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1. Discovery of the shape coexisting 0+ state in 32Mg by a two neutron transfer reaction

Author

Wimmer, K., Kröll, T., Krücken, R., Bildstein, V., Gernhäuser, R., Bastin, B., Bree, N., Diriken, J., Van Duppen, P., Huyse, M., Patronis, N., Vermaelen, P., Voulot, D., Van de Walle, J., Wenander, F., Fraile, L. M., Chapman, R., Hadinia, B., Orlandi, R., Smith, J. F., Lutter, R., Thirolf, P. G., Labiche, M., Blazhev, A., Kalkühler, M., Reiter, P., Seidlitz, M., Warr, N., Macchiavelli, A. O., Jeppesen, H. B., Fiori, E., Georgiev, G., Schrieder, G., Gupta, S. Das, Bianco, G. Lo, Nardelli, S., Butterworth, J., Johansen, J., and Riisager, K.

Subjects
Nuclear Experiment
Abstract

The Island of Inversion nucleus 32Mg has been studied by a (t,p) two neutron transfer reaction in inverse kinematics at REX-ISOLDE. The shape coexistent excited 0+ state in 32Mg has been identified by the characteristic angular distribution of the protons of the DeltaL = 0 transfer. The excitation energy of 1058 keV is much lower than predicted by any theoretical model. The low gamma-ray intensity observed for the decay of this 0+ state indicates a lifetime of more than 10 ns. Deduced spectroscopic amplitudes are compared with occupation numbers from shell model calculations., Comment: Phys. Rev. Lett. accepted for publication http://prl.aps.org

Published
2010
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2. Search for Oscillation of the Electron-Capture Decay Probability of $^{142}$Pm

Author

Vetter, P. A., Clark, R. M., Dvorak, J., Freedman, S. J., Gregorich, K. E., Jeppesen, H. B., Mittelberger, D., and Wiedeking, M.

Subjects
Nuclear Experiment
Abstract

We have searched for time modulation of the electron capture decay probability of $^{142}$Pm in an attempt to confirm a recent claim from a group at the Gesellschaft f\"{u}r Schwerionenforschung (GSI). We produced $^{142}$Pm via the $^{124}$Sn($^{23}$Na, 5n)$^{142}$Pm reaction at the Berkeley 88-Inch Cyclotron with a bombardment time short compared to the reported modulation period. Isotope selection by the Berkeley Gas-filled Separator is followed by implantation and a long period of monitoring the $^{142}$Nd K$_{\alpha}$ x-rays from the daughter. The decay time spectrum of the x-rays is well-described by a simple exponential and the measured half-life of 40.68(53) seconds is consistent with the accepted value. We observed no oscillatory modulation at the proposed frequency at a level 31 times smaller than that reported by Litvinov {\it et al.} (Phys. Lett. B 664 (2008) 162; arXiv:0801.2079 [nucl-ex]). A literature search for previous experiments that might have been sensitive to the reported modulation uncovered another example in $^{142}$Eu electron-capture decay. A reanalysis of the published data shows no oscillatory behavior., Comment: 12 pages (double-spaced), 6 figures

Published
2008
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3. Study of beta-delayed 3-body and 5-body breakup channels observed in the decay of ^11Li

Author

Madurga, M., Borge, M. J. G., Angelique, J. C., Bao, L., Bergmann, U., Bută, A., Cederkäll, J., Diget, C. Aa., Fraile, L. M., Fynbo, H. O. U., Jeppesen, H. B., Jonson, B., Maréchal, F., Marqués, F. M., Nilsson, T., Nyman, G., Perrot, F., Riisager, K., Tengblad, O., Tengborn, E., Turrión, M., and Wilhelmsen, K.

Subjects
Nuclear Experiment
Abstract

The beta-delayed charged particle emission from ^11Li has been studied with emphasis on the three-body n+alpha+^6He and five-body 2alpha+3n channels from the 10.59 and 18.15 MeV states in ^11Be. Monte Carlo simulations using an R-matrix formalism lead to the conclusion that the ^AHe resonance states play a significant role in the break-up of these states. The results exclude an earlier assumption of a phase-space description of the break-up process of the 18.15 MeV state. Evidence for extra sequential decay paths is found for both states., Comment: 16 pages, 9 figures. Submitted to Nuclear Physics A

Published
2008
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5. Effects of seven days’ fasting on physical performance and metabolic adaptation during exercise in humans

Author

Kolnes, Kristoffer J., Nilsen, Emelie T. F., Brufladt, Steffen, Meadows, Allison M., Jeppesen, Per B., Skattebo, Øyvind, Johansen, Egil I., Birk, Jesper B., Højlund, Kurt, Hingst, Janne, Skålhegg, Bjørn S., Kjøbsted, Rasmus, Griffin, Julian L., Kolnes, Anders J., O’Rahilly, Stephen, Wojtaszewski, Jørgen F. P., and Jensen, Jørgen

