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Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor with a need for novel therapies. So far, monotherapies have failed to prolong survival for these patients, and combinatorial strategies have often shown severe, dose-limiting toxicities. In this issue of the JCI, Duchatel, Jackson, and colleagues address this challenge by introducing a drug combination that mitigates side effects and overcomes resistance. After identifying the PI3K/mTOR pathway as a therapeutic vulnerability, they treated DIPG-bearing mice with paxalisib and saw responses but also observed hyperglycemia as a severe side effect. Combining paxalisib with metformin mitigated this toxicity, but also upregulated protein kinase C (PKC) signaling. To tackle this mechanism of resistance, the authors added the PKC inhibitor enzastaurin to their drug combination and showed that this triple therapy led to improved survival. This approach paves the way for improved outcomes for patients with DIPG and other brain tumors., Balancing safety and efficacy in treatment of DIPG The Swiss physician and philosopher Paracelsus famously said, 'All things are poison and nothing is without poison. Solely the dose determines that [...]

Background and Aims: The effect of a single intraoperative dose of steroids on perioperative blood sugar levels is uncertain. We hypothesised that a single dose of dexamethasone would not unfavourably alter the glucose levels of non-diabetic patients. This study aimed to evaluate the post-operative glycaemic profile after a single dose of intraoperative dexamethasone in non-diabetic patients. The presence of post-operative nausea and vomiting (PONV), pain, surgical site infection (SSI) and length of hospital stay were also evaluated. Methods: This randomised, double-blind, controlled study was done by recruiting 150 non-diabetic adult patients of the American Society of Anesthesiologists physical status I/II undergoing elective surgery. Patients in the study group were administered a single dose of dexamethasone (0.15 mg/kg). Blood glucose levels were assessed at various time points for up to 72 hours post-operatively using point-of-care testing. Secondary outcomes such as PONV, pain, fever and SSI were also documented. Data were compared and analysed using Student's t-test, Chi-square test, Mann-Whitney test and analysis of variance test. Results: There was an earlier, higher and prolonged elevation in blood glucose levels in patients receiving dexamethasone. The mean (standard deviation) of fasting/postprandial blood sugars on the first, second and third postoperative days respectively was significantly higher in the study group 98.04 (21.89)/139.16 (20.59), 96.64 (19.20)/138.17 (18.05), 96.60 (17.40)/138.32 (15.10) mg/dl as compared to control group 86.9 6 (10.28)/128.95 (10.53), 88.81 (8.87)/131.97 (9.68), 88.16 (8.50)/130.88 (9.48) mg/dl. About 10.7 of the patients who received dexamethasone had blood glucose levels greater than 180 mg/dl. There were no significant differences in the secondary outcomes. Conclusion: Even a single dose of dexamethasone in non-diabetic adults causes significant and prolonged postoperative hyperglycaemia. Keywords: Dexamethasone, hyperglycaemia, intraoperative period, postoperative period, Author(s): Vigil Peter (corresponding author) [1]; Usha Shenoy [1]; Buena Rukkiyabeevi [1] INTRODUCTION A single dose of dexamethasone is often administered in the intraoperative period for its anti-inflammatory, antiemetic, analgesic [...]

Byline: S. Parthasarathy, Sanjay. Kalra, Madhuri. Kurdi, Sukhminder. Singh Bajwa In spite of so many advancements in the medical sciences, precise control of hyperglycaemia has always been a tough challenge [...]

Byline: Sachin. Sogal, Priyanka. Mishra, Nishith. Govil Sir, Cytoreductive surgery (CRS)-hyperthermic intraperitoneal chemotherapy (HiPEC) is a popular topic of investigation for cancers with diffuse peritoneal metastasis.[1] Perioperative management for these [...]

Purpose Hyperglycaemia is common in the critically ill. The objectives of this study were to determine the prevalence of critical illness-associated hyperglycaemia (CIAH) and recognised and unrecognised diabetes in the critically ill as well as to evaluate the impact of premorbid glycaemia on the association between acute hyperglycaemia and mortality. Methods In 1,000 consecutively admitted patients we prospectively measured glycated haemoglobin (HbA.sub.1c) on admission, and blood glucose concentrations during the 48 h after admission, to the intensive care unit. Patients with blood glucose [greater than or equal to]7.0 mmol/l when fasting or [greater than or equal to]11.1 mmol/l during feeding were deemed hyperglycaemic. Patients with acute hyperglycaemia and HbA.sub.1c Results Of 1,000 patients, 498 (49.8 %) had CIAH, 220 (22 %) had recognised diabetes, 55 (5.5 %) had unrecognised diabetes and 227 (22.7 %) were normoglycaemic. The risk of death increased by approximately 20 % for each increase in acute glycaemia of 1 mmol/l in patients with CIAH and those with diabetes and HbA.sub.1c levels Conclusions Critical illness-associated hyperglycaemia is the most frequent cause of hyperglycaemia in the critically ill. Peak glucose concentrations during critical illness are associated with increased mortality in patients with adequate premorbid glycaemic control, but not in patients with premorbid hyperglycaemia. Optimal glucose thresholds in the critically ill may, therefore, be affected by premorbid glycaemia., Author(s): Mark P. Plummer [sup.1] [sup.2], Rinaldo Bellomo [sup.3] [sup.4], Caroline E. Cousins [sup.1], Christopher E. Annink [sup.1], Krishnaswamy Sundararajan [sup.1] [sup.2], Benjamin A. J. Reddi [sup.1] [sup.2], John P. [...]

