[DOTS AND TREATMENT RESULTS IN PATIENTS WITH EXTRA-PULMONARY TUBERCULOSIS IN OSAKA CITY].

[Purpose] To improve the treatment outcomes by analyzing/evaluating the association between DOTS and treatment outcomes in patients with extra-pulmonary tuber- culosis. [Methods] The subjects were patients with extra-pulmonary tuberculosis newly registered in Osaka City between 2012 and 2014. As controls, patients with pulmonary tuberculosis during this period were enrolled. Patients in whom compli- ance was confirmed once a month or more were regarded as completing DOTS. [Results] There were 434 patients with extra-pulmonary tuberculosis. Treatment was completed in 73.3% of these patients. Defaulted rates accounted for 9.4%. The mortality rate was 13.4%. Treatment is being conducted in 2.8%. Furthermore, 0.7% was transferred out. The results were unclear in 0.5%. We investigated changes in the DOTS and defaulted rates, excluding patients who died, those who were referred to other hospitals, those receiving treatment, and those whose results were unclear. The DOTS rates in 2012, 2013, and 2014 were 85.5, 87.5, and 91.2%, respectively, showing a slight increase. The defaulted rates were 14.5, 10.7, and 7.8%, respectively, showing a decrease. When compar- ing the results between the extra-pulmonary and pulmonary tuberculosis patients, the defaulted rates were 11.4 and 6.2 %, respectively; the percentage was significantly higher in the extra-pulmonary tuberculosis patients. The DOTS rates were 87.7 and 97.2%, respectively; the percentage was sig- nificantly lower in the extra-pulmonary tuberculosis patients. There were 41 defaulted cases. The reasons were "side effects" in 41.5%, "physicians' instructions" in 24.4%, "self- discontinuation/refusal" in 22.0%, and "preferential treatment for other diseases" in 12.2%. In the extra-pulmonary tuberculosis patients, the proportion of those in whom "side effects" led to defaulted was higher than in the pulmonary tubercu- losis patients, and that of those "self-discontinuation/refusal" was significantly lower. [Conclusion] Although the defaulted rate has decreased with an increase in the DOTS rate in patients with extra- pulmonary tuberculosis, both the DOTS and defaulted rates were less favorable than in patients with pulmonary tuber- culosis. In the future, it may be necessary to decrease the defaulted rate by intensifying DOTS. Of the reasons for defaulted, "side effects" and "physicians' instructions" account- ed for a high percentage. Therefore, it may be important to provide medical institutions with information.

The 2014 measles outbreak in Osaka An epidemiological study for the elimination of measles.

OBJECTIVES: To examine and analyze the spread of measles in Osaka in 2014 and determine effective measures to prevent such occurrences. METHODS: We analyzed 47 cases of measles reported in Osaka, including one measles patient living in another prefecture where there was an outbreak. We focused on age distribution, the number of patients reported each week, estimated infection routes, history of measles vaccination, detection of viruses, and number of days it took to report the case after the onset of measles. RESULTS: Patients aged 20-39 years accounted for 24 cases (51.1%). The number of patients reported started from 2nd week with relatively broad peak to 27(th) week, and the measles epidemic was brought under control in the 47(th) week. Among the 47 cases, no source could be identified in 16 cases (34.0%). Household exposure was the main cause of the infection (25.5%), followed by imported cases (21.3%). Eighty-three percent of the overall patients had not received a measles vaccination at all or it was unclear whether they previously had been vaccinated. Genotype B3, H1, and D8 were detected in our patients and these genotypes originated overseas. It took significantly more days, from the onset of measles, for the case to be reported in patients aged 15 years and over compared with those aged under 15 years (P=0.001). CONCLUSION: For eradicating measles in Osaka, it is important to raise awareness about this issue among medical institutions, especially institutions for adults, in order for them to report cases as soon as possible, upon discovery in their patients. In addition, "catch-up" supplementary immunizations are effective for all people, including adults who are susceptible to measles.

Role of cadherin-mediated cell-cell adhesion in pancreatic exocrine-to-endocrine transdifferentiation.

