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  • 201. Olausson, H
    et al.
    Lewitt, MS
    Brismar, K
    Sohlström, Annica
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Enhanced responsiveness of the insulin-like growth factor system in adult rat offspring from food restricted dams2003In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 53, no 6, p. 39A-39AConference paper (Other academic)
  • 202.
    Olofsson, Pia
    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.
    Experimental studies on Damage Control Surgery and Intraabdominal Hypertension2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Damage control surgery (DCS) offers an alternative to the traditional surgical management of complex or multiple injuries in critically injured patients. If a patient survives the initial phase of DCS, complications may occur, one of these being intraabdominal hypertension (IAH) and it´s potential development into the abdominal compartment syndrome.

    The indications for DCS have been widened and DCS principles can be applied in situations where time and resources are essential factors. The DCS principles of rapidly controlling intestinal spillage have not been evaluated. The aim of the studies in Papers I and II was to evaluate the principles of spillage control of intestinal contents according to the DCS concept and more specifically the effects of early rapid control of multiple bowel perforations on cardiovascular and pulmonary function compared with conventional small bowel resections in an animal model with abdominal trauma. In Paper I the animal model using anaesthetised pigs included a gunshot wound to the abdomen which caused multiple small bowel injuries. Haemorrhagic shock was combined with the gunshot wound in Paper II. The results presented in Paper I showed a significant reduction in rise in systemic vascular resistance and pulmonary vascular resistance, and a trend towards higher cardiac output and lower oxygen consumption in the bowel ligation group. In Paper II the results show a longer persistence of lactic acidaemia in the bowel ligation group. The aim of the study in Paper III was to assess visceral (intestinal, gastric and renal) microcirculation parallel with central haemodynamics and respiratory function during stepwise increases in intraabdominal pressure. In Paper IV we studied mucosal barrier function and morphology in the small bowel and colon of the pigs which were subjected to IAH. The IAP in anaesthetised pigs was increased stepwise using CO2 inflation, by 10 mm Hg at 10-minute intervals up to 50 mm Hg, and followed by exsufflation (Paper III). The microcirculation was selectively studied using a 4-channel laser Doppler flowmeter (Periflex 5000, Perimed, Sweden). The mucosal tissues were mounted in modified Ussing chambers for assessment of barrier function (E.coli K12 uptake and 51Cr-EDTA permeability) (Paper IV). The results showed that the microcirculation of the small bowel mucosa and colon mucosa was significantly less affected compared to the seromuscular layers. The microcirculation of gastric mucosa, renal cortex and the seromuscular layer of small bowel and colon were significantly reduced with each increase. Cardiac output (CO) decreased significantly at IAP levels above 10 mm Hg and the respiratory function data showed an increasing airway pressure and a concomitant reduction in thoracic compliance. Transmucosal passage of E. coli was increased three-fold in the small bowel after ACS with a significant correlation to the degree of mucosal microcirculatory reperfusion after exsufflation. 51Cr-EDTA permeability was unaffected. Bacterial passage in the colon was unchanged, whereas 51Cr-EDTA permeability after ACS increased by up to 181% of baseline and was correlated to significant histopathological changes in the mucosa.

    In Paper I we have demonstrated that early rapid control of multiple bowel perforations in a model with moderate shock resulted in less impairment of SVR and PVR than conventional resection and anastomosis. The use of DCS principles, however, had no beneficial effect on cardiovascular function when haemorrhagic shock was combined with abdominal missile trauma (Paper II), on the contrary bowel ligation was followed by more prolonged lactic acidosis than conventional repair. The studies in Paper III and IV indicate that the microcirculation of intestinal mucosa and especially small bowel mucosa seem better preserved in response to intraabdominal hypertension caused by CO2 insufflation than other intraabdominal microvascular beds. The short term ACS in this model caused morphological changes in the intestinal mucosa, and mucosal barrier dysfunction. The response pattern concerning barrier function changes after CO2 insufflation differs between small bowel and colonic mucosa. The small bowel mucosa showed increased bacterial passage, and the colonic mucosa an increase in paracellular permeability and secretory response.

    List of papers
    1. The effects of early rapid control of multiple bowel perforations after high-energy trauma to the abdomen: implications for damage control surgery
    Open this publication in new window or tab >>The effects of early rapid control of multiple bowel perforations after high-energy trauma to the abdomen: implications for damage control surgery
    Show others...
    2006 (English)In: Journal of Trauma, ISSN 0022-5282, E-ISSN 1529-8809, Vol. 61, no 1, p. 185-191Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: This study evaluates the effects of early rapid control of multiple bowel perforations on cardiovascular and pulmonary function in high-energy traumatic shock compared with conventional small bowel resection anastomosis.

    METHODS: Fifteen anesthetized pigs, 10 to 12 weeks old, were exposed to a reproducible high-energy trauma and were divided into two groups. In the first group, the resection anastomosis group (RA, n = 8), small-bowel injuries were treated with resection and anastomosis; in the second group, the multiple bowel ligation group (BL, n = 7), small-bowel injuries were treated by resection and ligation. Repeated measurement analysis of variance was used to study the within group change overtime, the between group difference, and the interaction between them. Mean outcome measures were intravascular pressures, cardiac output, vascular resistance, lactic acid, and blood gases.

    RESULTS: The high-energy injuries caused traumatic shock in both groups with reduced cardiac output (p < 0.001) and lactic acidemia (p < 0.001). The BL group had a trend for higher cardiac output (p = 0.06). The rise in systemic and pulmonary vascular resistance was significantly reduced in the BL group compared with the RA group (p < 0.05). The BL group had a strong trend for higher oxygen extraction ratio (p = 0.06). There was a trend for less oxygen consumption in the BL group (p = 0.07). There was no difference in the lactic acidemia between the two groups.

    CONCLUSIONS: Early rapid control of multiple bowel perforations after high-energy trauma resulted in less impairment of cardiovascular function than conventional resection anastomosis of the bowel.

    Keywords
    Bowel ligation, Damage control, Traumatic shock, Lactic acidemia, Cardiac output, Vascular resistance
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17794 (URN)10.1097/01.ta.0000221807.69844.63 (DOI)16832269 (PubMedID)
    Available from: 2009-04-21 Created: 2009-04-21 Last updated: 2017-12-13Bibliographically approved
    2. Multipel Small Bowel Ligation Compared to Conventional Primary Repair after Abdominal Gunshot Wound with Haemorrhagic Shock
    Open this publication in new window or tab >>Multipel Small Bowel Ligation Compared to Conventional Primary Repair after Abdominal Gunshot Wound with Haemorrhagic Shock
    Show others...
    2009 (English)In: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 98, no 1, p. 41-47Article in journal (Refereed) Published
    Abstract [en]

    Aims: The aim of this study was to evaluate the effects of early rapid control of multiple bowel perforations on cardiovascular function in combined abdominal missile trauma and haernorrhagic shock compared with conventional surgery.

    Methods: Eighteen anesthetised pigs were injured with a standardised abdominal missile trauma. The animals were bled to a mean arterial pressure of 50 mm Hg for 30 minutes, after which they were resuscitated and had laparotomy. They were divided into conventional surgery group (n=9) with primary resection and anastomosis of bowel injuries and early rapid multiple bowel ligation group (n=9). Repeated measurement analysis of variance was used for analysis.

    Results: There was profound hypotension, reduced cardiac output, increased vascular resistance and lactic acidaemia in both groups. Lactic acidaemia persisted longer in the early rapid multiple bowel ligation group. There were no significant differences in mean arterial pressure, cardiac output, stroke volume or systemic vascular resistance between the groups. The mean operation time was significantly shorter in the early rapid multiple bowel ligation group (13.3 (1.5) (SEM) minutes, compared with 116.4 (1.74) (SEM) minutes in the conventional surgery group, p = <0.001).

    Conclusions: Damage control principles have shortened the operating time in our model but did not improve the cardiovascular function and caused more lactic acidaemia than conventional repair.

    Keywords
    Animal model, bowel injuries, damage control surgery, haemorrhage, shock, trauma
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17604 (URN)
    Available from: 2009-04-06 Created: 2009-04-06 Last updated: 2017-12-13Bibliographically approved
    3. Gastrointestinal microcirculation and cardiopulmonary function during experimentally increased intra-abdominal pressure
    Open this publication in new window or tab >>Gastrointestinal microcirculation and cardiopulmonary function during experimentally increased intra-abdominal pressure
    Show others...
    2009 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 37, no 1, p. 230-239Article in journal (Refereed) Published
    Abstract [en]

    Objectives: The aim of this study was to assess gastric, intestinal, and renal cortex microcirculation parallel with central hemodynamics and respiratory function during stepwise increase of intra-abdominal pressure (IAP).

    Design: Prospective, controlled animal study.

    Setting: Research laboratory, University Hospital.