Diabetes is a condition associated with high morbidity, elevated mortality, and a decreased quality of life, (1,2) In the United States, diabetes affects 25.8 million people and is estimated to [...]

A hallmark of diabetes is an absolute or relative reduction in the number of functional [beta] cells. Therapies that could increase the number of endogenous [beta] cells under diabetic conditions would be desirable. Prevalent gene targeting mouse models for assessing [beta]-cell proliferation and diabetes pathogenesis only address whether deletion of a gene prevents the development of diabetes. Models testing whether acute excision of a single gene can ameliorate or reverse preexisting hyperglycemia in established diabetes remain to be explored, which could directly validate the effect of gene excision on treating diabetes. Here, we report that acute and temporally controlled excision of the Men1 gene, which encodes menin, ameliorated preexisting hyperglycemia in streptozotocin-treated mice. Moreover, Men1 excision also improved the preexisting hyperglycemia and glucose intolerance in genetic db/db diabetic mice. Furthermore, acute Men1 excision reversed preexisting glucose intolerance in high-fat diet-fed mice. Men1 excision improved glucose metabolism at least partly through increasing proliferation of endogenous [beta] cells and islet size. Acute Men1 excision up-regulated a group of proproliferative genes in pancreatic islets. Together, these findings demonstrate that established hyperglycemia can be reversed through repression of a single gene, Men1, in diabetic conditions, and suggest that menin is a vital regulator in pathogenesis of diabetes. cell proliferation | db/db | high-fat diet | type 2 diabetes doi/ 10.1073/pnas.1012257107

Hyperglycemia is an indication of poor outcome for heart attack patients, even for nondiabetic patients with stress-induced hyperglycemia. Previous studies showed that inhibition of aldose reductase, the first and rate-limiting enzyme of the polyol pathway, attenuated contractile dysfunction in diabetic animals, but the mechanism is unclear. We therefore wanted to find out whether the polyol pathway also contributes to acute hyperglycemia-induced cardiac contractile dysfunction, and determine the mechanism involved. Rat hearts were isolated and retrogradely perfused with Krebs buffer containing either normal or high concentrations of glucose for 2 h. Short exposure to high-glucose medium led to contractile dysfunction as indicated by decreased -dP/[dt.sub.max], as well as elevation in left ventricular end-diastolic pressure. Cardiomyocytes incubated in high-glucose medium showed abnormal [Ca.sup.2+] signaling, most likely because of decreased activity of sarco(endo)plasmic reticulum [Ca.sup.2+]-ATPase (SERCA) inactivated by oxidative stress. Inhibition of aldose reductase or sorbitol dehydrogenase, the second enzyme in the polyol pathway, ameliorated contractile dysfunction, attenuated oxidative stress, and normalized [Ca.sup.2+] signaling and SERCA activity caused by high glucose, indicating that the polyol pathway is the major contributor to acute hyperglycemia-induced oxidative stress leading to the inactivation of SERCA and contractile dysfunction. sarco(endo)plasmic reticulum [Ca.sup.2+]-ATPase; sorbitol dehydrogenase; aldose reductase doi: 10.1152/ajpcell.00137.2010.

