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2. Stimulation of small intestinal burst activity in the postprandial state differentially affects lipid and glucose absorption in healthy adult humans

Author

Bryant, L.K., Fraser, R.J., Vozzo, R., Zacharakis, B., Matthews, G.M., and Butler, R.

Subjects
Intestine, Small -- Research, Biological sciences
Abstract

Stimulation of small intestinal burst activity in the postprandial state differentially affects lipid and glucose absorption in healthy adult humans. Am J Physiol Gastrointest Liver Physiol 287: G1028-G1034, 2004. First published June 10, 2004; doi:10.1152/ajpgi.00091.2004.--Small intestinal motor activity is important lot the optimal digestion and absorption of nutrients. These motor responses to feeding are frequently abnormal during critical illness, with the persistence of migrating bursts of contractions during enteral feeding. Whether this disturbance influences nutrient absorption is not known. In this study, the effects of small intestinal burst activity on lipid and glucose absorption were evaluated in 10 healthy human adults (6 males, 4 females, 19-47 yr). Upper gastrointestinal manometry was recorded for 6 h during and shortly after a 20-min intravenous infusion of either erythromycin (1 mg/kg), to stimulate burst activity, or saline (0.9%) in a double-blind randomized fashion. Simultaneously with the start of the intravenous infusion, 60 ml liquid teed mixed with 200 [micro]l [sup.13]C-triolein and 2 g 3-O-methylglucose (3-OMG) was infused intraduodenally/or 30 min, Absorption of lipid and glucose was assessed using the [[sup.13]C]triolein breath test and plasma concentrations of 3-OMG, respectively. Infusion of erythromycin was followed by a more rapid onset of burst activity following commencement of the duodenal infusion compared with saline (30 [+ or -] 6.1 vs. 58 [+ or -] 10,7 min; P < 0.05). Erythromycin was associated with a slower recovery of [sup.13]C[O.sub.2] (P < 0.01). A positive correlation existed between the time to onset of burst activity and [sup.13]C[O.sub.2] recovery (P < 0.001). Erythromycin had no effect on 3-OMG absorption. In conclusion, stimulation of small intestinal burst activity reduces the rate of lipid absorption but not glucose absorption in healthy human adults. motor activity; erythromycin; triolein: 3-O-methylglucose

Published
2004

9. Lack of diagnostic accuracy of the monoclonal stool antigen test for detection of helicobacter pylori infection in young Australian aboriginal children

Author

Ritchie, B., Brewster, D., Tran, C., McNeil, Yvette, Zacharakis, B., Davidson, G., Butler, R., Ritchie, B., Brewster, D., Tran, C., McNeil, Yvette, Zacharakis, B., Davidson, G., and Butler, R.

Abstract

BACKGROUND:: The prevalence of Helicobacter pylori infection among Aboriginal Australians children is unclear. The aims of the present study are to determine the prevalence of H. pylori infection among young Aboriginal children recovering from acute diarrheal disease in hospital and to evaluate the H. pylori stool antigen test as a noninvasive diagnostic test in this setting. METHODS:: This was a prospective comparative study using the C-Urea Breath Test as reference standard. Fifty-two children between 4 months and 2 years of age were consecutively enrolled. These children comprised a representative sample of Australian Aboriginal children admitted to hospital with acute diarrheal disease from remote and rural communities across Northern Territory of Australia. RESULTS:: The overall prevalence of H. pylori was 44.2%. The stool antigen test had a sensitivity of 0.55 (95% confidence interval [CI]: 0.35-0.73) with a positive predictive value of 0.65 (95% CI: 0.42-0.82). The specificity was 0.68 (95% CI: 0.46-0.84) with a negative predictive value of 0.58 (95% CI: 0.39-0.75). Analysis of receiver operator characteristic curve yielded an overall accuracy of the stool antigen test of 61% (48%-75%). CONCLUSIONS:: The prevalence of H. pylori infection among very young Aboriginal children from remote and rural communities was high and consistent with early acquisition. The diagnostic accuracy of the stool antigen test to diagnose H. pylori in this setting was poor.

