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  • 251.
    Sydsjö, Gunilla
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Wadsby, Marie
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Child and Adolescent Psychiatry.
    Kjellberg, Svante
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Sydsjö, Adam
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Relationships and parenthood in couples after assisted reproduction and in spontaneous primiparous couples: A prospective long-term follow-up study2002In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 17, no 12, p. 3242-3250Article in journal (Refereed)
    Abstract [en]

    Background: The aim of this study was to analyse relationships and parenthood in primiparous IVF couples and spontaneous primiparous couples. Method: In total, 110 consecutive IVF couples were studied. The control group was matched for women's age and selected out of the total spontaneous pregnant population in the study area. Questionnaires and semi-structured telephone interviews were used to gain information about sociodemographic data, couples' relationships, and the children's health, temperament and behaviour. Obstetrical variables concerning the course and outcome of pregnancy and delivery as well as the health status of the new-borns were obtained from standardized antenatal care and delivery files. Results: There weere no differences concerning gestational age, mode of delivery or neonatal health between the two groups. The IVF couples were more stable over time - from pregnancy until the child was 1 year old - in their relationship, while the control group experienced a decrease in marital satisfaction. The children in the IVF group were assessed by their parents as being more regular/habitual, sensitive and manageable than the control children. Conclusion: The differences present between the groups were in favour of the IVF families, and the effects of the infertility crisis were not notable when the children were 1 year old.

  • 252.
    Sydsjö, Gunilla
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Wadsby, Marie
    Linköping University, Faculty of Health Sciences. Linköping University, Department of health and environment.
    Svedin, CG
    Linköping University, Faculty of Health Sciences. Linköping University, Department of health and environment. Östergötlands Läns Landsting, CPS - Centrum för psykiatri och samhällsmedicin, BUP - Barn- och ungdomspsykiatri.
    Psychosocial risk mothers: Early mother-child interaction and behavioural disturbances in children at 8 years of age2001In: Journal of Reproductive and Infant Psychology, ISSN 0264-6838, E-ISSN 1469-672X, Vol. 19, no 2, p. 135-146Article in journal (Refereed)
    Abstract [en]

    Mother-child interaction in a group of women with psychosocial risks, identified during pregnancy, was assessed at birth, when the infants were 6 months old, and again when they were 18 months old. Presence of behavioural disturbances in the children was assessed when they were 8 years of age. The at-risk index group was comprised of 45 mothers and their children, with the risk criteria consisting of alcohol/drug abuse, psychiatric problems, and disadvantageous social circumstances. Another 57 mother-child pairs lacking in risk criteria comprised a reference group. Most aspects of mother-child interaction were shown to be significantly poorer in the index group than in the reference group at the three points of assessment during infancy. At 8 years of age, the index children, especially the boys, were found to display significantly more behavioural disturbances than the reference children. A significant correlation was also found in the index group, but not in the reference group, between the quality of mother-infant interaction at birth and the extent of behavioural disturbance in children at 8 years of age. Overall, the results suggest that identification can be made, even during pregnancy, of children who are at risk of poor interaction with mothers during infancy and at risk of behavioural problems later in development.

  • 253.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Mast Cells and Mastocytosis2009In: DIGESTIVE DISEASES, ISSN 0257-2753, Vol. 27, p. 129-136Article in journal (Refereed)
    Abstract [en]

    Mast cells (MCs) typically reside at barrier sites of the body, including the intestinal mucosa, and play a vital role in innate host defence. Activated MCs release a wide variety of bioactive mediators. These include preformed mediators stored in the granules (e. g. histamine and tryptase) and newly synthesised mediators (e. g. prostaglandins, leukotrienes and cytokines). MCs are present in all layers throughout the gastrointestinal (GI) tract and there is a close bi-directional connection between MCs and enteric nerves that is of vital importance in the regulation of GI functions. Some gain-of-function mutations in c-kit, encoding the tyrosine kinase-receptor for stem cell factor, are associated with the rare disease entity, systemic mastocytosis. These patients present symptoms arising from MC mediator release or infiltration. GI manifestations are common in this patient group, mainly abdominal pain and diarrhoea. Endoscopy with biopsies reveals MC infiltration in the mucosa. Other diagnostic tools include bone marrow biopsy and serum tryptase. Treatment is symptomatic with antihistamines or cromoglycate in mild cases, whereas severe cases need cytoreductive therapy that should be managed with expert haematologists. From a day-to-day clinical perspective, the important role of MCs in neuroimmune interaction has been implicated in the intestinal response to stress, in alterations of mucosal and neuromuscular function in irritable bowel syndrome or inflammatory bowel disease, and in the pathogenesis of nonerosive oesophageal reflux disease. Thus, MCs have important regulatory and protective roles in innate defence, in addition to being a potential mediator of mucosal pathophysiology in GI diseases. We need to learn how to balance the response of these volatile cells to be able to benefit from their versatility.

  • 254.
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Stress-related changes in oesophageal permeability: Filling the gaps of GORD?2007In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 56, no 9, p. 1177-1180Article, review/survey (Refereed)
    Abstract [en]

    Albeit remaining a controversial issue, it has become increasingly recognised that psychological stress has a major impact on gut mucosal function and affects the course of gastrointestinal disorders. Research during the last decade has shown that stress causes barrier dysfunction of the gastrointestinal mucosa by mechanisms that mainly involve neuropeptides and mast cells. Moreover, accumulating evidence implicates increased permeability as a pathogenic factor in gastroesophageal reflux disease (GORD). Recent data demonstrating that psychological stress may induce a permeability defect in stratified epithelia, including the oesophagus, shed new light on the pathophysiological events leading to heartburn and GORD.

  • 255.
    Söderholm, Johan D
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Juliusson, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Sjödahl, Rune
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Long-term endoscopic remission in a case of Crohn's disease after autologous bone marrow transplantation.2000In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 118, no 4, p. 4212-Conference paper (Other academic)
  • 256.
    Söderholm, Johan D
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Malm, Claes
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Hematology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Juliusson, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Hematology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Sjödahl, Rune
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Long-term endoscopic remission of Crohn disease after autologous stem cell transplantation for acute myeloid leukaemia2002In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 37, no 5, p. 613-616Article in journal (Refereed)
    Abstract [en]

    A favourable course of Crohn disease has been observed after allogeneic bone marrow transplantation, and there is now mounting evidence that autologous stem cell may be an effective treatment for severe autoimmune diseases. Here, we present the first long-term endoscopic follow-up of a patient with Crohn disease undergoing autologous stem cell transplantation for haematological disease. A 54-year-old woman developed Crohn disease and was submitted to ileocaecal resection. Four months after surgery, the patient contracted acute myeloid leukaemia. She was initially treated with chemotherapy, and subsequently underwent autologous stem cell transplantation. Following transplantation, the patient has remained in clinical remission regarding both diseases, without anti-inflammatory medication. She has undergone ileo-colonoscopy with normal findings at 1, 2, 3 and 5 years after transplantation. This case suggests that autologous stem cell transplantation can change not only the clinical course, but also the natural history of intestinal inflammation in Crohn disease. This has pathophysiological as well as therapeutic implications.

  • 257.
    Söderholm, Johan D
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Olaison, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Peterson, KH
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Franzén, LE
    Lindmark, T
    Wirén, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Tagesson, Christer
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Östergötlands Läns Landsting, Pain and Occupational Centre, Occupational and Environmental Medicine Centre.
    Sjödahl, Rune
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Augmented increase in tight junction permeability by luminal stimuli in the non-inflamed ileum of crohn's disease2002In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 50, no 3, p. 307-313Article in journal (Refereed)
    Abstract [en]

    Background: Crohn's disease is associated with deranged intestinal permeability in vivo, suggesting dysfunction of tight junctions. The luminal contents are important for development of neoinflammation following resection. Regulation of tight junctions by luminal factors has not previously been studied in Crohn's disease. Aims: The aim of the study was to investigate the effects of a luminal stimulus, known to affect tight junctions, on the distal ileum in patients with Crohn's disease. Patients: Surgical specimens from the distal ileum of patients with Crohn's disease (n=l 2) were studied, and ileal specimens from colon cancer patients (n=l 3) served as controls. Methods: Mucosal permeability to 51Cr-EDTA and electrical resistance were studied in Ussing chambers during luminal exposure to sodium caprate (a constituent of milk fat, affecting tight junctions) or to buffer only. The mechanisms involved were studied by mucosal ATP levels, and by electron and confocal microscopy. Results: Baseline permeability was the same in non-inflamed ileum of Crohn's disease and controls. Sodium caprate induced a rapid increase in paracellular permeability - that is, increased permeation of 51Cr-EDTA and decreased electrical resistance - which was more pronounced in non-inflamed ileum of Crohn's disease, and electron microscopy showed dilatations within the tight junctions. Moreover, sodium caprate induced disassembly of perijunctional filamentous actin was more pronounced in Crohn's disease mucosa. Mucosal permeability changes were accompanied by mitochondrial swelling and a fall in epithelial ATP content, suggesting uncoupling of oxidative phosphorylation. Conclusions: The tight junctions in the non-inflamed distal ileum of Crohn's disease were more reactive to luminal stimuli, possibly mediated via disturbed cytoskeletal contractility. This could contribute to the development of mucosal neoinflammation in Crohn's disease.