Delayed gastric emptying is common following severe large cutaneous burns; however, the mechanisms of burn-induced delayed gastric emptying remain unknown. The aim of this study was to explore the possible involvement of hyperglycemia and cyclooxygenase-2 receptors in the burn-induced gastric dysrhythmias. Gastric slow waves and gastric emptying were assessed in rats 6 h following sham or burn injury. Animals were randomized to one sham-burn and seven burn groups: untreated; two groups of saline treated (control); insulin treated (5 IU/kg); cyclooxygenase-2 inhibitor treated (10 mg/kg); ghrelin treated (2 nmol/rat); and gastric electrical stimulation treated. It was found that 1) severe burn injury impaired gastric slow waves postprandially and delayed gastric emptying; 2) the impairment in gastric slow waves included a decrease in the slow-wave frequency and in the percentage of normal slow waves, and an increase in the percentage of bradygastria (P = 0.001, 0.01, and 0.01, respectively vs. preburn values). None of the gastric slow-wave parameters was significantly correlated with gastric emptying; 3) cyclooxygenase-2 inhibitor normalized burn-induced delayed gastric emptying (P = 0.3 vs. sham-burn), but not gastric dysrhythmias (P < 0.002 vs. sham), whereas insulin normalized both gastric emptying (P = 0.4 vs. sham-burn) and gastric dysrhythmias (P = 0.3 vs. sham-burn); 4) both gastric electrical stimulation and ghrelin accelerated burn-induced delayed gastric emptying (P = 0.002 and 0.04, respectively, vs. untreated burn). In conclusion, hyperglycemia alters gastric slow-wave activity and delayed gastric emptying, while cyclooxygenase-2 inhibition delays gastric emptying without altering gastric slow-wave activity. cyclooxygenase inhibitor; gastric electrical stimulation; ghrelin; insulin doi: 10.1152/ajpregu.00135.2010.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2009.05.036 Byline: Satish Arora (a)(b)(c), PA[yen]l Aukrust (b)(c), Arne Andreassen (a), Svein Simonsen (a), Einar Gude (a), Ingelin Grov (a), Odd Geiran (c)(d), Arnt Fiane (d), Lars Gullestad (a)(c) Abstract: It is well established that the treatment of modifiable risk factors can reduce cardiovascular mortality in the general population. However, there is limited data evaluating the importance of modifiable risk factors for survival following heart transplantation (HTx). Hence, we evaluated the prognostic importance of smoking, obesity, hyperglycemia and hyperlipidemia at 1 year after HTx for all-cause and cardiac mortality. Author Affiliation: (a) Department of Cardiology, Rikshospitalet Medical Center, Oslo, Norway (b) Research Institute for Internal Medicine, Rikshospitalet Medical Center, Oslo, Norway (c) Faculty Division Rikshospitalet, University of Oslo, Norway (d) Department of Thoracic and Cardiovascular Surgery, Rikshospitalet Medical Center, Oslo, Norway Article History: Received 15 December 2008; Accepted 25 May 2009

A study to establish a relationship between mild hyperglycemia and chances of adverse outcomes during pregnancy is conducted. Results indicate that some sort of relationship between mild hyperglycemia and increased birth weight and increased cord-blood serum C-peptide levels.

OBJECTIVE: To evaluate whether elevated intraoperative blood glucose concentrations are associated with an increased risk of long-term neurologic dysfunction in patients at risk for ischemic brain injury. PATIENTS AND METHODS: Data from 1000 patients were retrieved from the Intraoperative Hypothermia for Aneurysm Surgery Trial database. All patients were recruited between February 2000 and April 2003, and underwent surgery for aneurysm clipping within 14 days of subarachnoid hemorrhage. Gross neurologic and neuropsychological function was evaluated at 3 months after surgery using certified observers and standardized assessment instruments. Intraoperative blood glucose concentrations, measured once when the aneurysm clip was placed, were correlated with neurologic outcome using both univariable and multivariable logistic regression analyses. RESULTS: Blood glucose concentrations at the time of aneurysm clipping ranged from 59 to 331 mg/dL. At 3 months after surgery, those with blood glucose concentrations of 129 mg/dL or more (upper 2 quartiles) were more likely to have impaired cognition (P=.03). Those with glucose concentrations of 152 mg/dL or more (upper quartile) were more likely to experience deficits in gross neurologic function assessed by the National Institutes of Health Stroke Scale (P CONCLUSION: In patients at high risk for ischemic brain injury, intraoperative hyperglycemia, of a magnitude commonly encountered clinically, was associated with long-term changes in cognition and gross neurologic function. Mayo Clin Proc. 2008;83(4):406-417, Both animal models and human case series have demonstrated an association between elevated blood glucose concentration and poor outcome after ischemic brain injury. (1-8) In many of these studies, glucose [...]

OBJECTIVES: To determine the accuracy of bedside glucose strip assay on capillary blood and on whole blood and to identify factors predictive of discrepancies with the laboratory method. PATIENTS AND METHODS: We conducted a prospective 3-month (July 1-September 30, 2003) study in 85 consecutive patients who required blood glucose monitoring. Values obtained with a glucose test strip on capillary blood and on whole blood were compared with those obtained in the laboratory during serial blood sampling (up to 4 samples per patient). The test strip values were considered to disagree significantly with the laboratory values when the difference exceeded 20%. Clinical and biological parameters and the perfusion index, based on percutaneous oxygen saturation monitoring, were recorded when each sample was obtained. RESULTS: Capillary glucose values conflicted with laboratory reference values in 15% of samples. A low perfusion index was predictive of conflicting values (P=.04). Seven percent of values obtained with glucose strip on whole-blood samples conflicted with laboratory reference values; factors associated with these discrepancies were mean arterial hypotension (P=.007) and generalized mottling (P=.04). CONCLUSION: Bedside blood glucose values must be interpreted with care in critically ill patients. A low perfusion index, reflecting peripheral hypoperfusion, is associated with poor glucose strip performance. Bedside measurements in whole blood seem to be most reliable, except in patients with arterial hypotension and generalized mottling. Mayo Clin Proc. 2008;83(4):400-405, In critically ill patients, hyperglycemia is associated with increased mortality, (1-3) with no threshold effect. (4) Intensive insulin therapy with close finger-stick glucose monitoring reduced mortality in a medical-surgical population [...]

