Bench-to-bedside review: The gut as an endocrine organ in the critically ill

In health, hormones secreted from the gastrointestinal tract have an important role in regulating gastrointestinal motility, glucose metabolism and immune function. Recent studies in the critically ill have established that the secretion of a number of these hormones is abnormal, which probably contributes to disordered gastrointestinal and metabolic function. Furthermore, manipulation of endogenous secretion, physiological replacement and supra-physiological treatment (pharmacological dosing) of these hormones are likely to be novel therapeutic targets in this group. Fasting ghrelin concentrations are reduced in the early phase of critical illness, and exogenous ghrelin is a potential therapy that could be used to accelerate gastric emptying and/or stimulate appetite. Motilin agonists, such as erythromycin, are effective gastrokinetic drugs in the critically ill. Cholecystokinin and peptide YY concentrations are elevated in both the fasting and postprandial states, and are likely to contribute to slow gastric emptying. Accordingly, there is a rationale for the therapeutic use of their antagonists. So-called incretin therapies (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) warrant evaluation in the management of hyperglycaemia in the critically ill. Exogenous glucagon-like peptide-2 (or its analogues) may be a potential therapy because of its intestinotropic properties

The effect of exogenous glucagon-like peptide-1 on the glycaemic response to small intestinal nutrient in the critically ill: a randomised double-blind placebo-controlled cross over study

IntroductionHyperglycaemia occurs frequently in the critically ill, affects outcome adversely, and is exacerbated by enteral feeding. Furthermore, treatment with insulin in this group is frequently complicated by hypoglycaemia. In healthy patients and those with type 2 diabetes, exogenous glucagon-like peptide-1 (GLP-1) decreases blood glucose by suppressing glucagon, stimulating insulin and slowing gastric emptying. Because the former effects are glucose-dependent, the use of GLP-1 is not associated with hypoglycaemia. The objective of this study was to establish if exogenous GLP-1 attenuates the glycaemic response to enteral nutrition in patients with critical illness induced hyperglycaemia.MethodsSeven mechanically ventilated critically ill patients, not previously known to have diabetes, received two intravenous infusions of GLP-1 (1.2 pmol/kg/min) and placebo (4% albumin) over 270 minutes. Infusions were administered on consecutive days in a randomised, double-blind fashion. On both days a mixed nutrient liquid was infused, via a post-pyloric feeding catheter, at a rate of 1.5 kcal/min between 30 and 270 minutes. Blood glucose and plasma GLP-1, insulin and glucagon concentrations were measured.ResultsIn all patients, exogenous GLP-1 infusion reduced the overall glycaemic response during enteral nutrient stimulation (AUC30-270 min GLP-1 (2077 +/- 144 mmol/l min) vs placebo (2568 +/- 208 mmol/l min); P = 0.02) and the peak blood glucose (GLP-1 (10.1 +/- 0.7 mmol/l) vs placebo (12.7 +/- 1.0 mmol/l); P ConclusionsAcute, exogenous GLP-1 infusion markedly attenuates the glycaemic response to enteral nutrition in the critically ill. These observations suggest that GLP-1 and/or its analogues have the potential to manage hyperglycaemia in the critically ill.Trial registrationAustralian New Zealand Clinical Trials Registry number: ACTRN12609000093280.Adam M. Deane, Marianne J. Chapman, Robert J.L. Fraser, Carly M. Burgstad, Laura K. Besanko and Michael Horowit

Fasting and nutrient-stimulated plasma peptide-YY levels are elevated in critical illness and associated with feed intolerance: an observational, controlled study

