Neurogenin3 (ngn3), a basic helix-loop-helix (bHLH) transcription factor, functions as a pro-endocrine factor in the developing pancreas: by itself, it is sufficient to force undifferentiated pancreatic epithelial cells to become islet cells. Because ngn3 expression determines which precursor cells will differentiate into islet cells, the signals that regulate ngn3 expression control islet cell formation. To investigate the factors that control ngn3 gene expression, we mapped the human and mouse ngn3 promoters and delineated transcriptionally active sequences within the human promoter. Surprisingly, the human ngn3 promoter drives transcription in all cell lines tested, including fibroblast cell lines. In contrast, in transgenic animals the promoter drives expression specifically in regions of ngn3 expression in the developing pancreas and gut; and the addition of distal sequences greatly enhances transgene expression. Within the distal enhancer, binding sites for several pancreatic transcription factors, including hepatocyte nuclear factor (HNF)-1 and HNF-3, form a tight cluster. HES1, an inhibitory bHLH factor activated by Notch signaling, binds to the proximal promoter and specifically blocks promoter activity. Together with previous genetic data, these results suggest a model in which the ngn3 gene is activated by the coordinated activities of several pancreatic transcription factors and inhibited by Notch signaling through HES1. Diabetes 50:928 -936, 2001
Critical Care 2017, 21(Suppl 1):P349 Introduction Imbalance in cellular energetics has been suggested to be an important mechanism for organ failure in sepsis and septic shock. We hypothesized that such energy imbalance would either be caused by metabolic changes leading to decreased energy production or by increased energy consumption. Thus, we set out to investigate if mitochondrial dysfunction or decreased energy consumption alters cellular metabolism in muscle tissue in experimental sepsis. Methods We submitted anesthetized piglets to sepsis (n = 12) or placebo (n = 4) and monitored them for 3 hours. Plasma lactate and markers of organ failure were measured hourly, as was muscle metabolism by microdialysis. Energy consumption was intervened locally by infusing ouabain through one microdialysis catheter to block major energy expenditure of the cells, by inhibiting the major energy consuming enzyme, N+/K + -ATPase. Similarly, energy production was blocked infusing sodium cyanide (NaCN), in a different region, to block the cytochrome oxidase in muscle tissue mitochondria. Results All animals submitted to sepsis fulfilled sepsis criteria as defined in Sepsis-3, whereas no animals in the placebo group did. Muscle glucose decreased during sepsis independently of N+/K + -ATPase or cytochrome oxidase blockade. Muscle lactate did not increase during sepsis in naïve metabolism. However, during cytochrome oxidase blockade, there was an increase in muscle lactate that was further accentuated during sepsis. Muscle pyruvate did not decrease during sepsis in naïve metabolism. During cytochrome oxidase blockade, there was a decrease in muscle pyruvate, independently of sepsis. Lactate to pyruvate ratio increased during sepsis and was further accentuated during cytochrome oxidase blockade. Muscle glycerol increased during sepsis and decreased slightly without sepsis regardless of N+/K + -ATPase or cytochrome oxidase blocking. There were no significant changes in muscle glutamate or urea during sepsis in absence/presence of N+/K + -ATPase or cytochrome oxidase blockade. ConclusionsThese results indicate increased metabolism of energy substrates in muscle tissue in experimental sepsis. Our results do not indicate presence of energy depletion or mitochondrial dysfunction in muscle and should similar physiologic situation be present in other tissues, other mechanisms of organ failure must be considered. , and long-term follow up has shown increased fracture risk [2]. It is unclear if these changes are a consequence of acute critical illness, or reduced activity afterwards. Bone health assessment during critical illness is challenging, and direct bone strength measurement is not possible. We used a rodent sepsis model to test the hypothesis that critical illness causes early reduction in bone strength and changes in bone architecture. Methods 20 Sprague-Dawley rats (350 ± 15.8g) were anesthetised and randomised to receive cecal ligation and puncture (CLP) (50% cecum length, 18G needle single pass through anterior and posterior wa...
ImportanceAdvance care planning (ACP) prepares patients and caregivers for medical decision-making, yet it is underused in the perioperative surgical setting, particularly among older adults undergoing high-risk procedures who are at risk for postoperative complications. It is unknown what patient factors are associated with perioperative ACP documentation among older surgical patients.ObjectiveTo assess ACP documentation among high-risk patients 65 years and older undergoing elective surgery.Design, Setting, and ParticipantsIn this observational cohort study including 3671 patients 65 years and older undergoing elective surgery at a tertiary academic center in California, electronic health record data were linked to the National Surgical Quality Improvement Project outcomes data and the California statewide death registry. The study was conducted from January 1 to December 31, 2019. Data were analyzed from January to May 2022.ExposuresElective surgery requiring an inpatient admission.Main Outcomes and MeasuresACP documentation, defined as a discussion regarding goals of care documented in an ACP note, an advance directive, or a physician order for life-sustaining treatment (POLST) form, within 90 days before elective surgery requiring inpatient admission. Multivariate regression was performed to identify factors associated with missing ACP.ResultsAmong 3671 patients (median [IQR] age 72 [65-94] years; 1784 [48.6%] female; 401 [10.9%] Asian, 155 [4.2%] Black, 284 [7.7%] Latino/Latina, 2647 [72.1%] White, and 184 [5.0%] of other races or ethnicities, including American Indian or Alaska Native, Native Hawaiian or Pacific Islander, multiple races or ethnicities, other, and unknown or declined to respond, combined owing to small numbers), 539 (14.7%) had ACP documentation in the 90-day presurgery window. Of these 539, 448 (83.1%) had advance directives, and 60 (11.1%) had POLST forms. The 30-day and 1-year mortality were 0.7% (n = 27) and 6.6% (n = 244), respectively. Missing ACP was significantly associated with male sex (adjusted odds ratio [aOR], 1.39; 95% CI, 1.14-1.69) and having a non-English preferred language (aOR, 1.78; 95% CI, 1.18-2.79). Medicare insurance was significantly associated with having ACP (aOR for missing ACP, 0.63; 95% CI, 0.40-0.95).Conclusions and RelevanceIn this study, perioperative ACP was uncommon, particularly in men, individuals with a non-English preferred language, and those without Medicare insurance coverage. The perioperative setting may represent a missed opportunity for ACP for older surgical patients. When addressing ACP for surgical patients, particular attention should be paid to overcoming language-related disparities.
The Current State of Surgical Care for Patients Who Are Homeless Homelessness is a national crisis. In the US, 580 466 people experienced homelessness on 1 night in 2020, up by 2.2% from 2019. 1 Compared with housed individuals, unhoused people have higher rates of chronic health conditions and mental illness, are hospitalized younger, and face barriers to obtaining adequate primary and preventive health care. To date, much of the scientific literature has focused on the medical and psychiatric care of the homeless population, with little research performed to guide surgical teams in tailoring surgical care and ensuring equitable delivery to the unhoused. Housing status undoubtedly affects surgical management, from preoperative assessment and preparation to intraoperative decision-making to postoperative care and rehabilitation (Figure). As homelessness rates rise, equipping surgeons with the tools to provide equitable, patient-centered care for this vulnerable population will be vital.The intersection of homelessness and surgical conditions has been evaluated in few studies. The largest cohorts come from national registries, like the Veterans Administration (VA), including a study by Titan et al 2 that found disproportionately higher rates of readmissions in patients who are homeless discharged to the community following surgery. The limited literature highlights risk factors for surgical complications or issues with postoperative care in the homeless individuals, like increased risk of infection or higher rates of readmission, usually in small series. Very few studies have identified strategies to address these inequities.
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