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Sökning: WFRF:(Ekelund Mats) > (2005-2009)

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1.
  • Ekelund, Mikael, et al. (författare)
  • Effects of total parenteral nutrition on rat enteric nervous system, intestinal morphology, and motility.
  • 2005
  • Ingår i: Journal of Surgical Research. - Elsevier. - 1095-8673. ; 124:2, s. 187-193
  • Tidskriftsartikel (refereegranskat)abstract
    • Total parenteral nutrition (TPN) is often crucial for patients not being able to feed enterally or having intestinal absorptive deficits. Enteral nutrition is, however, frequently regarded vital for maintaining functional and structural intestinal integrity. The aim of this study was to investigate possible effects of TPN on rat distal small intestine compared to enterally fed identically housed controls, regarding the enteric nervous system (ENS), motility in vitro, and morphology. This study shows that motor responses evoked by electrical stimulation or exposure to vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptide-27 (PACAP-27), and nitric oxide (NO) donor were unchanged. By using immunohistochemistry, the numbers of submucous (P < 0.05) and myenteric (P < 0.05) nerve cells were found to increase, expressed as numbers per unit length. The percentage of neurons expressing VIP, PACAP-27, NO-synthase, and galanin remained unchanged, however. By in situ hybridization the number of submucous neurons expressing neuropeptide Y-mRNA was found to decrease (P < 0.05); the other populations were unaltered. Morphometry revealed an increased submucosal thickness (P < 0.05), while intestinal circumference markedly decreased (P < 0.0001) in TPN-treated rats. In conclusion, TPN treatment resulted in reduced intestinal circumference leading to condensation of enteric neurons. No marked changes in neurotransmitter expression of the enteric neurons or in motor activity were noted.
2.
  • Ekelund, Mikael, et al. (författare)
  • Total Parenteral Nutrition Causes Circumferential Intestinal Atrophy, Remodeling of the Intestinal Wall, and Redistribution of Eosinophils in the Rat Gastrointestinal Tract.
  • 2007
  • Ingår i: Digestive Diseases and Sciences. - Springer. - 1573-2568. ; 52:8, s. 1833-1839
  • Tidskriftsartikel (refereegranskat)abstract
    • Total parenteral nutrition (TPN) is held to cause intestinal atrophy and weaken mechanical and immunological barriers. To monitor the degree of atrophy caused by TPN, female Sprague-Dawley rats were, for 8 days, maintained on TPN (n = 6) and compared to identically housed controls given food and water ad libitum (n = 6). Specimens from jejunum, ileum, and colon were taken for histology and morphometric analysis. Topographic distribution and presence of eosinophils, by eosinophil peroxidase (EPO) staining, were examined in the gastric fundus, jejunum, ileum, and colon. Atrophy in terms of a markedly reduced circumference was noted throughout the intestinal tract in all rats subjected to TPN. The width of jejunal and ileal villi was narrowed and the length of jejunal villi was decreased. Furthermore, submucosal thickness in the jejunum and ileum increased. The height of ileal enterocytes remained unaltered. The number of goblet cells decreased in jejunal but not in ileal villi. The Paneth cells, suggested to play important roles in innate defense, increased in size. In the gastric fundus a marked increase in eosinophils was revealed predominantly in the mucosa and submucosa. The number and distribution of jejunal and ileal eosinophils were identical to those of controls. In colon from TPN rats, a redistribution of eosinophils was noted, causing a "band-like" accumulation of eosinophils in the basal portion of the mucosa. In conclusion, TPN causes gut atrophy and an increase in Paneth cell size. Eosinophils increase in number in the gastric fundus and a topographic redistribution occurs in the colon.
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3.
  • Berggren, Sofia, et al. (författare)
  • Gene and protein expression of P-glycoprotein, MRP1, MRP2 and CYP3A4 in the small and large human intestine
  • 2007
  • Ingår i: Molecular Pharmaceutics. - 1543-8384. ; 4:2, s. 252-257
  • Tidskriftsartikel (refereegranskat)abstract
    • The cytochrome P450 3A4 enzyme and the ABC-transporters may affect the first-pass extraction and bioavailability of drugs and metabolites. Conflicting reports can be found in the literature on the expression levels of efflux transporters in human intestine and how they vary along the intestine. The relative levels of mRNA and protein of CYP3A4 and the ABC tranporters Pgp (ABCB1), MRP1 (ABCC1), and MRP2 (ABCC2) were determined using RT-PCR and Western blot for human intestinal tissues (n = 14) from jejunum, ileum and colon. The expression of mRNA for CYP3A4, Pgp, and MRP2 was highest in jejunum and decreased toward more distal regions, whereas MRP1 was equally distributed in all intestinal regions. For CYP3A4, a more significant correlation could be established between mRNA and protein expression than for the ABC transporters. The samples showed considerable interindividual variability, especially at the protein level. The apically located Pgp and MRP2 showed a similar expression pattern along the human intestine as for CYP3A4. The gene expression of MRP1 exhibited a more uniform distribution.
