The pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the oxidation of glucose to acetyl-CoA. Phosphorylation of PDC by the pyruvate dehydrogenase kinases (PDK2 and PDK4) inhibits PDC activity. Expression of the PDK genes is elevated in diabetes, leading to the decreased oxidation of pyruvate to acetyl-CoA. In these studies we have investigated the transcriptional regulation of the PDK4 gene by the estrogenrelated receptors (ERR␣ and ERR␥). The ERRs are orphan nuclear receptors whose physiological roles include the induction of fatty acid oxidation in heart and muscle. Previously, we found that the peroxisome proliferator-activated receptor ␥ coactivator (PGC-1␣) stimulates the expression of PDK4. Here we report that ERR␣ and ERR␥ stimulate the PDK4 gene in hepatoma cells, suggesting a novel role for ERRs in controlling pyruvate metabolism. In addition, both ERR isoforms recruit PGC-1␣ to the PDK4 promoter. Insulin, which decreases the expression of the PDK4 gene, inhibits the induction of PDK4 by ERR␣ and ERR␥. The forkhead transcription factor (FoxO1) binds the PDK4 gene and contributes to the induction of PDK4 by ERRs and PGC-1␣. Insulin suppresses PDK4 expression in part through the dissociation of FoxO1 and PGC-1␣ from the PDK4 promoter. Our data demonstrate a key role for the ERRs in the induction of hepatic PDK4 gene expression. The pyruvate dehydrogenase complex (PDC)3 catalyzes the irreversible oxidative decarboxylation of pyruvate to acetylCoA (1). Long term changes in PDC activity entail changes in PDC phosphorylation, whereas short term inhibition is mediated by the reaction products acetyl-CoA and NADH (1, 2). The pyruvate dehydrogenase kinases (PDK) decrease PDC activity via phosphorylation, whereas the pyruvate dehydrogenase phosphatases activate the PDC activity by dephosphorylation (3, 4). There are three serine phosphorylation sites on the ␣-subunit of pyruvate dehydrogenase (E1) that are targeted by PDKs, and phosphorylation of the ␣-subunit of the E1 element completely inhibits the activity of PDC (4). There is increased phosphorylation of PDC in the heart and skeletal muscle in starvation and diabetes, allowing pyruvate to be conserved while fatty acid oxidation is increased (5-7). In diabetes the decrease in PDC activity is due primarily to the increased PDK activity (5).Four PDK isoenzymes (PDK1, -2, -3, -4) have been identified and characterized in mammalian tissues (1). The expression patterns of the PDK isoforms are tissue-specific (8). The PDK2 and PDK4 isoforms are highly expressed in liver, heart, and skeletal muscle (9). PDK2 and PDK4 gene expression is elevated with diabetes and starvation, with PDK4 being the most highly regulated isoform (2, 4). Insulin administration and refeeding inhibit the induction of PDK4 gene expression in the skeletal muscles and heart of diabetic and fasted animals, respectively (7, 10). In Morris hepatoma cells, long chain fatty acids, glucocorticoids, and peroxisome...

The pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the oxidation of glucose to acetyl-CoA. Phosphorylation of PDC by the pyruvate dehydrogenase kinases (PDK) inhibits its activity. The expression of the pyruvate dehydrogenase kinase 4 (PDK4) gene is increased in fasting and other conditions associated with the switch from the utilization of glucose to fatty acids as an energy source. Transcription of the PDK4 gene is elevated by glucocorticoids and inhibited by insulin. In this study, we have investigated the factors involved in the regulation of the PDK4 gene by these hormones. Glucocorticoids stimulate PDK4 through two glucocorticoid receptor (GR) binding sites located more than 6,000 base pairs upstream of the transcriptional start site. Insulin inhibits the glucocorticoid induction in part by causing dissociation of the GR from the promoter. Previously, we found that the estrogen related receptor alpha (ERRα) stimulates the expression of PDK4. Here, we determined that one of the ERRα binding sites contributes to the insulin inhibition of PDK4. A binding site for the forkhead transcription factor (FoxO1) is adjacent to the ERRα binding sites. FoxO1 participates in the glucocorticoid induction of PDK4 and the regulation of this gene by insulin. Our data demonstrate that glucocorticoids and insulin each modulate PDK4 gene expression through complex hormone response units that contain multiple factors.

The goal of this study was to assess the overtreatment of asymptomatic bacteriuria (ASB) in hospitalized patients, calculate the total costs of inappropriate treatment, and determine if a multi-faceted educational intervention was effective in reducing the overtreatment of ASB in a resource-limited community hospital. The study encompassed three phases: a retrospective pre-intervention assessment of the baseline cost and treatment of ASB, the implementation of a multi-faceted educational intervention, and a prospective post-intervention assessment of the efficacy of the intervention. A positive urine culture was defined by bacterial counts ≥105 cfu/mL. In the pre-intervention group, 64 (83%) of 109 patients were asymptomatic: 30 (47%) were treated. In the post-intervention group, 13 (17%) of 55 patients were asymptomatic: 2 (15%) were treated, (p=0.04). Fewer urine cultures were collected during the post-intervention period than the pre-intervention period (3,127 and 3,419, respectively) (p<0.001). The total cost of inappropriately treating ASB in the pre-intervention group was $1200 compared to $600 in the post-intervention group. The results demonstrated a significant decrease in the inappropriate treatment of ASB and the associated costs.