  • 258.
    Söderholm, Johan D
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Pettersson, S.
    Institutionen för mikrobiologi, tumör- och cellbiologi (MTC), Karolinska institutet, Stockholm, Sweden.
    Polygenetisk störning i första linjens mukosaförsvar2009In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 106, no 45, p. 2974-2978Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 259.
    Söderholm, Johan D
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Streutker, C
    Yang, P-C
    Paterson, C
    Singh, PK
    McKay, DM
    Sherman, PM
    Croitoru, K
    Perdue, MH
    Increased epithelial uptake of protein antigens in the ileum of Crohn's disease mediated by tumour necrosis factor α2004In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 53, no 12, p. 1817-1824Article in journal (Refereed)
    Abstract [en]

    Background and aims: The exact nature of the epithelial barrier defect in Crohn's disease remains to be elucidated. Previously we showed increased permeability to proteins in ileal Crohn's disease. Our aims were to study if this barrier defect (a) involves endocytotic uptake of antigens and (b) is related to low grade inflammation not detectable by histology. Methods: Macroscopically normal segments of distal ileum of Crohn's disease patients (n = 10) were subgrouped into non-inflamed (histologically unaffected) and slightly inflamed tissues and studied in Ussing chambers, with normal ileal specimens from colon cancer patients (n = 9) as controls. Endocytotic uptake into enterocytes of the protein antigen horseradish peroxidase was assessed by measuring the area of horseradish peroxidase containing endosomes in electron photomicrographs. Mucosal tumour necrosis factor α (TNF-α) mRNA was quantified using real time polymerase chain reaction. For comparison, the effects of low doses of TNF-α on endosomal uptake of horseradish peroxidase were studied in cultured T84 cells grown on filter supports. Results: The area of horseradish peroxidase containing endosomes was increased (p<0.001) in enterocytes of non-inflamed ileum of Crohn's disease (2.8 (0.7) μm2/300 μm2) compared with control ileum (0.6 (0.06)). In non-inflamed mucosa, a significant association between endosomal uptake and mucosal expression of TNF-α mRNA (p = 0.03) was found. Low concentrations of TNF-α (0.25-1.0 ng/ml) enhanced the endosomal uptake of horseradish peroxidase in polarised T84 cells, without affecting transepithelial electrical resistance. Conclusions: Our findings suggest increased endosomal uptake of antigens in ileal Crohn's disease that may be mediated by TNF-α. These data highlight the transcellular route of antigen uptake in barrier dysfunction and implicate the interaction between epithelial cells and the innate immune system in the development of mucosal inflammation.

  • 260.
    Söderholm, Johan D
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Wiren, M
    Linkoping Univ, Linkoping, Sweden McMaster Univ, Hamilton, ON, Canada.
    Franzén, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Perdue, MH
    Linkoping Univ, Linkoping, Sweden McMaster Univ, Hamilton, ON, Canada.
    Olaison, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    "Topical" phase effects of acetysalicylic acid on human small bowel epithelium: Inhibition of oxidative phosphorylation and increased tight junction permeability.2000In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 118, no 4, p. 4298-Conference paper (Other academic)
  • 261.
    Söderholm, Johan D
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Yang, Ping-Chang
    Ceponis, Peter
    Vohra, Angeli
    Riddell, Robert
    Sherman, Philip M
    Perdue, Mary
    Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine2002In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 123, p. 1099-1108Article in journal (Refereed)
  • 262.
    Söderholm, Johan D
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Yates, Derrick
    Gareau, Mélanie
    Yang, Ping-Chang
    MacQueen, Glenda
    Perdue, Mary
    Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress2002In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 283, p. 1257-1263Article in journal (Refereed)
  • 263. Tejler, G
    et al.
    Norberg, B
    Dufmats, Monika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Nordenskjöld, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Arnesson, Lars-Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Survival after treatment for breast cancer in a geographically defined population2004In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 91, no 10, p. 1307-1312Article in journal (Refereed)
    Abstract [en]

    Background: South East Sweden with 976000 inhabitants is served by nine hospitals with specialized breast surgeons. Population-based mammographic screening was introduced in 1986 for women aged 40-74 years. Patients with primary breast cancer were treated according to a joint management programme. Methods: All patients were reported to a regional cancer registry from which breast cancer incidence, treatment and survival in this defined population were reported. Results: A total of 7892 women had their first invasive breast cancer diagnosed between 1986 and 1999. The median tumour size was 17 mm and 29.9 per cent had axillary metastases. Some 49.8 per cent of these women had a modified radical mastectomy and 31.9 per cent had a segmental resection with axillary clearance. Postoperative radiotherapy was given to 40.3 per cent of the women after mastectomy and to 87.1 per cent after breast-conserving surgery. Tamoxifen and chemotherapy were used as adjuvant treatment except in low-risk patients. Breast cancer-specific survival rate for all stages was 83.5 per cent at 5 years and 74.0 per cent at 10 years. Respective values were 95.8 and 90.9 per cent for patients with stage T1 N0 M0 tumours, and 77.7 and 62.4 per cent for those with T1-2 N1 M0 tumours. Conclusion: Breast specialists treating women with breast cancer according to a joint management programme have achieved very good survival rates.

  • 264.
    Tibbling Grahn, Lita
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Blackadder, L
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Franzén, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Kullman, Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Gastric bile monitoring: An in vivo and in vitro study of bilitec reliability2002In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 37, no 11, p. 1334-1337Article in journal (Refereed)
    Abstract [en]

    Background: It has been claimed that the combination of bile and hydrochloride acid (HCl) has a noxious effect on intestinal mucosa. The aim was to study the reliability of the Bilitec 2001 method in monitoring the presence of bile in repeated tests and at different pH and water dilutions. Methods: 24-h esophageal pH and gastric Bilitec monitoring were performed twice with an interval of 6 weeks in 23 patients with symptomatic gastroesophageal reflux (GER). In vitro tests of pH and Bilitec recordings were performed with different mixtures of bile, HCl and water. Results: Gastric bile was present in 37% of the recording time, 28% during day time and 47% during nights. No significant difference was found between the two test occasions. The maximum bile concentration in the stomach was significantly lower in patients with severe pathological GER than in those with normal GER. When concentrated bile was diluted with the same volume of HCl, the pH level fell below 4. The maximum absorption limit with Bilitec in concentrated bile was gradually reduced with decreasing pH. The Bilitec technique recorded the presence of bile even at a pH of 1.4, but not if the bile was diluted with water at a ratio of 1:100 or more. Conclusions: Bilitec gastric recordings show the same clinical result when repeated under standardized conditions. The Bilitec technique is not reliable for monitoring the amount and concentration of bile in the stomach. Bile reflux cannot be monitored with the pH recording technique.

  • 265.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Niklasson, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Druid, Henrik
    Department of Oncology-pathology, Karolinska Institutet, Stockholm, Sweden.
    Bratthall, Charlotte
    Division of Oncology, Kalmar hospital, Kalmar, Sweden.
    Messmer, Davorka
    Cancer Center, University of California San Diego, La Jolla, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Pancreatic cancer microenvironment has a high degree of inflammation and infiltrating immune cells in its stroma2010Manuscript (preprint) (Other academic)
    Abstract [en]

    Tumor microenvironment is composed of tumor cells, fibroblasts, and infiltrating immune cells, and other cellular components, which work together and create an inflammatory environment favoring tumor progression. The present study aimed to characterize the expression and location of immune cells and investigate inflammatory factors that influence pancreatic ductal adenocarcinoma (PDAC).

    Methods: qPCRs and immunohistological stainings were performed for inflammatory factors and immune cells localized in tumor tissues from patients with PDAC (N=30).

    Results: All PDAC tissues had significant increased levels of inflammatory and chemotactic factors such as IL-1α, COX-2, CXCL8, CCL2, and CCL20 as compared to controls. The PDAC stroma, i.e. the fibrosis surrounding the tumor, was the main producer of these factors with the exception of IL-1α, which was expressed by tumor cells and some infiltrating immune cells. The gene expression for immune cell specific markers CD163, CD1c, CD303, and CD8, corresponding to macrophages, myeloid dendritic cells (DCs), plasmacytoid DCs, and cytotoxic T lymphocytes (CTL), respectively, were all significantly increased in PDAC tissues. Immunostaining of the tumor tissue confirmed the elevated levels of infiltrating macrophages, DCs, mature DCs, and cytotoxic T lymphocytes (CTL). The different immune cells were in nearly all cases localized in the fibrotic tissue adjacent to tumor nests. Production of CXCL8 mRNA and protein by the stroma was dependent on the tumor expression of IL-1α. Of importance, we found a correlation in expression of the proinflammatory factor IL-1α and the PDAC patients’ survival time.

