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Diabetic nephropathy is currently the leading cause of end-stage renal disease worldwide, and occurs in approximately one third of all diabetic patients. The molecular pathogenesis of diabetic nephropathy has not been fully characterized and novel mediators and drivers of the disease are still being described. Previous data from our laboratory has identified the developmentally regulated gene Gremlin as a novel target implicated in diabetic nephropathy in vitro and in vivo. We used bioinformatic analysis to examine whether Gremlin gene sequence and structure could be used to identify other genes implicated in diabetic nephropathy. The Notch ligand Jagged1 and its downstream effector, hairy enhancer of split-1 (Hes1), were identified as genes with significant similarity to Gremlin in terms of promoter structure and predicted microRNA binding elements. This led us to discover that transforming growth factor-beta (TGFbeta1), a primary driver of cellular changes in the kidney during nephropathy, increased Gremlin, Jagged1 and Hes1 expression in human kidney epithelial cells. Elevated levels of Gremlin, Jagged1 and Hes1 were also detected in extracts from renal biopsies from diabetic nephropathy patients, but not in control living donors. In situ hybridization identified specific upregulation and co-expression of Gremlin, Jagged1 and Hes1 in the same tubuli of kidneys from diabetic nephropathy patients, but not controls. Finally, Notch pathway gene clustering showed that samples from diabetic nephropathy patients grouped together, distinct from both control living donors and patients with minimal change disease. Together, these data suggest that Notch pathway gene expression is elevated in diabetic nephropathy, co-incident with Gremlin, and may contribute to the pathogenesis of this disease.

Transforming growth factor-beta (TGF-β1) is implicated in the onset and progression of renal fibrosis and diabetic nephropathy (DN), leading to a loss of epithelial characteristics of tubular cells. The transcriptional profile of renal tubular epithelial cells stimulated with TGF-β1 was assessed using RNA-Seq, with 2027 differentially expressed genes identified. Promoter analysis of transcription factor binding sites in the TGF-β1 responsive gene set predicted activation of multiple transcriptional networks, including NFκB. Comparison of RNA-Seq with microarray data from identical experimental conditions identified low abundance transcripts exclusive to RNA-Seq data. We compared these findings to human disease by analyzing transcriptomic data from renal biopsies of patients with DN versus control groups, identifying a shared subset of 179 regulated genes. ARK5, encoding an AMP-related kinase, and TGFBI - encoding transforming growth factor, beta-induced protein were induced by TGF-β1 and also upregulated in human DN. Suppression of ARK5 attenuated fibrotic responses of renal epithelia to TGF-β1 exposure; and silencing of TGFBI induced expression of the epithelial cell marker – E-cadherin. We identified low abundance transcripts in sequence data and validated expression levels of several transcripts (ANKRD56, ENTPD8) in tubular enriched kidney biopsies of DN patients versus living donors. In conclusion, we have defined a TGF-β1-driven pro-fibrotic signal in renal epithelial cells that is also evident in the DN renal transcriptome.

Objectives: We evaluated internal medicine residents' confidence and knowledge of personal finance, perceptions of burnout, and relations between these issues before and after an educational intervention.Methods: We surveyed internal medicine residents at two university-based training programs in 2018. We developed and implemented a curriculum at both sites, covering topics of budgeting, saving for retirement, investment options, and the costs of investing. Each site used the same content but different strategies for dissemination. One used a condensed-form lecture series (two 1-hour sessions) and the other used a microlecture series (four 30-minute sessions) series. Residents were resurveyed following the intervention for comparison. Results:The preintervention survey response rate was 41.2% (122/296) and the postintervention response rate was 44.3% (120/271). Postintervention mean scores for personal finance knowledge improved for basic concepts (52.6% vs 39.4%, P < 0.001), mutual fund elements (30.8% vs 19.7%, P < 0.001), investment plans (68.5% vs. 49.2%, P < 0.001), and overall knowledge (50.1% vs 36.1%, P < 0.001). A significantly smaller proportion of residents reported feelings of burnout following the intervention (23.3% vs 36.9%, P = 0.022).Conclusions: Our findings show that residents want to learn about finances. Our brief educational intervention is a practical way to improve overall knowledge. Our intervention suggests that improving knowledge of finance may be associated with decreased feelings of burnout.

Helicobacter pylori is associated with primary antral gastritis, duodenal ulceration, and gastric cancer. Current regimens for treating infection in children using bismuth and antibiotics for two to six weeks are cumbersome. The aim of this study was to evaluate a one week course of treatment. All children undergoing endoscopy were assessed for the presence of H pylori by culture, histology, rapid urease test, and 13 C urea breath test. Infected children received a one week course of colloidal bismuth subcitrate 480 mg/1.73 m 2 /day (maximum 120 mg four times a day), combined with metronidazole 20 mg/kg/day (maximum 200 mg three times a day), and clarithromycin 15 mg/kg/day (maximum 250 mg twice a day). To optimise compliance, drugs were dispensed in a 'Redidose' box containing a compartment for each day, and subcompartments marked 'breakfast', 'lunch', 'dinner', and 'bedtime'. Compliance and side eVects were assessed immediately after treatment. A urea breath test was performed at least one month after treatment. Twenty two children infected with H pylori were entered into the study; 20 of these took all doses; two children suVered significant side eVects (diarrhoea and vomiting). H pylori was eradicated in 21 of the 22 children (95.45%; 95% confidence interval 77% to 100%). This study shows that H pylori infection in children can be cleared by a one week course of treatment. (Arch Dis Child 1997;76:352-355) Keywords: treatment; Helicobacter pylori Helicobacter pylori is associated with primary antral gastritis in children and adults.1-5 Eradication of H pylori from the gastric mucosa results in healing of gastritis. [6][7][8] There is also a strong association between H pylori gastritis and duodenal ulceration in both adults and children.2 4 5 9 10 Duodenal ulcer disease does not relapse if H pylori is eradicated from the gastric mucosa.7 11-13 Infection with H pylori also appears to be associated with an increased risk of carcinoma of the stomach, especially in those infected as children. [14][15][16][17] Current treatment regimens for H pylori infection in children using bismuth combined with one or two antibiotics for two to six weeks are cumbersome and compliance is diYcult. 11Studies on adult patients suggest that one week courses of treatment are eVective. 18-24The aim of this study was to test the eYcacy of a one week course of treatment combining colloidal bismuth subcitrate, metronidazole, and clarithromycin in eradicating H pylori in children. MethodsChildren undergoing upper endoscopy were routinely assessed for the presence of H pylori. Endoscopy was performed under general anaesthetic using Olympus paediatric gastroscopes QIF-P10 or XQ200. Three biopsy specimens were taken from the antral mucosa. One specimen was used for a rapid urease test (Clo, Delta West, Australia). A second specimen was fixed in 10% neutral formalin, embedded in paraYn wax, and cut at five micron thickness. The sections were then stained with haematoxylin and eosin for light microscopy. Further staining with cresy...