Published
2025
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13. GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans

Author

Patel, S., Alvarez-Guaita, A., Melvin, A., Rimmington, D., Dattilo, A., Miedzybrodzka, E. L., Cimino, I., Maurin, Anne-Catherine, Roberts, G. P., Meek, C. L., Virtue, S., Sparks, L. M., Parsons, S. A., Redman, L. M., Bray, G. A., Liou, A. P., Woods, R. M., Parry, S. A., Jeppesen, P. B., Kolnes, A. J., Harding, H. P., Ron, D., Vidal-Puig, A., Reimann, F., Gribble, F. M., Hulston, C. J., Farooqi, I. S., Fafournoux, Pierre, Smith, S. R., Jensen, J., Breen, D., Wu, Z., Zhang, B. B., Coll, A. P., Savage, D. B., O'Rahilly, S., Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Wellcome Trust-MRC Institute of Metabolic Science (IMS), University of Cambridge, Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Pennington Biomedical Research Center, Internal Medicine Research Unit (IMRU - BUENOS AIRES), Hospital Italiano - BUENOS AIRES (Hop It - BUENOS AIRES), School of Sport, Exercise and Health Sciences, Loughborough University, Department of Clinical Medicine, Örebro University, Aarhus University, Department of Endocrinology, John Vane Science Center-Barts and the London Medical School, Metabolic Research Laboratories, Department of Physical Performance, Norwegian School of Sport Sciences, Aarhus University [Aarhus], Norwegian School of Sport Sciences = Norges idrettshøgskole [Oslo] (NIH), Patel, Satish [0000-0002-5345-8942], Cimino, Irene [0000-0003-1397-5408], Meek, Claire [0000-0002-4176-8329], Harding, Heather [0000-0002-7359-7974], Ron, David [0000-0002-3014-5636], Vidal-Puig, Antonio [0000-0003-4220-9577], Reimann, Frank [0000-0001-9399-6377], Gribble, Fiona [0000-0002-4232-2898], Farooqi, Ismaa [0000-0001-7609-3504], Coll, Anthony [0000-0003-2594-7463], Savage, David [0000-0002-7857-7032], O'Rahilly, Stephen [0000-0003-2199-4449], and Apollo - University of Cambridge Repository

Subjects
Adult, Gdf15, Growth Differentiation Factor 15, Endocrinology, Diabetes and Metabolism, MEDLINE, overnutrion, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Bioinformatics, Diet, High-Fat, Article, Cell Line, Mice, Young Adult, Endocrinology, Text mining, Gfral, Stress (linguistics), Medicine, Animals, Humans, conditioned taste aversion, health care economics and organizations, ComputingMilieux_MISCELLANEOUS, GFRAL, business.industry, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, integrated stress response, Middle Aged, Mice, Inbred C57BL, GDF15, business, Energy Intake, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

Summary GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress., Graphical Abstract, Highlights • Dietary changes influencing adipose/gut-derived hormones do not alter GDF15 levels • Chronic high-fat or acute lysine-deficient diet exposure increases GDF15 levels • GDF15 administration triggers conditioned taste aversion in mice • GDF15 is a stress-induced hormone that may mediate an aversive dietary response, Patel et al. show that whereas short-term overfeeding or fasting does not change GDF15 levels substantially, prolonged high-fat feeding and lysine-deficient diets activate the integrated stress response and increase GDF15 levels. GDF15 administration triggers conditioned taste aversion in mice, suggesting that GDF15 might induce an aversive response to nutritional stress.

Published
2019
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19. Randomised clinical trial:2% taurolidine versus 0.9% saline locking in patients on home parenteral nutrition

Author

Wouters, Y, Theilla, M, Singer, P, Tribler, S, Jeppesen, P B, Pironi, L, Vinter-Jensen, L, Rasmussen, H H, Rahman, F, Wanten, G J A, Wouters, Y, Theilla, M, Singer, P, Tribler, S, Jeppesen, P B, Pironi, L, Vinter-Jensen, L, Rasmussen, H H, Rahman, F, and Wanten, G J A