    Subjects: Twenty-six anesthetized and mechanically ventilated pigs.

    Interventions: Following baseline registrations, CO2 peritoneum was inflated (n = 20) and IAP increased stepwise by 10 mm Hg at 10 mins intervals up to 50 mm Hg and subsequently exsufflated. Control animals (n = 6) were not insufflated with CO2.

    Measurements and Main Results: The microcirculation of gastric mucosa, small bowel mucosa, small bowel seromuscular layer, colon mucosa, colon seromuscular layer, and renal cortex were selectively studied at all pressure levels and after exsufflation using a four-channel laser Doppler flowmeter (Periflex 5000, Perimed). Central hemodynamic and respiratory function data were registered at each level and after exsufflation. Cardiac output decreased significantly at IAP levels above 10 mm Hg. The microcirculation of gastric mucosa, renal cortex and the seromuscular layer of small bowel and colon was significantly reduced with each increase of IAP. The microcirculation of the small bowel mucosa and colon mucosa was significantly less affected compared with the serosa (p < 0.01).

    Conclusions: Our animal model of low and high IAP by intraperitoneal CO2-insufflation worked well for studies of microcirculation, hemodynamics, and pulmonary function. During stepwise increases of pressure there were marked effects on global hemodynamics, respiratory function, and microcirculation. The results indicate that intestinal mucosal flow, especially small bowel mucosal flow, although reduced, seems better preserved in response to intra-abdominal hypertension caused by CO2-insufflation than other intra-abdominal microvascular beds.

    Keywords
    intra-abdominal hypertension, gastrointestinal microcirculation, cardiopulmonary function
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16533 (URN)10.1097/CCM.0b013e318192ff51 (DOI)
    Available from: 2009-01-30 Created: 2009-01-30 Last updated: 2017-12-14Bibliographically approved
    4. Increased transmucosal uptake of E. coli K12 in porcine small bowel following experimental short term abdominal compartment syndrome
    Open this publication in new window or tab >>Increased transmucosal uptake of E. coli K12 in porcine small bowel following experimental short term abdominal compartment syndrome
    Show others...
    2009 (English)Article in journal (Other academic) Submitted
    Abstract [en]

    Background: Abdominal compartment syndrome (ACS) may lead to bacterial translocation and possibly be of importance for development of multiorgan failure. However, the underlying mechanisms have not been fully elucidated. In a porcine model we recently demonstrated preserved intestinal mucosal blood flow during experimental short duration ACS. In the present study we used the same model to determine mucosal barrier function and morphology in the small bowel and colon of pigs before and after short term ACS.

    Methods: The study comprised 12 anaesthetized pigs exposed to experimental ACS and 6 control animals. Via laparotomy, samples of small bowel and colon were taken out for studies before short term ACS, where the abdomen was inflated with CO2 and IAP was increased stepwise by 10 mm Hg at 10-minute intervals up to 50 mm Hg, and again 10 minutes after exsufflation. Mucosal microcirculation was measured by laser Doppler flowmetry, and mucosal tissues were mounted in modified Ussing chambers for assessment of barrier function (E. coli K12 uptake and 51Cr-EDTA permeability). Specimens were also fixed in formaldehyde, stained with eosin-hematoxylin and evaluated blindly using an 8-grade scale for assessment of mucosal damage.

    Results: Transmucosal passage of E. coli was three-fold increased in the small bowel after ACS (22.6 [18.2 – 54.4] units) vs. baseline (8.1 [2.0 – 13.9]; P< 0.050) with a significant correlation to alterations of mucosal microcirculation. In the colon bacterial passage was unchanged, whereas 51Cr-EDTA permeability after ACS increased to 181% of baseline (P<0.05) and was correlated to significant mucosal histopathological changes (P<0.03).

    Conclusion: Short term ACS with reperfusion induced significant dysfunction of the intestinal mucosal barrier. The response patterns concerning barrier dysfunction differed between small bowel and colonic mucosa, with increased bacterial passage and paracellular permeability, respectively.

    Keywords
    Short term ACS, intestinal barrier function, animal model, Ussing chamber
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17795 (URN)
    Available from: 2009-04-21 Created: 2009-04-21 Last updated: 2010-04-23Bibliographically approved
  • 203.
    Olofsson, Pia
    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.
    Berg, Sören
    Linköping University, Department of Medicine and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Casimir Ahn, Henrik
    Linköping University, Department of Medicine and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Brudin, Lars
    Linköping University, Department of Medicine and Health Sciences, Clinical Physiology . Linköping University, Faculty of Health Sciences.
    Wikström, Thore
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Johansson, Kenth J M
    Department of Surgery, Västervik, Sweden.
    Gastrointestinal microcirculation and cardiopulmonary function during experimentally increased intra-abdominal pressure2009In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 37, no 1, p. 230-239Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to assess gastric, intestinal, and renal cortex microcirculation parallel with central hemodynamics and respiratory function during stepwise increase of intra-abdominal pressure (IAP).

    Design: Prospective, controlled animal study.

    Setting: Research laboratory, University Hospital.

    Subjects: Twenty-six anesthetized and mechanically ventilated pigs.

    Interventions: Following baseline registrations, CO2 peritoneum was inflated (n = 20) and IAP increased stepwise by 10 mm Hg at 10 mins intervals up to 50 mm Hg and subsequently exsufflated. Control animals (n = 6) were not insufflated with CO2.

    Measurements and Main Results: The microcirculation of gastric mucosa, small bowel mucosa, small bowel seromuscular layer, colon mucosa, colon seromuscular layer, and renal cortex were selectively studied at all pressure levels and after exsufflation using a four-channel laser Doppler flowmeter (Periflex 5000, Perimed). Central hemodynamic and respiratory function data were registered at each level and after exsufflation. Cardiac output decreased significantly at IAP levels above 10 mm Hg. The microcirculation of gastric mucosa, renal cortex and the seromuscular layer of small bowel and colon was significantly reduced with each increase of IAP. The microcirculation of the small bowel mucosa and colon mucosa was significantly less affected compared with the serosa (p < 0.01).

    Conclusions: Our animal model of low and high IAP by intraperitoneal CO2-insufflation worked well for studies of microcirculation, hemodynamics, and pulmonary function. During stepwise increases of pressure there were marked effects on global hemodynamics, respiratory function, and microcirculation. The results indicate that intestinal mucosal flow, especially small bowel mucosal flow, although reduced, seems better preserved in response to intra-abdominal hypertension caused by CO2-insufflation than other intra-abdominal microvascular beds.

  • 204.
    Olofsson, Pia H.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Mellblom, Lennart
    Department of Pathology, County Hospital, Kalmar, Sweden.
    Berg, Sören
    Linköping University, Department of Medicine and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences.
    Ahn, Henrik Casimir
    Linköping University, Department of Medicine and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences.
    Wikström, Thore
    Linköping University, Department of Clinical and Experimental Medicine, Disaster Medicine and Traumatology. Linköping University, Faculty of Health Sciences.
    Johansson, Kenth J. M.
    Department of Surgery, Västervik Hospital, Sweden.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Increased transmucosal uptake of E. coli K12 in porcine small bowel following experimental short term abdominal compartment syndrome2009Article in journal (Other academic)
    Abstract [en]

    Background: Abdominal compartment syndrome (ACS) may lead to bacterial translocation and possibly be of importance for development of multiorgan failure. However, the underlying mechanisms have not been fully elucidated. In a porcine model we recently demonstrated preserved intestinal mucosal blood flow during experimental short duration ACS. In the present study we used the same model to determine mucosal barrier function and morphology in the small bowel and colon of pigs before and after short term ACS.

    Methods: The study comprised 12 anaesthetized pigs exposed to experimental ACS and 6 control animals. Via laparotomy, samples of small bowel and colon were taken out for studies before short term ACS, where the abdomen was inflated with CO2 and IAP was increased stepwise by 10 mm Hg at 10-minute intervals up to 50 mm Hg, and again 10 minutes after exsufflation. Mucosal microcirculation was measured by laser Doppler flowmetry, and mucosal tissues were mounted in modified Ussing chambers for assessment of barrier function (E. coli K12 uptake and 51Cr-EDTA permeability). Specimens were also fixed in formaldehyde, stained with eosin-hematoxylin and evaluated blindly using an 8-grade scale for assessment of mucosal damage.

    Results: Transmucosal passage of E. coli was three-fold increased in the small bowel after ACS (22.6 [18.2 – 54.4] units) vs. baseline (8.1 [2.0 – 13.9]; P< 0.050) with a significant correlation to alterations of mucosal microcirculation. In the colon bacterial passage was unchanged, whereas 51Cr-EDTA permeability after ACS increased to 181% of baseline (P<0.05) and was correlated to significant mucosal histopathological changes (P<0.03).

