beta cell dysfunction is a central component of the pathogenesis of type 2 diabetes. Using oligonucleotide microarrays and real-time PCR of pancreatic islets isolated from humans with type 2 diabetes versus normal glucose-tolerant controls, we identified multiple changes in expression of genes known to be important in beta cell function, including major decreases in expression of HNF4alpha, insulin receptor, IRS2, Akt2, and several glucose-metabolic-pathway genes. There was also a 90% decrease in expression of the transcription factor ARNT. Reducing ARNT levels in Min6 cells with small interfering RNA (siRNA) resulted in markedly impaired glucose-stimulated insulin release and changes in gene expression similar to those in human type 2 islets. Likewise, beta cell-specific ARNT knockout mice exhibited abnormal glucose tolerance, impaired insulin secretion, and changes in islet gene expression that mimicked those in human diabetic islets. Together, these data suggest an important role for decreased ARNT and altered gene expression in the impaired islet function of human type 2 diabetes.

The molecular mechanisms underlying general anesthesia are unknown. For volatile general anesthetics (VAs), indirect evidence for both lipid and protein targets has been found. However, no in vivo data have implicated clearly any particular lipid or protein in the control of sensitivity to clinical concentrations of VAs. Genetics provides one approach toward identifying these mechanisms, but genes strongly regulating sensitivity to clinical concentrations of VAs have not been identified. By screening existing mutants of the nematode Caenorhabditis elegans, we found that a mutation in the neuronal syntaxin gene dominantly conferred resistance to the VAs isof lurane and halothane. By contrast, other mutations in syntaxin and in the syntaxin-binding proteins synaptobrevin and SNAP-25 produced VA hypersensitivity. The syntaxin allelic variation was striking, particularly for isof lurane, where a 33-fold range of sensitivities was seen. Both the resistant and hypersensitive mutations decrease synaptic transmission; thus, the indirect effect of reducing neurotransmission does not explain the VA resistance. As assessed by pharmacological criteria, halothane and isof lurane themselves reduced cholinergic transmission, and the presynaptic anesthetic effect was blocked by the resistant syntaxin mutation. A single gene mutation conferring highlevel resistance to VAs is inconsistent with nonspecific membrane-perturbation theories of anesthesia. The genetic and pharmacological data suggest that the resistant syntaxin mutant directly blocks VA binding to or efficacy against presynaptic targets that mediate anesthetic behavioral effects. Syntaxin and syntaxin-binding proteins are candidate anesthetic targets.

BACKGROUND Although numerous studies have demonstrated the feasibility of cardiac surgery for blood refusal patients, few studies match to controls, and fewer examine cost. This historical cohort study aims to compare costs and outcomes after cardiac surgery in Jehovah's Witness patients who refuse blood transfusion with a group of matched patients accepting transfusion. STUDY DESIGN AND METHODS A retrospective database review was performed to find all patients having cardiac surgery who refused blood products from January 2005 to July 2012 at Duke University Medical Center. These 45 patients were closely matched 1:2 with controls who accepted transfusion based on characteristics likely to influence transfusion. Cost from day of surgery to hospital discharge and other outcome data (length of stay [LOS], discharge hemoglobin [Hb], acute kidney injury) were analyzed retrospectively. RESULTS Forty‐five Witnesses having cardiac surgery were temporally matched to two controls having the same surgery. Median euroSCORE was the same in both groups (6.0, p = 0.9981). In the matched‐pairs comparison of cost, there was no significant difference in total cost for Witnesses and controls. There was no difference in intensive care unit LOS (median, 1 day, both groups) or total LOS (median, 9 days for Witnesses vs. 7 days for controls). Mean Hb at discharge was higher in Witnesses than in controls (11.7 g/dL vs. 9.8 g/dL, p < 0.001). Thirty‐day mortality was zero in both groups. CONCLUSION Utilizing applicable blood conservation measures, cardiac surgery may be performed with similar outcomes and cost from day of surgery to discharge compared to controls in select patients without blood transfusion.

Background Based on biblical doctrines, patients of the Jehovah's Witness faith refuse allogeneic blood transfusion. Cardiac surgery carries a high risk of blood transfusion, but has been performed in Jehovah's Witnesses for many years. The literature contains information on the outcomes of this cohort, but does not detail the perioperative care of these patients. This article describes a single institution's experience in perioperative care of Jehovah's Witnesses undergoing cardiac surgery. Study Design and Methods A chart review of adult Jehovah's Witness patients undergoing cardiac surgery at Duke University between January 2005 and June 2012 was completed. Institutional protocols regarding preoperative erythropoietin (EPO) therapy and intraoperative isovolemic hemodilution are detailed. Patient demographics and use of various blood conservation techniques are described. Hemoglobin (Hb) at various points throughout the perioperative management, hospital length of stay, and mortality are reviewed as indicators of outcome. Results Forty‐five Jehovah's Witness patients underwent cardiac surgery at Duke University Medical Center. Preoperative EPO increased the mean Hb by 1.2 g/dL before surgery. Intraoperative normovolemic hemodilution was used in 37 patients with intraoperative mean nadir Hb of 10.3 g/dL. Antifibrinolytics and desmopressin were commonly used as coagulation adjuncts. Mean cardiopulmonary bypass time was 137 minutes, with mean nadir temperature of 30.5°C. The mean length of hospital stay was 6.2 days, with mean intensive care unit stay of 1.7 days. This cohort had zero 90‐day mortality in the perioperative period. Conclusions This case series demonstrates that bloodless cardiac surgery can be performed in select patients refusing allogeneic blood transfusion.