New Insights into the Beneficial Electrophysiologic Profile of Ranolazine in Heart Failure: Prevention of Ventricular Fibrillation With Increased Postrepolarization Refractoriness and Without Drug-Induced Proarrhythmia

BackgroundRanolazine inhibits late Na⁺ and K⁺ currents. Earlier studies have reported an antiarrhythmic effect. The aim of the present study was to understand whether ranolazine could still preserve its antiarrhythmic properties in the settings of chronic heart failure (CHF).Methods and ResultsIn 12 female rabbits, CHF was induced by 4 weeks of rapid ventricular pacing leading to a decrease in ejection fraction. Twelve rabbits underwent sham operation. Isolated hearts were Langendorff perfused and demonstrated a significant QT prolongation after induction of heart failure. Ranolazine caused a concentration-dependent (10 and 30 μmol/L) increase of action potential duration (APD₉₀) in sham-operated and failing hearts. Eight endo- and epicardial monophasic action potentials revealed a nonsignificant increase in spatial and temporal dispersion of repolarization. The increase in APD₉₀ was accompanied by a greater increase in refractory period, resulting in a significant increase in postrepolarization refractoriness in sham-operated (+29 ms and +55 ms; P < .01) and failing (+22 ms and +30 ms; P < .05) hearts. In control conditions, programmed ventricular stimulation and a burst pacing protocol led to ventricular fibrillation (VF) in 5 of the 12 sham-operated (6 episodes) and in 7 of the 12 failing (18 episodes) hearts. In the presence of ranolazine, VF was inducible in only 2 of 12 failing hearts (5 episodes). In the presence of low [K⁺], only 1 ranolazine-treated sham-operated heart developed early afterdepolarizations and ventricular tachyarrhythmias despite significant QT prolongation.ConclusionsRanolazine decreases inducibility of VF in the presence of a significant increase in postrepolarization refractoriness. This antiarrhythmic effect in the intact heart is preserved in CHF and is not associated with drug-induced proarrhythmia.     

Causes of thrombocytopenia in chronic hepatitis C viral infection

We retrospectively studied 89 patients with chronic hepatitis C virus (HCV) infection, including 50 chronic hepatitis (CH) cases, 18 liver cirrhosis (LC) cases, and 21 LC with hepatocellular carcinoma (LC + HCC) cases, with regard to various factors related with thrombocytopenia. The platelet count decreased with the stage advancement of liver diseases. Multiple regression analysis revealed that splenomegaly and von Willebrand factor (vWF) were explanatory variables that correlated with thrombocytopenia. Splenomegaly appears to be the most responsible factor, although there are a considerable number of thrombocytopenic cases without splenomegaly, suggesting other factors may also be responsible. The vWF level is inversely correlated with the platelet count. Soluble thrombomodulin, a marker of endothelial dysfunction, increases with the advancement of liver fibrosis. It is positively correlated with vWF and inversely with the platelet count. Our present results imply that vascular endothelial dysfunction is also involved in thrombocytopenia during chronic HCV infection.     

Reconstruction method after pancreaticoduodenectomy. Idea to prevent serious complications

Pancreatic fistula after pancreaticoduodenectomy represents a critical trigger of potentially life-threatening complications and is also associated with markedly prolonged hospitalization. Many arguments have been proposed for the method to anastomosis the pancreatic stump with the gastrointestinal tract, such as invagination vs. duct-to-mucosa, Billroth I (Imanaga) vs. Billroth II (Whipple and/or Child) or pancreaticogastrostomy vs. pancreaticojejunostomy. Although the best method for dealing with the pancreatic stump after pancreaticoduodenectomy remains in question, recent reports described the invagination method to decrease the rate of pancreatic fistula significantly compared to the duct-to-mucosa anastomosis. In Billroth I reconstruction, more frequent anastomotic failure has been reported, and disadvantages of pancreaticogastrostomy have been identified, including an increased incidence of delayed gastric emptying and of pancreatic duct obstruction due to overgrowth by the gastric mucosa. We review recent several safety trials and methods of treating the pancreatic stump after pancreaticoduodenectomy, and demonstrate an operative procedure with its advantage of the novel reconstruction method due to our experiences.     

Facial reanimation by transposition of the masseter muscle combined with tensor fascia lata,using the zygomatic arch as a pulley

We have created a new way of reanimating the face, involving transposition of the masseter muscle combined with tensor fascia lata, and using the zygomatic arch as a trochlea to reconstruct the inferior facial paralysis. We used it on five patients who had facial palsy after excision of malignant parotid tumours. The wide skin defect that exposed the masseter muscle after total parotidectomy was reconstructed with a free flap. This method differs from those of other methods of transposing the masseter muscle in that force is applied at an upper lateral angle. Our method provided dynamic raising of the upper lip, the corner of the mouth, and the nasolabial fold in four patients. We consider it to be useful, particularly for prompt surgical reconstruction of facial palsy after total parotidectomy with a wide defect in the skin of the cheek.     

Assessment of swallowing in motor neuron disease and Asidan/SCA36 patients with new methods

BackgroundWe report on a unique complication of cerebellar ataxia and motor neuron disease named Asidan/SCA36 with a high frequency of tongue atrophy. We aimed to elucidate dysphagia in amyotrophic lateral sclerosis (ALS) and spinal, bulbar muscular atrophy (SBMA), and Asidan/SCA36 patients with new methods.MethodsPatients diagnosed with ALS (n = 20), SBMA (n = 6), and Asidan (n = 12) were included. A videofluoroscopic swallow study (VFS), an assessment of maximal tongue pressure (MTP), and impedance pharyngography (IPG) were applied.ResultsThe frequencies of VFS abnormalities were 70%, 50%, and 33% in ALS, SBMA, and Asidan/SCA36, respectively. Compared with control subjects (31.6 ± 6.3 kPa, mean ± SD), MTP was significantly decreased in ALS patients and SBMA patients, but was relatively preserved in Asidan patients. ALS patients performed more swallowing actions (Ns) detected by IPG than did control subjects, but SBMA and Asidan/SCA36 patients performed similar Ns to control subjects.ConclusionsVFS showed a higher frequency of swallowing abnormalities in ALS patients. MTP and IPG measurements showed the most severe involvement in ALS patients and a relatively preserved swallowing function in SBMA and Asidan/SCA36 patients.     

Identification and structure–activity relationship of purine derivatives as novel MTH1 inhibitors

The human mutT homolog‐1 (MTH1) protein prevents the incorporation of oxidized nucleotides such as 2‐OH‐dATP and 8‐oxo‐dGTP during DNA replication by hydrolyzing them into their corresponding monophosphates. It was found previously that cancer cells could tolerate oxidative stress due to this enzymatic activity of MTH1 and its inhibition could be a promising approach to treat several types of cancer. This finding has been challenged recently with increasing line of evidence suggesting that the cancer cell‐killing effects of MTH1 inhibitors may be related to their engagement of off‐targets. We have previously reported a few purine‐based MTH1 inhibitors that enabled us to elucidate the dispensability of MTH1 in cancer cell survival. Here, we provide a detailed process of the identification of purine‐based MTH1 inhibitors. Several new compounds with potency in the submicromolar range are disclosed. Furthermore, the structure–activity relationship and associated binding mode prediction using molecular docking have provided insights for the development of highly potent MTH1 inhibitors.