    Conclusion: Short term ACS with reperfusion induced significant dysfunction of the intestinal mucosal barrier. The response patterns concerning barrier dysfunction differed between small bowel and colonic mucosa, with increased bacterial passage and paracellular permeability, respectively.

  • 205.
    Olofsson, Pia
    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.
    Wikström, Thore
    Linköping University, Department of Clinical and Experimental Medicine, Disaster Medicine and Traumatology. Linköping University, Faculty of Health Sciences.
    Nagelkerke, N
    Abu-Zidan, Fikiri M.
    UAE University.
    Wang, J
    Östergötlands Läns Landsting, Centre for Teaching and Research in Disaster Medicine and Traumatology, Centre for Teaching and Research in Disaster Medicine and Traumatology.
    Multipel Small Bowel Ligation Compared to Conventional Primary Repair after Abdominal Gunshot Wound with Haemorrhagic Shock2009In: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 98, no 1, p. 41-47Article in journal (Refereed)
    Abstract [en]

    Aims: The aim of this study was to evaluate the effects of early rapid control of multiple bowel perforations on cardiovascular function in combined abdominal missile trauma and haernorrhagic shock compared with conventional surgery.

    Methods: Eighteen anesthetised pigs were injured with a standardised abdominal missile trauma. The animals were bled to a mean arterial pressure of 50 mm Hg for 30 minutes, after which they were resuscitated and had laparotomy. They were divided into conventional surgery group (n=9) with primary resection and anastomosis of bowel injuries and early rapid multiple bowel ligation group (n=9). Repeated measurement analysis of variance was used for analysis.

    Results: There was profound hypotension, reduced cardiac output, increased vascular resistance and lactic acidaemia in both groups. Lactic acidaemia persisted longer in the early rapid multiple bowel ligation group. There were no significant differences in mean arterial pressure, cardiac output, stroke volume or systemic vascular resistance between the groups. The mean operation time was significantly shorter in the early rapid multiple bowel ligation group (13.3 (1.5) (SEM) minutes, compared with 116.4 (1.74) (SEM) minutes in the conventional surgery group, p = <0.001).

    Conclusions: Damage control principles have shortened the operating time in our model but did not improve the cardiovascular function and caused more lactic acidaemia than conventional repair.

  • 206.
    Olsson, Hans
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Fyhr, Ing-Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Jahnson, Staffan
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    HER2 status in primary stage T1 urothelial cell carcinoma of the urinary bladder2012In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 46, no 2, p. 102-107Article in journal (Refereed)
    Abstract [en]

    Objective. The HER2 receptor is involved in pathways essential for cell proliferation, and is an important predictive and prognostic factor in breast cancer. HER2 probably plays a critical role in many types of cancer, including urothelial carcinoma of the bladder (UCB). Stage T1 UCB exhibits heterogeneous clinical behaviour, and the frequency of HER2 expression in such disease has not been thoroughly examined. The aim of this study was to use an immunohistochemical technique to evaluate the frequency of HER2 expression in a defined population-based cohort of patients registered as having primary stage T1 UCB. Material and methods. The initial study population comprised 285 patients registered as having primary stage T1 UCB. The original histological specimens were re-evaluated with regard to T stage and World Health Organization grade. Hospital records provided information on tumour size, multiplicity, possible presence of histologically proven recurrence and progression. The patients were followed for at least 5 years or until death. In tumours still considered stage T1 after re-evaluation, HER2 was investigated by immunohistochemistry of paraffin-embedded material and scored according to the guidelines used in breast cancer. Results. After histopathological re-evaluation, 201 patients were still T1 UCB and could be investigated regarding HER2 expression. HER2 overexpression was observed in 25 of those patients (12.4%). HER2 status was not significantly associated with recurrence or progression. Conclusions. HER2 was overexpressed in 12.4% of the present cohort of patients with primary stage T1 UCB. There was no significant association between tumour HER2 status and prognosis.

  • 207.
    Olsson, Hans
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Rosell, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Regional Cancer Center South East Sweden.
    Jahnson, Staffan
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Population-based study on prognostic factors for recurrence and progression in primary stage T1 bladder tumours2013In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 47, no 3, p. 188-195Article in journal (Refereed)
    Abstract [en]

    Objective. Stage T1 urothelial carcinoma of the bladder (UCB) exhibits heterogeneous clinical behaviour, and the treatment is controversial. The aim of this study was to evaluate prognostic factors for UCB in a defined, population-based cohort comprising patients with a first time diagnosis of primary stage T1 UCB.

    Material and methods. The study population initially consisted of 285 patients with primary stage T1 UCB reported to the regional Bladder Cancer Registry in the Southeast Healthcare Region of Sweden from 1992 to 2001. The histological specimens were re-evaluated concerning stage, substaging of T1, World Health Organization (WHO) grade, lymphovascular invasion (LVI), tumour volume and total resected volume. Hospital records provided data on tumour size and multiplicity, occurrence of possible relapse and/or progression, death from UCB and whether treatment was given.

    Results. After re-evaluation, the study population comprised 211 patients. The median follow-up time was 60 months. LVI was a prognostic factor for UCB progression and recurrence. Tumour size larger than 30 mm and multiplicity increased the risk of recurrence. T1 substaging, tumour volume and total resected volume were not associated with recurrence or tumour progression.

    Conclusions. LVI is significantly correlated with progression and recurrence in patients with primary stage T1 UCB. Therefore, the presence of LVI should be evaluated in every new case of T1 UCB.

  • 208.
    Olsson, Hans
    et al.
    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.
    Jahnson, Staffan
    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 Urology in Östergötland.
    SUB STAGING OF T1 BLADDER TUMOURS2009In: in EUROPEAN UROLOGY SUPPLEMENTS, vol 8, issue 4, 2009, Vol. 8, no 4, p. 287-287Conference paper (Refereed)
    Abstract [en]

    n/a

  • 209.
    Olsson, Hans
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Rosell, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Health and Developmental Care, Regional Cancer Centre.
    Jahnson, Staffan
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    MDM2 SNP309 promoter polymorphism and p53 mutations in urinary bladder carcinoma stage T12013In: BMC Urology, ISSN 1471-2490, E-ISSN 1471-2490, Vol. 13, no 5Article in journal (Refereed)
    Abstract [en]

    Background: Urinary bladder carcinoma stage T1 is an unpredictable disease that in some cases has a good prognosis with only local or no recurrence, but in others can appear as a more aggressive tumor with progression to more advanced stages. The aim here was to investigate stage T1 tumors regarding MDM2 promoter SNP309 polymorphism, mutations in the p53 gene, and expression of p53 and p16 measured by immunohistochemistry, and subsequently relate these changes to tumor recurrence and progression. We examined a cohort of patients with primary stage T1 urothelial carcinoma of the bladder and their tumors.

    Methods: After re-evaluation of the original slides and exclusions, the study population comprised 141 patients, all with primary stage T1 urothelial carcinoma of the bladder. The hospital records were screened for clinical parameters and information concerning presence of histologically proven recurrence and progression. The paraffin-embedded tumor material was evaluated by immunohistochemistry. Any mutations found in the p53 gene were studied by single-strand conformation analysis and Sanger sequencing. The MDM2 SNP309 polymorphism was investigated by pyrosequencing. Multivariate analyses concerning association with prognosis were performed, and Kaplan-Meier analysis was conducted for a combination of changes and time to progression.

    Results: Of the 141 patients, 82 had at least one MDM2 SNP309 G allele, and 53 had a mutation in the p53 gene, but neither of those anomalies was associated with a worse prognosis. A mutation in the p53 gene was associated with immunohistochemically visualized p53 protein expression at a cut-off value of 50%. In the group with p53 mutation Kaplan-Meier analysis showed higher rate of progression and shorter time to progression in patients with immunohistochemically abnormal p16 expression compared to them with normal p16 expression (p = 0.038).

    Conclusions: MDM2 SNP309 promoter polymorphism and mutations in p53 were not associated with worse prognosis in this cohort of patients with primary stage T1 urinary bladder carcinoma. However, patients with abnormal p16 expression and a mutated p53 gene had a higher rate of and a shorter time to progression, and p53 gene mutation was associated with an abnormal immunohistochemistry for p53 at a cut-off of 50%.