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4.
  • Ekelund, Mats, et al. (författare)
  • Selective induction of inducible nitric oxide synthase in pancreatic islet of rat after an intravenous glucose or intralipid challenge.
  • 2006
  • Ingår i: Nutrition. - Elsevier. - 1873-1244. ; 22:2006 Apr 22, s. 652-660
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Constant exposure of pancreatic islets to high levels of glucose or free fatty acids can lead to irreversible beta-cell dysfunction, a process referred to as glucotoxicity or lipotoxicity, respectively. In this context a role for nitric oxide generated by pancreatic islet has been suggested. The present investigation examined whether the route of glucose administration, i.e., given orally (OG) or infused intravenously (IVG), could have any effect on the expression and activity of inducible nitric oxide synthase (iNOS) in pancreatic islets. Methods: Rats were infused with glucose (50%) or Intralipid intravenously for 24 h or given glucose orally. A freely fed control group (FF) was also included. At 24 h rats were killed and blood samples were drawn for analysis of plasma insulin, glucagon, and glucose. Pancreatic islets were harvested from each animal and investigated for the occurrence of iNOS by the use of confocal microscopy, western blot, and high-performance liquid chromatographic analysis. The effect of intravenously infused glucose was then compared with the effect of an intravenous infusion of Intralipid (IL). Results: Plasma insulin levels were markedly decreased after 24 h of infusion of glucose (IVG group) or Intralipid (IL group) compared with the FF or OG group. Plasma glucagon and glucose levels were markedly increased in the IVG group, whereas both parameters were decreased in the IL group. No significant differences in plasma insulin, glucagon, or glucose were found between the OG and FF groups. Immunocytochemical (confocal microscopy), western blot, and biochemical (high-performance liquid chromatographic) analyses showed that a sustained increase in plasma level of glucose or free fatty acids by an intravenous infusion of either nutrient for 24 h resulted in a marked expression and activity of iNOS in pancreatic islets. No sign of iNOS expression could, however, be detected in the islets of FF control or OG rats. Conclusion: The data suggest that impaired beta-cell function found after 24 It of an intravenous infusion of glucose or Intralipid might be mediated, at least in part, by the induction of iNOS in pancreatic islets. This may subsequently result in an exclusive production of nitric oxide, which is deleterious for beta-cells. (C) 2006 Elsevier Inc. All rights reserved.
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5.
  • Gunnlaugsson, Adalsteinn, et al. (författare)
  • Multicentre phase II trial of capecitabine and oxaliplatin in combination with radiotherapy for unresectable colorectal cancer: The CORGI-L study.
  • 2009
  • Ingår i: European Journal of Cancer. - Elsevier. - 1879-0852. ; 45, s. 807-813
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: This study assessed radiotherapy combined with capecitabine and oxaliplatin in patients with primary, inextirpable colorectal adenocarcinoma. PATIENTS AND METHODS: Forty-nine patients entered the trial. Two cycles of XELOX (capecitabine 1000mg/m(2) bid d1-14+oxaliplatin 130mg/m(2) d1, q3w) were followed by radiotherapy (50.4Gy), combined with capecitabine 825mg/m(2) bid every radiotherapy day and oxaliplatin 60mg/m(2) once weekly. The primary end-point was objective response. RESULTS: Forty-seven patients were evaluable. Twenty-nine (62% [95% CI: 46-75%]) achieved complete or partial response. Thirty-eight (81%) went through surgery of whom 37 (97%) had an R0 resection and five (13%) had a pathological complete response. Seventy-eight percent were alive and estimated local progression rate was 11% at 2 years. The most common grade 3+ toxicity during chemoradiotherapy was diarrhoea (24%). CONCLUSIONS: XELOX-RT was feasible and showed promising efficacy when treating patients with primary inextirpable colorectal cancer, establishing high local control rate.
