Glucokinase activation or inactivation: Which will lead to the treatment of type 2 diabetes?

Glucokinase, which phosphorylates glucose to form glucose-6-phosphate, plays a critical role in regulating blood glucose levels. On the basis of data of glucokinase-knockout and transgenic mice and humans with glucokinase mutations, glucokinase was targeted for drug development aiming to augment its activity, and thereby reduce hyperglycaemia in patients with diabetes. In fact, various small molecule compounds have been developed and clinically tested as glucokinase activators. However, some have been discontinued because of efficacy and safety issues. One of these issues is loss of the drug's efficacy over time. This unsustained glycaemic efficacy may be associated with the excess glycolysis by glucokinase activation in pancreatic beta cells, resulting in beta-cell failure. Recently, we have shown that glucokinase haploinsufficiency ameliorated glucose intolerance by increasing beta-cell function and mass in a mouse model of diabetes. Given that a similar phenotype has been observed in glucokinase-activated beta cells and diabetic beta cells, glucokinase inactivation may be a new therapeutic target for type 2 diabetes.     

Predictive value of preoperative echocardiographic assessment for postoperative atrial fibrillation after esophagectomy for esophageal cancer

Esophagus - Postoperative atrial fibrillation (POAF) after esophagectomy for esophageal cancer is not uncommon. The aim of this study is to examine whether preoperative transthoracic...     

Risk factors for adrenal crisis in patients with adrenal insufficiency

Patients with adrenal insufficiency have a life-threatening risk of adrenal crisis, thus preventing adrenal crisis is an important clinical issue. In order to clarify the risk factors for adrenal crisis, the medical records of 137 patients with established adrenal insufficiency were retrospectively investigated. The explanatory variables analyzed were gender, etiology of hypoadrenalism, class of adrenocortical hormone replaced, duration of steroid replacement, age at time of survey, age at time of diagnosis of hypoadrenalism, state of other hormone deficiencies (growth hormone and sex steroids), diabetes insipidus, and mental disorder. Diagnosis of adrenal crisis was based on physical and laboratory findings. Forty (29%) of the 137 patients had at least one episode of adrenal crisis. Based on the Akaike Information Criterion (AIC), steroid replacement therapy of more than 4 yrs' duration was the largest single contributor to the occurrence of an adrenal crisis, followed by mental disorder and sex steroid deficiency. In the subclass of patients with secondary adrenal insufficiency (N = 115), sex steroid deficiency was the greatest risk factor. Patients with untreated hypogonadism had a significantly higher relative risk of 3.70 (95% confidential interval: 1.71-7.98) compared to those without hypogonadism or with treated hypogonadism. Furthermore, among patients with hypogonadism aged younger than 50 yrs, those treated with sex hormone (5/51: 10%) suffered less frequently from adrenal crisis than those untreated (7/11: 64%, p = 0.0004). In conclusion, the present study has, for the first time, clarified the risk factors of adrenal crisis. Among them, sex hormone deficiency has an especially important implication because it can be treated by hormone replacement therapy with the hope of reducing the risk of adrenal crisis.     

Electrophysiological effects of flecainide acetate on stretched guinea pig left atrial muscle fibers

Summary The electrophysiological effects of flecainide acetate (3×10^–6 M) on stretched atrial tissue were investigated using guinea-pig left atrial muscle fibers. Before stretching, the resting membrane potential was not affected by flecainide at 1 Hz, although the overshoot potential (Eov) and the action potential duration at 50% repolarization (APD₅₀) were slightly but significantly decreased by 2±1 mV and 2±1 msec, respectively. The effective refractory period (ERP) was increased by 3±1 msec. The reduction of max was 20.6±1.2%. The half-maximum potential (Vh) of the relationship between max and the resting potential was shifted to become more negative by flecainide (from –60.6±2.1 mV to –63.2±1.7 mV). After 90–120 min of washout with drug-free Tyrode's solution, the tissue was mechanically stretched to 150% of its slack length. Stretching significantly decreased the max by 16.9±3.1%, along with a slight but significant increase in ERP (3±1 msec) and shifted Vh to become more negative (from –60.6±2.1 to –63.1±1.8 mV). In the presence of flecainide, max further decreased by 20.2±2.6%, and Vh shifted from –63.1±1.8 to –65.0±1.5 mV. Comparison with the control unstretched fibers showed that flecainide significantly decreased max by 34.0±2.7%, reduced the resting membrane potential by 3±1 mV, decreased Eov by 4±1 mV, and shifted Vh from –60.6±2.1 to –65.0±1.5 mV, while the APD₅₀ and ERP did not change. In conclusion, the reduction of max in the presence of flecainide was much greater in the stretched atrial muscle fibers than in the unstretched fibers, because the max-resting potential relationship was shifted towards more negative potentials by both flecainide and stretching. These results suggest that flecainide exerts a stronger antiarrhythmic action on stretched atrial muscle fibers than on normal fibers.     