  • 210.
    Pahlman, L.
    et al.
    Påhlman, L., Department of Surgery, University Hospital, Uppsala, Sweden, Department of Surgery, University Hospital, SE-751 85 Uppsala, Sweden.
    Bohe, M.
    Department of Surgery, Malmö University Hospital, Malmö, Sweden.
    Cedermark, B.
    Department of Surgery, Karolinska University Hospital, Solna, Stockholm, Sweden.
    Dahlberg, M.
    Department of Surgery, Sunderby Hospital, Luleä, Sweden.
    Lindmark, G.
    Department of Surgery, Helsingborgs Hospital, Helsingborg, Sweden.
    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.
    Ojerskog, B.
    Öjerskog, B., Department of Surgery, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden.
    Damber, L.
    Regional Oncological Centre, University Hospital, Umeå, Sweden.
    Johansson, R.
    Regional Oncological Centre, University Hospital, Umeå, Sweden.
    The Swedish Rectal Cancer Registry2007In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 94, no 10, p. 1285-1292Article in journal (Refereed)
    Abstract [en]

    Background: An audit of all patients with rectal cancer in Sweden was launched in 1995. This is the first report from the Swedish Rectal Cancer Registry (SRCR). Methods: Between 1995 and 2003, 13 434 patients treated for adenocarcinoma of the rectum were registered with the SRCR, there were approximately 1500 new patients annually. Results: Approximately half had an anterior resection, a quarter an abdominoperineal resection and 15 per cent a Hartmann's procedure. The median 30-day postoperative mortality rate was 2.4 per cent and the overall postoperative morbidity rate was 35.0 per cent. The 5-year cancer-specific survival rate was 62.3 percent. The 5-year relative survival rate was 70.1 percent after anterior resection, 59.8 per cent after abdominoperineal resection and 39.8 per cent after a Hartmann's procedure. The crude 5-year local recurrence rate was 9.5 per cent overall, 6.1 per cent after preoperative radiotherapy and 11.4 per cent after surgery alone. For 3868 patients who had a locally curative procedure the local recurrence rate was 7-4 per cent overall, 5.9 per cent for those who had radiotherapy and 10.2 per cent for those who did not. The local recurrence rate was 2.9 per cent (28 of 968) for stage I disease, 7.9 per cent (112 of 1418) for stage II, 13.9 per cent (188 of 1357) for stage III and 8.5 per cent (45 of 532) for stage IV. Conclusion: These good population-based results are due, in part, to the nationwide prospective quality assurance registration. Copyright © 2007 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd.

  • 211.
    Persborn, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Studies of barrier function in patients with ulcerative colitis and pouchitis2011Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background and aim: The cause of ulcerative colitis (UC) is largely unknown. However, there is a presumed genetic component to susceptibility and altered intestinal barrier function has been implicated in the pathophysiology of ulcerative colitis. There is evidence that the increased intestinal permeability in IBD is partly controlled by delicate intercellular circuits in the colonic tissue linked to the enteric nervous system. Little is, however, known about how this is regulated in detail.

    Ileal pouch-anal anastomosis (IPAA) is a good surgical reconstructive option in UC patients after proctocolectomy. However 10-15% of IPAA patients develop a severe and recurrent inflammation in the constructed pouch. The standard treatment for pouchitis is long and/or frequent use of antibiotics. Probiotics have been shown to reduce the risk of recurrence of pouchitis after induction treatment with antibiotics.

    The aim was to characterize macromolecular permeability in non inflamed colon of UC and elucidate the role of cholinergic signaling, mast cells and eosinophils in the regulation of the human colonic permeability. Furthermore, we examine the mucosal barrier function in relation to pouchitis, before and after treatment with probiotics.

    Material and methods: In the first study 23 UC patients in remission and 53 healthy volunteers were included. Biopsies from the sigmoid colon were assed for macromolecular permeability (horseradish peroxidase (HRP) and 51CrEDTA) and electrophysiology during challenge with carbachol. Experiments were repeated with CRF receptor antagonists, carbachol receptor antagonists and mast cell stabilizers in Ussing chambers. Further, pouch biopsies from 16 IPAA patients with pouchitis and 13 IPAA controls were assed in Ussing chambers for macromolecular permeability and electrophysiology as above. In addition E. coli K12 were used to assess the barrier to bacteria. Biopsies were taken on three occasions; before treatment, after antibiotics and after probiotics. Pouchitis Disease Activity Index (PDAI) was used in all subjects.

    Results: Colonic tissues from UC patients had significant increase in permeability to protein antigens compared with controls. Permeability was normalized by atropine, α-helical CRF(9-41) and lodoxamide. Eosinophils were increased in number in UC tissues, expressed M2 and M3 muscarinic receptors and showed immunoreactivity to CRF. In pouchitis patients,  PDAI was significantly improved after treatment with antibiotics and probiotics. There was a significantly enhanced passage of E. coli K12 and HRP in patients with active pouchitis, which was unchanged during treatment with antibiotics, but significantly normalized by probiotics.

    Conclusions and discussion: We identified a neuroimmune intercellular circuit (from cholinergic nerves, via eosinophils to mast cells) that mediates colonic mucosal barrier dysfunction in UC patients. Furthermore we found that probiotics restored the increased permeation to E. coli and HRP in patients with pouchitis. Pouchitis, resembling symptoms in active UC, may well constitute a good model to study acquired intestinal barrier dysfunction in IBD.

    List of papers
    1. Eosinophils Express Muscarinic Receptors and Corticotropin-Releasing Factor to Disrupt the Mucosal Barrier in Ulcerative Colitis
    Open this publication in new window or tab >>Eosinophils Express Muscarinic Receptors and Corticotropin-Releasing Factor to Disrupt the Mucosal Barrier in Ulcerative Colitis
    Show others...
    2011 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 140, no 5, p. 1597-1607Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND andamp; AIMS: Altered intestinal barrier function has been implicated in the pathophysiology of ulcerative colitis (UC) in genetic, functional, and epidemiological studies. Mast cells and corticotropinreleasing factor (CRF) regulate the mucosal barrier in human colon. Because eosinophils are often increased in colon tissues of patients with UC, we assessed interactions among mast cells, CRF, and eosinophils in the mucosal barrier of these patients. METHODS: Transmucosal fluxes of protein antigens (horseradish peroxidase) and paracellular markers (51Cr-EDTA, fluorescein isothiocyanate-dextran 4000) were studied in noninflamed, colonic mucosal biopsy samples collected from 26 patients with UC and 53 healthy volunteers (controls); samples were mounted in Ussing chambers. We also performed fluorescence and electron microscopy of human tissue samples, assessed isolated eosinophils, and performed mechanistic studies using in vitro cocultured eosinophils (15HL-60), mast cells (HMC-1), and a colonic epithelial cell line (T84). RESULTS: Colon tissues from patients with UC had significant increases in permeability to protein antigens compared with controls. Permeability was blocked by atropine (a muscarinic receptor antagonist), alpha-helical CRF(9-41) (a CRF receptor antagonist), and lodoxamide (a mast-cell stabilizer). Eosinophils were increased in number in UC tissues (compared with controls), expressed the most M2 and M3 muscarinic receptors of any mucosal cell type, and had immunoreactivity to CRF. In coculture studies, carbachol activation of eosinophils caused production of CRF and activation of mast cells, which increased permeability of T84 epithelial cells to macromolecules. CONCLUSIONS: We identified a neuroimmune intercellular circuit (from cholinergic nerves, via eosinophils to mast cells) that mediates colonic mucosal barrier dysfunction in patients with UC. This circuit might exacerbate mucosal inflammation.

    Place, publisher, year, edition, pages
    Elsevier Science B.V. Amsterdam, 2011
    Keywords
    Intestinal Permeability, Inflammatory Bowel Disease, Immune Response, Stress
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-68223 (URN)10.1053/j.gastro.2011.01.042 (DOI)000290028200040 ()
    Available from: 2011-05-13 Created: 2011-05-13 Last updated: 2017-12-11
    2. Effects of probiotics (Ecologic 825) on barrier function during maintenance treatment for severe pouchitis
    Open this publication in new window or tab >>Effects of probiotics (Ecologic 825) on barrier function during maintenance treatment for severe pouchitis
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background : About 10-15% of patients with an ileoanal pouch develop a severe, form of pouchitis that necessitates long and/or frequent use of antibiotics and in rare cases even pouch excision. Probiotics have been shown to reduce the risk of recurrence after induction treatment with antibiotics. The mechanisms behind the positive effects of probiotics are not fully understood. The aim of our study was to examine the mucosal barrier function in relation to pouchitis, before and after treatment with probiotics.

    Methods: 16 patients with a history of severe pouchitis underwent endoscopy with biopsies of the pouch on three occasions: Once during active pouchitis, second after 4 weeks of treatment with antibiotics until clinical remission and third after eight weeks of probiotic treatment. 13 controls with an ileoanal pouch with no recent history of pouchitis were used. The biopsies were mounted in Ussing chambers and mucosal barrier function was assessed by electrophysiology, transmucosal uptake of E coli K12, permeability to Cr-EDTA and Horseradish peroxidase (HRP). Pouchitis Disease Activity Index (PDAI) was used in all subjects.