Abstract

BACKGROUND: The catheter lock solutions 2% taurolidine and 0.9% saline are both used to prevent catheter-related bloodstream infections (CRBSIs) in home parenteral nutrition patients.AIMS: To compare the effectiveness and safety of taurolidine and saline.METHODS: This multicentre double-blinded trial randomly assigned home parenteral nutrition patients to use either 2% taurolidine or 0.9% saline for 1 year. Patients were stratified in a new catheter group and a pre-existing catheter group. Primary outcome was the rate of CRBSIs/1000 catheter days in the new catheter group and pre-existing catheter group, separately.RESULTS: We randomised 105 patients, of which 102 were analysed as modified intention-to-treat population. In the new catheter group, rates of CRBSIs/1000 catheter days were 0.29 and 1.49 in the taurolidine and saline arm respectively (relative risk, 0.20; 95% CI, 0.04-0.71; P = 0.009). In the pre-existing catheter group, rates of CRBSIs/1000 catheter days were 0.39 and 1.32 in the taurolidine and saline arm respectively (relative risk, 0.30; 95% CI, 0.03-1.82; P = 0.25). Excluding one outlier patient in the taurolidine arm, mean costs per patient were $1865 for taurolidine and $4454 for saline (P = 0.03). Drug-related adverse events were rare and generally mild.CONCLUSIONS: In the new catheter group, taurolidine showed a clear decrease in CRBSI rate. In the pre-existing catheter group, no superiority of taurolidine could be demonstrated, most likely due to underpowering. Overall, taurolidine reduced the risk for CRBSIs by more than four times. Given its favourable safety and cost profile, taurolidine locking should be considered as an additional strategy to prevent CRBSIs.TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT01826526.

Published
2018

21. European Society of Coloproctology consensus on the surgical management of intestinal failure in adults

Author

Vaizey, C J, Maeda, Y, Barbosa, E, Bozzetti, F, Calvo, J, Irtun, Ø., Jeppesen, P B, Klek, S, Panisic-Sekeljic, M, Papaconstantinou, I, Pascher, A, Panis, Y, Wallace, W D, Carlson, G, Boermeester, M, Vaizey, C J, Maeda, Y, Barbosa, E, Bozzetti, F, Calvo, J, Irtun, Ø., Jeppesen, P B, Klek, S, Panisic-Sekeljic, M, Papaconstantinou, I, Pascher, A, Panis, Y, Wallace, W D, Carlson, G, and Boermeester, M

Abstract

Intestinal failure (IF) is a debilitating condition of inadequate nutrition due to an anatomical and/or physiological deficit of the intestine. Surgical management of patients with acute and chronic IF requires expertise to deal with technical challenges and make correct decisions. Dedicated IF units have expertise in patient selection, operative risk assessment and multidisciplinary support such as nutritional input and interventional radiology, which dramatically improve the morbidity and mortality of this complex condition and can beneficially affect the continuing dependence on parenteral nutritional support. Currently there is little guidance to bridge the gap between general surgeons and specialist IF surgeons. Fifteen European experts took part in a consensus process to develop guidance to support surgeons in the management of patients with IF. Based on a systematic literature review, statements were prepared for a modified Delphi process. The evidence for each statement was graded using Oxford Centre for Evidence-Based Medicine Levels of Evidence. The current paper contains the statements reflecting the position and practice of leading European experts in IF encompassing the general definition of IF surgery and organization of an IF unit, strategies to prevent IF, management of acute IF, management of wound, fistula and stoma, rehabilitation, intestinal and abdominal reconstruction, criteria for referral to a specialist unit and intestinal transplantation.

Published
2016

22. Factors Associated With Response to Teduglutide in Patients With Short-Bowel Syndrome and Intestinal Failure.

Author

Jeppesen, Palle B., Gabe, Simon M., Seidner, Douglas L., Lee, Hak-Myung, and Olivier, Clément

Abstract

Background & Aims Clinical studies showed teduglutide to increase urine production and reduce need for parenteral support volume in patients with short bowel syndrome (SBS) with intestinal failure, increasing intestinal wet weight absorption and reducing diarrhea. However, the effects of teduglutide on parenteral support vary among patients. We performed a post hoc analysis of a phase III placebo-controlled study to identify characteristics of patients in whom teduglutide has the largest effects on parenteral support volume response. Methods We collected data from 85 patients with SBS with intestinal failure, according to the European Society for Clinical Nutrition and Metabolism classification system, who received teduglutide or placebo between November 25, 2008, and January 4, 2011, at 27 sites in 10 countries. Changes in parenteral support volume were evaluated according to baseline parenteral support volume, bowel anatomy (group 1, jejunostomy/ileostomy; group 2, ≥50% colon-in-continuity without stoma; and group 3, other colon anatomies), and disease features (with inflammatory bowel disease, mesenteric vascular diseases, or other conditions). Correlation analyses were conducted using simple linear regression models, with unadjusted r 2 values reported. Two-sided t tests were used for comparisons between treatment groups. Results We correlated parenteral support volume reduction with teduglutide treatment and baseline parenteral support volume (y = –0.3870x + 90.0279, r 2 = 0.61; P < .0001). The effects of teduglutide on absolute parenteral support volume were significantly greater in group 1 patients (reduction of 919 ± 644 mL/d), not only compared with patients given placebo (reduction of 340 ± 436 mL/d; P = .0112) but also compared with teduglutide-treated patients in group 2 (reduction of 355 ± 306 mL/d; P = .0066). Teduglutide had an intermediate effect on patients in group 3. A minority of patients with SBS and inflammatory bowel diseases had colon-in-continuity (10.5% [n = 2/19]), whereas most patients with SBS and vascular or other diseases had colon-in-continuity (84.4% [n = 27/32] and 67.6% [n = 23/34], respectively). Conclusions In a post hoc analysis of data from a phase III study of the effects of teduglutide on patients with SBS, we associated reduced parenteral support volume with baseline parenteral support volume, bowel anatomy, and SBS features. These findings may inform initial parenteral support volume adjustments and management of these severely disabled patients. ClinicalTrials.gov no: NCT00798967 ; ClinicalTrialsRegister.eu no: 2008-006193-15. [ABSTRACT FROM AUTHOR]

