DPP-4 Inhibition Ameliorates Pancreatic β-Cell Failure and Improves Glucose Tolerance in the Mouse Model of Wolfram Syndrome

Wolfram syndrome, an autosomal recessive disorder associated with diabetes and optic atrophy, is caused by mutations in the WFS1 gene encoding wolframin, an endoplasmic reticulum membrane protein. Recent development of incretin-based drugs demonstrates promising outcomes for treatment of diabetes mellitus. The aim of this study is to evaluate whether dipeptidyl peptidase-4 inhibition is effective for treating endoplasmic reticulum stress-mediated β-dell failure and impaired glucose tolerance in WFS1-deficient mice (Wfs1-/-). Wfs1-/- mice were orally administrated with vildagliptin (50 mg/kg), a dipeptidyl peptidase-4 inhibitor, twice a day for 4 weeks. The pancreases of these mice were subjected to morphological and biochemical analyses and their glucose tolerance was studied. Electron microscopic studies revealed that vildagliptin reduced number of β-cell containing swollen endoplasmic reticulum in Wfs1-/-?mice. Vildagliptin treatment increased pancreatic insulin content by 30% in Wfs1-/- mice. Oral and intraperitoneal glucose tolerance tests showed improved glucose tolerance in vildagliptin-treated Wfs1-/- mice with increased glucose responsiveness of insulin secretion as compared with vehicle-treated mutant mice. These effects by dipeptidyl peptidase-4 inhibition were partly prevented by glucagon-like peptide-1 receptor blockade. These findings provide evidence that activation of the incretin system by dipeptidyl peptidase-4 inhibition plays a protective role against β-cell failure in wolframin-deficiency. Our data suggest that diabetes in patients affected with Wolfram syndrome could be treated by incretin-based drugs. Furthermore, since WFS1 dysfunction could be involved in common forms of type 2 diabetes mellitus, our results strengthen the mechanistic rational of using this drug for the disease.

Barium appendicitis: A single institution review in Japan

AIM To review clinical experience with barium appendicitis at a single institution.METHODS A retrospective review of patients admitted with a diagnosis of acute appendicitis, from January 1, 2013 to December 31, 2015 was performed. Age, gender, computed tomography(CT) scan findings if available, past history of barium studies, pathology, and the presence of perforation or the development of complications were reviewed. If the CT scan revealed high density material in the appendix, the maximum CT scan radiodensity of the material is measured in Hounsfield units(HU). Barium appendicitis is defined as:(1) patients diagnosed with acute appendicitis;(2) the patient has a history of a prior barium study; and(3) the CT scan shows high density material in the appendix. Patients who meet all three criteria are considered to have barium appendicitis.RESULTS In total, 396 patients were admitted with the diagnosis of acute appendicitis in the study period. Of these, 12 patients(3.0%) met the definition of barium appendicitis. Of these 12 patients, the median CT scan radiodensity of material in the appendix was 10000.8 HU, ranging from 3066 to 23423 HU(± 6288.2). In contrast, the median CT scan radiodensity of fecaliths in the appendix, excluding patients with barium appendicitis, was 393.1 HU, ranging from 98 to 2151 HU(± 382.0). The CT scan radiodensity of material in the appendices of patients with barium appendicitis wassignificantly higher than in patients with nonbarium fecaliths(P < 0.01).CONCLUSION Barium appendicitis is not rare in Japan. Measurement of the CT scan radiodensity of material in the appendix may differentiate barium appendicitis from routine appendicitis.

Tour Planning for Sightseeing with Time-Dependent Satisfactions of Activities and Traveling Times

This paper proposes a new personal tour planning problem with time-dependent satisfactions, traveling and activity duration times for sightseeing. It is difficult to represent the time-dependent model using general static network models, and hence, Time-Expanded Network (TEN) is introduced. The TEN contains a copy to the set of nodes in the underlying static network for each discrete time step, and it turns the problem of determining an optimal flow over time into a classical static network flow problem. Using the proposed TEN-based model, it is possible not only to construct various variations with time of costs and satisfactions flexibly in a single network, but also to select optimal departure places and accommodations according to the tour route with tourist’s favorite places and to obtain the time scheduling of tour route, simultaneously. The proposed model is formulated as a 0 - 1 integer programming problem which can be applied by existing useful combinatorial optimization and soft computing algorithms. It’s also equivalently transformed into several existing tour planning problems using some natural assumptions. Furthermore, comparing the proposed model with some previous models using a numerical example with time-dependent parameters, both the similarity of these models in the static network and the advantage of the proposed TEN-based model are obtained.