Induction of pancreatic islet cell differentiation by the neurogenin-neuroD cascade.

The related basic helix-loop-helix transcription factors neurogenin3 (Neurog3) and neurogenic differentiation 1 (NeuroD1) regulate pancreatic islet cell formation. The transient expression of Neurog3 initiates endocrine differentiation and activates its target, NeuroD1, which continues the endocrine differentiation process. Despite their distinct developmental roles, the expression of either factor can drive islet differentiation in progenitor cells. To determine whether Neurog3 and NeuroD1 function by targeting a common set of genes, we compared gene expression patterns in cells ectopically expressing these two factors using cDNA microarrays. The array data demonstrated that both factors regulated largely overlapping sets of genes, providing the molecular basis for their functional equivalence in gain-of-functions approaches. Distinct differences in the timing and level of expression of a subset of target genes, however, show that the functions of these two factors are not completely redundant. Interestingly, in addition to NeuroD1, Neurog3 also induced both NeuroD2 and NeuroD4 gene expression. NeuroD2 mRNA peaked in the embryonic pancreas during endocrine differentiation and induced endocrine differentiation in vitro. These data suggest possible redundant roles for the NeuroD1 paralogs NeuroD2 and NeuroD4 in pancreatic endocrine differentiation and their potential utility in cell-based therapies for diabetes mellitus.

The HMG box transcription factor Sox4 contributes to the development of the endocrine pancreas.

To investigate the role of the Sry/hydroxymethylglutaryl box (Sox) transcription factors in the development of the pancreas, we determined the expression pattern of Sox factors in the developing mouse pancreas. By RT-PCR, we detected the presence of multiple Sox family members in both the developing pancreas and mature islets and then focused on two factors, Sox2 and Sox4. The expression field of Sox2, which plays a role in the maintenance of some stem cell populations, included the developing duodenum, but Sox2 was specifically excluded from the pancreatic buds. In contrast, Sox4 was detected broadly in the early pancreatic buds and eventually became restricted to the nuclei of all islet cells in the adult mouse. Mice homozygous for a null mutation of the sox4 gene showed normal pancreatic bud formation and endocrine cell differentiation up to embryonic day 12.5. Beyond that date, cultured pancreatic explants lacking sox4 failed to form normal islets. Instead, a markedly reduced number of endocrine cells were found scattered through the explant. We show here that several Sox transcription factors are expressed in the developing pancreas and in the islet, and that one of these factors, Sox4, is required for the normal development of pancreatic islets.

Research fellowship programs as a pathway for training independent clinical pharmacy scientists.

The American College of Clinical Pharmacy (ACCP) Research Affairs Committee published a commentary in 2013 on training clinical pharmacy scientists in the context of changes in economic, professional, political, and research environments. The commentary centered on the opportunities for pharmacists in clinical/translational research including strategies for ACCP, colleges of pharmacy, and the profession to increase the number and impact of clinical pharmacy scientists. A postdoctoral fellowship is cited as a current training pathway, capable of producing independent and productive pharmacy researchers. However, a decline in the number of programs, decreased funding availability, and variability in fellowship program activities and research focus have brought into question the relevance of this research training pathway to meet demand and opportunities. In response to these points, this commentary examines the state of research fellowship training including the current ACCP research fellowship review process, the need for standardization of research fellowship programs, and strategies to strengthen and promote research fellowships as relevant researcher training pathways.

Novel role for SGK3 in glucose homeostasis revealed in SGK3/Akt2 double-null mice.

The phosphatidylinositol-3-kinase-dependent kinase, Akt2, plays a central role in mediating insulin effects in glucose-metabolizing tissues. Akt2 knockout mice display insulin resistance with a reactive increase in pancreatic islet mass and hyperinsulinemia. The related phosphatidylinositol-3-kinase-dependent kinase, serum- and glucocorticoid-regulated kinase 3 (SGK3), is essential for normal postnatal hair follicle development but plays no apparent role in glucose homeostasis. We report here an unexpected role of SGK3 in islet ß-cell function, which is revealed in Akt2/SGK3 double-knockout (DKO) mice. DKO mice have markedly worse glucose homeostasis than Akt2 single-null animals, including greater baseline glucose, and greater rise in blood glucose after glucose challenge. However, surprisingly, our data strongly support the idea that this exacerbation of the glucose-handling defect is due to impaired ß-cell function, rather than increased insulin resistance in peripheral tissues. DKO mice had lower plasma insulin and C-peptide levels, lower ß-cell mass, reduced glucose-stimulated insulin secretion, and greater sensitivity to exogenous insulin than Akt2 single nulls. We further demonstrated that SGK3 is strongly expressed in normal mouse islets and, interestingly, that ß-catenin expression is dramatically lower in the islets of DKO mice than in those of Akt2(-/-)/SGK3(+/+) or Akt2(-/-)/SGK3(+/-) mice. Taken together, these data strongly suggest that SGK3 plays a previously unappreciated role in glucose homeostasis, likely through direct effects within ß-cells, to stimulate proliferation and insulin release, at least in part by controlling the expression and activity of ß-catenin.

Variation in outpatient antibiotic prescribing in the United States.

OBJECTIVE: To evaluate variation in outpatient antibiotic utilization among US commercial health plans and the implications of this variation for cost and quality. STUDY DESIGN AND METHODS: We measured antibiotic utilization rates among 229 US commercial health plans that participated in the 2005 Healthcare Effectiveness Data and Information Set. Rates were adjusted to account for health plan age and sex distribution. To estimate antibiotic costs, we multiplied utilization data for each drug class by national estimates of intraclass distribution of drugs, duration of therapy, and median average wholesale price. RESULTS: Antibiotic utilization rates varied markedly among plans, ranging from 0.64 antibiotic fills per member per year (PMPY) at the 5th percentile of plans to 1.08 fills PMPY at the 95th percentile, with a mean of 0.88 (SD +/- 0.15) antibiotic fills PMPY. US census region was the strongest predictor of antibiotic utilization. Antibiotic costs averaged $49 PMPY and ranged from $34 to $63 PMPY among plans at the 5th and 95th percentiles of cost, respectively. If a health plan with 250,000 members at the 90th percentile of antibiotic costs reduced its costs to the 25th percentile, annual drug cost savings would be approximately $4.1 million. CONCLUSIONS: Antibiotic utilization varies substantially among commercial health plans and is not accounted for by differences in the age and sex distribution of plan members. Because reducing rates of antibiotic utilization is likely to lower costs and improve quality, high-utilizing plans may reap considerable rewards from investing in programs to reduce the overuse of antibiotics.