    Conclusion: PDAC cells seem to take advantage of IL-1α to create an inflammatory microenvironment with high degree of fibrosis and the ability to both recruit and activate immune cells and the level of inflammation in this environment influenced the clinical outcome for the patients. Therapies targeting the inflammation might be beneficial for the survival of patients with PDAC.

  • 266.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Spangeus, Anna
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences.
    Messmer, Davorka
    University of California.
    Emilsson, Johan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Falkmer, Ursula
    Jonköping Hospital.
    Falkmer, Sture
    Jonköping Hospital.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Pancreatic adenocarcinoma exerts systemic effects on the peripheral blood myeloid and plasmacytoid dendritic cells: an indicator of disease severity?2010In: BMC CANCER, ISSN 1471-2407, Vol. 10, no 87Article in journal (Refereed)
    Abstract [en]

    Background: Dendritic cells (DCs) isolated from tumor bearing animals or from individuals with solid tumors display functional abnormalities and the DC impairment has emerged as one mechanism for tumor evasion from the control of the immune system. Ductal pancreatic adenocarcinoma (PDAC), the most common pancreatic cancer, is recognized as a very aggressive cancer type with a mortality that almost matches the rate of incidence. Methods: We examined the systemic influence ductal pancreatic adenocarcinoma ( PDAC) exerted on levels of peripheral blood DCs and inflammatory mediators in comparison to the effects exerted by other pancreatic tumors, chronic pancreatitis, and age-matched controls. Results: All groups examined, including PDAC, had decreased levels of myeloid DCs (MDC) and plasmacytoid DCs (PDC) and enhanced apoptosis in these cells as compared to controls. We found elevated levels of PGE2 and CXCL8 in subjects with PDAC, and chronic pancreatitis. Levels of these inflammatory factors were in part restored in PDAC after tumor resection, whereas the levels of DCs were impaired in the majority of these patients similar to 12 weeks after tumor removal. Our results prove that solid pancreatic tumors, including PDAC, systemically affect blood DCs. The impairments do not seem to be tumor-specific, since similar results were obtained in subjects with chronic pancreatitis. Furthermore, we found that PDAC patients with a survival over 2 years had significant higher levels of blood DCs compared to patients with less than one year survival. Conclusions: Our findings points to the involvement of inflammation in the destruction of the blood MDCs and PDCs. Furthermore, the preservation of the blood DCs compartment in PDAC patients seems to benefit their ability to control the disease and survival.

  • 267.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Messmer, Davorka
    University of California San Diego, CA 92093, USA.
    Larsson, Marie
    University of California San Diego, CA 92093, USA.
    Semi Mature Blood Dendritic Cells Exist in Patients with Ductal Pancreatic Adenocarcinoma Owing to Inflammatory Factors Released from the Tumor2010In: PLOS ONE, ISSN 1932-6203, Vol. 5, no 10Article in journal (Refereed)
    Abstract [en]

    Background: Much evidence exists regarding the fact that blood DCs, both myeloid DCs (MDCs) and plasmacytoid DCs (PDCs), are negatively affected in different types of cancer, with both reduced numbers and impaired functionality. Functional impairment of DCs in patients with pancreatic ductal adenocarcinoma (PDAC), may contribute to the poor clinical outcome. The aim of this study was to examine the effects PDAC had on blood DCs and elucidate the underlying mechanism responsible for the DC impairment. Methodology/Principal Findings: We examined the systemic influence PDAC exerted on blood DCs by ex vivo measuring numerous activation and maturation markers expressed on these cells. Furthermore, the effect patient plasma and the inflammatory factors CXCL8 and PGE(2) had on purified MDCs and PDCs from healthy donors was assessed and compared to the DCs existing in PDAC patients. We found a partial maturation of the blood MDCs and PDCs in PDAC patients with significantly enhanced expression of CD83, CD40, B7H3, PDL-1, CCR6, and CCR7 and decreased expression of ICOSL, and DCIR. These changes lead to impairment in their immunostimulatory function. Furthermore, chronic pancreatitis gave rise to DCs with similar semi-mature phenotype as seen in PDAC. Low expression of ICOSL was associated with poor prognosis. We found that the mechanism underlying this semi-maturation of DCs was inflammatory factors existing in the PDAC patients plasma. Of note, PGE2, which is elevated PDAC patient plasma, was one contributing factor to the changes seen in MDCs and PDCs phenotype. Conclusion/Significance: Our findings point to a role for the systemic inflammation in transforming blood MDCs and PDCs into semi-mature cells in PDAC patients and we show a correlation between maturation status and clinical outcome. Thus, means to preserve a functional blood DC compartment in PDAC patients by diminishing the inflammation could facilitate their ability to control the disease and improve survival.

  • 268.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Välilä, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Druid, Henrik
    Department of Oncology-pathology, Karolinska Institutet, Stockholm, Sweden.
    Falkmer, Sture
    Department of Clinical Pathology, County Hospital Ryhov, Jönköping, Sweden.
    Falkmer, Ursula
    Department of Oncology, County Hospital Ryhov, Jönköping, Sweden.
    Messmer, Davorka
    Cancer Center, University of California San Diego, La Jolla, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    IL-1α Sustains the Inflammation in Human Pancreatic Cancer Microenvironment by Targeting Cancer Associated Fibroblasts2010Manuscript (preprint) (Other academic)
    Abstract [en]

    The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is dynamic with an extensive interaction between the stroma and tumor cells. Our aim for this study was to delineate the cross-talk between PDAC and cancer-associated fibroblasts (CAFs) with focus on the mechanism creating the chronic inflammatory tumor milieu. We assessed the effect cross talk between primary PDAC and CAF cell lines propagated from tumors had on the creation and sustenance of an inflammatory environment and what factors that were involved in establishing the inflammation.

    The coculture of PDAC and CAF cell lines, propagated from tumor tissues, enhanced the levels of inflammatory factors including IL-1α, IL-6, CXCL8, VEGFA, CCL20, and COX-2. The production of these factors correlated with the expression detected in vivo in PDAC tissues. The key producers of nearly all inflammatory factors were the CAFs and not the tumor cells.

    IL-1α was produced by the tumor cell lines, whereas almost all IL-1RI was expressed by CAFs thus corresponding to their in vivo expression profile in PDAC tissues, indicating a role for the IL-1 signaling cascade in a tumor favorable microenvironment. Neutralization of the IL-1α pathway efficiently diminished the cross talk induced production of inflammatory factors, both in stroma and tumor cells. These data suggest that the cross-talk between PDAC cells and the main stroma cell type, i.e. CAFs, is one contributing factor in the formation of the inflammatory tumor environment and we propose that the neutralization of IL-1α pathway might be a potential therapy for this cancer.

  • 269.
    Tornroos, Alexander
    et al.
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics. Linköping University, Faculty of Health Sciences.
    Shabo, Ivan
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland. Linköping University, Faculty of Health Sciences.
    Druvefors, Bengt
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland. Linköping University, Faculty of Health Sciences.
    Arbman, Gunnar
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland. Linköping University, Faculty of Health Sciences.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Postoperative intra-arterial methylene blue injection of colorectal cancer specimens increases the number of lymph nodes recovered2011In: HISTOPATHOLOGY, ISSN 0309-0167, Vol. 58, no 3, p. 408-413Article in journal (Refereed)
    Abstract [en]

    Aims: To determine the possible advantage of intra-arterial injection of methylene blue with a view to improving lymph node recovery in postoperative examination of colorectal cancer specimens. Methods and results: Thirty-two colorectal cancer specimens were assigned randomly to either dissection with intra-arterial methylene blue injection or to routine dissection (without methylene blue injection). Immediately postoperatively, the specimens in the staining group were injected intra-arterially with methylene blue dye. The two procedures were compared with respect to the number of lymph nodes recovered. The number of recovered lymph nodes was significantly higher in the intra-arterial methylene blue injection group than in the group investigated with routine procedures (P andlt; 0.0001). Conclusion: The intra-arterial methylene blue injection method is fairly easy to use postoperatively and increases significantly the number of lymph nodes recovered in colorectal cancer specimens.