Published
2018
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25. Glucagon-like peptide-2 stimulates mucosal microcirculation measured by laser Doppler flowmetry in end-jejunostomy short bowel syndrome patients

Author

Høyerup, P., Hellström, Per M., Schmidt, P. T., Brandt, C. F., Askov-Hansen, C., Mortensen, P. B., Jeppesen, P. B., Høyerup, P., Hellström, Per M., Schmidt, P. T., Brandt, C. F., Askov-Hansen, C., Mortensen, P. B., and Jeppesen, P. B.

Abstract

Background: In animal and human studies glucagon-like peptide-2 (GLP-2) has been shown to increase blood flow in the superior mesenteric artery and the portal vein. This study describes the effect of GLP-2 measured directly on the intestinal mucosal blood flow by laser Doppler flowmetry (LDF) in end-jejunostomy short bowel syndrome (SBS) patients. Methods: In five SBS patients with end-jejunostomy a specially designed laser Doppler probe was inserted into the stoma nipple, and blood flow measured directly on the jejunal mucosa for 105. min in relation to no treatment, systemic saline infusion, topical adrenaline application and a subcutaneous injection of 800μg native GLP-2. Results: The GLP-2 injection increased jejunal mucosal blood flow by 79 ± 37% compared to conditions, where no treatment was given (p < 0.001). The significant effect was present at least 105. min. Systemic saline infusion and topical, mucosal adrenaline application did not affect mucosal microcirculation. Conclusions: GLP-2 raises jejunal microcirculation in SBS patients with end-jejunostomy. This may explain the redness and increase in the end-jejunostomy nipple size imminently after commencing GLP-2 injections. The potential beneficial effects of this GLP-2-mediated increase of blood flow in the mesenteric bed should be investigated in clinical conditions other than the short bowel syndrome.

Published
2013
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26. A dose-equivalent comparison of the effects of continuous subcutaneous glucagon-like peptide 2 (GLP-2) infusions versus meal related GLP-2 injections in the treatment of short bowel syndrome (SBS) patients

Author

Naimi, R M, Madsen, K B, Askov-Hansen, C, Brandt, C F, Hartmann, B, Holst, Jens Juul, Mortensen, P B, Jeppesen, P B, Naimi, R M, Madsen, K B, Askov-Hansen, C, Brandt, C F, Hartmann, B, Holst, Jens Juul, Mortensen, P B, and Jeppesen, P B

Abstract

Glucagon-like peptide 2 (GLP-2), secreted endogenously from L-cells in the distal bowel in relation to meals, modulates intestinal absorption by adjusting gastric emptying and secretion and intestinal growth. Short bowel syndrome (SBS) patients with distal intestinal resections have attenuated endogenous GLP-2 secretion, which may contribute to their rapid gastric emptying, gastric hypersecretion and poor intestinal adaptation, whereas SBS patients with preserved terminal ileum and colon, who have a constantly elevated GLP-2 secretion, seem to do better in these respects. This study compared effects of continuous, subcutaneous (s.c.), exogenous GLP-2 infusion (CONT-GLP-2) versus three daily s.c. GLP-2 injections (TID-GLP-2) on intestinal absorption in SBS patients.

Published
2013

27. Acute effects of continuous infusions of glucagon-like peptide (GLP)-1, GLP-2 and the combination (GLP-1+GLP-2) on intestinal absorption in short bowel syndrome (SBS) patients. A placebo-controlled study

Author

Madsen, K B, Askov-Hansen, C, Naimi, R M, Brandt, C F, Hartmann, B, Holst, Jens Juul, Mortensen, P B, Jeppesen, P B, Madsen, K B, Askov-Hansen, C, Naimi, R M, Brandt, C F, Hartmann, B, Holst, Jens Juul, Mortensen, P B, and Jeppesen, P B

Abstract

The ileocolonic brake is impaired in short bowel syndrome (SBS) patients with distal bowel resections. An attenuated meal-stimulated hormone secretion may cause gastric hypersecretion, rapid gastric and intestinal transit and a poor adaptation. Attempting to restore this ileocolonic brake, this study evaluated the acute effects of continuous intravenous administration of glucagon-like peptide (GLP) 1 and 2, alone or in combination, on gastrointestinal function in SBS patients.