Intravenous fat emulsion (IFE) is emerging as a novel antidote in clinical toxicology. Its current usage is extending beyond local anaesthetic toxicity into management of severe toxicity from some lipophilic drugs. We present a 51-year-old woman with severe bupropion toxicity whose haemodynamic status transiently improved after IFE. Serum analysis demonstrated an increase in serum concentration of hydroxybupropion, an active metabolite of bupropion, after IFE administration, lending support to one of the proposed mechanisms of IFE. A 51-year-old woman presented to the emergency department with generalised tonic-clonic convulsions lasting approximately 30 sec., and a wide complex rhythm on her ECG that was suggestive of myocardial sodium channel blockade. Despite sodium bicarbonate therapy, the patient developed profound hypo-tension refractory to high-dose norepinephrine. IFE was administered with haemodynamic improvement over the course of 30 min., followed by a significant decrease in norepinephrine requirement. The patient had an episode of ventricular tachycar-dia 24 hr after presentation, and received a second infusion of IFE. Analysis of serum for a panel of myocardial sodium channel blocking drugs revealed that significant bupropion ingestion had occurred. Bupropion poisoning may produce life-threatening clinical effects, and IFE may be considered in cases of severe haemodynamic instability. Further studies would be instrumental in determining the optimal clinical situations for utilisation of IFE. Poisoned patients with severe haemodynamic compromise present a unique challenge to clinicians. Unlike sepsis or car-diogenic shock, the haemodynamic compromise in poisoned patients can generally reverse if the offending drug is removed from the target organ. Intravenous fat emulsion (IFE) is a relatively novel antidote that is well studied in animal models but only has anecdotal support in human poisoning [1,2]. Although the currently proposed mechanisms of action (lipid sink, improved cellular metabolism and modulation of ion channels) all have experimental support [3], the exact therapeutic mechanism remains unknown. By acting as a lipid sink, IFE may remove a portion of the lipo-philic drug from the target receptor and sequester it in the lipid phase of the blood. A previous case report chronicled haemodynamic and neurological recovery in a 17-year-old girl after administration of IFE in the setting of prolonged cardiac arrest from bupropion and lamotrigine toxicity [4]. Serum bupropion concentration increased markedly after IFE administration, presumably from redistribution from affected tissue into the lipid, lending support to the 'lipid sink' hypothesis. We report a 51-year-old woman who developed severe haemodynamic compromise after an ingestion of bupropion and received IFE with clinical improvement. Case Report A 51-year-old woman with a history of depression was brought to the hospital after two tonic-clonic convulsions at home. The husband reported that an undetermined number of diphenhydramine tab...

358 Background: The median age at diagnosis for metastatic pancreatic cancer (mPC) is 72. Gemcitabine and Nab-Paclitaxel (GA) is often the preferred chemo regimen in this population due to presumed reduced toxicity compared with FOLFIRINOX. While the traditional GA schedule (TDS) includes treatment on days 1, 8, and 15 of a 28-day cycle, it can cause side effects and patients often require dose reductions. There is data for a modified dosing schedule (MDS) treating only on day 1 and 15. Therefore, we retrospectively analyzed our older adults treated with GA using the TDS versus the MDS and compared tolerability and outcomes between the two groups. Methods: We identified pts with mPC >64 y/o treated with GA at Fox Chase Cancer Center between 1/2010 - 7/2018 and collected their demographic, disease and treatment information. We analyzed discrete variables using Fisher’s exact test and continuous variables using Wilcoxon tests. Overall survival (OS) was analyzed by the Kaplan-Meier method and Cox proportional hazards regression. Results: Fifty-six pts were identified with a median age at diagnosis of 71 (range: 64-90) and 67.8% with metastatic disease at presentation. 57% received GA in the first line. 44% were treated with TDS while 56% received a MDS; an older median age was seen in the MDS group (73 vs 69 y/o, p<0.001). Up front dose reductions of GA were seen in 24% in the TDS vs 48% in MDS, and they were more common with nab-paclitaxel (26% in MDS vs 10% in TDS) than with gemcitabine (two pts in TDS vs one pt in MDS). Of pts who began with TDS only 11 (19% of all pts) were able to tolerate it without adjustment throughout treatment; 14 (25%) transitioned to the MDS. More pts suffered grade ≥3 toxicity with the TDS vs. MDS (68% vs. 51%; p=0.27) and more required a dose reduction (TDS 72% vs. MDS 48%; p=0.1). 58% required an additional GA dose reduction over the course of treatment. Median OS among GA treated pts in the front line (n=32) was not significantly different (MDS: 11.7 mo vs. TDS: 13 mo; p=0.1). Conclusions: These results demonstrate tolerability and similar efficacy of the GA MDS among older adults with mPC. Given the limited sample size, further studies are required to help establish the appropriate therapy for older patients.