  • 270. Trampal, C
    et al.
    Engler, H
    Juhlin, Claes
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Bergström, M
    Langström, B
    Pheochromocytomas: detection with 11C hydroxyephedrine PET2004In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 230, p. 423-428Article in journal (Refereed)
  • 271.
    Trulsson, Lena
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Gasslander, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Permerth, J
    Svanvik, Joar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    The balance of mitogenesis and apoptosis in the rat pancreas in response to CCK-8.2000In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 118, no 4, p. 5324-Conference paper (Other academic)
  • 272.
    Trulsson, Lena
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery.
    Gasslander, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Svanvik, Joar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Cholecystokinin-8-induced hypoplasia of the rat pancreas: Influence of nitric oxide on cell proliferation and programmed cell death2004In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 95, no 4, p. 183-190Article in journal (Refereed)
    Abstract [en]

    The background of cholecystokinin-8 (CCK-8)-induced hypoplasia in the pancreas is not known. In order to increase our understanding we studied the roles of nitric oxide and NF-κB in rats. CCK-8 was injected for 4 days, in a mode known to cause hypoplasia, and the nitric oxide formation was either decreased by means of Nω-nitro-L-arginine (L-NNA) or increased by S-nitroso-N-acetylpencillamine (SNAP). The activation of NF-κB was quantified by ELISA detection, apoptosis with caspase-3 and histone-associated DNA-fragmentation and mitotic activity in the acinar, centroacinar and ductal cells were visualized by the incorporation of [3H]-thymidine. Pancreatic histology and weight as well as protein- and DNA contents were also studied. Intermittent CCK injections reduced pancreatic weight, protein and DNA contents and increased apoptosis, acinar cell proliferation and nuclear factor κB (NF-κB) activation. It also caused vacuolisation of acinar cells. The inhibition of endogenous nitric oxide formation by L-NNA further increased apoptosis and NF-κB activation but blocked the increased proliferation and vacuolisation of acinar cells. The DNA content was not further reduced. SNAP given together with CCK-8 increased apoptosis and other pathways of cell death, raised proliferation of acinar cells and strongly reduced the DNA content in the pancreas. Histological examination showed no inflammation in any group. We conclude that during CCK-8-induced pancreatic hypoplasia, endogenously formed nitric oxide suppresses apoptosis but increases cell death along non-apoptotic pathways and stimulates regeneration of acinar cells. Exogenous nitric oxide enhances the acinar cell turnover by increasing both apoptotic and non-apoptotic cell death and cell renewal. In this situation NF-κB activation seems not to inhibit apoptosis nor promote cell proliferation.

  • 273.
    Trulsson, Lena
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Velin, Åsa
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Herder, Anders
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Rüter, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Smeds, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Telomerase activity in surgical specimens and fine-needle aspiration biopsies from hyperplastic and neoplastic human thyroid tissues2003In: American Journal of Surgery, ISSN 0002-9610, E-ISSN 1879-1883, Vol. 186, no 1, p. 83-88Article in journal (Refereed)
    Abstract [en]

    Background: Telomerase activity (TA) indicates malignancy, but activated lymphocytes also express TA. Correlation between TA in thyroid tissues and fine-needle aspiration (FNA) samples and knowledge about TA in adjacent tissue are of importance. Methods: The telomeric repeat amplification protocol assay followed by enzyme-linked immunosorbent assay detection was performed on 78 thyroid cases including 53 suspected malignancies, preoperative and perioperative FNA specimens, and adjacent tissue. Results: Benign lesions in cancer-suspected cases were TA negative. Eight of 13 papillary (62%) and 4 of 5 follicular (80%) tumors were TA positive (TA+). Lower TA was observed in conventional papillary cancer than in follicular, tall cell variant of papillary and anaplastic cancers. Adjacent tissues with lymphocyte infiltration were TA+ in 9 of 17 cases (53%). Nine of 65 adjacent tissues (14%) were TA+. Three of 6 preoperative and 9 of 11 perioperative FNA samples from malignant tumors corresponded to the tissue TA. Conclusions: High TA may reflect more severe thyroid cancer. Telomerase activity in FNA biopsies does not add reliable diagnostic information, and presence of lymphocytes can give false-positive results.

  • 274. Tågsjö, E-B
    et al.
    Andreescu, Gheorghe
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Rosenberg, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Jacobs index - enkelt sätt att avgöra om bäckentumör hos kvinna är malign.2003In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 100, p. 3231-3233Article in journal (Other academic)
  • 275.
    Van Assche, Gert
    et al.
    University Hospital Gasthuisberg.
    Dignass, Axel
    Frankfurter Diakonie Kliniken.
    Reinisch, Walter
    AKH Wien, Vienna, Austria .
    Janneke van der Woude, C
    Erasmus MC, Rotterdam, Netherlands .
    Sturm, Andreas
    Ghent University Hospital.
    Guslandi, Mario
    IRCCS San Raffaele, Milan, Italy .
    Oldenburg, Bas
    Tel Aviv University.
    Marteau, Philippe
    Lariboisiere Hospital, Paris.
    Ardizzone, Alessandro
    Osped L Sacco, Milan, Italy .
    C Baumgart, Daniel
    Humboldt University.
    DHaens, Geert
    Imelda GI Clin Research Centre, Bonheiden, Belgium .
    Gionchetti, Paolo
    University Bologna.
    Portela, Francisco
    Coimbra University Hospital.
    Vucelic, Boris
    University Hospital Rebro.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Escher, Johanna
    Erasmus MC, Sophia Childrens Hospital, Rotterdam, Netherlands .
    Koletzko, Sibylle
    Dr V Haunersches Kinderspital, Munich, Germany .
    Kolho, Kaija-Leena
    Hospital Children and Adolescents, Helsinki, Finland .
    Lukas, Milan
    Clin Centre ISACRE Lighthouse, Prague.
    Mottet, Christian
    University Lausanne Hospital.
    Tilg, Herbert
    Bezirkskrankenhaus Hall Tirol, Hall In Tirol, Austria .
    Vermeire, Severine
    University Hospital Gasthuisberg.
    Carbonnel, Frank
    Besancon University Hospital.
    Cole, Andrew
    Derby Hospital NHS Fdn Trust.
    Novacek, Gottfried
    Med University Vienna.
    Reinshagen, Max
    Klinikum Braunschweig.
    Tsianos, Epameinondas
    University Ioannina.
    Herrlinger, Klaus
    Robert Bosch Krankenhaus.
    Oldenburg, Bas
    University Med Centre Utrecht.
    Bouhnik, Yoram
    Beaujon Hospital.
    Kiesslich, Ralf
    Johannes Gutenberg University Mainz.
    Stange, Eduard
    Robert Bosch Krankenhaus.
    Travis, Simon
    John Radcliffe Hospital.
    Lindsay, James
    Barts and London NHS Trust.
    The second European evidence-based Consensus on the diagnosis and management of Crohns disease: Special situations2010In: JOURNAL OF CROHNS and COLITIS, ISSN 1873-9946, Vol. 4, no 1, p. 63-101Article in journal (Refereed)
    Abstract [en]

    n/a

  • 276.
    Velin Keita, Åsa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Ericson, Ann-Charlott
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Braaf, Ylva
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Wallon, Conny
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Increased antigen and bacterial uptake in follicle-associated epithelium induced by chronic psychological stress in rats2004In: Gut, ISSN 0017-5749, Vol. 53, no 4, p. 494-500Article in journal (Refereed)
    Abstract [en]

    Background: Chronic stress affects the course of inflammatory bowel disease and experimental colitis, and may also initiate intestinal inflammation in rats.

    Aim: To investigate the effects of stress on the M cell containing follicle associated epithelium, specialised in antigen uptake.

    Subjects and methods: Wistar rats were submitted to acute water avoidance stress for one hour or chronic water avoidance stress for 1 hour/day for 10 consecutive days. Permeability to 51Cr-EDTA, horseradish peroxidase, and chemically killed Escherichia coli K-12 was studied in both villus and follicle associated epithelium in Ussing chambers. Segments were further examined by light, electron, and confocal microscopy.

    Results: Acute stress increased horseradish peroxidase flux in villus as well as in follicle associated epithelium. Chronic stress further increased permeability to horseradish peroxidase in villus and follicle associated epithelium, in the latter by almost fourfold. Moreover, chronic stress induced over 30 times increased E coli passage in follicle associated epithelium whereas there was no significant increase in villus epithelium. Bacterial uptake was confirmed by confocal microscopy showing fluorescent bacteria penetrating and passing through the epithelial surface.

    Conclusions: These results show that the barrier function of follicle associated epithelium can be modulated, and that chronic stress enhances the uptake of luminal antigens and bacteria via the follicle associated epithelium. This can increase antigen exposure in Peyer’s patches thereby having implications in the initiation of proinflammatory immune responses within the intestinal mucosa.