Published
2013

28. Short bowel patients treated for two years with glucagon-like Peptide 2: effects on intestinal morphology and absorption, renal function, bone and body composition, and muscle function

Author

Jeppesen, P B, Lund, P, Gottschalck, I B, Nielsen, H B, Holst, Jens Juul, Mortensen, J, Poulsen, S S, Quistorff, B, Mortensen, P B, Jeppesen, P B, Lund, P, Gottschalck, I B, Nielsen, H B, Holst, Jens Juul, Mortensen, J, Poulsen, S S, Quistorff, B, and Mortensen, P B

Abstract

Udgivelsesdato: 2009, BACKGROUND AND AIMS: In a short-term study, Glucagon-like peptide 2 (GLP-2) has been shown to improve intestinal absorption in short bowel syndrome (SBS) patients. This study describes longitudinal changes in relation to GLP-2 treatment for two years. METHODS: GLP-2, 400 micrograms, s.c.,TID, were offered, to eleven SBS patients keeping parenteral support constant. 72-hour nutritional balance studies were performed at baseline, weeks 13, 26, 52 during two years intermitted by an 8-week washout period. In addition, mucosal morphometrics, renal function (by creatinine clearance), body composition and bone mineral density (by DEXA), biochemical markers of bone turnover (by s-CTX and osteocalcin, PTH and vitamin D), and muscle function (NMR, lungfunction, exercise test) were measured. RESULTS: GLP-2 compliance was >93%. Three of eleven patients did not complete the study. In the remaining 8 patients, GLP-2 significantly reduced the fecal wet weight from approximately 3.0 to approximately 2.0 kg/day. This was accompanied by a decline in the oral wet weight intake, maintaining intestinal wet weight absorption and urinary weight constant. Renal function improved. No significant changes were demonstrated in energy intake or absorption, and GLP-2 did not significantly affect mucosal morphology, body composition, bone mineral density or muscle function. CONCLUSIONS: GLP-2 treatment reduces fecal weight by approximately 1000 g/d and enables SBS patients to maintain their intestinal fluid and electrolyte absorption at lower oral intakes. This was accompanied by a 28% improvement in creatinine clearance.

Published
2009

29. Short bowel patients treated for two years with glucagon-like peptide 2 (GLP-2): compliance, safety, and effects on quality of life

Author

Jeppesen, P B, Lund, P, Gottschalck, I B, Nielsen, H B, Holst, Jens Juul, Mortensen, J, Poulsen, S S, Quistorff, Bjørn, Mortensen, P B, Jeppesen, P B, Lund, P, Gottschalck, I B, Nielsen, H B, Holst, Jens Juul, Mortensen, J, Poulsen, S S, Quistorff, Bjørn, and Mortensen, P B

Abstract

Udgivelsesdato: 2009, BACKGROUND AND AIMS: Glucagon-like peptide 2 (GLP-2) has been shown to improve intestinal absorption in short bowel syndrome (SBS) patients in a short-term study. This study describes safety, compliance, and changes in quality of life in 11 SBS patients at baseline, week 13, 26, and 52 during two years of subcutaneous GLP-2 treatment, 400 microgram TID, intermitted by an 8-week washout period. METHODS: Safety and compliance was evaluated during the admissions. The Sickness Impact Profile (SIP), Short Form 36 (SF 36), and Inflammatory Bowel Disease Questionnaire (IBDQ) evaluated quality of life. RESULTS: The predominant adverse event was transient abdominal discomfort in 5 of 11 patients, but in 2, both suffering from Crohns disease, it progressed to abdominal pain and led to discontinuation of GLP-2 treatment. One had a fibrostenotic lesion electively resected at the jejuno-ascendo-anastomosis. The investigator excluded a patient due to unreliable feedback. Stoma nipple enlargement was seen in all 9 jejunostomy patients. Reported GLP-2 compliance was excellent (>93%). GLP-2 improved the overall quality of life VAS-score (4.1 +/- 2.8 cm versus 6.0 +/- 2.4 cm, P < .01), the overall SIP score (10.3 +/- 8.9% versus 6.2 +/- 9.5%, P < .001), the mental component of the SF-36 (45 +/- 13% versus 53 +/- 11%, P < .05), and the overall IBDQ score (5.1 +/- 0.9 versus 5.4 +/- 0.9, P < .007) in the 8 patients completing the study. CONCLUSIONS: Long-term treatment with GLP-2 is feasible in SBS patients, although caution must be exercised in patients with a history of abdominal pain. Although conclusions cannot be made in a noncontrolled trial, the high reported compliance might reflect a high treatment satisfaction, where the clinical benefits of GLP-2 may outweigh the discomforts of injections.

