomy. Pathological findings revealed that the tumor was composed of small cuboidal cells and showed irregular anastomosis small grand. Immunohistochemical findings showed that the tumor cells were negative for Hep-par 1 and positive for cytokeratin 19. Epithelial membrane antigen staining was positive for the membranous side of the lumen. According to these pathological findings, the tumor was diagnosed as CoCC. Conclusion Although some characteristic imaging findings are reported for CoCC, they are not specific because of the variety in pathological findings. Especially, small CoCCs might have poor characteristic imaging findings and may be difficult to distinguish from CCC in the images. However, slow tumor growth might be one of the characteristics to suspect the possibility of a CoCC