Hyperglycemia triggers an exponential increase in reactive oxygen species (ROS) at the cellular level. Here, we demonstrate induction of the oxidant-resistant phenotype in mesangial cells by silencing the wild-type (WT) p66ShcA gene. Two approaches were employed to inhibit WTp66ShcA in SV40 murine mesangial cells and normal human mesangial cells: transient transfection with isoform-specific p66ShcA short-intervening RNA and stable transfection with mutant 36 p66ShcA expression vector. At high ambient glucose (HG), p66ShcA-deficient cells exhibit resistance to HG-induced ROS generation and attenuation in the amplitude of the kinetic curves for intracellular ROS metabolism, indicative of the pivotal role of WTp66ShcA in the generation of HG oxidant stress. We next examined phosphorylation and subcellular distribution of FKHRL1 (FOXO3a), a potent stress response regulator and downstream target of WTp66ShcA redox function. At HG, cell extracts of p66ShcA-deficient cells analyzed by immunoblotting show attenuation of FOXO3a phosphorylation at Thr-32, and indirect immunofluorescence of p66ShcA-deficient cells, cotransfected with HA-FOXO3a, show predominant HA-FOXO3a nuclear localization. Conversely, parental cells at HG show upregulation of phos-Thr-32 and nuclear export of HA-FOXO3a. To determine whether inhibition of cross talk between WTp66ShcA and FOXO3a confers protection against oxidant-induced DNA damage, DNA strand breaks (DSB) and apoptosis were examined. At HG, p66ShcA-deficient cells exhibit increased resistance to DSB and apoptosis, while parental cells show a striking increase in both parameters. We conclude that knockdown of WTp66ShcA redox function prevents HG-dependent FOXO3a regulation and promotes the survival phenotype. reactive oxygen species; DNA damage; redox function

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2005.07.030 Byline: Isabella Sudano (a), Lukas E. Spieker (a), Georg Noll (a), Roberto Corti (a), Rainer Weber (b), Thomas F. Luscher (a) Abstract: The survival of patients with HIV infection who have access to highly active antiretroviral therapy has dramatically increased. In HIV-infected persons, cardiovascular disease can be associated with HIV infection, opportunistic infections or neoplasias, use of antiretroviral drugs or treatment of opportunistic complications, mode of HIV acquisition (such as intravenous drug use), or with the classic non-HIV-related cardiovascular risk factors (such as smoking or age). Diseases of the heart associated with HIV infection or its opportunistic complications include pericarditis and myocarditis. Pericarditis may lead to pericardial effusion rarely causing tamponade. Cardiomyopathy is often clinically silent with asymptomatic left ventricular systolic dysfunction. Endocarditis is mainly the consequence of intravenous drug abuse, possibly leading to life-threatening valvular insufficiency with the need for cardiac surgery. A further serious condition associated with HIV infection is pulmonary hypertension potentially leading to right heart failure. The cardiovascular complications of HIV infection such as cardiomyopathy and pericarditis have been reduced by highly active antiretroviral therapy, but premature coronary atherosclerosis is now a growing problem because antiretroviral drugs can lead to serious metabolic disturbances resembling those in the metabolic syndrome. Lipodystrophy, a clinical syndrome of peripheral fat wasting, central adiposity, dyslipidemia, and insulin resistance, is most prevalent among patients treated with protease inhibitors. These patients should thus be screened for hyperlipidemia, hyperglycemia, and hypertension, and they may be candidates for lipid-lowering therapies. When initiating lipid-lowering therapy, interactions between statins and HIV protease inhibitors affecting cytochrome P450 function must be considered. Restenosis rate after percutaneous coronary intervention may be unexpectedly high. Author Affiliation: (a) Cardiology, Cardiovascular Center, University Hospital Zurich, Switzerland (b) Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Switzerland Article History: Received 21 July 2004; Accepted 30 July 2005

Assessment of the respective contributions of sustained chronic hyperglycemia and of acute glucose fluctuations to oxidative stress in type 2 diabetes was done. It was found that glucose fluctuations during postprandial periods and more generally, during glucose swings exhibited a more specific triggering effect on oxidative stress than chronic sustained hyperglycemia.