Published
2009

10. A novel non-invasive biomarker for assessment of small intestinal mucositis in children with cancer undergoing chemotherapy

Author

Tooley, K., Saxon, B., Webster, B., Zacharakis, B., McNeil, Yvette, Davidson, G., Butler, R., Tooley, K., Saxon, B., Webster, B., Zacharakis, B., McNeil, Yvette, Davidson, G., and Butler, R.

Abstract

Background: Small intestinal mucositis is a common side-effect following high-dose chemotherapy, causing patients to experience pain and abdominal complications often leading to extended stays in hospital. A biomarker to detect these small intestinal changes does not exist in clinical practice. This study aimed to assess the non-invasive 13C-Sucrose breath test (SBT) to detect small intestinal damage associated with mucositis in pediatric cancer patients having chemotherapy. Patients and Methods: Small intestinal function was assessed in 15 pediatric cancer patients and 26 healthy children. Subjects were studied for small intestinal permeability (SIP; lactulose/rhamnose), digestive and absorptive capacity (SBT; sucrose), and oro-cecal transit time (OCTT; lactulose), by ingesting two sugar drinks containing the respective sugars. Combined tests were carried out at baseline, day1, day3-5 and day6-9, and in healthy individuals on two separate occasions. A total of 25 cycles of chemotherapy were assessed. Breath samples for the SBT were collected every 15min for 3 h (expressed as % cumulative dose at 90min (CD)), a 5 h urine collection for SIP and breath hydrogen determined every 30min for 3 h for OCTT. Results: Clinical mucositis occurred in seven of the 25 cycles of chemotherapy (28%). No significant difference was observed for SIP and OCTT. The SBT %CD at 90min was significantly lower in the mucositis group compared to the unaffected group and controls at baseline (p < 0.05). Patients who developed mucositis maintained a significantly lower %CD, for all test points (p < 0.05) compared to the unaffected patients. In patients who developed mucositis the SBT was below the reference range of the controls at all time points. Conclusion: The findings show for the first time that it is possible to non-invasively detect and monitor gut damage associated with chemotherapy-inducedmucositis in pediatric cancer patients.

Published
2006

14. The apoptosis-inducing granulocyte-macrophage colony-stimulating factor (GM-CSF) analog E21R functions through specific regions of the heterodimeric GM-CSF receptor and requires interleukin-1beta-converting enzyme-like proteases.

Author

Iversen, P O, Hercus, T R, Zacharakis, B, Woodcock, J M, Stomski, F C, Kumar, S, Nelson, B H, Miyajima, A, and Lopez, A F

Abstract

The granulocyte-macrophage colony-stimulating factor (GM-CSF) analog E21R induces apoptosis of hemopoietic cells. We examined the GM-CSF receptor subunit requirements and the signaling molecules involved. Using Jurkat T cells transfected with the GM-CSF receptor we found that both receptor subunits were necessary for E21R-induced apoptosis. Specifically, the 16 membrane-proximal residues of the alpha subunit were sufficient for apoptosis. This sequence could be replaced by the corresponding sequence from the interleukin-2 receptor common gamma subunit, identifying this as a conserved cytokine motif necessary for E21R-induced apoptosis. Cells expressing the alpha subunit and truncated betac mutants showed that the 96 membrane-proximal residues of betac were sufficient for apoptosis. E21R, in contrast to GM-CSF, did not alter tyrosine phosphorylation of betac, suggesting that receptor-associated tyrosine kinases were not activated. Consistent with this, E21R decreased the mitogen-activated protein kinase ERK (extracellular signal-regulated kinase). E21R-induced apoptosis was independent of Fas/APO-1 (CD95) and required interleukin-1beta-converting enzyme (ICE)-like proteases. In contrast, Bcl-2, which protects cells from growth factor deprivation-induced cell death, did not prevent this apoptosis. These findings demonstrate the GM-CSF receptor and ICE-like protease requirements for E21R-induced apoptosis.