  • 277. Veress, B
    et al.
    Franzén, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Bodin, L
    Borch, Kurt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Duodenal intraepithelial lymphocyte-count revisited2004In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 39, no 2, p. 138-144Article in journal (Refereed)
    Abstract [en]

    Background: The number of intraepithelial lymphocytes in the duodenum was determined 30 years ago, the suggested normal upper limit being 40 lymphocytes per 100 epithelial cells. Methods: Duodenal mucosa was analysed from 18 healthy individuals and 56 consecutive patients biopsied because of epigastralgia (17 cases), diarrhoea (10 cases), oesophagitis (10 cases), iron-deficiency (9 cases) and B12-deficiency (10 cases) showing normal histology, along with 10 cases of active coeliac disease. The biopsies were fixed in 4% formalin overnight and embedded in paraffin. Three micrometre thick sections were stained with haematoxylin and eosin and CD3. At least 300 epithelial cells were counted, the number of intraepithelial lymphocytes was given as the mean/100 epithelial cells. Extensive statistical analyses were performed. Results: In the healthy individuals the mean number (s) of intraepithelial lymphocytes/100 epithelial cells was 10.8 (2.6) and 13.2 (3.8) in H&E and CD3 stained sections, respectively. The upper limit of the confidence interval for CD3 staining was 29. There was no significant difference between normal individuals and the clinical groups, with the exception of coeliac disease. Conclusion: Two-step analysis of intraepithelial lymphocyte-determination is suggested: (a) semi-quantitative estimate on H&E-stained sections (normal ratio of 1:5 between lymphocytes and enterocytes, upper normal limit 20 lymphocytes) and (b) CD3-staining and counting if intraepithelial lymphocytosis is suspected. The upper normal range of intraepithelial lymphocytes is set at 25 CD3+ lymphocytes/100 epithelial cells. Values between 25 and 29 are regarded as 'borderline' and 30 or more represent pathologic intraepithelial lymphocytosis in the duodenum.

  • 278. Verheul, HAM
    et al.
    Coelingh-Bennink, HJT
    Kenemans, PD
    Atsma, WJ
    Burger, CW
    Eden, JA
    Hammar, Mats
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Marsden, JB
    Purdie, DW
    Effects of estrogens and hormone replacement therapy on breast cancer risk and on efficacy of breast cancer therapies2000In: Maturitas, ISSN 0378-5122, E-ISSN 1873-4111, Vol. 36, no 1Article in journal (Refereed)
    Abstract [en]

    This review summarises preclinical and clinical data on effects of endogenous and exogenous estrogens on probability of breast cancer diagnosis, and on the course and efficacy of breast cancer therapies. The data indicate that higher endogenous estrogen exposure (e.g. pregnancy, early menarche and late menopause, estrogen levels in future breast cancer patients, obesity) or exogenous estrogens (oral contraceptives, hormone replacement therapies) may be associated with an increased probability of breast cancer diagnosis. However, there is little evidence that estrogens have deleterious effects on the course of breast cancer. Moreover, increased incidence of breast cancer diagnosis after prolonged hormone replacement therapy (HRT) use seems to be associated with clinically less advanced disease. In studies assessing both diagnosis and mortality, HRT is frequently associated with reduced mortality compared to never users. The interaction of progestagens and estrogens on the probability of breast cancer diagnosis is complex and dependent on type of progestagens and regimens employed. Efficacy of current treatment modalities for breast cancer (surgery, irradiation, adjuvant therapy or chemotherapy) is not negatively influenced by estrogens at concentrations considerably higher than those attained with current HRT preparations. Although it cannot be excluded that estrogens increase the probability of breast cancer diagnosis, available data fail to demonstrate that, once breast cancer has been diagnosed, estrogens worsen prognosis, accelerate the course of the disease, reduce survival or interfere with the management of breast cancer. It may therefore be concluded that the prevalent opinion that estrogens and estrogen treatment are deleterious for breast cancer, needs to be revisited. However, results of ongoing prospective, randomised clinical trials with different HRT regimens in healthy women or breast cancer survivors are needed to provide more definite conclusions about risks and benefits of HRT.

  • 279.
    Wadsby, Marie
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of health and environment.
    Sydsjö, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Från graviditet till föräldraskap: En studie av parrelationen.2001In: Nordisk Psykologi: teori, forskning, praksis, ISSN 0029-1463, Vol. 53, p. 275-288Article in journal (Refereed)
  • 280.
    Wadsby, Marie
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of health and environment.
    Sydsjö, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Svedin, CG
    Linköping University, Faculty of Health Sciences. Linköping University, Department of health and environment. Östergötlands Läns Landsting, CPS - Centrum för psykiatri och samhällsmedicin, BUP - Barn- och ungdomspsykiatri.
    Evaluation of an intervention programme to support mothers and babies at psychosocial risk: Assessment of mother/child interaction and mother's perceptions of benefit2001In: Health & Social Care in the Community, ISSN 0966-0410, E-ISSN 1365-2524, Vol. 9, no 3, p. 125-133Article in journal (Refereed)
    Abstract [en]

    The outcome of a short-term intervention programme for mothers at psychosocial risk was evaluated. The study included 63 mothers and their 0-6-month-old babies who participated in a 6-week intensive treatment programme. Mother-child interaction was assessed in the beginning and at the end of treatment by two independent staff members based on direct observation, and by two control raters who observed video recordings which were arranged in blind order. The mothers were interviewed about the treatment retrospectively. A positive change in several aspects of mother-child interaction, according to the assessments made by the raters and according to the mothers themselves. The number of mothers who were positive toward the treatment rose from 34 in the beginning of the treatment to 56 at the end. In conclusion, a short but intensive intervention seems to have a positive outcome on mother-child interaction, and was in most cases linked to a positive attitude.

  • 281.
    Wallin, Åsa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Francis, P.
    Department of Oncology, Institute of Clinical Sciences, Lund University, Lund, Sweden.
    Nilbert, N.
    Department of Oncology, Institute of Clinical Sciences, Lund University, Lund, Sweden.
    Svanvik, Joar
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Gene expression profile of colon cancer cell lines treated with SN-382010In: Chemotherapy, ISSN 0009-3157, E-ISSN 1421-9794, Vol. 56, no 1, p. 17-25Article in journal (Refereed)
    Abstract [en]

    Aim: Colorectal cancer is the third most common form of cancer in the industrialcountries. Due to advances regarding the treatments, primarily development ofimproved surgical methods, and the ability to make the earlier diagnosis, the mortalityhas remained constant during the past decades even though the incidence in fact hasincreased. To improve chemotherapy and enable personalised treatment, the need ofbiomarkers is of great significance. In this study we evaluated the gene expressionprofiles of the colon cancer cell lines treated with SN-38, the active metabolite oftopoisomerase-1 inhibitor irinotecan which leads to cell cycle arrest and apoptosis.Material and Methods: The study included three colon cancer cell lines KM12C,KM12SM and KM12l4a. The three cell lines were treated with SN-38, and sampleswere obtained after 24 and 48 hour treatments. The gene expression analyses wereperformed using oligonucleotide microarrays comprising of ~27,000 spots where theuntreated controls were compared to the SN-38 treated samples. Results: Unsupervisedclustering clearly distinguished the treated cell lines from the untreated. Supervisedanalysis identified 3974 significant genes (p=0.05) differentiating the treated samplesfrom the untreated, majority of which were downregulated after treatment. The toprankeddownregulated genes in the treated cell lines included those related to receptorand kinase activity, signal transduction, apoptosis, RNA processing, protein metabolismand transport, cell cycle and transcription. A smaller number of genes were upregulatedin the cell lines after treatment and included genes involved in apoptosis, transcription,development and differentiation. Conclusions: These results demonstrate that theexpression of the genes involved in cell proliferation and apoptosis as well as RNA,DNA and protein metabolism were affected by SN-38. The impact of certain genes oncolorectal cancer development needs to be further evaluated, however these resultscould serve as a basis for further studies in order to find targets for irinotecan treatment.

  • 282.
    Wallin, Åsa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Svanvik, Joar
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Holmlund, Birgitta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ferreud, Lillianne
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Anticancer effect of SN-38 on colon cancer cell lines with different metastatic potential2008In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 19, no 6, p. 1493-1498Article in journal (Refereed)
    Abstract [en]

    SN-38 is an active metabolite of the topoisomerase I inhibitor irinotecan. The mechanism behind its antitumor effect in colorectal cancer is not fully understood. In this study, we examined the response of colon cancer cell lines with different metastatic potential to SN-38. The parental human colon cancer cell line KM12C and its two highly metastatic derivatives KM12SM and KM12L4a were cultivated in 5% CO2 at 37°C for 24 h and then exposed to SN-38 (2.5 µg/ml) at 37°C for 4, 24 and 48 h, respectively. The cell cycle was measured by flow cytometry, apoptotic activity was determined by flow cytometry and immunocytochemistry and the expression of topoisomerase I, Bax and survivin proteins were examined by Western blot. The exposure of the cells to SN-38 induced S-phase and G2 arrest (P<0.0001) and the KM12L4a cells had the highest response in a time-dependent manner (P<0.0001). The rates of apoptosis in the KM12SM (P=0.001) and KM12L4a cell lines (P=0.01) were increased time-dependently, though there was no such change in the KM12C cells. The expression of topoisomerase I protein was decreased in each cell line tested and the expression of Bax protein was increased, especially in KM12L4a. In conclusion, the effect of SN-38 on the colon cancer cell lines was mediated via conducting S-phase and G2 arrest and apoptosis. This effect was found in the cell lines with higher metastatic potentials, indicating that SN-38 can be used to treat advanced colon cancers.

