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The basic helix-loop-helix transcription factor Neurog3 (Neurogenin3 or Ngn3) actively drives endodermal progenitor cells towards endocrine islet cell differentiation during embryogenesis. Here, we manipulate Neurog3 expression levels in endocrine progenitor cells without altering its expression pattern using heterozygosity and a hypomorph. Lowered Neurog3 gene dosage in the developing pancreatic epithelium reduces the overall production of endocrine islet cells without significantly affecting the proportions of various islet cell types that do form. A reduced Neurog3 production level in the endocrine-directed pancreatic progenitor population activates the expression of Neurog3 in an increased number of epithelial progenitors. Yet a significant number of these Neurog3+ cells detected in heterozygous and hypomorphic pancreata, possibly those that express low levels of Neurog3, move on to adopt pancreatic ductal or acinar fates. These data directly demonstrate that achieving high levels of Neurog3 expression is a critical step for endocrine commitment from multipotent pancreatic progenitors. These findings also suggest that a high level of Neurog3 expression could mediate lateral inhibition or other unknown feedback mechanisms to regulate the number of cells that initiate Neurog3 transcription and protein production. The control of Neurog3+ cell number and the Neurog3 threshold-dependent endocrine differentiation mechanism combine to select a specific proportion of pancreatic progenitor cells to adopt the islet cell fate.
Copyright 2009 Elsevier Inc. All rights reserved.
BACKGROUND - In recent years, there has been a growing interest in endocrine surgery. Educational objectives have been published by the American Association of Endocrine Surgeons (AAES), but data have not been collected describing the recruitment pool, fellowship, or postfellowship experiences.
METHODS - A survey was distributed to endocrine surgeons in practice <7 years and endocrine surgery fellows. Demographic, training, and practice data were collected.
RESULTS - The survey response rate was 69% (46/67); 85% were practicing endocrine surgeons and 15% were fellows. In all, 72% of respondents completed an endocrine surgery fellowship, 17% completed surgical oncology, and the remaining individuals completed no fellowship. The mean age was 38 (32-49) years; 39% were women, 67% were white, 26% were Asian, 11% were Hispanic, and 2% were black. A total of 89% completed residency at academic centers. Endocrine surgery fellows performed significantly more endocrine surgery cases in residency than the average graduating chief resident. Mentorship was a critical factor in fellows' decisions to pursue endocrine surgery. Fellows graduated with a median (range) of 150 (50-300) thyroid, 80 (35-200) parathyroid, 10 (2-50) neck dissection, 13 (0-60) laparoscopic adrenal, and 3 (0-35) endocrine-pancreas. Fellows felt the least prepared in neck dissection and pancreas. Of the respondents, 76% of endocrine surgeons in practice are at academic centers, and 75% have practices where most cases are endocrine based.
CONCLUSION - Exposure to endocrine surgery and mentorship are powerful factors that influence residents to pursue careers in endocrine surgery. Significant variation is found in the case distribution of fellowships with a relative paucity in neck dissection, pancreas procedures, and research. Recruitment to endocrine surgery should begin in residency, and the standardization of training should be a goal.
Copyright 2010 Mosby, Inc. All rights reserved.
We studied the effect of salt intake and hypertension on the systemic kallikrein-kinin system (KKS), as measured by bradykinin (BK) 1-5, a stable circulating bradykinin metabolite, and the tissue KKS, as measured by urinary kallikrein excretion. Venous BK 1-5, urinary kallikrein, and components of the renin-angiotensin-aldosterone system were measured in 35 normotensive and 19 hypertensive subjects who were maintained on a high (200 mmol/day) or low (10 mmol/day) salt diet. Salt restriction decreased mean arterial pressure (MAP) (P < 0.001 overall) and the plasma angiotensin-converting enzyme (P = 0.017) and increased plasma renin activity (P < 0.001) and serum aldosterone (P < 0.001). There was an interactive effect of salt intake and hypertension on plasma BK 1-5 (P = 0.043), with BK 1-5 significantly lower during low compared with high salt intake in normotensive (24.7 +/- 2.6 versus 34.9 +/- 5.6 fmol/ml, P = 0.002) but not hypertensive subjects (30.6 +/- 4.6 versus 27.5 +/- 2.8 fmol/ml, P = 0.335). In normotensives, the change in plasma BK 1-5 from high to low salt intake correlated with the change in MAP (r = 0.533, P = 0.004). Urinary kallikrein was higher during low compared with high salt intake (P < 0.001) in both groups. There was no effect of salt intake on urinary BK 1-5. In summary, the systemic and renal KKSs act in tandem to modulate the response to salt intake. The systemic system is activated during high salt intake and counterbalances increased vascular response to pressors. With sodium restriction, the renal system is activated and counterbalances the increased sodium-retaining state induced by activation of the renin-angiotensin-aldosterone system. With hypertension, these modulating effects are diminished or lost, supporting a role for both systems in the development/maintenance of hypertension.
Current renal substitution therapy with hemodialysis or hemofiltration has been an important life-sustaining technology, but it still has suboptimal clinical outcomes in patients with end-stage renal disease or acute renal failure. This therapy replaces the small solute clearance function of the glomerulus but does not replace the metabolic and endocrinologic functions of the tubular cells. This article shows that the combination of a synthetic hemofiltration cartridge and a renal tubule cell assist device (RAD) containing human cells in an extracorporeal circuit replaces filtration, metabolic, and endocrinologic functions in acutely uremic dogs. The RAD maintained excellent performance and durability characteristics for 24 hours of continuous use in the uremic animals. The RAD increased ammonia excretion, glutathione metabolism, and 1,25-dihydroxyvitamin D3 production. Cardiovascular stability in the animals was documented in these studies during this extracorporeal treatment. With these results, clinical evaluation of this device in the treatment of severely ill patients with acute renal failure in an intensive care unit has been initiated.
Copyright 2002 by the National Kidney Foundation, Inc.
We used transgenesis to explore the requirement for downregulation of hepatocyte nuclear factor 6 (HNF6) expression in the assembly, differentiation, and function of pancreatic islets. In vivo, HNF6 expression becomes downregulated in pancreatic endocrine cells at 18. 5 days post coitum (d.p.c.), when definitive islets first begin to organize. We used an islet-specific regulatory element (pdx1(PB)) from pancreatic/duodenal homeobox (pdx1) gene to maintain HNF6 expression in endocrine cells beyond 18.5 d.p.c. Transgenic animals were diabetic. HNF6-overexpressing islets were hyperplastic and remained very close to the pancreatic ducts. Strikingly, alpha, delta, and PP cells were increased in number and abnormally intermingled with islet beta cells. Although several mature beta cell markers were expressed in beta cells of transgenic islets, the glucose transporter GLUT2 was absent or severely reduced. As glucose uptake/metabolism is essential for insulin secretion, decreased GLUT2 may contribute to the etiology of diabetes in pdx1(PB)-HNF6 transgenics. Concordantly, blood insulin was not raised by glucose challenge, suggesting profound beta cell dysfunction. Thus, we have shown that HNF6 downregulation during islet ontogeny is critical to normal pancreas formation and function: continued expression impairs the clustering of endocrine cells and their separation from the ductal epithelium, disrupts the spatial organization of endocrine cell types within the islet, and severely compromises beta cell physiology, leading to overt diabetes.