Published
1997

15. Identification of a Cys motif in the common beta chain of the interleukin 3, granulocyte-macrophage colony-stimulating factor, and interleukin 5 receptors essential for disulfide-linked receptor heterodimerization and activation of all three receptors.

Author

Stomski, F C, Woodcock, J M, Zacharakis, B, Bagley, C J, Sun, Q, and Lopez, A F

Abstract

The human interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors undergo covalent dimerization of the respective specific alpha chains with the common beta subunit (betac) in the presence of the cognate ligand. We have now performed alanine substitutions of individual Cys residues in betac to identify the Cys residues involved and their contribution to activation of the IL-3, GM-CSF, and IL-5 receptors. We found that substitution of Cys-86, Cys-91, and Cys-96 in betac but not of Cys-100 or Cys-234 abrogated disulfide-linked IL-3 receptor dimerization. However, although Cys-86 and Cys-91 betac mutants retained their ability to form non-disulfide-linked dimers with IL-3Ralpha, substitution of Cys-96 eliminated this interaction. Binding studies demonstrated that all betac mutants with the exception of C96A supported high affinity binding of IL-3 and GM-CSF. In receptor activation experiments, we found that betac mutants C86A, C91A, and C96A but not C100A or C234A abolished phosphorylation of betac in response to IL-3, GM-CSF, or IL-5. These data show that although Cys-96 is important for the structural integrity of betac, Cys-86 and Cys-91 participate in disulfide-linked receptor heterodimerization and that this linkage is essential for tyrosine phosphorylation of betac. Sequence alignment of betac with other cytokine receptor signaling subunits in light of these data shows that Cys-86 and Cys-91 represent a motif restricted to human and mouse beta chains, suggesting a unique mechanism of activation utilized by the IL-3, GM-CSF, and IL-5 receptors.

Published
1998

16. A single tyrosine residue in the membrane-proximal domain of the granulocyte-macrophage colony-stimulating factor, interleukin (IL)-3, and IL-5 receptor common beta-chain is necessary and sufficient for high affinity binding and signaling by all three ligands.

Author

Woodcock, J M, Bagley, C J, Zacharakis, B, and Lopez, A F

Abstract

The beta-chain of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) receptors functions as a communal receptor subunit and is often referred to as beta common (betac). Analogous to other shared receptor subunits including gp130 and the IL-2R gamma chain, betac mediates high affinity binding and signal transduction of all of its ligands. It is not clear, however, how these common receptor subunits can recognize several ligands and indeed whether they exhibit a common binding pocket to accomplish this. We have performed molecular modeling of betac based on the known structures of the growth hormone and prolactin receptors and targeted the putative F'-G' loop for mutagenesis. Substitution of this whole predicted loop region with alanines completely abrogated high affinity binding of GM-CSF, IL-3, and IL-5. Individual alanine substitutions across the loop revealed that a single residue, Tyr421, is critical for high affinity binding of GM-CSF, IL-3, and IL-5, whereas alanine substitution of adjacent residues has little or no effect on high affinity binding. Significantly, reintroducing Tyr421 into the polyalanine-substituted mutant restored high affinity ligand binding of GM-CSF, IL-3, and IL-5, indicating that within this region the tyrosine residue alone is sufficient for high affinity ligand interaction. Functional studies measuring STAT5 activation revealed that alanine substitution of Tyr421 severely impaired the ability of betac to signal. These results show for the first time that a single residue in a shared receptor subunit acts as a binding determinant for different ligands and may have implications for other receptor systems where communal receptor subunits exhibit hydrophobic residues in their putative F'-G' loops. These results also raise the possibility that a single compound targeted to this region may simultaneously inhibit the binding and function of multiple cytokines.

