Pharmacological conversion of gut epithelial cells into insulin-producing cells lowers glycemia in diabetic animals

As a highly regenerative organ, the intestine is a promising source for cellular reprogramming for replacing lost pancreatic β cells in diabetes. Gut enterochromaffin cells can be converted to insulin-producing cells by forkhead box O1 (FoxO1) ablation, but their numbers are limited. In this study, we report that insulin-immunoreactive cells with Paneth/goblet cell features are present in human fetal intestine. Accordingly, lineage-tracing experiments show that, upon genetic or pharmacologic FoxO1 ablation, the Paneth/goblet lineage can also undergo conversion to the insulin lineage. We designed a screening platform in gut organoids to accurately quantitate β-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process in mice and human adult intestinal organoids. We identified a triple blockade of FOXO1, Notch, and TGF-β that, when tested in insulin-deficient streptozotocin (STZ) or NOD diabetic animals, resulted in near normalization of glucose levels, associated with the generation of intestinal insulin-producing cells. The findings illustrate a therapeutic approach for replacing insulin treatment in diabetes.     

Can malocclusion provide clinicians with information for differential diagnosis of temporomandibular joint diseases?: A review

The aim of this literature review was to summarize the clinical characteristics and symptoms of temporomandibular joint diseases, and to discuss the associations between temporomandibular joint diseases and categorization of malocclusion. Electronic literature searches were performed using the PubMed database. The authors established a differential diagnostic method for temporomandibular joint diseases related to malocclusion. A literature search using PubMed yielded 213 texts, of which based on exclusion criteria, 28 were included in this study. Malocclusions were categorized into 5 types. The authors suggested a diagnostic tree of temporomandibular joint diseases based on the types of malocclusion and 4 variables in clinical characteristics and symptoms. Clinicians treating malocclusions must attempt to clarify the cause of the occlusal condition. If caused by temporomandibular joint disease, it is important to make a proper differential diagnosis at first, and not to overlook the causative disease. Further clinical knowledge of associations between temporomandibular joint diseases and malocclusions should be accumulated, and the diagnostic tree should be improved based on new information.     

Muscular Metastasis of Hepatocellular Carcinoma: Case Report and Literature Review

There are few case reports of hepatocellular carcinoma (HCC) metastasis to the skeletal muscle. A 78-year-old man developed a mass in the right shoulder. Washout of contrast medium during contrast-enhanced ultrasonography (CEUS) in both the primary HCC and the metastatic site was detected. Several nodules were scattered throughout the liver on an autopsy. In addition, the moderately differentiated HCC had metastasized to the right teres major muscle. Rare muscular metastasis should be considered if a hepatic tumor is moderately or poorly differentiated HCC. Early washout during CEUS is consistent with a pathological diagnosis of moderately or poorly differentiated HCC.     

Maxillary third molars with horizontal impaction: A cross-sectional study using computed tomography in young Japanese patients

ObjectiveTo examine the anatomical characteristics of impacted maxillary third molars to help predict and prevent possible adverse events during extraction.MethodsThis retrospective study enrolled young Japanese patients that were assessed for third molar extraction. Patients with maxillary third molar impaction presenting with no space between the maxillary second molar and the occlusal surface of the maxillary third molar were analysed using computed tomography data.ResultsIn this study, a total of 663 patients aged 20–29 years were examined for third molar extraction and 26 teeth in 23 patients were analysed. The mean ± SD angle between the second and third molar axes was 54.2° ± 7.5° and the mean ± SD length of the maxillary third molar was 16.1 ± 1.9 mm. The maxillary third molars showed close or extensive contact with the maxillary sinus and computed tomography did not show any bone from the maxillary sinus floor. Furthermore, in all patients, the crowns of the third molars were not completely covered by the alveolar bone.ConclusionsMaxillary third molars with horizontal impaction showed close or extensive contact with the maxillary sinus and their crowns were not completely covered by the alveolar bone.     