INTRODUCTION: Delayed gastric emptying and feed intolerance occur frequently in the critically ill. In these patients, gastric motor responses to nutrients are disturbed. Peptide YY (PYY) slows gastric emptying. The aim of this study was to determine fasting and nutrient-stimulated plasma PYY concentrations and their relationship to cholecystokinin (CCK) in critically ill patients. METHODS: Studies were performed in 19 unselected mechanically ventilated critically ill patients (12 males; 48 ± 7 years old) in a randomised, single-blind fashion. Subjects received a 60-minute duodenal infusion of Ensure(® )at either 1 or 2 kcal/minute. Blood samples were collected at baseline and at 20, 40, 60, and 180 minutes following commencement of the nutrient infusion for the measurement of plasma PYY and CCK concentrations (using radioimmunoassay). Patient data were compared to 24 healthy subjects (17 males; 43 ± 2 years old). RESULTS: Fasting PYY concentration was higher in patients (P < 0.05), particularly in those with feed intolerance (P < 0.05). Plasma PYY concentrations were higher in patients during nutrient infusion (area under the curve [AUC] at 1 kcal/minute: 2,265 ± 718 versus 1,125 ± 138 pmol/l.min, P < 0.05; at 2 kcal/minute: 2,276 ± 303 versus 1,378 ± 210 pmol/l.min, P = 0.01) compared to healthy subjects. The magnitude of PYY elevation was greater in patients during the 1 kcal/minute infusion (AUC: 441 ± 153 versus 186 ± 58 pmol/l.min, P < 0.05), but not the 2 kcal/minute infusion. Fasting and nutrient-stimulated plasma CCK concentrations were higher in patients (P < 0.05). There was a relationship between plasma PYY and CCK concentrations during fasting (r = 0.52, P < 0.05) and nutrient infusion (r = 0.98, P < 0.0001). CONCLUSION: In critical illness, both fasting and nutrient-stimulated plasma PYY concentrations are elevated, particularly in patients with feed intolerance, in conjunction with increased CCK concentrations

Exogenous glucagon-like peptide-1 attenuates the glycaemic response to postpyloric nutrient infusion in critically ill patients with type-2 diabetes

Extent: 11p.Introduction: Glucagon-like peptide-1 (GLP-1) attenuates the glycaemic response to small intestinal nutrient infusion in stress-induced hyperglycaemia and reduces fasting glucose concentrations in critically ill patients with type-2 diabetes. The objective of this study was to evaluate the effects of acute administration of GLP-1 on the glycaemic response to small intestinal nutrient infusion in critically ill patients with pre-existing type-2 diabetes. Methods: Eleven critically ill mechanically-ventilated patients with known type-2 diabetes received intravenous infusions of GLP-1 (1.2 pmol/kg/minute) and placebo from t = 0 to 270 minutes on separate days in randomised double-blind fashion. Between t = 30 to 270 minutes a liquid nutrient was infused intraduodenally at a rate of 1 kcal/min via a naso-enteric catheter. Blood glucose, serum insulin and C-peptide, and plasma glucagon were measured. Data are mean ± SEM. Results: GLP-1 attenuated the overall glycaemic response to nutrient (blood glucose AUC30-270 min: GLP-1 2,244 ± 184 vs. placebo 2,679 ± 233 mmol/l/minute; P = 0.02). Blood glucose was maintained at < 10 mmol/l in 6/11 patients when receiving GLP-1 and 4/11 with placebo. GLP-1 increased serum insulin at 270 minutes (GLP-1: 23.4 ± 6.7 vs. placebo: 16.4 ± 5.5 mU/l; P < 0.05), but had no effect on the change in plasma glucagon. Conclusions: Exogenous GLP-1 in a dose of 1.2 pmol/kg/minute attenuates the glycaemic response to small intestinal nutrient in critically ill patients with type-2 diabetes. Given the modest magnitude of the reduction in glycaemia the effects of GLP-1 at higher doses and/or when administered in combination with insulin, warrant evaluation in this group.Adam M Deane, Matthew J Summers, Antony V Zaknic, Marianne J Chapman, Robert JL Fraser, Anna E Di Bartolomeo, Judith M Wishart, Michael Horowit