Published
1996

21. Long-standing type II diabetes mellitus is not a risk factor for slow gastric emptying in critically ill patients

Author

Ross N. Butler, Nam Q. Nguyen, Richard H. Holloway, Geoffrey P. Davidson, Marianne J. Chapman, Betty Zacharakis, Laura K. Bryant, Robert J. Fraser, Marc A Ritz, Nguyen, Nam, Chapman, Marianne, Fraser, R, Ritz, Marc, Bryant, L, Butler, Ross Norman, Davidson, Geoffrey, Zacharakis, B, and Holloway, R

Subjects
Male, medicine.medical_specialty, critically ill, Critical Illness, Clinical Sciences, Gastric emptying, Type 2 diabetes, Critical Care and Intensive Care Medicine, Gastroenterology, Risk Factors, Internal medicine, Intensive care, Diabetes mellitus, medicine, Humans, Risk factor, APACHE, Retrospective Studies, Breath test, Chi-Square Distribution, medicine.diagnostic_test, APACHE II, business.industry, breath test, Stomach, Middle Aged, medicine.disease, Respiration, Artificial, medicine.anatomical_structure, Endocrinology, Breath Tests, Diabetes Mellitus, Type 2, Gastric Emptying, Case-Control Studies, diabetes mellitus, Female, business
Abstract

Delayed gastric emptying (GE) is common both in critical illness and in patients with diabetes mellitus (DM). The effect of DM on the incidence of slow GE in these patients is unknown. We evaluated the effect of DM on liquid GE in critically ill patients. Retrospective analysis of GE using a standard [13C]octanoic acid breath test in 12 type 2 DM patients compared with (a) 44 critically ill patients without DM, including (b) a subgroup of 15 age- and sex-matched patients and (c) 15 healthy volunteers. We determined the gastric emptying coefficient (GEC) and the gastric half-emptying time (t 50). Mean APACHE II scores, blood glucose levels and use of morphine were similar between patient groups. GE was faster in critically ill patients with DM (t 50 122 ± 11 min, GEC: 3.8 ± 0.3) than in patients without DM (t 50 168 ± 16 min, GEC 2.8 ± 0.1) and in age- and sex-matched controls (t 50 165 ± 13 min, GEC 2.7 ± 0.2) and was similar to that in healthy volunteers (t 50 148 ± 13 min, GEC 3.5 ± 0.1). The proportion of patients with slow emptying (GEC

Published
2006
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22. Gastric emptying and the organization of antro-duodenal pressures in the critically ill

Author

Chapman, M, Fraser, R, Bryant, L, Vozzo, R, Nguyen, Nam, Tam, W, Zacharakis, B, Davidson, G, Butler, Ross Norman, and Horowitz, Michael

Subjects
Clinical Sciences, Neurosciences
Abstract

The motor dysfunctions underlying delayed gastric emptying (GE) in critical illness are poorly defined. Our aim was to characterize the relationship between antro-duodenal (AD) motility and GE in critically ill patients. AD pressures were recorded in 15 mechanically ventilated patients and 10 healthy volunteers for 2 h (i) during fasting, (ii) following an intragastric nutrient bolus with concurrent assessment of GE using the 13C-octanoate breath test and (iii) during duodenal nutrient infusion. Propagated waves were characterized by length and direction of migration. Critical illness was associated with: (i) slower GE (GEC: 3.47 ± 0.1 vs 2.99 ± 0.2; P = 0.046), (ii) fewer antegrade (duodenal: 44% vs 83%, AD: 16% vs 83%; P < 0.001) and more retrograde (duodenal: 46% vs 12%, AD: 38% vs 4%; P < 0.001) waves, (iii) shorter wave propagation (duodenal: 4.7 ± 0.3 vs 6.0 ± 0.4 cm; AD: 7.7 ± 0.6 vs 10.9 ± 0.9 cm; P = 0.004) and (iv) a close correlation between GE with the percentage of propagated phase 3 waves that were antegrade (r = 0.914, P = 0.03) and retrograde (r = )0.95, P = 0.014). In critical illness, the organization of AD pressure waves is abnormal and associated with slow GE.

Published
2008

25. Lack of diagnostic accuracy of the monoclonal stool antigen test for detection of Helicobacter pylori infection in young Australian aboriginal children.