    Results: PDAI was significantly improved after treatment with antibiotics and probiotics. There was a significant difference in E. coli K12 passage before treatment compared to controls (3.7 units (3.4-8.5) vs 1.7 units (1.0-2.4) p< 0.01). E. coli K12 passage did not change after antibiotic treatment (5.0 units (3.3-7.1) p = ns vs controls). In contrast a significant reduction in bacterial uptake was seen after probiotics (2.2 units (1.8-3.3) p< 0.05). Likewise, a significant normalization of HRP flux was seen after probiotic treatment. Pouchitis did not affect paracellular permability or electrophysiology.

    Conclusion: Probiotic treatment restored the increased permeation to E. coli and HRP in patients with chronic pouchitis. This could be an important factor behind the positive effects of probiotics in patients with chronic pouchitis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-70829 (URN)
    Available from: 2011-09-20 Created: 2011-09-20 Last updated: 2011-09-20Bibliographically approved
  • 212.
    Persborn, Mats
    et al.
    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 for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Carlsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Timmerman, Harro
    Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, 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 for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Effects of probiotics (Ecologic 825) on barrier function during maintenance treatment for severe pouchitisManuscript (preprint) (Other academic)
    Abstract [en]

    Background : About 10-15% of patients with an ileoanal pouch develop a severe, form of pouchitis that necessitates long and/or frequent use of antibiotics and in rare cases even pouch excision. Probiotics have been shown to reduce the risk of recurrence after induction treatment with antibiotics. The mechanisms behind the positive effects of probiotics are not fully understood. The aim of our study was to examine the mucosal barrier function in relation to pouchitis, before and after treatment with probiotics.

    Methods: 16 patients with a history of severe pouchitis underwent endoscopy with biopsies of the pouch on three occasions: Once during active pouchitis, second after 4 weeks of treatment with antibiotics until clinical remission and third after eight weeks of probiotic treatment. 13 controls with an ileoanal pouch with no recent history of pouchitis were used. The biopsies were mounted in Ussing chambers and mucosal barrier function was assessed by electrophysiology, transmucosal uptake of E coli K12, permeability to Cr-EDTA and Horseradish peroxidase (HRP). Pouchitis Disease Activity Index (PDAI) was used in all subjects.

    Results: PDAI was significantly improved after treatment with antibiotics and probiotics. There was a significant difference in E. coli K12 passage before treatment compared to controls (3.7 units (3.4-8.5) vs 1.7 units (1.0-2.4) p< 0.01). E. coli K12 passage did not change after antibiotic treatment (5.0 units (3.3-7.1) p = ns vs controls). In contrast a significant reduction in bacterial uptake was seen after probiotics (2.2 units (1.8-3.3) p< 0.05). Likewise, a significant normalization of HRP flux was seen after probiotic treatment. Pouchitis did not affect paracellular permability or electrophysiology.

    Conclusion: Probiotic treatment restored the increased permeation to E. coli and HRP in patients with chronic pouchitis. This could be an important factor behind the positive effects of probiotics in patients with chronic pouchitis.

  • 213.
    Petersson, Fredrik
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Rehfeld, J.F.
    Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Denmark.
    Franzén, Lennart E.
    Department of Pathology, University Hospital, Örebro, Sweden.
    A morphometric study of antral G-cell density in a sample of adult general population: comparison of three different methods and correlation with patient demography, helicobacter pylori infection, histomorphology and circulating gastrin levels2009In: International Journal of Clinical and Experimental Pathology, ISSN 1936-2625, E-ISSN 1936-2625, Vol. 2, no 3, p. 239-248Article in journal (Refereed)
    Abstract [en]

    Helicobacter pylori infection has been linked to hypergastrinemia and either decreased or normal G-cell content in the antral mucosa. To clarify this controversial issue, we quantitatively determined antral G-cell content on the same biopsy specimens with three different methods and examined whether these methods are intercorrelated and the relation of these methods to plasma gastrin concentrations, demography, the occurrence of H. pylori infection and chronic gastritis. Gastric antral mucosal biopsy sections from 273 adults (188 with and 85 without H pylori infection) from a general population sample were examined immunohistochemically for G-cells using cell counting, stereology (point counting) and computerized image analysis. Gastritis was scored according to the updated Sydney system. Basal plasma gastrin concentrations were measured by radioimmunoassay. The three methods for G-cell quantification were poorly correlated and the results showed no correlation with basal plasma gastrin concentrations. The antral G-cell density and scores for H. pylori colonization were positively related to age. Neither the scores for chronic inflammation, nor the scores for inflammatory activity, atrophy or intestinal metaplasia were consistently related to the antral G-cell content. In conclusion, the results of three techniques for G-cell quantification in the gastric antral mucosa were poorly intercorrelated and none of the methods correlated with plasma gastrin concentrations. Age and scores for H pylori colonization seem to be determinants of the G-cell density. That common morphometric techniques correlate poorly is of utmost importance to bear in mind when quantitative morphological studies are planned, compared or interpreted.

  • 214.
    Petersson, Fredrik
    et al.
    Pathology Research Department, Ryhov Hospital, Jönköping, Sweden and Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Franzén, Lennart E
    Department of Pathology, Medical Centre Hospital, Örebro, Sweden.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Characterization of the gastric cardia in volunteers from the general population: type of mucosa, helicobacter pylori infection, inflammation, mucosal proliferative activity, p53 and p21 expression, and relations to gastritis2010In: Digestive Diseases and Sciences, ISSN 0163-2116, E-ISSN 1573-2568, Vol. 55, no 1, p. 46-53Article in journal (Refereed)
    Abstract [en]

    The aim of this research was to characterize the mucosa of the gastric cardia in relation to infection with Helicobacter pylori and the occurrence of chronic gastritis in other parts of the stomach in a sample of the general population. In this study, 80 adult volunteers underwent esophagogastroscopy with biopsies from the gastric cardia, corpus, and antrum. Gastritis was classified according to the Sydney system. Chronic gastritis (cardia excepted) was diagnosed in 35 subjects, 30 with Hpylori infection. Epithelial proliferative activity (Ki-67), p53- and p21 expression were examined quantitatively with cell counting after immunohistochemical stainings. Esophagitis was diagnosed macroscopically. Fourty eight subjects had cardia-type and 32 corpus-type mucosa in the anatomical cardia. The prevalence of esophagitis (nine cases) did not differ between these groups. Carditis was more prevalent among subjects with cardia-type mucosa (73 vs. 28%, P < 0.0001). Hpylori was present in 48% of those with cardia-type and 25% of those with corpus-type mucosa (P = 0.06). Of the 44 subjects with carditis, 31 had Hpylori in this location. The group with Hpylori infection had significantly higher mucosal proliferative activity when compared to uninfected subjects. Among the subjects with H. pylori-associated carditis, more p53-positive epithelial cells were detected compared to both the non-infected group (P = 0.0004) and to subjects with non-Hpylori-associated carditis (P = 0.03). In subjects with cardia-type mucosa, and both carditis and gastritis, the degree of chronic inflammation was higher in the cardia compared to the corpus and antrum and the p53 expression was significantly higher in the cardia compared to the corpus, but similar to that in the antrum. The proliferative activity was significantly higher in the antrum compared to the cardia and corpus, respectively. In conclusion, H. pylori infection, carditis, and increased p53 expression are more common in subjects with cardia- than corpus-type mucosa in the gastric cardia. Carditis is mainly related to Hpylori infection. There are some differences regarding inflammation, proliferative activity, and p53 expression between the cardia and other regions of the stomach, yet the significance of these differences remains to be clarified.

  • 215.
    Pettersson, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Biodegradable gelatin microcarriers in tissue engineering: In vitro studies on cartilage and bone2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tissue engineering is a multidisciplinary field that combines cells, biomaterial scaffolds and environmental factors to achieve functional tissue repair. This thesis focuses on the use of macroporous gelatin microcarriers as scaffolds in tissue engineering applications, with a special focus on cartilage and bone formation by human adult cells in vitro.

    In our first study, human articular chondrocytes were seeded on macroporous gelatin microcarriers. The microcarriers were subsequently encapsulated in coagulated blood-derived biological glues and cultured under free-swelling conditions for up to 17 weeks. Even in the absence of recombinant chondrogenic growth factors, the chondrocytes remained viable and metabolically active for the duration of the culture period, as indicated by an increased amount of cell nuclei and extracellular matrix (ECM). The ECM showed several cartilage characteristics, but lacked the cartilage specific collagen type II. Furthermore, ECM formation was seen primarily in a capsule surrounding the tissue-engineered constructs, leading to the conclusion that the used in vitro models were unable to support true cartilage formation.

    The capacity of human dermal fibroblasts to produce cartilage- and bone-like tissue in the previously mentioned model was also investigated. Under the influence of chondrogenic induction factors, including TGF-β1 and insulin, the fibroblasts produced cartilage specific molecules, as confirmed by indirect immunohistochemistry, however not collagen type II. Under osteogenic induction, by dexamethasone, ascorbate-2-phosphate and β–glycerophosphate, the fibroblasts formed a calcified matrix with bone specific markers, and an alkaline phosphatase assay corroborated a shift towards an osteoblast like phenotype. The osteogenic induction was enhanced by flow-induced shear stress in a spinner flask system.