Glucose absorption and gastric emptying in critical illness

Introduction: Delayed gastric emptying occurs frequently in critically ill patients and has the potential to adversely affect both the rate, and extent, of nutrient absorption. However, there is limited information about nutrient absorption in the critically ill, and the relationship between gastric emptying (GE) and absorption has hitherto not been evaluated. The aim of this study was to quantify glucose absorption and the relationships between GE, glucose absorption and glycaemia in critically ill patients. Methods: Studies were performed in nineteen mechanically ventilated critically ill patients and compared to nineteen healthy subjects. Following 4 hours fasting, 100 ml of Ensure, 2 g 3-Omethyl glucose (3-OMG) and ⁹⁹mTc sulphur colloid were infused into the stomach over 5 minutes. Glucose absorption (plasma 3- OMG), blood glucose levels and GE (scintigraphy) were measured over four hours. Data are mean ± SEM. A P-value 0.51; P < 0.05). Conclusions In critically ill patients; (i) the rate and extent of glucose absorption are markedly reduced; (ii) GE is a major determinant of the rate of absorption, but does not fully account for the extent of impaired absorption; (iii) blood glucose concentration could be one of a number of factors affecting GE.Marianne J Chapman, Robert JL Fraser, Geoffrey Matthews, Antonietta Russo, Max Bellon, Laura K Besanko, Karen L Jones, Ross Butler, Barry Chatterton and Michael Horowit

The Main Belt Comets and ice in the Solar System

We review the evidence for buried ice in the asteroid belt; specifically the questions around the so-called Main Belt Comets (MBCs). We summarise the evidence for water throughout the Solar System, and describe the various methods for detecting it, including remote sensing from ultraviolet to radio wavelengths. We review progress in the first decade of study of MBCs, including observations, modelling of ice survival, and discussion on their origins. We then look at which methods will likely be most effective for further progress, including the key challenge of direct detection of (escaping) water in these bodies

Using Dynamic Stochastic Modelling to Estimate Population Risk Factors in Infectious Disease: The Example of FIV in 15 Cat Populations

BACKGROUND:In natural cat populations, Feline Immunodeficiency Virus (FIV) is transmitted through bites between individuals. Factors such as the density of cats within the population or the sex-ratio can have potentially strong effects on the frequency of fight between individuals and hence appear as important population risk factors for FIV. METHODOLOGY/PRINCIPAL FINDINGS:To study such population risk factors, we present data on FIV prevalence in 15 cat populations in northeastern France. We investigate five key social factors of cat populations; the density of cats, the sex-ratio, the number of males and the mean age of males and females within the population. We overcome the problem of dependence in the infective status data using sexually-structured dynamic stochastic models. Only the age of males and females had an effect (p = 0.043 and p = 0.02, respectively) on the male-to-female transmission rate. Due to multiple tests, it is even likely that these effects are, in reality, not significant. Finally we show that, in our study area, the data can be explained by a very simple model that does not invoke any risk factor. CONCLUSION:Our conclusion is that, in host-parasite systems in general, fluctuations due to stochasticity in the transmission process are naturally very large and may alone explain a larger part of the variability in observed disease prevalence between populations than previously expected. Finally, we determined confidence intervals for the simple model parameters that can be used to further aid in management of the disease

Seroprevalence of 13 common pathogens in a rapidly growing U.S. minority population: Mexican Americans from San Antonio, TX

<p>Abstract</p> <p>Background</p> <p>Infection risks vary among individuals and between populations. Here we present information on the seroprevalence of 13 common infectious agents in a San Antonio-based sample of Mexican Americans. Mexican Americans represent the largest and most rapidly growing minority population in the U.S., and they are also considered a health disparities population.</p> <p>Methods</p> <p>We analyzed 1227 individuals for antibody titer to <it>Chlamydophila pneumoniae, Helicobacter pylori, Toxoplasma gondii</it>, cytomegalovirus, Epstein-Barr virus, herpes simplex virus-1, herpes simplex virus-2 (HSV-2), human herpesvirus-6 (HHV-6), varicella zoster virus (VZV), adenovirus-36, hepatitis A virus, and influenza A and B. Seroprevalence was examined as a function of sex, age, household income, and education.</p> <p>Results</p> <p>Seroprevalence estimates ranged from 9% for <it>T. gondii</it> to 92% for VZV, and were similar in both sexes except for HSV-2, which was more prevalent in women. Many pathogens exhibited a significant seroprevalence change over the examined age range (15-94 years), with 7 pathogens increasing and HHV-6 decreasing with age. Socioeconomic status significantly correlated with serostatus for some pathogens.</p> <p>Conclusions</p> <p>Our findings demonstrate substantial seroprevalence rates of these common infections in this sample of Mexican Americans from San Antonio, Texas that suffers from high rates of chronic diseases including obesity and type-2 diabetes.</p