Author

Ritchie B, Brewster D, Tran CD, McNeil Y, Zacharakis B, Davidson GP, and Butler RN

Subjects
Australia, Breath Tests, Carbon Isotopes analysis, Data Interpretation, Statistical, Diagnostic Errors, Diarrhea microbiology, Feces chemistry, Female, Helicobacter pylori immunology, Humans, Infant, Male, ROC Curve, Antigens, Bacterial analysis, Feces microbiology, Helicobacter Infections diagnosis, Helicobacter Infections ethnology, Helicobacter pylori isolation & purification
Abstract

Background: : The prevalence of Helicobacter pylori infection among Aboriginal Australians children is unclear. The aims of the present study are to determine the prevalence of H. pylori infection among young Aboriginal children recovering from acute diarrheal disease in hospital and to evaluate the H. pylori stool antigen test as a noninvasive diagnostic test in this setting., Methods: : This was a prospective comparative study using the C-Urea Breath Test as reference standard. Fifty-two children between 4 months and 2 years of age were consecutively enrolled. These children comprised a representative sample of Australian Aboriginal children admitted to hospital with acute diarrheal disease from remote and rural communities across Northern Territory of Australia., Results: : The overall prevalence of H. pylori was 44.2%. The stool antigen test had a sensitivity of 0.55 (95% confidence interval [CI]: 0.35-0.73) with a positive predictive value of 0.65 (95% CI: 0.42-0.82). The specificity was 0.68 (95% CI: 0.46-0.84) with a negative predictive value of 0.58 (95% CI: 0.39-0.75). Analysis of receiver operator characteristic curve yielded an overall accuracy of the stool antigen test of 61% (48%-75%)., Conclusions: : The prevalence of H. pylori infection among very young Aboriginal children from remote and rural communities was high and consistent with early acquisition. The diagnostic accuracy of the stool antigen test to diagnose H. pylori in this setting was poor.

Published
2009
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26. A novel non-invasive biomarker for assessment of small intestinal mucositis in children with cancer undergoing chemotherapy.

Author

Tooley KL, Saxon BR, Webster J, Zacharakis B, McNeil Y, Davidson GP, and Butler RN

Subjects
Adolescent, Antineoplastic Agents adverse effects, Breath Tests, Child, Child, Preschool, Female, Humans, Intestinal Mucosa drug effects, Male, Mucositis drug therapy, Patient Selection, Reference Values, Sucrose analysis, Antineoplastic Agents therapeutic use, Biomarkers analysis, Intestinal Mucosa pathology, Intestine, Small pathology, Mucositis chemically induced
Abstract

Background: Small intestinal mucositis is a common side-effect following high-dose chemotherapy, causing patients to experience pain and abdominal complications often leading to extended stays in hospital. A biomarker to detect these small intestinal changes does not exist in clinical practice. This study aimed to assess the noninvasive 13C-Sucrose breath test (SBT) to detect small intestinal damage associated with mucositis in pediatric cancer patients having chemotherapy., Patients and Methods: Small intestinal function was assessed in 15 pediatric cancer patients and 26 healthy children. Subjects were studied for small intestinal permeability (SIP; lactulose/rhamnose), digestive and absorptive capacity (SBT; sucrose), and oro-cecal transit time (OCTT; lactulose), by ingesting two sugar drinks containing the respective sugars. Combined tests were carried out at baseline, day 1, day 3-5 and day 6-9, and in healthy individuals on two separate occasions. A total of 25 cycles of chemotherapy were assessed. Breath samples for the SBT were collected every 15 min for 3 h (expressed as % cumulative dose at 90 min (CD)), a 5 h urine collection for SIP and breath hydrogen determined every 30 min for three hours for OCTT., Results: Clinical mucositis occurred in seven of the 25 cycles of chemotherapy (28%). No significant difference was observed for SIP and OCTT. The SBT %CD at 90 min was significantly lower in the mucositis group compared to the unaffected group and controls at baseline (p<0.05). Patients who developed mucositis maintained a significantly lower %CD, for all test points (p<0.05) compared to the unaffected patients. In patients who developed mucositis the SBT was below the reference range of the controls at all time points., Conclusion: The findings show for the first time that it is possible to noninvasively detect and monitor gut damage associated with chemotherapy-induced mucositis in pediatric cancer patients.

Published
2006
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