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6.
  • Norlén, Per, et al. (författare)
  • The vagus regulates histamine mobilization from rat stomach ECL cells by controlling their sensitivity to gastrin
  • 2005
  • Ingår i: Journal of Physiology. - The Physiological Society. - 1469-7793. ; 564:3, s. 895-905
  • Tidskriftsartikel (refereegranskat)abstract
    • The ECL cells in the oxyntic mucosa secrete histamine in response to gastrin, stimulating parietal cells to produce acid. Do they also operate under nervous control? The present study examines histamine mobilization from rat stomach ECL cells in situ in response to acute vagal excitation and to food or gastrin following vagal or sympathetic denervation. Applying the technique of microdialysis, we monitored the release of histamine by radioimmunoassay. Microdialysis probes were placed in the submucosa on either side of the stomach, 3 days before experiments. The rats were awake during microdialysis except when subjected to electrical vagal stimulation. One-sided electrical vagal stimulation raised serum gastrin and mobilized gastric histamine. However, gastrin receptor blockade prevented the histamine mobilization, indicating that circulating gastrin accounts for the response. Vagal excitation by hypoglycaemia (insulin) or pylorus ligation did not mobilize either gastrin or histamine. The histamine response to food was almost abolished by gastrin receptor blockade, and it was halved on the denervated side after unilateral subdiaphragmatic vagotomy. While the histamine response to a near-maximally effective dose of gastrin was unaffected by vagotomy, the response to low gastrin doses was reduced significantly. Abdominal ganglionic sympathectomy failed to affect the histamine response to either food or gastrin. In conclusion, gastrin is responsible for most of the food-evoked mobilization of ECL-cell histamine. The histamine response to electrical vagal stimulation reflects the effect of circulating gastrin rather than a direct action of the vagus on the ECL cells. Vagal denervation was accompanied by an impaired histamine response to food intake, probably reflecting the right-ward shift of the serum gastrin concentration-histamine response curve. The results suggest that the vagus controls the sensitivity of the ECL cells to gastrin.
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7.
  • Pettersson, Jonas, et al. (författare)
  • Muscular exercise can cause highly pathological liver function tests in healthy men.
  • 2008
  • Ingår i: British Journal of Clinical Pharmacology. - John Wiley and Sons Inc.. - 1365-2125. ; 65:2, s. 253-259
  • Tidskriftsartikel (refereegranskat)abstract
    • What is already known about this subject • The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the leading cause of postmarketing warnings and withdrawals. • Physical exercise can result in transient elevations of liver function tests. • There is no consensus in the literature on which forms of exercise may cause changes in liver function tests and to what extent. What this study adds • Weightlifting results in profound increases in liver function tests in healthy men used to moderate physical activity, not including weightlifting. • Liver function tests are significantly increased for at least 7 days after weightlifting. • It is important to impose relevant restrictions on heavy muscular exercise prior to and during clinical studies. Aim To investigate the effect of intensive muscular exercise (weightlifting) on clinical chemistry parameters reflecting liver function in healthy men. Methods Fifteen healthy men, used to moderate physical activity not including weightlifting, performed an 1 h long weightlifting programme. Blood was sampled for clinical chemistry parameters [aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LD), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), bilirubin, creatine kinase (CK) and myoglobin] at repeated intervals during 7 days postexercise and at a follow-up examination 10–12 days postexercise. Results Five out of eight studied clinical chemistry parameters (AST, ALT, LD, CK and myoglobin) increased significantly after exercise (P < 0.01) and remained increased for at least 7 days postexercise. Bilirubin, γGT and ALP remained within the normal range. Conclusion The liver function parameters, AST and ALT, were significantly increased for at least 7 days after the exercise. In addition, LD and, in particular, CK and myoglobin showed highly elevated levels. These findings highlight the importance of imposing restrictions on weightlifting prior to and during clinical studies. Intensive muscular exercise, e.g. weightlifting, should also be considered as a cause of asymptomatic elevations of liver function tests in daily clinical practice.
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8.
  • Qader, Saleem, et al. (författare)
  • Expression of islet iNOS and inhibition of glucose stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27.
