The epidemiology and burden of gastroparesis: Real-world data from a large healthcare provider in Israel.

BACKGROUND: Gastroparesis is a gastrointestinal motility dysfunction characterized by delayed gastric emptying in the absence of gastric mechanical obstruction. Data on the epidemiology of gastroparesis are sparse even though the condition substantially impairs patients' quality of life. The aim of this study was to describe the epidemiology and estimate the short-term healthcare resource use burden of gastroparesis in a large population. METHODS: This cross-sectional study utilized computerized data from Maccabi Healthcare Services, a 2.5-million member state-mandated health organization in Israel. Data were collected between 2003 and 2018 to assess the prevalence of gastroparesis. Definite gastroparesis was defined by gastroparesis diagnosis and gastric emptying test. Probable gastroparesis was defined by gastroparesis diagnosis only. To compare the healthcare resource utilization (HCRU), data were also collected on controls that were individually matched (1:2) for age, sex, and comorbidities. KEY RESULTS: A total of 522 patients with gastroparesis were identified (21.1 per 100,000 WHO age-standardized), including 204 with definite gastroparesis (8.6 per 100,000 WHO). Male to female ratio was 1:2 and mean ± SD age of 54.7 ± 17.1 years. Diabetes accounted for 25.9% of gastroparesis cases and the rest were idiopathic. Gastroparesis patients were more likely to have cardiovascular diseases (10% vs. 6.9% for controls, p = 0.034) and lower prevalence of obesity (17% vs. 24.4%, p < 0.001). HCRU within the 2 years after index date were higher with more hospitalizations than controls (26.4% vs. 15.4%, p < 0.001), and more emergency room visits (31.6% vs. 24.1%, p = 0.002). CONCLUSIONS & INFERENCES: Gastroparesis is uncommon or under-documented in community care settings. Gastroparesis in general is associated with cardiovascular morbidities, lower BMI, and elevated utilization of healthcare services.

Insulin-producing cells generated from dedifferentiated human pancreatic beta cells expanded in vitro.

BACKGROUND: Expansion of beta cells from the limited number of adult human islet donors is an attractive prospect for increasing cell availability for cell therapy of diabetes. However, attempts at expanding human islet cells in tissue culture result in loss of beta-cell phenotype. Using a lineage-tracing approach we provided evidence for massive proliferation of beta-cell-derived (BCD) cells within these cultures. Expansion involves dedifferentiation resembling epithelial-mesenchymal transition (EMT). Epigenetic analyses indicate that key beta-cell genes maintain open chromatin structure in expanded BCD cells, although they are not transcribed. Here we investigated whether BCD cells can be redifferentiated into beta-like cells. METHODOLOGY/PRINCIPAL FINDING: Redifferentiation conditions were screened by following activation of an insulin-DsRed2 reporter gene. Redifferentiated cells were characterized for gene expression, insulin content and secretion assays, and presence of secretory vesicles by electron microscopy. BCD cells were induced to redifferentiate by a combination of soluble factors. The redifferentiated cells expressed beta-cell genes, stored insulin in typical secretory vesicles, and released it in response to glucose. The redifferentiation process involved mesenchymal-epithelial transition, as judged by changes in gene expression. Moreover, inhibition of the EMT effector SLUG (SNAI2) using shRNA resulted in stimulation of redifferentiation. Lineage-traced cells also gave rise at a low rate to cells expressing other islet hormones, suggesting transition of BCD cells through an islet progenitor-like stage during redifferentiation. CONCLUSIONS/SIGNIFICANCE: These findings demonstrate for the first time that expanded dedifferentiated beta cells can be induced to redifferentiate in culture. The findings suggest that ex-vivo expansion of adult human islet cells is a promising approach for generation of insulin-producing cells for transplantation, as well as basic research, toxicology studies, and drug screening.

MicroRNAs are essential for development and function of inner ear hair cells in vertebrates.

MicroRNAs (miRNAs) inhibit the translation of target mRNAs and affect, directly or indirectly, the expression of a large portion of the protein-coding genes. This study focuses on miRNAs that are expressed in the mouse cochlea and vestibule, the 2 inner ear compartments. A conditional knock-out mouse for Dicer1 demonstrated that miRNAs are crucial for postnatal survival of functional hair cells of the inner ear. We identified miRNAs that have a role in the vertebrate developing inner ear by combining miRNA transcriptome analysis, spatial and temporal expression patterns, and bioinformatics. Microarrays revealed similar miRNA profiles in newborn-mouse whole cochleae and vestibules, but different temporal and spatial expression patterns of six miRNAs (miR-15a, miR-18a, miR-30b, miR-99a, miR-182, and miR-199a) may reflect their roles. Two of these miRNAs, miR-15a-1 and miR-18a, were also shown to be crucial for zebrafish inner ear development and morphogenesis. To suggest putative target mRNAs whose translation may be inhibited by selected miRNAs, we combined bioinformatics-based predictions and mRNA expression data. Finally, we present indirect evidence that Slc12a2, Cldn12, and Bdnf mRNAs may be targets for miR-15a. Our data support the hypothesis that inner ear tissue differentiation and maintenance are regulated and controlled by conserved sets of cell-specific miRNAs in both mouse and zebrafish.