| 1. |
- Abdulla, Aree, et al.
(författare)
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CD40L is not involved in acute experimental pancreatitis
- 2011
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 659:1, s. 85-88
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Tidskriftsartikel (refereegranskat)abstract
- Recent data suggest that platelets not only control thrombosis and hemostasis but may also regulate inflammatory processes such as acute pancreatitis. However, the specific role of platelet-derived mediators in the pathophysiology of acute pancreatitis is not known. Herein, we examined the role of CD40 ligand (CD40L, CD154) in different models of acute pancreatitis. Acute pancreatitis was induced by repetitive caerulein administration (50 mu g/kg, i.p.) or infusion of sodium taurocholate (5%-10 mu l) into the pancreatic duct in wild-type C578L/6 and CD40L-deficient mice. Neutrophil infiltration, myeloperoxidase (MPO), macrophage inflammatory protein-2 (MIP-2) levels, acinar cell necrosis, edema and hemorrhage in the pancreas as well as serum amylase activity and lung levels of MPO were quantified 24 h after induction of acute pancreatitis. Caerulein and taurocholate challenge caused a clear-cut pancreatic damage characterized by increased acinar cell necrosis, neutrophil infiltration, focal hemorrhage, edema formation as well as increased levels of serum amylase and MIP-2 in the pancreas and lung MPO and histological damage. Notably, CD40L gene-deficient animals exhibited a similar phenotype as wild-type mice after challenge with caerulein and taurocholate. Similarly, administration of an antibody directed against CD40L had no effect against acute pancreatitis. Our data suggest that CD40L does not play a functional role in experimental acute pancreatitis. Thus, other candidates than CD40L needs to be explored in order to identify platelet-derived mediators in the pathophysiology of acute pancreatitis. (C) 2011 Elsevier B.V. All rights reserved.
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| 2. |
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| 3. |
- Abdulla, Aree, et al.
(författare)
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Platelets regulate P-selectin expression and leukocyte rolling in inflamed venules of the pancreas
- 2012
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 682:1-3, s. 153-160
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Tidskriftsartikel (refereegranskat)abstract
- Recent data suggest that platelets regulate inflammatory changes and tissue damage in acute pancreatitis although the role of platelets in leukocyte-endothelium interactions in the pancreatic microcirculation is not known. The aim of this study was to define the impact of platelets on leukocyte rolling and adhesion in acute pancreatitis. Acute pancreatitis was induced in C57BL/6 mice by caerulein challenge. Mice were treated with an a anti-GP1b alpha (CD42b) antibody, which depletes platelets, or a control antibody before caerulein. Leukocyte rolling and adhesion were determined by the use of intravital fluorescence microscopy 18 h after the last dose of caerulein. In separate experiments, leukocyte-endothelium interactions were determined before and after administration of an anti-P-selectin, anti-PSGL-1 and a control antibody in mice with caerulein pancreatitis. Circulating platelet-neutrophil aggregates and pancreatic P-selectin mRNA were quantified 1 and 6 h respectively after caerulein challenge. Caerulein administration increased leukocyte and platelet interactions in the pancreatic microvasculature, increased tissue damage and expression of P-selectin mRNA in the pancreas as well as platelet-neutrophil complexes in the circulation. Notably, platelet depletion markedly reduced caerulein-provoked leukocyte rolling and adhesion in postcapillary venules. Interestingly, depletion of platelets significantly decreased caerulein-induced gene expression of P-selectin in the pancreas. Moreover, immunoneutralization of P-selectin and PSGL-1 abolished leukocyte rolling in the pancreatic venules triggered by caerulein. Our novel findings demonstrate that platelets regulate leukocyte rolling in acute pancreatitis via induction of P-selectin, which was critical in supporting leukocyte rolling in inflamed venules of the pancreas. (C) 2012 Elsevier B.V. All rights reserved.
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| 4. |
- Abdulla, Aree, et al.
(författare)
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Role of platelets in experimental acute pancreatitis.
