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- Lutgendorff, Femke, et al.
(författare)
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Probiotics prevent intestinal barrier dysfunction in acute pancreatitis in rats via induction of ileal mucosal glutathione biosynthesis.
- 2009
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:2, s. e4512-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: During acute pancreatitis (AP), oxidative stress contributes to intestinal barrier failure. We studied actions of multispecies probiotics on barrier dysfunction and oxidative stress in experimental AP. METHODOLOGY/PRINCIPAL FINDINGS: Fifty-three male Spraque-Dawley rats were randomly allocated into five groups: 1) controls, non-operated, 2) sham-operated, 3) AP, 4) AP and probiotics and 5) AP and placebo. AP was induced by intraductal glycodeoxycholate infusion and intravenous cerulein (6 h). Daily probiotics or placebo were administered intragastrically, starting five days prior to AP. After cerulein infusion, ileal mucosa was collected for measurements of E. coli K12 and (51)Cr-EDTA passage in Ussing chambers. Tight junction proteins were investigated by confocal immunofluorescence imaging. Ileal mucosal apoptosis, lipid peroxidation, and glutathione levels were determined and glutamate-cysteine-ligase activity and expression were quantified. AP-induced barrier dysfunction was characterized by epithelial cell apoptosis and alterations of tight junction proteins (i.e. disruption of occludin and claudin-1 and up-regulation of claudin-2) and correlated with lipid peroxidation (r>0.8). Probiotic pre-treatment diminished the AP-induced increase in E. coli passage (probiotics 57.4+/-33.5 vs. placebo 223.7+/-93.7 a.u.; P<0.001), (51)Cr-EDTA flux (16.7+/-10.1 vs. 32.1+/-10.0 cm/s10(-6); P<0.005), apoptosis, lipid peroxidation (0.42+/-0.13 vs. 1.62+/-0.53 pmol MDA/mg protein; P<0.001), and prevented tight junction protein disruption. AP-induced decline in glutathione was not only prevented (14.33+/-1.47 vs. 8.82+/-1.30 nmol/mg protein, P<0.001), but probiotics even increased mucosal glutathione compared with sham rats (14.33+/-1.47 vs. 10.70+/-1.74 nmol/mg protein, P<0.001). Glutamate-cysteine-ligase activity, which is rate-limiting in glutathione biosynthesis, was enhanced in probiotic pre-treated animals (probiotics 2.88+/-1.21 vs. placebo 1.94+/-0.55 nmol/min/mg protein; P<0.05) coinciding with an increase in mRNA expression of glutamate-cysteine-ligase catalytic (GCLc) and modifier (GCLm) subunits. CONCLUSIONS: Probiotic pre-treatment diminished AP-induced intestinal barrier dysfunction and prevented oxidative stress via mechanisms mainly involving mucosal glutathione biosynthesis.
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- den Dulk, Marcel, et al.
(författare)
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The abdominoperineal resection itself is associated with an adverse outcome : The European experience based on a pooled analysis of five European randomised clinical trials on rectal cancer
- 2009
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 45:7, s. 1175-1183
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of this study is to identify factors associated with the decision to perform an abdominoperineal resection (APR) and to assess if these factors or the surgical procedure itself is associated with circumferential resection margin (CRM) involvement, local recurrence (LR), overall survival (OS) and cancer-specific survival (CSS). PATIENTS AND METHODS: The Swedish Rectal Cancer Trial (SRCT), TME trial, CAO/ARO/AIO-94 trial, EORTC 22921 trial and Polish Rectal Cancer Trial (PRCT) were pooled. A propensity score was calculated, which indicated the predicted probability of undergoing an APR given gender, age and distance, and used in the multivariate analyses. RESULTS: An APR procedure was associated with an increased risk of CRM involvement [odd ratio (OR) 2.52, p<0.001], increased LR rate [hazard ratio (HR) 1.53, p=0.001] and decreased CSS rate (HR 1.31, p=0.002), whereas the propensity score was not. CONCLUSION: The results suggest that the APR procedure itself is a significant predictor for non-radical resections and increased risk of LR and death due to cancer for patients with advanced rectal cancer.
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- Hosseini Maaf, Bahram, et al.
(författare)
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Structural basis for red cell phenotypic changes in newly identified, naturally occurring subgroup mutants of the human blood group B glycosyltransferase.