  • 283.
    Wallon, Conny
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Neuro-immune regulation of macromolecular permeability in the normal human colon and in ulcerative colitis2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background and aim: Persistent stress and life events affect the course of ulcerative colitis (UC) by largely unknown mechanisms. Regulation of epithelial permeability to antigens is crucial for the balance between inflammation and immuno-surveillance, and increased intestinal permeability has been shown in patients with ulcerative colitis. Corticotropin releasing hormone (CRH) has been implicated as an important mediator of stress-induced abnormalities in intestinal mucosal function in animal models. Further cholinergic signalling during stress

    has been reported to increase bowel ion secretion in humans and uptake of HRP in rodents via activation of mast cells.

    The overall aim of this thesis was to examine the role of CRH-mediated and cholinergic signalling, and their interaction with mast cells and eosinophils, in the regulation of the mucosal barrier function in the normal human colon and in UC. In vivo studies or the use of surgical specimens for such studies have major shortcomings. Therefore a method with endoscopic biopsies in Ussing chambers was established for studies of protein antigen uptake and electrophysiology in human colonic biopsies, and used in subsequent investigations.

    Materials and methods: In the four studies a total of 91 healthy volunteers, 3 patients with rectal cancer, and 15 UC patients were included. Biopsies from the sigmoid colon were assessed for macromolecular permeability (Horseradish peroxidase (HRP), and 51Cr-EDTA), and electrophysiology during challenge with sodium caprate (C10), CRH or carbachol. Experiments were repeated with CRH receptor antagonists, carbachol receptor antagonists, mast cell stabilizers and nerve conductance blockers in Ussing chambers. The biopsies were examined by electron and light microscopy for endocytosis of HRP, morphological changes and receptor expression. Moreover, the human mast cell line, HMC-1; was used in studying expression of CRH receptors on mast cells.

    Results: Endoscopic biopsies of human colon were viable in Ussing chambers, and the technique was shown to be a reliable tool for studies of mucosal permeability to HRP. CRH stimulates transcellular uptake of HRP in human colon via CRH receptor subtypes R1 and R2 on subepithelial mast cells. Further, carbachol acts on muscarinic receptors, located on subepithelial eosinophils. Activated muscarinic M2 and M3 receptors on increased numbers of CRHproducing eosinophils in UC, lead to activation of mast cells and increased macromolecular uptake across the colonic mucosa. This signalling cascade is previously unrecognized, and may be involved in the inflammatory process in UC.

    Conclusions: In conclusion, we have demonstrated a chain of events leading to increased permeability to the protein antigen HRP in biopsies from healthy volunteers and patients with UC. The important steps begin with a cholinergic signal to muscarinic receptors on the CRH containing eosinophils. The next step includes activation of CRH receptors on mast cells leading to degranulation and increased macromolecular uptake across the epithelium. This explanatory model will have implications for understanding of the pathogenesis of UC and future treatment of the disease.

    List of papers
    1. Endoscopic biopsies in Ussing chambers evaluated for studies of macromolecular permeability in the human colon
    Open this publication in new window or tab >>Endoscopic biopsies in Ussing chambers evaluated for studies of macromolecular permeability in the human colon
    Show others...
    2005 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, Vol. 40, no 5, p. 586-595Article in journal (Refereed) Published
    Abstract [en]

    Objective Studies of mucosal permeability to protein antigens in humans are limited to in vitro techniques. The use of surgical specimens for such studies has major shortcomings. Endoscopic biopsies in Ussing chambers have been introduced as a means of studying secretion and transepithelial permeability, but have not been evaluated for studies of protein antigen uptake in human intestine.

    Material and methods Standard forceps biopsies from the sigmoid colon of 24 healthy volunteers were mounted in Ussing chambers with an exposed tissue area of 1.76 mm2. 51Cr-EDTA (paracellular probe) and horseradish peroxidase (HRP; 45 kDa protein antigen) were used as permeability markers. Mucosal permeability, electrophysiology, histology and energy contents of the biopsies were studied over time. To evaluate the ability of the technique to detect permeability changes, the mucosa was modulated with capric acid, a medium-chain fatty acid, known to affect tight junctions.

    Results In the Ussing chamber the mucosal biopsies were viable for 160 min with stable levels of ATP and lactate, and only minor changes in morphology. Steady-state permeability with low variability was seen for both markers during the 30-90 min period. Exposure to capric acid induced a rapid decrease in short-circuit current (Isc) and a slower reversible decrease in transepithelial resistance (TER), as well as an increased permeability to 51Cr-EDTA and HRP.

    Conclusions Endoscopic biopsies of human colon are viable in Ussing chambers and are reliable tools for studies of mucosal permeability to protein antigens. The technique offers a broad potential for studies of mucosal function in the pathophysiology of human gastrointestinal diseases.

    Keywords
    ATP; histology; horseradish peroxidase; intestinal absorption; intestinal mucosa; lactate; short-circuit current; sodium caprate; transepithelial electrical resistance
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13152 (URN)10.1080/00365520510012235 (DOI)
    Available from: 2008-04-07 Created: 2008-04-07 Last updated: 2009-06-08
    2. Corticotropin releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro
    Open this publication in new window or tab >>Corticotropin releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro
    Show others...
    2008 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 57, no 1, p. 50-58Article in journal (Refereed) Published
    Abstract [en]

    Objective: Persistent stress and life events affect the course of ulcerativecolitis and irritable bowel syndrome by largely unknown mechanisms.Corticotropin-releasing hormone (CRH) has been implicated asan important mediator of stress-induced abnormalities in intestinalmucosal function in animal models, but to date no studies inhuman colon have been reported. The aim was to examine the effectsof CRH on mucosal barrier function in the human colon and toelucidate the mechanisms involved in CRH-induced hyper-permeability.

    Design: Biopsies from 39 volunteers were assessed for macromolecularpermeability (horseradish peroxidise (HRP), 51Cr-EDTA), andelectrophysiology after CRH challenge in Ussing chambers. Thebiopsies were examined by electron and confocal microscopy forHRP and CRH receptor localisation, respectively. Moreover, CRHreceptor mRNA and protein expression were examined in the humanmast cell line, HMC-1.

    Results: Mucosal permeability to HRP was increased by CRH (2.8±0.5pmol/cm2/h) compared to vehicle exposure (1.5±0.4 pmol/cm2/h),p = 0.032, whereas permeability to 51Cr-EDTA and transmucosalelectrical resistance were unchanged. The increased permeabilityto HRP was abolished by -helical CRH (9-41) (1.3±0.6pmol/cm2/h) and the mast cell stabiliser, lodoxamide (1.6±0.6pmol/cm2/h). Electron microscopy showed transcellular passageof HRP through colonocytes. CRH receptor subtypes R1 and R2were detected in the HMC-1 cell line and in lamina propria mastcells in human colon.

    Conclusions: Our results suggest that CRH mediates transcellular uptake ofHRP in human colonic mucosa via CRH receptor subtypes R1 andR2 on subepithelial mast cells. CRH-induced macromolecular uptakein human colon mucosa may have implications for stress-relatedintestinal disorders.