  • 2007
  • Ingår i: American Journal of Physiology: Endocrinology and Metabolism. - American Physiological Society. - 1522-1555. ; 292:5, s. 1447-1455
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic exposure of pancreatic islets to elevated plasma lipids ( lipotoxicity) can lead to beta-cell dysfunction, with overtime becoming irreversible. We examined, by confocal microscopy and biochemistry, whether the expression of islet inducible nitric oxide synthase ( iNOS) and the concomitant inhibition of glucose-stimulated insulin release seen after lipid infusion in rats was modulated by the islet neuropeptide pituitary adenylate cyclase-activating polypeptide ( PACAP) 27. Lipid infusion for 8 days induced a strong expression of islet iNOS, which was mainly confined to beta-cells and was still evident after incubating islets at 8.3 mmol/l glucose. This was accompanied by a high iNOS-derived NO generation, a decreased insulin release, and increased cyclic GMP accumulation. No iNOS expression was found in control islets. Addition of PACAP27 to incubated islets from lipid-infused rats resulted in loss of iNOS protein expression, increased cyclic AMP, decreased cyclic GMP, and suppression of the activities of neuronal constitutive ( nc) NOS and iNOS and increased glucose-stimulated insulin response. These effects were reversed by the PKA inhibitor H-89. The suppression of islet iNOS expression induced by PACAP27 was not affected by the proteasome inhibitor MG-132, which by itself induced the loss of iNOS protein, making a direct proteasomal involvement less likely. Our results suggest that PACAP27 through its cyclic AMP- and PKA-stimulating capacity strongly suppresses not only ncNOS but, importantly, also the lipid-induced stimulation of iNOS expression, possibly by a nonproteasomal mechanism. Thus PACAP27 restores the impairment of glucose-stimulated insulin release and additionally might induce cytoprotection against deleterious actions of iNOS-derived NO in beta-cells.
9.
10.
  • Qader, Saleem, et al. (författare)
  • Long-term infusion of nutrients (total parenteral nutrition) suppresses circulating ghrelin in food-deprived rats.
  • 2005
  • Ingår i: Regulatory Peptides. - Elsevier. - 1873-1686. ; 131:Aug 12, s. 82-88
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Ghrelin derives from endocrine cells (A-like cells) in the stomach (mainly the oxyntic mucosa). Its concentration in the circulation increases during fasting and decreases upon re-feeding. This has fostered the notion that the absence of food in the upper gastrointestinal (GI) tract stimulates the secretion of ghrelin. The purpose of the present study was to determine the concentration of ghrelin in serum and oxyntic mucosa after replacing food with intravenous (iv) infusion of nutrients for 8 days using the technique known as total parenteral nutrition (TPN). Materials and methods: Male Sprague-Dawley rats (200-250 g) were given nutrients (lipids, glucose, amino acids, minerals and vitamins) by iv infusion for 8 days during which time they were deprived of food and water; another group was deprived of food for 24-48 h (fasted controls), while fed controls had free access to food and water. Serum ghrelin, gastrin and pancreastatin concentrations were measured together with the ghrelin content of the oxyntic mucosa. Plasma insulin and glucose as well as serum lipid concentrations were also determined. Results: Fasted rats had higher serum ghrelin than TPN rats and fed controls. The oxyntic mucosal ghrelin concentration (and content) was lower in TPN rats than in fasted rats or fed controls. The serum gastrin and pancreastatin concentrations were lower in TPN rats and fasted rats than in fed controls. The plasma insulin concentration was 87 pmol/l +/- 8 (SEM) in TPN rats compared to 101 16 pmol/l in fed controls; it was 26 14 pmol/l in fasted rats. The basal plasma glucose level was 11 +/- 0.6 mmol/l in TPN rats and 12 +/- 0.8 mmol/l in fed controls; it was 7 +/- 0.3 mmol/l in fasted rats. In TPN rats, the serum concentrations of free fatty acids, triglycerides and cholesterol were increased by 100%, 50% and 25%, respectively, compared to fed controls. Fasted rats had higher circulating concentrations of free fatty acids (20%) and lower concentrations of triglycerides (- 40%) than fed controls; fasted rats did not differ from fed controls with respect to serum cholesterol. Conclusion: The circulating ghrelin concentration is high in situations of nutritional deficiency (starvation) and low in situations of nutritional plenty (free access to food or TPN). The actual presence or absence of food in the GI tract seems irrelevant. Circulating insulin and glucose concentrations did not differ much between TPN rats and fed controls, serum lipids, however, were elevated in the TPN rats. We suggest that elevated blood lipid levels contribute to the suppression of circulating ghrelin in rats subjected to TPN for 8 days.
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