    In addition, four different types of gelatin microcarriers, differing by their internal pore diameter and their degree of gelatin cross-linking, were evaluated for their ability to support chondrocyte expansion. Chondrocyte densities on the microcarriers were monitored every other day over a twoweek period, and chondrocyte growth was analyzed by piecewise linear regression and analysis of variance (ANOVA). No differences were seen between the different microcarriers during the first week. However, during the second week of culture both microcarrier pore diameter and gelatin crosslinking had significant impacts on chondrocyte density.

    Lastly, a dynamic centrifugation regime (f=12.5 mHz for 16 minutes every other day) was administered to chondrocyte-seeded microcarriers, with or without encapsulation in platelet rich plasma (PRP), to study the possible effect of dynamic stimuli on cartilage formation. Presence of PRP enhanced the structural stability of the tissue-engineered constructs, but we were not able to confirm any dose-response pattern between ECM formation and the applied forces. After 12 weeks, distinct gelatin degradation had occurred independent of both dynamic stimuli and presence of PRP.

    In summary, this thesis supports a plausible use for gelatin microcarriers in tissue engineering of cartilage and bone. Microcarrier characteristics, specifically gelatin cross-linking and pore diameter, have been shown to affect chondrocyte expansion. In addition, the use of human dermal fibroblasts as an alternative cell source for cartilage and bone formation in vitro was addressed.

    List of papers
    1. Human articular chondrocytes on macroporous gelatin microcarriers form structurally stable constructs with blood-derived biological glues in vitro
    Open this publication in new window or tab >>Human articular chondrocytes on macroporous gelatin microcarriers form structurally stable constructs with blood-derived biological glues in vitro
    2009 (English)In: JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, ISSN 1932-6254, Vol. 35, no 6, p. 450-460Article in journal (Refereed) Published
    Abstract [en]

    Biodegradable macroporous gelatin microcarriers fixed with blood-derived biodegradable glue are proposed as a delivery system for human autologous chondrocytes. Cell-seeded microcarriers were embedded in four biological glues - recalcified citrated whole blood, recalcified citrated plasma with or without platelets, and a commercially available fibrin glue - and cultured in an in vitro model under static conditions for 16 weeks. No differences could be verified between the commercial fibrin glue and the blood-derived alternatives. Five further experiments were conducted with recalcified citrated platelet-rich plasma alone as microcarrier sealant, using two different in vitro culture models and chondrocytes from three additional donors. The microcarriers supported chondrocyte adhesion and expansion as well as extracellular matrix (ECM) synthesis. Matrix formation occurred predominantly at sample surfaces under the static conditions. The presence of microcarriers proved essential for the glues to support the structural takeover of ECM proteins produced by the embedded chondrocytes, as exclusion of the microcarriers resulted in unstable structures that dissolved before matrix formation could occur. Immunohistochemical analysis revealed the presence of SOX-9- and S-100-positive chondrocytes as well as the production of aggrecan and collagen type I, but not of the cartilage-specific collagen type II. These results imply that blood-derived glues are indeed potentially applicable for encapsulation of chondrocyte-seeded microcarriers. However, the static in vitro models used in this study proved incapable of supporting cartilage formation throughout the engineered constructs.

    Keywords
    cartilage, chondrocyte, microcarrier, tissue engineering, fibrin glue, platelet-rich plasma
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-20597 (URN)10.1002/term.179 (DOI)
    Available from: 2009-09-15 Created: 2009-09-15 Last updated: 2015-06-29
    2. Engineering three-dimensional cartilage- and bone-like tissues using human dermal fibroblasts and macroporous gelatine microcarriers
    Open this publication in new window or tab >>Engineering three-dimensional cartilage- and bone-like tissues using human dermal fibroblasts and macroporous gelatine microcarriers
    Show others...
    2010 (English)In: Journal of plastic, reconstructive & aesthetic surgery : JPRAS, ISSN 1878-0539, Vol. 63, no 6, p. 1036-1046Article in journal (Refereed) Published
    Abstract [en]

    The creation of tissue-engineered cartilage and bone, using cells from an easily available source seeded on a suitable biomaterial, may have a vast impact on regenerative medicine. While various types of adult stem cells have shown promising results, their use is accompanied by difficulties associated with harvest and culture. The proposed inherent plasticity of dermally derived human fibroblasts may render them useful in tissue-engineering applications. In the present study, human dermal fibroblasts cultured on macroporous gelatine microcarriers encapsulated in platelet-rich plasma into three-dimensional constructs were differentiated towards chondrogenic and osteogenic phenotypes using specific induction media. The effect of flow-induced shear stress on osteogenic differentiation of fibroblasts was also evaluated. The generated tissue constructs were analysed after 4, 8 and 12 weeks using routine and immunohistochemical stainings as well as an enzyme activity assay. The chondrogenic-induced tissue constructs were composed of glycosaminoglycan-rich extracellular matrix, which stained positive for aggrecan. The osteogenic-induced tissue constructs were composed of mineralised extracellular matrix containing osteocalcin and osteonectin, with cells showing an increased alkaline phosphatase activity. Increased osteogenic differentiation was seen when applying flow-induced shear stress to the culture. Un-induced fibroblast controls did not form cartilage- or bone-like tissues. Our findings suggest that primary human dermal fibroblasts can be used to form cartilage- and bone-like tissues in vitro when cultured in specific induction media.

    Keywords
    Dermal fibroblast; Chondrogenesis; Osteogenesis; Microcarrier; Tissue engineering; Regenerative medicine
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-54113 (URN)10.1016/j.bjps.2009.02.072 (DOI)000277356900025 ()19329368 (PubMedID)
    Available from: 2010-02-23 Created: 2010-02-23 Last updated: 2010-10-29
    3. Cell expansion of human articular chondrocytes on macroporous gelatine scaffolds: — impact of micro carrier selection on cell proliferation
    Open this publication in new window or tab >>Cell expansion of human articular chondrocytes on macroporous gelatine scaffolds: — impact of micro carrier selection on cell proliferation
    2011 (English)In: Biomedical Materials, ISSN 1748-6041, E-ISSN 1748-605X, Vol. 6, no 6, p. 065001-Article in journal (Refereed) Published
    Abstract [en]

    This study investigates human chondrocyte expansion on four macroporous gelatine microcarriers (CultiSpher) differing with respect to two manufacturing processes—the amount of emulsifier used during initial preparation and the gelatine cross-linking medium. Monolayer-expanded articular chondrocytes from three donors were seeded onto the microcarriers and cultured in spinner flask systems for a total of 15 days. Samples were extracted every other day to monitor cell viability and establish cell counts, which were analysed using analysis of variance and piecewise linear regression. Chondrocyte densities increased according to a linear pattern for all microcarriers, indicating an ongoing, though limited, cell proliferation. A strong chondrocyte donor effect was seen during the initial expansion phase. The final cell yield differed significantly between the microcarriers and our results indicate that manufacturing differences affected chondrocyte densities at this point. Remaining cells stained positive for chondrogenic markers SOX-9 and S-100 but extracellular matrix formation was modest to undetectable. In conclusion, the four gelatine microcarriers supported chondrocyte adhesion and proliferation over a two week period. The best yield was observed for microcarriers produced with low emulsifier content and cross-linked in water and acetone. These results add to the identification of optimal biomaterial parameters for specific cellular processes and populations.