    Place, publisher, year, edition, pages
    London UK: BMJ Group, 2008
    Keywords
    CRH receptor subtypes, barrier function, electron microscopy, human mast cell line, intestinal mucosa
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13153 (URN)10.1136/gut.2006.117549 (DOI)000251778400013 ()
    Available from: 2008-04-07 Created: 2008-04-07 Last updated: 2017-12-13Bibliographically approved
    3. Carbachol regulates transcellular antigen permeability in human sigmoid colon biopsies in vitro
    Open this publication in new window or tab >>Carbachol regulates transcellular antigen permeability in human sigmoid colon biopsies in vitro
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:liu:diva-13154 (URN)
    Available from: 2008-04-07 Created: 2008-04-07 Last updated: 2010-01-13
    4. Cholinergic stimulation-induced release of CRH from eosinophils mediates increased macromolecular permeability in ulcerative colitis
    Open this publication in new window or tab >>Cholinergic stimulation-induced release of CRH from eosinophils mediates increased macromolecular permeability in ulcerative colitis
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:liu:diva-13155 (URN)
    Available from: 2008-04-07 Created: 2008-04-07 Last updated: 2010-01-13
  • 284.
    Wallon, Conny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Juhlin, Claes
    Linköping University, Department of Biomedicine and Surgery, Division of surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Melander, Helen
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Sjödahl, Rune
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Oplanerade återinläggningar på kirurgisk klinik2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 23, p. 1548-1551Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 285.
    Wallon, Conny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Corticotropin-Releasing Hormone and Mast Cells in the Regulation of Mucosal Barrier Function in the Human Colon2009In: MOLECULAR STRUCTURE AND FUNCTION OF THE TIGHT JUNCTION: FROM BASIC MECHANISMS TO CLINICAL MANIFESTATIONS, ISSN 0077-8923, Vol. 1165, p. 206-210Article in journal (Refereed)
    Abstract [en]

    Corticotropin-releasing hormone (CRH) is an important neuro-endocrine mediator of the stress response. Local effects of CRH in the intestinal mucosa have become evident in recent years. We showed that CRH activates CRH receptor subtypes R1 and R2 on subepithelial mast cells, thereby inducing increased transcellular uptake of protein antigens in human colonic biopsies in Ussing chambers. Ongoing studies also implicate local cholinergic signaling in regulation of macromolecular permeability in the human colon. Since increased uptake of antigenic molecules is associated with mucosal inflammation, our findings may have implications for understanding stress-related intestinal disorders.

  • 286.
    Wallon, Conny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Yang, P.
    Intestinal Disease Research Programme, McMaster University, Hamilton, Canada.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Ericson, Ann-Charlott
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    McKay, D. M.
    Department of Physiology and Biophysics, University of Calgary, Canada.
    Sherman, P. M.
    Departments of Paediatrics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
    Perdue, M. H.
    Intestinal Disease Research Programme, McMaster University, Hamilton, Canada.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Corticotropin releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro2008In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 57, no 1, p. 50-58Article in journal (Refereed)
    Abstract [en]

    Objective: Persistent stress and life events affect the course of ulcerativecolitis and irritable bowel syndrome by largely unknown mechanisms.Corticotropin-releasing hormone (CRH) has been implicated asan important mediator of stress-induced abnormalities in intestinalmucosal function in animal models, but to date no studies inhuman colon have been reported. The aim was to examine the effectsof CRH on mucosal barrier function in the human colon and toelucidate the mechanisms involved in CRH-induced hyper-permeability.

    Design: Biopsies from 39 volunteers were assessed for macromolecularpermeability (horseradish peroxidise (HRP), 51Cr-EDTA), andelectrophysiology after CRH challenge in Ussing chambers. Thebiopsies were examined by electron and confocal microscopy forHRP and CRH receptor localisation, respectively. Moreover, CRHreceptor mRNA and protein expression were examined in the humanmast cell line, HMC-1.

    Results: Mucosal permeability to HRP was increased by CRH (2.8±0.5pmol/cm2/h) compared to vehicle exposure (1.5±0.4 pmol/cm2/h),p = 0.032, whereas permeability to 51Cr-EDTA and transmucosalelectrical resistance were unchanged. The increased permeabilityto HRP was abolished by -helical CRH (9-41) (1.3±0.6pmol/cm2/h) and the mast cell stabiliser, lodoxamide (1.6±0.6pmol/cm2/h). Electron microscopy showed transcellular passageof HRP through colonocytes. CRH receptor subtypes R1 and R2were detected in the HMC-1 cell line and in lamina propria mastcells in human colon.

    Conclusions: Our results suggest that CRH mediates transcellular uptake ofHRP in human colonic mucosa via CRH receptor subtypes R1 andR2 on subepithelial mast cells. CRH-induced macromolecular uptakein human colon mucosa may have implications for stress-relatedintestinal disorders.

  • 287.
    Walter, Susanna
    et al.
    Linköping University, Department of Molecular and Clinical Medicine. Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Hallböök, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Gotthard, Ricci
    Bergmark, M.
    Sjödahl, Rune
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    A population-based study on bowel habits in a Swedish community: prevalence of faecal incontinence and constipation2002In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, Vol. 37, no 8, p. 911-916Article in journal (Refereed)
    Abstract [en]

    Background: The self-reported bowel habits and the prevalence of faecal incontinence and constipation in men and women between the ages of 31 and 76 are assessed.

    Methods: A postal questionnaire was sent to a random sample ( n = 2000) of the total population of persons between the ages of 31 and 76 living in the County of Östergötland, Sweden.

    Results: The response rate was 80.5%. Overall, 67.8% reported one bowel movement per day and 4.4% had more than 21 or less than 3 bowel movements per week. This means that 95.6% had between 3 bowel movements a day to 3 bowel movements a week. Among women, 4.3%, and among men, 1.7%, reported less than 3 bowel movements per week. Women and men used the same terms to describe the definition of constipation. Women had a significantly higher self-reported prevalence of constipation than men ( P < 0.0001). About 20% of all women considered themselves constipated. The use of laxatives increased with age and 22% and 10% of elderly women and men, respectively, used laxatives including bulking agents for at least every fourth toilet procedure. About 10% reported leakage of faeces more often than once a month in the case of loose stools. With solid faeces, the rate of leakage was 1.4% and 0.4% for women and men, respectively. Soiling of underclothes more than once a month occurred in 21% of men and in 14.5% of women ( P = 0.006) and involuntary daily leakage of gas in 5.9% of men and 4.9% of women (n.s.).

    Conclusions: Constipation and faecal incontinence are common problems in a general Swedish population.

  • 288.
    Widegren, Emma
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Önnesjö, Sofia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Arbman, Gunnar
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Kayed, Hany
    Univ Heidelberg, Inst Clin Radiol and Nucl Med, Univ Hosp Mannheim, Heidelberg, Germany.
    Zentgraf, Hanswalter
    German Canc Res Ctr, D-6900 Heidelberg, Germany.
    Kleeff, Joerg
    Tech Univ Munich, Dept Surg, Munich, Germany.
    Zhang, Hong
    Univ Skovde, Sch Life Sci, Skovde, Sweden.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Expression of FXYD3 Protein in Relation to Biological and Clinicopathological Variables in Colorectal Cancers2009In: Chemotherapy, ISSN 0009-3157, E-ISSN 1421-9794, Vol. 55, no 6, p. 407-413Article in journal (Refereed)
    Abstract [en]

    Background: FXYD3 is up-/down-regulated in different types of cancers. We examined FXYD3 expression in colorectal cancers and its relationship to biological and clinicopathological variables. Patients and Methods: Expression of FXYD3 protein was immunohistochemically examined in distant normal mucosa (n = 34), adjacent normal mucosa (n = 72), primary tumour (n = 150) and lymph node metastasis (n = 35) from colorectal cancer patients. Results: FXYD3 was highly expressed in primary tumour compared to adjacent normal mucosa (p = 0.02). FXYD3 was or tended to be positively related to the expression of ras (p = 0.02), p53 (p = 0.06), legumain (p = 0.02) and proliferating cell nuclear antigen (p = 0.03). Moreover, there was a higher frequency of strong FXYD3 expression in Dukes A-C tumours than in D tumours (p = 0.04). The strong FXYD3 expression tended to predict worse survival in the patients with Dukes A + B tumour (p = 0.07), while there was no such tendency in the patients with Dukes C + D tumour (p = 0.94). The tumours located in the colon had a higher degree of FXYD3 expression than the tumours located in the rectum (p = 0.05). Conclusion: The FXYD3 was associated with certain biological variables and may be involved in the development of the relative earlier stages of colorectal cancers.

  • 289.
    Wijma, Barbo
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gender and medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
    Jansson Engman, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Gender and medicine . Linköping University, Faculty of Health Sciences.
    Nilsson, S.
    Hallböök, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Wijma, Klaas
    Linköping University, Department of Clinical and Experimental Medicine, Gender and medicine . Linköping University, Faculty of Health Sciences.
    Vulvar vestibulitis syndrome and vaginismus: A case report2000In: Journal of reproductive medicine, ISSN 0024-7758, E-ISSN 1943-3565, Vol. 45, p. 219-223Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Recent reports have argued for a revision of the criteria used for the establishment of a diagnosis of vulvar vestibulitis syndrome (VVS). On theoretical grounds it might be hypothesized that women with VVS also suffer from vaginismus.

    CASE: A young woman presented with a history, symptoms and objective findings typical of vaginismus, yet she suffered from continuous, burning pain and itching in the vestibule. Earlier in the course of the problem she had received a diagnosis VVS. The patient was treated with behavioral therapy developed for vaginismus. Notations made during the course of therapy supported the assumption that the pain and itching were conditioned responses to penetration in the same way that a vaginal muscular reflex is.

     

    CONCLUSION: Differential diagnostic difficulties exist in the field of VVS and vaginismus. Psychophysiologic theories are needed as the basis for research to clarify the connections between different diagnostic entities associated with coital burning pain and itching in the vestibule.