- 2011
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 98, s. 93-103
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:: Platelets not only control thrombosis and haemostasis but may also regulate inflammatory processes. Acute pancreatitis (AP) is characterized by changes in both coagulation and proinflammatory activities. The role of platelets in AP is not yet known. METHODS:: AP was induced in C57BL/6 mice by repeated caerulein administration (50 µg/kg intraperitoneally). Mice received a platelet-depleting or control antibody before caerulein challenge. Neutrophil infiltration, myeloperoxidase (MPO) and macrophage inflammatory protein (MIP) 2 levels, acinar cell necrosis and haemorrhage in the pancreas, as well as serum amylase activity, were determined 24 h after caerulein injection. In an alternative model of pancreatitis, L-arginine (4 g/kg intraperitoneally) was given twice with an interval of 1 h and tissue samples were taken after 72 h [Correction added after online publication 29 September 2010: in the preceding sentence, 4 mg/kg was corrected to 4 g/kg]. RESULTS:: Caerulein administration increased acinar cell necrosis, neutrophil infiltration, focal haemorrhage and serum amylase levels. Platelet depletion reduced acinar cell necrosis, haemorrhage and serum amylase levels in AP. Depletion of platelets decreased caerulein-induced MPO levels and neutrophil recruitment in the pancreas. Platelet depletion abolished caerulein-induced MIP-2 generation in the pancreas and circulation. The effects of platelet depletion on necrosis, neutrophils and MPO levels were confirmed in L-arginine-induced pancreatitis. CONCLUSION:: Platelets play a crucial role in AP by regulating neutrophil infiltration, most likely mediated by MIP-2 production in the pancreas. Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
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| 5. |
- Awla, Darbaz, et al.
(författare)
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Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis.
- 2012
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Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 91, s. 711-719
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Tidskriftsartikel (refereegranskat)abstract
- MMPs are generally considered to regulate degradation and remodeling of the ECM. Convincing data also implicate a role for MMPs in inflammatory conditions, such as AP, although the mechanisms are not known. The aim of this study was to define the role of MMPs in regulating activation of trypsinogen and tissue damage in AP, which was induced by infusion of taurocholate into the pancreatic duct in mice. A broad-spectrum MMP inhibitor (BB-94) and MMP-9 gene-deficient mice were used. Neutrophil secretions and rMMP-9 were used to stimulate trypsinogen activation in isolated acinar cells. Taurocholate challenge increased serum amylase, neutrophil infiltration, MIP-2 (CXCL2) formation, trypsinogen activation, and tissue damage in the pancreas. Treatment with the broad-spectrum inhibitor of MMPs, BB-94, markedly reduced activation of trypsinogen, levels of CXCL2, infiltration of neutrophils, and tissue damage in AP. Taurocholate challenge increased serum levels of MMP-9 but not MMP-2. Taurocholate-induced amylase levels, neutrophil accumulation, production of CXCL2, trypsinogen activation, and tissue damage in the pancreas were abolished in MMP-9-deficient mice. Moreover, secretions from activated neutrophils isolated from WT but not from MMP-9-deficient animals stimulated trypsinogen activation in acinar cells. Notably, rMMP-9 greatly enhanced activation of trypsinogen in acinar cells. These findings demonstrate that neutrophil-derived MMP-9 is a potent activator of trypsinogen in acinar cells and regulates pathological inflammation and tissue damage in AP.
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| 7. |
- Dold, Stefan, et al.
(författare)
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P-selectin glycoprotein ligand-1-mediated leukocyte recruitment regulates hepatocellular damage in acute obstructive cholestasis in mice.
- 2010
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 59, s. 291-298
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Leukocytes mediate hepatocellular injury in obstructive cholestasis. The aim of the present study was to define the role of P-selectin glycoprotein ligand-1 (PSGL-1) in cholestasis-induced leukocyte recruitment and liver damage. METHODS: C57BL/6 mice were pre-treated with an anti-PSGL-1 antibody or a control antibody prior to bile duct ligation (BDL) for 12 h. Hepatic recruitment of leukocytes and sinusoidal perfusion were determined by means of intravital fluorescence microscopy. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic levels of CXC chemokines were determined by ELISA. RESULTS: BDL caused significant hepatocellular damage indicated by increased serum activities of ALT and AST as well as decreased sinusoidal perfusion and clear-cut hepatic infiltration of leukocytes. Administration of the anti-PSGL-1 antibody reduced BDL-induced levels of ALT by 78% and AST by 77%. Inhibition of PSGL-1 decreased BDL-provoked leukocyte rolling and adhesion in post-sinusoidal venules by more than 81%. Moreover, we found that immunoneutralisation of PSGL-1 restored sinusoidal perfusion and decreased hepatic formation of CXC chemokines in cholestatic mice. CONCLUSIONS: Our novel data show that PSGL-1 plays an important role in cholestatic liver damage by regulating leukocyte rolling in post-sinusoidal venules. Consequently, interference with PSGL-1 attenuates cholestasis-provoked leukocyte adhesion and extravasation in the liver. Thus, inhibition of PSGL-1 may help to protect against hepatocellular damage in cholestatic diseases.
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| 8. |
- Dykstra, Natalie S, et al.
(författare)
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Pulse Probiotic Administration Induces Repeated Small Intestinal Muc3 Expression in Rats.