    Place, publisher, year, edition, pages
    Bristol, UK: Institute of Physics Publishing Ltd., 2011
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-54114 (URN)10.1088/1748-6041/6/6/065001 (DOI)000298241800001 ()
    Note
    Funding agencies|Swedish foundation for strategic research| A302:319 |Linkoping University and Landstinget i Ostergotland||Available from: 2010-02-23 Created: 2010-02-23 Last updated: 2017-12-12
    4. The Role of Platelet Rich Plasma and Dynamic Centrifugation on Extracellular Matrix Formation of Human Articular Chondrocytes on Macroporous Gelatin Microcarriers in Pellet Culture
    Open this publication in new window or tab >>The Role of Platelet Rich Plasma and Dynamic Centrifugation on Extracellular Matrix Formation of Human Articular Chondrocytes on Macroporous Gelatin Microcarriers in Pellet Culture
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Platelet rich plasma (PRP) has been investigated for its beneficial use in cartilage tissue engineering previously. Here, we address the effect of using PRP as encapsulating agent for gelatin-supported chondrocyte pellet culture in vitro. Furthermore, the concept of using dynamic centrifugation to stimulate extracellular matrix (ECM) formation of the chondrocytes is explored. Human articular chondrocytes were expanded on macroporous gelatin microcarriers in a spinner flask system. The cell-seeded microcarriers were allowed to form pellets with or without re-calcified citrated PRP, and subjected to dynamic centrifugation (f = 0.0125 Hz) for a total of 16 min every other day using a standard tabletop centrifuge. Three acceleration curves with differing top speeds (corresponding to 500 g, 1500 g and 3000 g respectively) were used for the experimental groups and unstimulated controls were set for comparison. Pellets were kept in culture for up to 12 weeks, paraffin embedded and sectioned for histological and immunohistochemical analysis. Results showed increasing numbers of cells and ECM with time, as well as a gradual degradation of the gelatin microcarriers, indicating ongoing cell proliferation and metabolism throughout the culture period. Cell densities and ECM formation were more pronounced in the PRP-containing groups after four weeks, although this difference diminished with time. At the last time point several cartilage markers were found in the produced ECM, however including the fibrocartilaginous marker collagen type I. Dynamic centrifugation did not visibly increase the ECM accumulation over the 12-week duration of this experiment, although non-conclusive indications of collagen fiber organization were seen in the two groups with the highest acceleration limits at the last time point.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-54115 (URN)
    Available from: 2010-02-23 Created: 2010-02-23 Last updated: 2015-06-29
  • 216.
    Pettersson, Sofia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Kratz, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Plastic Surgery, Hand Surgery and Burns . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
    The Role of Platelet Rich Plasma and Dynamic Centrifugation on Extracellular Matrix Formation of Human Articular Chondrocytes on Macroporous Gelatin Microcarriers in Pellet CultureManuscript (preprint) (Other academic)
    Abstract [en]

    Platelet rich plasma (PRP) has been investigated for its beneficial use in cartilage tissue engineering previously. Here, we address the effect of using PRP as encapsulating agent for gelatin-supported chondrocyte pellet culture in vitro. Furthermore, the concept of using dynamic centrifugation to stimulate extracellular matrix (ECM) formation of the chondrocytes is explored. Human articular chondrocytes were expanded on macroporous gelatin microcarriers in a spinner flask system. The cell-seeded microcarriers were allowed to form pellets with or without re-calcified citrated PRP, and subjected to dynamic centrifugation (f = 0.0125 Hz) for a total of 16 min every other day using a standard tabletop centrifuge. Three acceleration curves with differing top speeds (corresponding to 500 g, 1500 g and 3000 g respectively) were used for the experimental groups and unstimulated controls were set for comparison. Pellets were kept in culture for up to 12 weeks, paraffin embedded and sectioned for histological and immunohistochemical analysis. Results showed increasing numbers of cells and ECM with time, as well as a gradual degradation of the gelatin microcarriers, indicating ongoing cell proliferation and metabolism throughout the culture period. Cell densities and ECM formation were more pronounced in the PRP-containing groups after four weeks, although this difference diminished with time. At the last time point several cartilage markers were found in the produced ECM, however including the fibrocartilaginous marker collagen type I. Dynamic centrifugation did not visibly increase the ECM accumulation over the 12-week duration of this experiment, although non-conclusive indications of collagen fiber organization were seen in the two groups with the highest acceleration limits at the last time point.

  • 217.
    Pettersson, Sofia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Tengvall, Pentti
    University of Gothenburg.
    Kratz, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Plastic Surgery, Hand Surgery and Burns. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
    Human articular chondrocytes on macroporous gelatin microcarriers form structurally stable constructs with blood-derived biological glues in vitro2009In: JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, ISSN 1932-6254, Vol. 35, no 6, p. 450-460Article in journal (Refereed)
    Abstract [en]

    Biodegradable macroporous gelatin microcarriers fixed with blood-derived biodegradable glue are proposed as a delivery system for human autologous chondrocytes. Cell-seeded microcarriers were embedded in four biological glues - recalcified citrated whole blood, recalcified citrated plasma with or without platelets, and a commercially available fibrin glue - and cultured in an in vitro model under static conditions for 16 weeks. No differences could be verified between the commercial fibrin glue and the blood-derived alternatives. Five further experiments were conducted with recalcified citrated platelet-rich plasma alone as microcarrier sealant, using two different in vitro culture models and chondrocytes from three additional donors. The microcarriers supported chondrocyte adhesion and expansion as well as extracellular matrix (ECM) synthesis. Matrix formation occurred predominantly at sample surfaces under the static conditions. The presence of microcarriers proved essential for the glues to support the structural takeover of ECM proteins produced by the embedded chondrocytes, as exclusion of the microcarriers resulted in unstable structures that dissolved before matrix formation could occur. Immunohistochemical analysis revealed the presence of SOX-9- and S-100-positive chondrocytes as well as the production of aggrecan and collagen type I, but not of the cartilage-specific collagen type II. These results imply that blood-derived glues are indeed potentially applicable for encapsulation of chondrocyte-seeded microcarriers. However, the static in vitro models used in this study proved incapable of supporting cartilage formation throughout the engineered constructs.

  • 218.
    Pfeifer, Daniella
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Arbman, Gunnar
    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.
    Polymorphism of the p73 gene in relation to colorectal cancer risk and survival2005In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 26, no 1, p. 103-107Article in journal (Refereed)
    Abstract [en]

    The results regarding a GC/AT polymorphism in the p73 gene in relation to cancer risk are inconsistent, and the significance of loss of heterozygosity (LOH) of the gene is unclear. In the present study, we investigated whether this polymorphism was related to the risk of colorectal cancer, and whether there were relationships between the polymorphism and LOH, protein expression or clinicopathological variables. 179 patients with colorectal cancer and 260 healthy controls were genotyped for the polymorphism by PCR-restriction fragment length polymorphism (RFLP). Fifty informative cases were examined for LOH in tumours. Immunohistochemistry was performed on distant (n = 42) and adjacent normal mucosa (n = 33), primary tumour (n = 6 9) and lymph node metastasis (n = 12). The frequencies of the genotypes were 63% for wild-type (GC/GC), 30% for heterozygotes (GC/AT) and 7% for variants (AT/AT) in patients, and 62, 36 and 2% in controls, respectively. The frequencies of the genotypes in the patients and controls were significantly different (P = 0.02). The patients carrying the AT allele had a better prognosis than those with the GC/GC genotype (OR = 0.42, 95% CI = 1.15-5.02, P = 0.02). No LOH was observed at the p73 locus. Expression of p73 protein was increased from normal mucosa to primary tumours (P = 0.02), but was not significantly changed between primary tumours and metastases (P = 1.0). In conclusion, the AT/AT homozygotes may have a greater risk of developing colorectal cancer, while the patients who carried the AT allele had a better prognosis.

  • 219.
    Radestad, Monica
    et al.
    Karolinska Institutet, Department of Clinical Science and Education and Section of Emergency Medicine, Södersjukhuset, Stockholm, Sweden .
    Nilsson, Heléne
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Castren, Maaret
    Karolinska Institutet, Department of Clinical Science and Education and Section of Emergency Medicine, Södersjukhuset, Stockholm, Sweden .
    Svensson, Leif
    Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden .
    Ruter, Anders
    Sophiahemmet University College, Stockholm, Sweden .
    Gryth, Dan
    Karolinska Institutet, Department of Physiology and Pharmacology and Section of Anaesthesiology and Intensive care, Stockholm, Sweden .
    Combining performance and outcome indicators can be used in a standardized way: a pilot study of two multidisciplinary, full-scale major aircraft exercises2012In: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, ISSN 1757-7241, E-ISSN 1757-7241, Vol. 20, no 58Article in journal (Refereed)
    Abstract [en]

    Background

    Disaster medicine is a fairly young scientific discipline and there is a need for the development of new methods for evaluation and research. This includes full-scale disaster exercisers. A standardized concept on how to evaluate these exercises, could lead to easier identification of pitfalls caused by system-errors in the organization. The aim of this study was to demonstrate the feasibility of using a combination of performance and outcome indicators so that results can be compared in standardized full-scale exercises.

    Methods

    Two multidisciplinary, full-scale exercises were studied in 2008 and 2010. The panorama had the same setup. Sets of performance indicators combined with indicators for unfavorable patient outcome were recorded in predesigned templates. Evaluators, all trained in a standardized way at a national disaster medicine centre, scored the results on predetermined locations; at the scene, at hospital and at the regional command and control.

    Results

    All data regarding the performance indicators of the participants during the exercises were obtained as well as all data regarding indicators for patient outcome. Both exercises could therefore be compared regarding performance (processes) as well as outcome indicators. The data from the performance indicators during the exercises showed higher scores for the prehospital command in the second exercise 15 points and 3 points respectively. Results from the outcome indicators, patient survival and patient complications, demonstrated a higher number of preventable deaths and a lower number of preventable complications in the exercise 2010. In the exercise 2008 the number of preventable deaths was lower and the number of preventable complications was higher.