  • 290.
    Wijma, Barbro
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Engman, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine.
    Wijma, Klaas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Linköping University, Department of Clinical and Experimental Medicine.
    Total och partiell vaginism2003In: Vulvasjukdomar / [ed] Eva Rylander, Lotti Helström, Anders Strand, Stockholm: Svensk Förening för Obstetrik och Gynekologi (SFOG) , 2003, p. 59-62Chapter in book (Other academic)
  • 291.
    Wijma, Barbro
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Heimer, G
    Wijma, Klaas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology.
    Kan patienten ha utsatts för vådl? Skall man ställa frågan - och i så fall hur?2002In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 99, p. 2260-2264Article in journal (Other academic)
  • 292.
    Wijma, Barbro
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of health and environment. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Jansson, M
    Psykosexuella aspekter på vulvovaginit.2000In: Information från Läkemedelsverket, ISSN 1101-7104, Vol. 5, p. 57-61Article in journal (Other (popular science, discussion, etc.))
  • 293.
    Wijma, Barbro
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Liss, P-E
    Jansson, MA
    Siwe, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Att vilja eller inte vilja.2002In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 99, p. 1716-1719Article in journal (Other academic)
  • 294.
    Wijma, Barbro
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Siwe, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Empowerment i gynstolen. Teori, empiri och möjligheter.2002In: Kvinnovetenskaplig tidskrift, ISSN 0348-8365, p. 61-73Article in journal (Other academic)
  • 295.
    Wijma, Klaas
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Söderquist, J
    Björklund, I
    Wijma, Barbro
    Linköping University, Faculty of Health Sciences. Linköping University, Department of health and environment. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Prevalence of post-traumatic stress disorder among gynecological patients with a history of sexual and physical abuse2000In: Journal of Interpersonal Violence, ISSN 0886-2605, E-ISSN 1552-6518, Vol. 15, no 9, p. 944-958Article in journal (Refereed)
    Abstract [en]

    All patients who visited the Department of Obstetrics and Gynaecology of Link÷ping, Sweden over a 2-week period were sent a questionnaire about experiences of sexual/physical abuse and the Traumatic Event Scale, assessing post-traumatic stress disorder (PTSD). Of 649 patients, 26.3% showed a history of sexual or physical abuse in childhood or adulthood. Childhood and adulthood sexual abuse were experienced by 11.6% and 6.5%, respectively, childhood and adulthood physical abuse by 16.9% and 7.9%, respectively. Twenty-nine of all participants (4.5%) met PTSD criteria, according to the Diagnostic and Statistical Manual. PTSD was associated with multiple experiences of abuse. The frequency of PTSD symptoms was positively related to the amount and recency of abuse. PTSD participants reported more visits to a physician than abused non-PTSD and nonabused participants. The PTSD group reported less satisfaction than the other two groups with (a) contact with the physician and (b) the help received during visits to the clinic.

  • 296. Wiklund, IK
    et al.
    Mattsson, L-Å
    Lindgren, R
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Limoni, C
    Effects of a standardized ginseng extract on quality of life and physiological parameters in symptomatic postmenopausal women: a double-blind, placebo-controlled trial.1999In: International Journal of Clinical Pharmacology Research, ISSN 0251-1649, Vol. 19, p. 89-99Article in journal (Refereed)
  • 297. Willis, M
    et al.
    Ödegaard, K
    Persson, U
    Hedbrant, J
    Mellström, D
    Hammar, Mats
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    A cost-effectiveness model of tibolone as treatment for the prevention of osteoporotic fractures in postmenopausal women in Sweden.2001In: Clinical drug investigation, ISSN 1173-2563, E-ISSN 1179-1918, Vol. 21, p. 115-127Article in journal (Refereed)
  • 298.
    Winbladh, Anders
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Gullstrand, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Svanvik, Joar
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Systematic review of cholecystostomy as a treatment option in acute cholecystitis2009In: HPB, ISSN 1365-182X, Vol. 11, no 3, p. 183-193Article, review/survey (Refereed)
    Abstract [en]

    Objectives: Percutaneous cholecystostomy (PC) is an established low-mortality treatment option for elderly and critically ill patients with acute cholecystitis. The primary aim of this review is to find out if there is any evidence in the literature to recommend PC rather than cholecystectomy for acute cholecystitis in the elderly population. Methods: In April 2007, a systematic electronic database search was performed on the subject of PC and cholecystectomy in the elderly population. After exclusions, 53 studies remained, comprising 1918 patients. Three papers described randomized controlled trials (RCTs), but none compared the outcomes of PC and cholecystectomy. A total of 19 papers on mortality after cholecystectomy in patients aged greater than65 years were identified. Results: Successful intervention was seen in 85.6% of patients with acute cholecystitis. A total of 40% of patients treated with PC were later cholecystectomized, with a mortality rate of 1.96%. Procedure mortality was 0.36%, but 30-day mortality rates were 15.4 % in patients treated with PC and 4.5% in those treated with acute cholecystectomy (P less than 0.001). Conclusions: There are no controlled studies evaluating the outcome of PC vs. cholecystectomy and the papers reviewed are of evidence grade C. It is not possible to make definitive recommendations regarding treatment by PC or cholecystectomy in elderly or critically ill patients with acute cholecystitis. Low mortality rates after cholecystectomy in elderly patients with acute cholecystitis have been reported in recent years and therefore we believe it is time to launch an RCT to address this issue.

  • 299.
    Winbladh, Anders
    et al.
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Svanvik, Joar
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Gullstrand, P
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Segmental ischemia of the liver - microdialysis in a novel porcine model.2009In: European surgical research. Europäische chirurgische Forschung. Recherches chirurgicales européennes, ISSN 1421-9921, Vol. 43, no 3, p. 276-285Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Segmental liver ischemia is often used in rodents to study ischemia and reperfusion injuries (IRI). There are no reports of protocols using segmental ischemia in porcine models. Microdialysis (MD) provides the opportunity to study local effects of IRI in vivo. METHODS: Eight pigs received an MD catheter placed in liver segments IV and V, respectively. All circulation to segment IV was stopped for 80 min, and reperfusion was followed for 240 min. RESULTS: During ischemia the levels of lactate, glycerol and glucose increased 3-fold (p < 0.001), 40-fold (p < 0.001) and 4-fold (p < 0.01), respectively, in the ischemic segment compared to the perfused segment, whereas the levels of pyruvate fell to a tenth of the preischemic level (p < 0.001). All values returned to baseline after reperfusion. Serum levels of aspartate aminotransferase increased (p < 0.05). Polymorphonuclear cells increased in both segments, although the density was significantly higher in segment IV. CONCLUSION: Clamping of one liver segment in pigs is a simple, stable and reproducible model to study IRI with minimal systemic effects. MD revealed no signs of anaerobic metabolism in the perfused segment but still there was an increase in the number of polymorphonuclear neutrophils in this segment, although it was lower than that in the ischemic segment.

  • 300. Woods, CM
    et al.
    Sandström, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Bond, M
    Michael, M
    Svanvik, Joar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Toouli, J
    Saccone, GTP
    Selective iNOS inhibition enhances spontaneous gallbladder motility in the Australian possum2007In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 19, no 6, p. 497-503Article in journal (Refereed)
    Abstract [en]

    Gallbladder inflammation is a common and painful disease. Inducible nitric oxide synthase (iNOS) plays a major role in inflammatory diseases, and iNOS inhibitors are being developed as therapeutic agents. Reports are inconsistent regarding iNOS expression in normal gallbladder. The aim of this study was to determine the effect of iNOS inhibition on spontaneous gallbladder motility. mRNA extracted from normal possum gallbladders was analysed by PCR. Gallbladder contractility was evaluated using a highly selective iNOS inhibitor AR-C102222AA (AR-C) in in vitro muscle strips (0.1-10 000 μm) and in vivo (0.1-30 μmol kg-1) experiments. Gene expression analysis revealed the presence of iNOS mRNA in normal gallbladder (n = 3). In vitro, AR-C (0.1-1000 μmol L-1) produced a concentration-dependent increase in spontaneous gallbladder contractile activity and basal tension (P < 0.05, n = 6). The maximum effect was a 1.8-fold increase in activity and 2.1-fold increase in basal tension. Pretreatment of muscle strips with tetrodotoxin (1 μmol L -1) did not block the AR-C-induced response (n = 5). In vivo, AR-C (30 μmol kg-1, i.v.) increased gallbladder contraction frequency (P < 0.05, n = 8). These data suggest that iNOS is continually expressed in the normal gallbladder, which presumably releases low levels of nitric oxide and in turn may modulate spontaneous gallbladder motility. AR-C may be a beneficial treatment for patients suffering from acute cholecystitis. © 2007 The Authors.

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