- 2007
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Ingår i: Transfusion. - : Wiley. - 1537-2995 .- 0041-1132. ; 47:5, s. 864-875
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Four amino-acid-changing polymorphisms differentiate the blood group A and B alleles. Multiple missense mutations are associated with weak expression of A and B antigens but the structural changes causing subgroups have not been studied. STUDY DESIGN AND METHODS: Individuals or families having serologically weak B antigen on their red cells were studied. Alleles were characterized by sequencing of exons 1 through 7 in the ABO gene. Single crystal X-ray diffraction, three-dimensional-structure molecular modeling, and enzyme kinetics showed the effects of the B allele mutations on the glycosyltransferases. RESULTS: Seven unrelated individuals with weak B phenotypes possessed seven different B alleles, five of which are new and result in substitution of highly conserved amino acids: M189V, I192T, F216I, D262N, and A268T. One of these (F216I) was due to a hybrid allele resulting from recombination between B and O-1v alleles. The two other alleles were recently described in other ethnic groups and result in V175M and L232P. The first crystal-structure determination (A268T) of a subgroup glycosyltransferase and molecular modeling (F216I, D262N, L232P) indicated conformational changes in the enzyme that could explain the diminished enzyme activity. The effect of three mutations could not be visualized since they occur in a disordered loop. CONCLUSION: The genetic background for B-w phenotypes is very heterogeneous but usually arises through seemingly random missense mutations throughout the last ABO exon. The targeted amino acid residues, however, are well conserved during evolution. Based on analysis of the resulting structural changes in the glycosyltransferase, the mutations are likely to disrupt molecular bonds of importance for enzymatic function.
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| 5. |
- Lutgendorff, Femke, 1981-, et al.
(författare)
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Probiotics enhance pancreatic glutathione biosynthesis and reduce oxidative stress in experimental acute pancreatitis
- 2008
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Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 295:5
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Tidskriftsartikel (refereegranskat)abstract
- Factors determining severity of acute pancreatitis (AP) are poorly understood. Oxidative stress causes acinar cell injury and contributes to the severity, whereas prophylactic probiotics ameliorate experimental pancreatitis. Our objective was to study how probiotics affect oxidative stress, inflammation, and acinar cell injury during the early phase of AP. Fifty-three male Sprague-Dawley rats were randomly allocated into groups: 1) control, 2) sham procedure, 3) AP with no treatment, 4) AP with probiotics, and 5) AP with placebo. AP was induced under general anesthesia by intraductal glycodeoxycholate infusion (15 mM) and intravenous cerulein (5 μg·kg-1·h-1, for 6 h). Daily probiotics or placebo were administered intragastrically, starting 5 days prior to AP. After cerulein infusion, pancreas samples were collected for analysis including lipid peroxidation, glutathione, glutamate-cysteine-ligase activity, histological grading of pancreatic injury, and NF-κB activation. The severity of pancreatic injury correlated to oxidative damage (r = 0.9) and was ameliorated by probiotics (1.5 vs. placebo 5.5, P = 0.014). AP-induced NF-κB activation was reduced by probiotics (0.20 vs. placebo 0.53 OD 450nm/mg nuclear protein, P < 0.001). Probiotics attenuated AP-induced lipid peroxidation (0.25 vs. placebo 0.51 pmol malondialdehyde/mg protein, P < 0.001). Not only was AP-induced glutathione depletion prevented (8.81 vs. placebo 4.1 μmol/mg protein, P < 0.001), probiotic pretreatment even increased glutathione compared with sham rats (8.81 vs. sham 6.18 μmol/mg protein, P < 0.001). Biosynthesis of glutathione (glutamate-cysteine-ligase activity) was enhanced in probiotic-pretreated animals. Probiotics enhanced the biosynthesis of glutathione, which may have reduced activation of inflammation and acinar cell injury and ameliorated experimental AP, via a reduction in oxidative stress. Copyright © 2008 the American Physiological Society.
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- Panday, Saadhna, et al.