- 2011
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Ingår i: Pediatric Research. - 1530-0447. ; 69, s. 206-211
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Tidskriftsartikel (refereegranskat)abstract
- Upon ingestion, probiotics may act to protect the host through a number of protective mechanisms including modulation of genes involved in intestinal innate mucosal defense such as epithelial cell derived mucin glycoproteins and inhibitor of apoptosis proteins. To determine the specificity of effect and sustainability of response in vivo, Lactobacillus plantarum 299v (Lp299v), Lactobacillus rhamnosus R0011 (LrR0011) and Bifidobacterium bifidum R0071 (BbR0071) were added repeatedly or intermittently to the drinking water of Sprague-Dawley rats. Following sacrifice via CO2 suffocation, Muc2, Muc3, NAIP, HIAP1/cIAP2 and HIAP2/cIAP1 mRNA and protein levels were analyzed via RT-PCR and immunohistochemistry. Live Lp299v, BbR0071 and LrR0011 increased Muc3 protein and mRNA expression in jejunum and ileum. Heat-killed and a non-adherent derivative of Lp299v failed to induce Muc3 expression. Lp299v did induce expression of HIAP2/cIAP1 and NAIP expression. Muc3 mucin expression was elevated for 5 days following oral administration of Lp299v but this effect was not sustained despite ongoing daily ingestion of a probiotic. Intermittent pulse ingestion of probiotics however, was found to repeatedly increase Muc3 expression. We conclude that selected probiotics can induce protective genes of mucosal intestinal epithelial cells, an effect that is reproducible with pulse probiotic administration. ABBREVIATIONS:
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| 9. |
- Edvardsson, Johanna, et al.
(författare)
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Mer tid för patienten hos läkare i England - En jämförande tidsstudie av svenska och engelska läkares arbetsdag.
- 2014
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Ingår i: Läkartidningen. - 0023-7205. ; 111
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Tidskriftsartikel (refereegranskat)abstract
- Little is known concerning the amount of time doctors spend doing different work tasks. A comparative study between four surgical departments in Sweden and England was performed. The time study shows that doctors in Sweden spent around 37% of working hours on administration and 40% on patient work. The numbers in England were 15% and 66% respectively. From the survey, only performed in Sweden, it appeared that doctors have insufficient time for all their assignments and as a consequence often deprioritize their continuous professional education. Problems within the administrative field have been identified and may be the starting point for task reduction.
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| 10. |
- Gaber, Alexander, et al.
(författare)
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Effects of radiation therapy on tissue and serum concentrations of tumour associated trypsin inhibitor and their prognostic significance in rectal cancer patients
- 2011
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Ingår i: Radiation Oncology. - 1748-717X. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Background: We have previously demonstrated that elevated concentrations of tumour-associated trypsin inhibitor (TATI) in both tumour tissue (t-TATI) and in serum (s-TATI) are associated with a poor prognosis in colorectal cancer patients. It was also found that s-TATI concentrations were lower in patients with rectal cancer compared to patients with colon cancer. In this study, we investigated the effects of neoadjuvant radiotherapy (RT) on concentrations of t-TATI and s-TATI in patients with rectal cancer. Methods: TATI was analysed in serum, normal mucosa and tumour tissue collected at various time points in 53 rectal cancer patients enrolled in a case-control study where 12 patients received surgery alone, 20 patients 5 x 5 Gy (short-term) preoperative RT and 21 patients 25 x 2 Gy (long-term) preoperative RT. T-TATI was analysed by immunohistochemistry and s-TATI was determined by an immunofluorometric assay. Mann-Whitney U test and Wilcoxon Z (Z) test were used to assess t-TATI and s-TATI concentrations in relation to RT. Spearman's correlation (R) test was used to explore the associations between t-TATI, s-TATI and clinicopathological parameters. Overall survival (OS) according to high and low t-TATI and s-TATI concentrations was estimated by classification and regression tree analysis, Kaplan-Meier analysis and the log rank test. Results: RT did not affect concentrations of t-TATI or s-TATI. In patients receiving short-term but not long-term RT, s-TATI concentrations were significantly higher 4 weeks post surgery than in serum drawn prior to surgery (Z = -3.366, P < 0.001). T-TATI expression correlated with male gender (R = 0.406, P = 0.008). High t-TATI expression in surgical specimens was associated with a significantly shorter OS (P = 0.045). S-TATI concentrations in serum drawn at all time points were associated with an impaired OS (P = 0.035 before RT, P = 0.001 prior to surgery, P = 0.043 post surgery). At all time points, s-TATI correlated with higher age (P < 0.001-0.021) and with increased s-creatinine concentrations assessed prior to surgery (P = 0.041). Conclusions: The results presented here further validate the utility of t-TATI and s-TATI as prognostic biomarkers in patients with rectal cancer, independent of neoadjuvant RT.
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