Alcohol and aldehyde dehydrogenase gene polymorphisms influence susceptibility to esophageal cancer in Japanese alcoholics

BACKGROUND: Studies have consistently demonstrated that inactive aldehyde dehydrogenase-2 (ALDH2), encoded by ALDH2*1/2*2, is closely associated with alcohol-related carcinogenesis. Recently, the contributions of alcohol dehydrogenase-2 (ADH2) polymorphism to alcoholism, esophageal cancer, and the flushing response have also been described. METHODS: To determine the effects of ALDH2 and ADH2 genotypes in genetically based cancer susceptibility, lymphocyte DNA samples from 668 Japanese alcoholic men more than 40 years of age (91 with and 577 without esophageal cancer) were genotyped and the results were expressed as odds ratios (ORs). This study also tested 82 of the alcoholics with esophageal cancer to determine whether cancer susceptibility is associated with patients' responses to simple questions about current or former flushing after drinking a glass of beer. RESULTS: The frequencies of ADH2*1/2*1 and ALDH2*1/2*2 were significantly higher in alcoholics with, than in those without, esophageal cancer (0.473 vs. 0.289 and 0.560 vs. 0.099, respectively). After adjustment for drinking and smoking, the analysis showed significantly increased cancer risk for alcoholics with either ADH2*1/2*I (OR = 2.03) or ALDH2*1/2*2 (OR = 12.76). For those having ADH2*1/2*1 combined with ALDH2*1/2*2, the esophageal cancer risk was enhanced in a multiplicative fashion (OR = 27.66). Responses to flushing questions showed that only 47.8% of the ALDH2*1/2*2 heterozygotes with ADH2*1/ 2*1, compared with 92.3% of those with ALDH2*1/2*2 and the ADH2*2 allele, reported current or former flushing. Genotyping showed that for alcoholics who reported ever flushing, the questionnaire was 71.4% correct in identifying ALDH2*1/2*2 and 87.9% correct in identifying ALDH2*1/2*1. CONCLUSION: Japanese alcoholics can be divided into cancer susceptibility groups on the basis of their combined ADH2 and ALDH2 genotypes. The flushing questionnaire can predict high risk ALDH2*1/2*2 fairly accurately in persons with ADH2*2 allele, but a reliable screening procedure for the highest risk gene combination (ADH2*1/2*1 and ALDH2*1/2*2) will require further investigation.     

Regenerative potential of basic fibroblast growth factor contained in biodegradable gelatin hydrogel microspheres applied following vocal fold injury: Early effect on tissue repair in a rabbit model

IntroductionPostoperative dysphonia is mostly caused by vocal fold scarring, and careful management of vocal fold surgery has been reported to reduce the risk of scar formation. However, depending on the vocal fold injury, treatment of postoperative dysphonia can be challenging.ObjectiveThe goal of the current study was to develop a novel prophylactic regenerative approach for the treatment of injured vocal folds after surgery, using biodegradable gelatin hydrogel microspheres as a drug delivery system for basic fibroblast growth factor.MethodsVideoendoscopic laryngeal surgery was performed to create vocal fold injury in 14 rabbits. Immediately following this procedure, biodegradable gelatin hydrogel microspheres with basic fibroblast growth factor were injected in the vocal fold. Two weeks after injection, larynges were excised for evaluation of vocal fold histology and mucosal movement.ResultsThe presence of poor vibratory function was confirmed in the injured vocal folds. Histology and digital image analysis demonstrated that the injured vocal folds injected with gelatin hydrogel microspheres with basic fibroblast growth factor showed less scar formation, compared to the injured vocal folds injected with gelatin hydrogel microspheres only, or those without any injection.ConclusionA prophylactic injection of basic fibroblast growth factor -containing biodegradable gelatin hydrogel microspheres demonstrates a regenerative potential for injured vocal folds in a rabbit model.     

Epidemiology of colonic diverticula and recent advances in the management of colonic diverticular bleeding

There is the East-West paradox in prevalence and phenotype of colonic diverticula, but colonic diverticular bleeding (CDB) is the most common cause of acute lower gastrointestinal bleeding worldwide. Death from CDB can occur in elderly patients with multiple comorbidities, thus the management of CDB is clinically pivotal amid the aging populations in the East and West. Colonoscopy is the key modality for managing the condition appropriately; however, conventional endoscopic hemostasis by thermal coagulation and clipping cannot achieve the expected results of preventing early rebleeding and conversion to intensive intervention by surgery or transcatheter arterial embolization. Ligation therapy by endoscopic band ligation or endoscopic detachable snare ligation has emerged recently to enable more effective hemostasis for CDB, with an early rebleeding rate of approximately 10% and very rare conversion to intensive intervention. Ligation therapy might in turn reduce long-term rebleeding rates by eliminating the target diverticulum itself. Adverse events have been reported with ligation therapy including diverticulitis of the ascending colon in less than 1% of cases and perforation of the sigmoid colon in a few cases, thus more data are necessary to verify the safety of ligation therapy. Endoscopic hemostasis is indicated only for diverticulum with stigmata of recent hemorrhage (SRH), but the detection rates of SRH are relatively low. Therefore, efforts to increase detection are also key for improving CDB management. Urgent colonoscopy and triage by early contrast-enhanced computed tomography may be candidates to increase detection but further data are necessary in order to make a conclusion.     

Two autopsy cases of desmoplastic small round cell tumor

Desmoplastic small round cell tumor (DSRCT) is a rare aggressive malignant tumor. It is a refractory tumor and the median overall survival is very short. We report two autopsy cases of DSRCT, both of which were already advanced and metastasized at the first medical examination. Both cases showed typical DSRCT findings in terms of localization of the lesions, histopathology and genetics, but the rate of disease progression was quite different. Survival after initial symptoms in Case 1 was only 12 months. On the other hand, survival after primary hospitalization in Case 2 was 42 months. The Case 2 patient initially received chemotherapy for advanced pancreatic carcinoma, because a nodule of the pancreatic tail was found on computed tomography (CT) scan. After chemotherapy, tumor regression was observed on CT scan. It is thus implied that adoption of the regimen for pancreatic carcinoma might have been one of reasons of the long survival in Case 2.