(författare)
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Nicotine dependence and withdrawal symptoms among occasional smokers
- 2007
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Ingår i: Journal of Adolescent Health. - : Elsevier BV. - 1054-139X .- 1879-1972. ; 40:2, s. 144-150
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Tidskriftsartikel (refereegranskat)abstract
- Purpose This study describes the levels of nicotine dependence, withdrawal symptoms, depressive mood, and risk behavior reported by male and female weekly and monthly adolescent smokers in South Africa. Methods A cross-sectional survey was conducted among 554 grade 9–11 weekly and monthly smokers in the Southern Cape-Karoo Region. Differences between the gender groups and smoking status were analyzed while controlling for demographic characteristics. Results Weekly and monthly smokers were classified as light smokers having smoked 6–10 cigarettes and 0–1 cigarettes a week, respectively. However, they displayed substantial levels of dependence, with 11.6% of weekly smokers classified as highly dependent. Furthermore, 55.9% of weekly smokers and 47.1% of the overall sample experienced more than two withdrawal symptoms. Although dependency levels and withdrawal symptoms were higher among weekly smokers, the levels were not negligible among monthly smokers. Weekly smokers reported higher levels of depressive mood and risk behavior than monthly smokers. Females reported higher levels of dependence, withdrawal symptoms, depressive mood, and lower levels of risk behavior than males. Gender differences were not found on the number of cigarettes smoked in a week. Conclusions This study demonstrates multiple symptoms of dependence among a large sample of adolescent occasional smokers in a multi-ethnic cultural setting. Smoking cessation programs may, therefore, be required to help adolescents quit smoking and possibly consider pharmacotherapy for highly dependent smokers. Prevention programs should also consider providing occasional smokers skills to identify and cope with withdrawal symptoms.
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- Peeters, Koen C. M.J., et al.
(författare)
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The TME trial after a median follow-up of 6 years : Increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma
- 2007
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Ingår i: Annals of Surgery. - : Ovid Technologies (Wolters Kluwer Health). - 0003-4932 .- 1528-1140. ; 246:5, s. 693-701
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the efficacy of preoperative short-term radiotherapy in patients with mobile rectal cancer undergoing total mesorectal excision (TME) surgery. Summary Background Data: Local recurrence is a major problem in rectal cancer treatment. Preoperative short-term radiotherapy has shown to improve local control and survival in combination with conventional surgery. The TME trial investigated the value of this regimen in combination with total mesorectal excision. Long-term results are reported after a median follow-up of 6 years. Methods: One thousand eight hundred and sixty-one patients with resectable rectal cancer were randomized between TME preceded by 5 × 5 Gy or TME alone. No chemotherapy was allowed. There was no age limit. Surgery, radiotherapy, and pathologic examination were standardized. Primary endpoint was local control. Results: Median follow-up of surviving patients was 6.1 year. Five-year local recurrence risk of patients undergoing a macroscopically complete local resection was 5.6% in case of preoperative radiotherapy compared with 10.9% in patients undergoing TME alone (P < 0.001). Overall survival at 5 years was 64.2% and 63.5%, respectively (P = 0.902). Subgroup analyses showed significant effect of radiotherapy in reducing local recurrence risk for patients with nodal involvement, for patients with lesions between 5 and 10 cm from the anal verge, and for patients with uninvolved circumferential resection margins. Conclusions: With increasing follow-up, there is a persisting overall effect of preoperative short-term radiotherapy on local control in patients with clinically resectable rectal cancer. However, there is no effect on overall survival. Since survival is mainly determined by distant metastases, efforts should be directed towards preventing systemic disease.
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| 10. |
- Stolk, Jan, et al.
(författare)
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Progression parameters for emphysema: A clinical investigation
- 2007
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 1532-3064 .- 0954-6111. ; 101:9, s. 1924-1930
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Tidskriftsartikel (refereegranskat)abstract
- In patients with airflow limitation caused by cigarette smoking, lung density measured by computed tomography is strongly correlated with quantitative pathology scores of emphysema, but the ability of lung densitometry to detect progression of emphysema is disputed. We assessed the sensitivity of lung densitometry as a parameter of disease progression of emphysema in comparison to FEV1 and gas transfer. At study baseline and after 30 months we measured computed tomography (CT)-derived lung density, spirometry and carbon monoxide diffusion coefficient in 144 patients with chronic obstructive pulmonary disease (COPD) in five different centers. Annual change in lung density was 1.31 g/L/year (CI 95%: -2.12 to -0.50 HU, p = 0.0015, 39.5 mL/year (CI 95%: -100.0-21.0 mL, p = 0.2) for FEV1, (-39.5 mL) and 24.3 mu mol/min/kPa/L/year for gas transfer (CI 95%: -61.0-12.5 mu mol/min/kPa/L/year, p = 0.2). Signal-to-noise ratio (mean change divided by standard error of the change) for the detection of annual change was 3.2 for lung densitometry, but 1.3 for both FEV1 and gas diffusion. We conclude that detection of progression of emphysema was found to be 2.5-fold more sensitive using lung densitometry than by using currently recommended lung function parameters. Our results support CT scan as an efficacious test for novel drugs for emphysema. (c) 2007 Published by Elsevier Ltd.
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