Immune checkpoint inhibitor-induced refractory polyarthritis rapidly improved by sarilumab and monitoring with joint ultrasonography: A case report

Rationale:Immune checkpoint inhibitors (ICIs) have shown efficacy for the treatment of various kinds of malignant tumors. However, ICIs can cause immune-related adverse events, such as arthritis. Nevertheless, the treatment of ICI-induced arthritis has not been established yet. Here we report a case of ICI-induced polyarthritis successfully treated using sarilumab and monitored using joint ultrasonography.Patient concerns:A 61-year-old man presented with polyarthritis. He had been treated with nivolumab for recurrent renal cell carcinoma 11 months before. He developed ICI-induced nephritis (proteinuria and elevated serum creatinine) 3 months before, which resolved after discontinuing nivolumab for 1 month. Two months after resuming nivolumab, he developed polyarthralgia and joint swelling, which were suspected to be associated with nivolumab administration, and hence we discontinued nivolumab again. Laboratory tests revealed elevated C-reactive protein level and erythrocyte sedimentation rate, but were negative for rheumatoid factor and anti-cyclic citrullinated peptide antibody. Joint ultrasonography revealed active synovitis in several joints, but a joint X-ray revealed no bone erosion.Diagnoses:We diagnosed polyarthritis as ICI-induced arthritis because the findings were not typical of rheumatoid arthritis (no bone erosion and seronegativity) and the patient had already developed other immune-related adverse events (ICI-induced nephritis).Interventions:After discontinuation of nivolumab, we started treatment with 15 mg daily prednisolone and 1000 mg daily sulfasalazine, although it was ineffective. Hence, we initiated 200 mg biweekly sarilumab.Outcomes:Following sarilumab administration, polyarthritis improved rapidly, and joint ultrasonography confirmed the rapid improvement of synovitis. Hence, we tapered off the glucocorticoid treatment. No recurrence of renal cell carcinoma was noted for 2 years after the initiation of sarilumab despite no anti-tumor therapy.Lessons:Sarilumab may serve as a good treatment option for treating refractory ICI-induced polyarthritis. Joint ultrasonography may contribute to the evaluation of ICI-induced polyarthritis and monitoring the effects of treatments.     

Appropriate definition of diabetes using an administrative database: A cross‐sectional cohort validation study

Aims/IntroductionThe purpose of the present study was to quantify errors in the diagnosis of diabetes for use in the national database, using a sufficient population size.Materials and methodsA claims database constructed by the JMDC (Tokyo, Japan), using standardized disease classifications and anonymous record linkage, was used in this validation study. We included patients with health insurance claims data from April 2005 to March 2019 in the JMDC claims database. We excluded patients without a record of specific health checkups in Japan. Sample size calculation was based on a 5% prevalence of diabetes and 0.4% absolute accuracy (i.e., 1,250,000 individuals), to calculate the sensitivity, specificity, positive predictive value and negative predictive value.ResultsIn total, 2,999,152 patients were included in this study, of which 165,515 were classified as having diabetes based on specific health checkups (validation cohort prevalence of 5.5%). The newly devised algorithm had three elements – the diagnosis‐related codes for diabetes without suspected flag, the medication codes for diabetes and then these two codes on the same record – and yielded a sensitivity of 74.6%, positive predictive value of 88.4% and Kappa Index of 0.80 (the highest values).ConclusionsIn future claims database studies, our validated algorithms will be useful as diagnostic criteria for diabetes.     

Voice rehabilitation for laryngeal cancer after radiotherapy: a systematic review and meta-analysis

European Archives of Oto-Rhino-Laryngology - We aimed to determine whether voice rehabilitation after radiotherapy improves the quality of life (QOL), voice function, and self-rated voice function...     

Analyses of very early hemopoietic regeneration after bone marrow transplantation: comparison of intravenous and intrabone marrow routes

In bone marrow transplantation (BMT), bone marrow cells (BMCs) have traditionally been injected intravenously. However, remarkable advantages of BMT via the intra-bone-marrow (IBM) route (IBM-BMT) over the intravenous route (IV-BMT) have been recently documented by several laboratories. To clarify the mechanisms underlying these advantages, we analyzed the kinetics of hemopoietic regeneration after IBM-BMT or IV-BMT in normal strains of mice. At the site of the direct injection of BMCs, significantly higher numbers of donor-derived cells in total and of c-kit(+) cells were observed at 2 through 6 days after IBM-BMT. In parallel, significantly higher numbers of colony-forming units in spleen were obtained from the site of BMC injection. During this early period, higher accumulations of both hemopoietic cells and stromal cells were observed at the site of BMC injection by the IBM-BMT route. The production of chemotactic factors, which can promote the migration of a BM stromal cell line, was observed in BMCs obtained from irradiated mice as early as 4 hours after irradiation, and the production lasted for at least 4 days. In contrast, sera collected from the irradiated mice showed no chemotactic activity, indicating that donor BM stromal cells that entered systemic circulation cannot home effectively into recipient bone cavity. These results strongly suggest that the concomitant regeneration of microenvironmental and hemopoietic compartments in the marrow (direct interaction between them at the site of injection) contributes to the advantages of IBM-BMT over IV-BMT. Disclosure of potential conflicts of interest is found at the end of this article.