Published
2009

30. Short-term administration of glucagon-like peptide-2. Effects on bone mineral density and markers of bone turnover in short-bowel patients with no colon

Author

Haderslev, K V, Jeppesen, P B, Hartmann, B, Thulesen, J, Sorensen, H A, Graff, J, Tofteng, F, Poulsen, S S, Madsen, J L, Holst, J J, Staun, M, Mortensen, P B, Poulsen, Steen Seier, Haderslev, K V, Jeppesen, P B, Hartmann, B, Thulesen, J, Sorensen, H A, Graff, J, Tofteng, F, Poulsen, S S, Madsen, J L, Holst, J J, Staun, M, Mortensen, P B, and Poulsen, Steen Seier

Abstract

Glucagon-like peptide 2 (GLP-2) is a newly discovered intestinotrophic hormone. We have recently reported that a 5-week GLP-2 treatment improved the intestinal absorptive capacity of short-bowel patients with no colon. Additionally, GLP-2 treatment was associated with changes in body composition that included a significant increase in total body bone mass. This article describes the effect of GLP-2 on spinal and hip bone mineral density (BMD) and biochemical markers of bone turnover in these patients.

Published
2002

33. Intestinal growth adaptation and glucagon-like peptide 2 in rats with ileal--jejunal transposition or small bowel resection

Author

Thulesen, J, Hartmann, B, Kissow, Hannelouise, Jeppesen, P B, Orskov, C, Holst, J J, Poulsen, S S, Thulesen, J, Hartmann, B, Kissow, Hannelouise, Jeppesen, P B, Orskov, C, Holst, J J, and Poulsen, S S

Abstract

Glucagon-like peptide 2 (GLP-2), produced by enteroendocrine L-cells, regulates intestinal growth. This study investigates circulating and intestinal GLP-2 levels in conditions with altered L-cell exposure to nutrients. Rats were allocated to the following experimental groups: ileal-jejunal transposition, resection of the proximal or distal half of the small intestine, and appropriate sham-operated controls. After two weeks, ileal-jejunal transposition led to pronounced growth of the transposed segment and also of the remaining intestinal segments. Plasma GLP-2 levels increased twofold, whereas GLP-2 levels in the intestinal segments were unchanged. In resected rats with reduced intestinal capacity, adaptive small bowel growth was more pronounced following proximal resection than distal small bowel resection. Circulating GLP-2 levels increased threefold in proximally resected animals, and twofold in the distally resected group. Tissue GLP-2 levels were unchanged in resected rats. The data indicate that transposition of a distal part of the small intestine, and thereby exposure of L cells to a more nutrient-rich chyme, leads to intestinal growth. The adaptive intestinal growth is associated with increased plasma levels of GLP-2, and GLP-2 seems to act in an endocrine as well as a paracrine manner.

Published
2001

34. Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon

Author

Jeppesen, P B, Hartmann, B, Thulesen, J, Graff, J, Lohmann, J, Hansen, B S, Tofteng, F, Poulsen, Steen Seier, Madsen, J L, Holst, J J, Mortensen, P B, Jeppesen, P B, Hartmann, B, Thulesen, J, Graff, J, Lohmann, J, Hansen, B S, Tofteng, F, Poulsen, Steen Seier, Madsen, J L, Holst, J J, and Mortensen, P B

Abstract

Glucagon-like peptide 2 (GLP-2) is intestinotrophic, antisecretory, and transit-modulating in rodents, and it is mainly secreted from the intestinal mucosa of the terminal ileum and colon after food ingestion. We assessed the effect of GLP-2 on the gastrointestinal function in patients without a terminal ileum and colon who have functional short-bowel syndrome with severe malabsorption of wet weight (>1.5 kg/day) and energy (>2.3 MJ/day) and no postprandial secretion of GLP-2.

Published
2001

35. Potential targets for glucagon-like peptide 2 (GLP-2) in the rat:distribution and binding of i.v. injected (125)I-GLP-2

Author

Thulesen, J, Hartmann, B, Orskov, C, Jeppesen, P B, Holst, J J, Poulsen, Steen Seier, Thulesen, J, Hartmann, B, Orskov, C, Jeppesen, P B, Holst, J J, and Poulsen, Steen Seier

Abstract

Glucagon-like peptide 2 (GLP-2) is a 33-amino acid (1-33) intestinotrophic peptide. In this study, the distribution and binding of i.v. injected radiolabeled GLP-2 (1-33) were investigated in rats using autoradiography in order to target possible binding sites. The major part of (125)I-GLP-2 (1-33) was distributed to kidneys, liver, and the gastrointestinal tract. In the small intestine, a high density of grains was localized in the epithelium with a predominance in the luminal part of the villus. The saturability of (125)I-GLP-2 (1-33) was investigated by administration of excess amounts of non-radioactive GLP-2 (1-33) or the primary metabolite of GLP-2 degradation, GLP-2 (3-33). In the small intestine, (125)I-GLP-2 was displaced both by non-radioactive GLP-2 (1-33) and (3-33), suggesting that the uptake of GLP-2 (1-33) in the small intestine is receptor-specific and that the metabolite GLP-2 (3-33) may interact with the GLP-2 receptor.