Although pancreatic exocrine acinar cells have the potential to transdifferentiate into pancreatic endocrine cells, the mechanisms are poorly understood. Here we report that intracellular signaling pathways, including those involving MAPK and phosphatidylinositol 3 (PI3)-kinase, are activated by enzymatic dissociation of pancreatic acinar cells and that spherical cell clusters are formed by cadherin-mediated cell-cell adhesion during transdifferentiation. Inhibition of PI3-kinase by LY294002 prevents spheroid formation by degrading E-cadherin and beta-catenin, blocking transdifferentiation into insulin-secreting cells. In addition, neutralizing antibody against E-cadherin suppresses the induction of genes characteristic of pancreatic beta-cells. We also show that loss of cadherin-mediated cell-cell adhesion induces and maintains a dedifferentiated state in isolated pancreatic acinar cells. Thus, disruption and remodeling of cadherin-mediated cell-cell adhesion is critical in pancreatic exocrine-to-endocrine transdifferentiation, in which the PI3-kinase pathway plays an essential role.

Induction by NeuroD of the components required for regulated exocytosis.

NeuroD is a transcriptional factor critical in differentiation of neuronal cells, enteroendocrine cells, and pancreatic endocrine cells. However, little is known of its roles in cellular functions. We show here that introduction of NeuroD into human fetal epithelial cell line Intestine 407 cells induces neuron-like morphology. In addition, multiple genes associated with vesicular trafficking and exocytotic machinery, including Sec24D, carboxypeptidase E, myosin Va, SNAP25, syntaxin 1A, Rab, Rims, Munc18-1, and adenylyl cyclase, were up-regulated by NeuroD gene transfer. Moreover, low osmotic pressure-induced exocytosis monitored by FM1-43 was enhanced by overexpression of NeuroD. These results suggest that NeuroD plays an important role in regulated exocytosis by inducing expressions of various components required in the process.

Generation of insulin-secreting cells from pancreatic acinar cells of animal models of type 1 diabetes.

We recently found that pancreatic acinar cells isolated from normal adult mouse can transdifferentiate into insulin-secreting cells in vitro. Using two different animal models of type 1 diabetes, we show here that insulin-secreting cells can also be generated from pancreatic acinar cells of rodents in the diabetic state with absolute insulin deficiency. When pancreatic acinar cells of streptozotocin-treated mice were cultured in suspension in the presence of epidermal growth factor and nicotinamide under low-serum condition, expressions of insulin genes gradually increased. In addition, expressions of other pancreatic hormones, including glucagon, somatostatin, and pancreatic polypeptide, were also induced. Analysis by the Cre/loxP-based direct cell lineage tracing system revealed that these newly made cells originated from amylase-expressing pancreatic acinar cells. Insulin secretion from the newly made cells was significantly stimulated by high glucose and other secretagogues. In addition, insulin-secreting cells were generated from pancreatic acinar cells of Komeda diabetes-prone rats, another animal model of type 1 diabetes. The present study demonstrates that insulin-secreting cells can be generated by transdifferentiation from pancreatic acinar cells of rodents in the diabetic state and further suggests that pancreatic acinar cells represent a potential source of autologous transplantable insulin-secreting cells for treatment of type 1 diabetes.

Lineage tracing and characterization of insulin-secreting cells generated from adult pancreatic acinar cells.

Although several studies have suggested that insulin-secreting cells can be generated in vitro from cells residing in adult exocrine pancreas, neither the origin of these cells nor their precise insulin secretory properties was obtained. We show here that insulin-secreting cells can be derived from adult mouse pancreatic exocrine cells by suspension culture in the presence of EGF and nicotinamide. The frequency of insulin-positive cells was only 0.01% in the initial preparation and increased to approximately 5% in the culture conditions. Analysis by the Cre/loxP-based direct cell lineage tracing system indicates that these newly made cells originate from amylase/elastase-expressing pancreatic acinar cells. Insulin secretion is stimulated by glucose, sulfonylurea, and carbachol, and potentiation by glucagon-like peptide-1 also occurs. Insulin-containing secretory granules are present in these cells. In addition, we found that the enzymatic dissociation of pancreatic acini itself leads to activation of EGF signaling, and that inhibition of EGF receptor kinase blocks the transdifferentiation. These data demonstrate that pancreatic acinar cells can transdifferentiate into insulin-secreting cells with secretory properties similar to those of native pancreatic beta cells, and that activation of EGF signaling is required in such transdifferentiation.