An international reproducibility study validating quantitative determination of ERBB2, ESR1, PGR, and MKI67 mRNA in breast cancer using MammaTyper (R)

Background: Accurate determination of the predictive markers human epidermal growth factor receptor 2 (HER2/ERBB2), estrogen receptor (ER/ESR1), progesterone receptor (PgR/PGR), and marker of proliferation Ki67 (MKI67) is indispensable for therapeutic decision making in early breast cancer. In this multicenter prospective study, we addressed the issue of inter- and intrasite reproducibility using the recently developed reverse transcription-quantitative real-time polymerase chain reaction-based MammaTyper (R) test. Methods: Ten international pathology institutions participated in this study and determined messenger RNA expression levels of ERBB2, ESR1, PGR, and MKI67 in both centrally and locally extracted RNA from formalin-fixed, paraffin-embedded breast cancer specimens with the MammaTyper (R) test. Samples were measured repeatedly on different days within the local laboratories, and reproducibility was assessed by means of variance component analysis, Fleiss' kappa statistics, and interclass correlation coefficients (ICCs). Results: Total variations in measurements of centrally and locally prepared RNA extracts were comparable; therefore, statistical analyses were performed on the complete dataset. Intersite reproducibility showed total SDs between 0.21 and 0.44 for the quantitative single-marker assessments, resulting in ICC values of 0.980-0.998, demonstrating excellent agreement of quantitative measurements. Also, the reproducibility of binary single-marker results (positive/negative), as well as the molecular subtype agreement, was almost perfect with kappa values ranging from 0.90 to 1.00. Conclusions: On the basis of these data, the MammaTyper (R) has the potential to substantially improve the current standards of breast cancer diagnostics by providing a highly precise and reproducible quantitative assessment of the established breast cancer biomarkers and molecular subtypes in a decentralized workup.Peer reviewe

Distinct Patterns of DNA Damage Response and Apoptosis Correlate with Jak/Stat and PI3Kinase Response Profiles in Human Acute Myelogenous Leukemia

BACKGROUND:Single cell network profiling (SCNP) utilizing flow cytometry measures alterations in intracellular signaling responses. Here SCNP was used to characterize Acute Myeloid Leukemia (AML) disease subtypes based on survival, DNA damage response and apoptosis pathways. METHODOLOGY AND PRINCIPAL FINDINGS:Thirty four diagnostic non-M3 AML samples from patients with known clinical outcome were treated with a panel of myeloid growth factors and cytokines, as well as with apoptosis-inducing agents. Analysis of induced Jak/Stat and PI3K pathway responses in blasts from individual patient samples identified subgroups with distinct signaling profiles that were not seen in the absence of a modulator. In vitro exposure of patient samples to etoposide, a DNA damaging agent, revealed three distinct "DNA damage response (DDR)/apoptosis" profiles: 1) AML blasts with a defective DDR and failure to undergo apoptosis; 2) AML blasts with proficient DDR and failure to undergo apoptosis; 3) AML blasts with proficiency in both DDR and apoptosis pathways. Notably, AML samples from clinical responders fell within the "DDR/apoptosis" proficient profile and, as well, had low PI3K and Jak/Stat signaling responses. In contrast, samples from clinical non responders had variable signaling profiles often with in vitro apoptotic failure and elevated PI3K pathway activity. Individual patient samples often harbored multiple, distinct, leukemia-associated cell populations identifiable by their surface marker expression, functional performance of signaling pathway in the face of cytokine or growth factor stimulation, as well as their response to apoptosis-inducing agents. CONCLUSIONS AND SIGNIFICANCE:Characterizing and tracking changes in intracellular pathway profiles in cell subpopulations both at baseline and under therapeutic pressure will likely have important clinical applications, potentially informing the selection of beneficial targeted agents, used either alone or in combination with chemotherapy