Published
2000

37. Deficiencies of essential fatty acids, vitamin A and E and changes in plasma lipoproteins in patients with reduced fat absorption or intestinal failure.

Author

Jeppesen, P B, Høy, C E, and Mortensen, P B

Abstract

Objective: Deficiencies of essential fatty acids (EFA), vitamin A (retinol) and vitamin E (alpha- and gamma-tocopherol) were studied in non-HPN patients with different degrees of fat malabsorption (managing without home parenteral nutrition (HPN)), and in HPN-patients receiving HPN with and without parenteral lipids.Design and Subjects: Phospholipid fatty acids (including EFA), cholesterol, retinol, alpha- and gamma-tocopherol in plasma and the intestinal absorption of fatty acids and energy (balance-studies) were measured in 40 non-HPN patients, 44 HPN patients and 35 controls. Subgroups were non-HPN patients with fat:total energy absorption ratios >25% (A), between 15 and 25% (B), and <15% (C), and HPN patients receiving (D) and not receiving parenteral lipids (E).Results: Intestinal absorption of the EFA linoleic acid was 8.2, 4.4, 3.8, 0.5 and 0.5 g/day and corresponding plasma concentrations were 17.3%, 15.5%, 13.1%, 12.1% and 8.9% in groups A-E, respectively (P<0.001). Deficiencies in EFA, defined as a Holman index >0.2 (20:3n-9/20:4n-6 ratio), were confined to 42% of the patients in group E. Plasma cholesterol was decreased in groups B-E. Plasma retinol was reduced (below the lower 2.5% confidence interval of controls) in 7% of non-HPN patients and in 20% of HPN patients. Plasma alpha-tocopherol was reduced in 64% of patients from groups B-E. Plasma gamma-tocopherol was decreased in 33% of the patients, except in HPN-patients receiving parenteral lipids.Conclusions: Plasma linoleic acid may decrease considerably (from 26% to 8-10%) as fat absorption decreases before secondary signs of essential fatty acid deficiencies occur (an increase in 20:3n-9 and the Holman index). In this study this was confined to patients on lipid-free HPN. Vitamin A deficiencies were mainly seen in HPN patients. Vitamin E deficiencies were common in both HPN and non-HPN patients, but administration of parenteral lipids normalized plasma gamma-tocopherol. European Journal of Clinical Nutrition (2000) 54, 632-642. [ABSTRACT FROM AUTHOR]

Published
2000
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38. Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B.

Author

Iversen, L F, Andersen, H S, Branner, S, Mortensen, S B, Peters, G H, Norris, K, Olsen, O H, Jeppesen, C B, Lundt, B F, Ripka, W, Møller, K B, and Møller, N P

Abstract

Several protein-tyrosine phosphatases (PTPs) have been proposed to act as negative regulators of insulin signaling. Recent studies have shown increased insulin sensitivity and resistance to obesity in PTP1B knockout mice, thus pointing to this enzyme as a potential drug target in diabetes. Structure-based design, guided by PTP mutants and x-ray protein crystallography, was used to optimize a relatively weak, nonphosphorus, nonpeptide general PTP inhibitor (2-(oxalyl-amino)-benzoic acid) into a highly selective PTP1B inhibitor. This was achieved by addressing residue 48 as a selectivity determining residue. By introducing a basic nitrogen in the core structure of the inhibitor, a salt bridge was formed to Asp-48 in PTP1B. In contrast, the basic nitrogen causes repulsion in other PTPs containing an asparagine in the equivalent position resulting in a remarkable selectivity for PTP1B. Importantly, this was accomplished while retaining the molecular weight of the inhibitor below 300 g/mol.

Published
2000

39. 2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases.

Author

Andersen, H S, Iversen, L F, Jeppesen, C B, Branner, S, Norris, K, Rasmussen, H B, Møller, K B, and Møller, N P

Abstract

Protein-tyrosine phosphatases (PTPs) are critically involved in regulation of signal transduction processes. Members of this class of enzymes are considered attractive therapeutic targets in several disease states, e.g. diabetes, cancer, and inflammation. However, most reported PTP inhibitors have been phosphorus-containing compounds, tight binding inhibitors, and/or inhibitors that covalently modify the enzymes. We therefore embarked on identifying a general, reversible, competitive PTP inhibitor that could be used as a common scaffold for lead optimization for specific PTPs. We here report the identification of 2-(oxalylamino)-benzoic acid (OBA) as a classical competitive inhibitor of several PTPs. X-ray crystallography of PTP1B complexed with OBA and related non-phosphate low molecular weight derivatives reveals that the binding mode of these molecules to a large extent mimics that of the natural substrate including hydrogen bonding to the PTP signature motif. In addition, binding of OBA to the active site of PTP1B creates a unique arrangement involving Asp(181), Lys(120), and Tyr(46). PTP inhibitors are essential tools in elucidating the biological function of specific PTPs and they may eventually be developed into selective drug candidates. The unique enzyme kinetic features and the low molecular weight of OBA makes it an ideal starting point for further optimization.

Published
2000

47. Safety and Efficacy of Teduglutide After 52 Weeks of Treatment in Patients With Short Bowel Intestinal Failure.

Author

O'Keefe, Stephen J.D., Jeppesen, Palle B., Gilroy, Richard, Pertkiewicz, Marek, Allard, Johane P., and Messing, Bernard

Abstract

Background & Aims: Although home parenteral nutrition (PN) can save the lives of patients with massive bowel loss that results in short-bowel syndrome and intestinal failure, quality of life is impaired by PN and its complications. We examined the 12-month tolerability and efficacy of teduglutide to reduce PN dependency. Methods: Patients who received teduglutide (0.05 or 0.10 mg/kg/d) for 24 weeks in a randomized controlled trial were eligible for a 28-week double-blind extension study; 52 patients were given 52 weeks of the same doses of teduglutide. We investigated the safety, tolerability, and clinical efficacy (defined as a clinically meaningful ≥20% reduction in weekly PN volume from baseline) at week 52. Results: The most common adverse events reported included headache (35%), nausea (31%), and abdominal pain (25%); 7 patients withdrew because of adverse events (gastrointestinal disorders in 4). Both groups had progressive reduction in PN. At week 52, 68% of the 0.05-mg/kg/d and 52% of the 0.10-mg/kg/d dose group had a ≥20% reduction in PN, with a reduction of 1 or more days of PN dependency in 68% and 37%, respectively. Four patients achieved complete independence from PN. Conclusions: For patients with short-bowel syndrome intestinal failure, the efficacy of teduglutide was maintained over 52 weeks and the safety profile was sufficient for it to be considered for long-term use. Further studies are needed to determine whether these effects will translate into improved quality of life and reduced PN complications. ClinicalTrials.gov number, NCT00172185. [Copyright &y& Elsevier]

Published
2013
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48. Teduglutide Reduces Need for Parenteral Support Among Patients With Short Bowel Syndrome With Intestinal Failure.

Author

Jeppesen, Palle B., Pertkiewicz, Marek, Messing, Bernard, Iyer, Kishore, Seidner, Douglas L., O'keefe, Stephen J.D., Forbes, Alastair, Heinze, Hartmut, and Joelsson, Bo

Subjects
SHORT bowel syndrome, PARENTERAL therapy, GLUCAGON, CLINICAL trials, PLACEBOS, ADVERSE health care events, GASTRIC emptying
Abstract

Background & Aims: Teduglutide, a glucagon-like peptide 2 analogue, might restore intestinal structural and functional integrity by promoting growth of the mucosa and reducing gastric emptying and secretion. These factors could increase fluid and nutrient absorption in patients with short bowel syndrome with intestinal failure (SBS-IF). We performed a prospective study to determine whether teduglutide reduces parenteral support in patients with SBS-IF. Methods: We performed a 24-week study of patients with SBS-IF who were given subcutaneous teduglutide (0.05 mg/kg/d; n = 43) or placebo (n = 43) once daily. Parenteral support was reduced if 48-hour urine volumes exceeded baseline values by ≥10%. The primary efficacy end point was number of responders (patients with >20% reduction in parenteral support volume from baseline at weeks 20 and 24). Results: There were significantly more responders in the teduglutide group (27/43 [63%]) than the placebo group (13/43 [30%]; P = .002). At week 24, the mean reduction in parenteral support volume in the teduglutide group was 4.4 ± 3.8 L/wk (baseline 12.9 ± 7.8 L/wk) compared with 2.3 ± 2.7 L/wk (baseline 13.2 ± 7.4 L/wk) in the placebo group (P < .001). The percentage of patients with a 1-day or more reduction in the weekly need for parenteral support was greater in the teduglutide group (21/39 [54%]) than in the placebo group (9/39 [23%]; P = .005). Teduglutide increased plasma concentrations of citrulline, a biomarker of mucosal mass. The distribution of treatment-emergent adverse events that led to study discontinuation was similar between patients given teduglutide (n = 2) and placebo (n = 3). Conclusions: Twenty-four weeks of teduglutide treatment was generally well tolerated in patients with SBS-IF. Treatment with teduglutide reduced volumes and numbers of days of parenteral support for patients with SBS-IF; ClinicalTrials.gov Number, NCT00798967. [ABSTRACT FROM AUTHOR]

Published
2012
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