    Conclusions

    Standardized multidisciplinary, full-scale exercises in different settings can be conducted and evaluated with performance indicators combined with outcome indicators enabling results from exercises to be compared. If exercises are performed in a standardized way, results may serve as a basis for lessons learned. Future use of the same concept using the combination of performance indicators and patient outcome indicators may demonstrate new and important evidence that could lead to new and better knowledge that also may be applied during real incidents.

  • 220.
    Ragnarsson, Eva Ge
    et al.
    Uppsala University.
    Schoultz, Ida
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Gullberg, Elisabet
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Carlsson, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Tafazoli, Farideh
    Linköping University, Department of health and environment. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    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.
    Artursson, Per
    Uppsala University.
    Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis2008In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 88, no 11, p. 1215-1226Article in journal (Refereed)
    Abstract [en]

    Crohns disease is characterized by a defect in intestinal barrier function, where bacteria are considered the most important inflammation-driving factor. Enteric bacteria, including E. coli and Yersinia spp, affect tight junctions in enterocytes, but little is known about bacterial effects on the transcellular pathway. Our objective was to study the short-term effects of Y. pseudotuberculosis on uptake of nanoparticles across human villus epithelium. Monolayers of human colon epithelium-derived Caco-2 cells and biopsies of normal human ileum were studied after 2 h exposure to Y. pseudotuberculosis expressing (inv+) or lacking (inv-) the bacterial adhesion molecule, invasin. Transepithelial transport of fluorescent nanoparticles (markers of transcytosis) was quantified by flow cytometry, and mechanisms explored by using inhibitors of endocytosis. Epithelial expressions of beta 1-integrin and particle uptake pathways were studied by confocal microscopy. The paracellular pathway was assessed by electrical resistance (TER), mannitol flux, and expression of tight junction proteins occludin and caludin-4 by confocal microscopy. Inv + Y. pseudotuberculosis adhered to the apical surface of epithelial cells and induced transcytosis of exogenous nanoparticles across Caco-2 monolayers (30-fold increase, P < 0.01) and ileal mucosa (268 +/- 47% of control; P < 0.01), whereas inv-bacteria had no effect on transcytosis. The transcytosis was concentration-, particle size-and temperature-dependent, and possibly mediated via macropinocytosis. Y. pseudotuberculosis also induced apical expression of beta 1-integrin on epithelial cells. A slight drop in TER was seen after exposure to inv+ Y. pseudotuberculosis, whereas mannitol flux and tight junction protein expression was unchanged. In summary, Y. pseudotuberculosis induced apical expression of beta 1-integrin and stimulated uptake of nanoparticles via invasin-dependent transcytosis in human intestinal epithelium. Our findings suggest that bacterial factors may initiate transcytosis of luminal exogenous particles across human ileal mucosa, thus presenting a novel mechanism of intestinal barrier dysfunction.

  • 221.
    Redéen, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology.
    Chronic Gastritis: Diagnosis, natural history and consequences2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background & alms: The main cause of chronic gastritis is Helicobacter pylori (H. pylori). Clinical manifestations of chronic gastritis are ulcer disease, gastric cancer and mucosa-associated lymphoma tissue (MALT) lymphoma in the stomach. It is uncertain whether gastritis can be diagnosed macroscopically at endoscopy. H. pylori infection may be diagnosed by several different methods, the accuracy of which needs to be explored. Some individuals with H. pylori related chronic gastritis will develop atrophy of the gastric mucosa. This condition is the main risk factor for cancer development and may also be associated with vitamin B12 deficiency leading to hyperhomocysteinaemia. The natural history of chronic gastritis in terms of development of atrophy and ulcer disease in the adult general population is largely unknown.

    Material & methods: A sample of 50 I volunteers from the general population in the municipality of Linköping was examined with esophago-gastro-duodenoscopy (EGD) with biopsy. Blood samples were collected in the fasting state and the subjects answered a questionnaire about lifestyle factors, medications and disease history. In-hospital diagnoses and causes of death during follow-up of the population were extracted from local and national patient files. Re-examination was done in 314 subjects after a median follow-up interval of 8.4 years. Five diagnostic tests (serology UBT, RUT, culture and microscopic examination) for H. pylori infection were used at re-examination.

    Results: The best values of sensitivity and specificity were for visible vessels in relation to microscopic presence of severe atrophy in the gastric corpus mucosa (80% and 87%, respectively). There was a positive relation of S-homocysteine to male gender, age, S-cystatin C (renal function), methylenetetrahydrofolate reductase 677TT genotype and atrophic gastritis. Logistic regression analysis showed an association of S-homocysteine higher than 14.5 Ilmol/L to cardiovascular diseases (OR 2.05), but not to dementia overall.

    The incidence ofulcer was 0.45 per 100 person years and was associated with weekly NSAID use, weekly alcohol consumption (OR 19.4) and smoking (OR 31.0), but not with H. pylori status. Among subjects with chronic gastritis, the incidence of atrophy of the corpus mucosa was 1.4 per 100 person years. Considering diagnostic test for H. pylori infection the accuracy was 0.86 for serology, 0.94 for UBT, 0.94 for RUT, 0.93 for culture, and 0.93 for histological examination. There was a strong correlation between the results of UBT and the histological scores of H. pylori colonisation as well as between the results of UBT and scores of RUT.

    Conclusions: The occurrence of chronic gastritis or H. pylori infection is not evaluable macroscopically at gastroscopy, except for the absence of rugae or visible vessels in the gastric corpus mucosa. Serum Hcy concentrations are dependent on gender, age, the levels of vitamin B12 and folate, renal function, the occurrence of atrophic gastritis and the MTHFR 677 TT genotype. Elevated S-Hcy is a risk factor for cardiovascular disease. The incidence of atrophy of the corpus mucosa is 1.4 per 100 person years for chronic gastritis overall. Chronic gastritis with or without H. pylori infection is a variable process in which milder degrees of atrophy of the corpus mucosa may appear or disappear. In contrast, moderate-to-severe atrophy of the corpus mucosa rarely regresses. Age and the degree of chronic inflammation in the gastric corpus mucosa are major risk factors for the development of atrophy. The incidence of ulcer was 0.45 per 100 person years. There are only minor differences in accuracy between the three invasive tests for H. pylori infection. The UBT is recommended for situations where endoscopy is not required. RUT may be recommended as the first non-invasive method of choice in the diagnosis of H. pylori infection.

    List of papers
    1. Relationship of gastroscopic features to histological findings in gastritis and Helicobacter pylori infection in a general population sample
    Open this publication in new window or tab >>Relationship of gastroscopic features to histological findings in gastritis and Helicobacter pylori infection in a general population sample
    2003 (English)In: Endoscopy, ISSN 0013-726X, E-ISSN 1438-8812, Vol. 35, no 11, p. 946-950Article in journal (Refereed) Published
    Abstract [en]

    Background and study aim: Various gastroscopic features may be interpreted as signs of gastritis, but the significance of such features in relation to histomorphology is uncertain. The aim of this study was to determine how macroscopic findings were related to histomorphological changes and the presence of Helicobacter pylori in the gastric mucosa, in a sample of the general population. Subjects and methods: 488 adult individuals, randomly selected from a general population, were screened with gastroscopy and biopsy. The macroscopic features recorded were erythema (diffuse, spotty, linear), erosions, absence of rugae in the gastric corpus, and presence of visible vessels. Gastritis was classified microscopically according to the Sydney system. The presence of H. pylori was determined histologically and using the urease test on fresh biopsy specimens. Results: The sensitivity and specificity of absence of rugae for moderate to severe atrophic gastritis in the gastric corpus were 67% and 85%, respectively. Corresponding valuers for severe atrophy were 90% and 84%. The sensitivity and specificity of the presence of visible vessels for moderate to severe atrophy in the corpus were 48% and 87%, and for severe atrophy the values were 80% and 87%, respectively. Considering the antrum, the sensitivity and specificity of the presence of visible vessels for moderate to severe atrophy was 14% and 91%, respectively. With regard to chronic inflammation (moderate to severe in the corpus or antrum), none of the features, alone or in combination, showed a sensitivity of more than 56%. No endoscopic features (alone or in combination) showed a sensitivity of more than 57 % for H. pylori infection. Conclusions: Except for the absence of rugae and visible vessels in the gastric corpus, macroscopic features as observed during gastroscopy are of very limited value in the evaluation of whether or not gastritis or H. pylori infection are present. This is in accordance with most previous studies in patient populations, and it must be emphasized that the diagnosis of gastritis should be based on histological examination of the gastric mucosa.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24965 (URN)10.1055/s-2003-43479 (DOI)9376 (Local ID)9376 (Archive number)9376 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
    2. Homocysteine Levels in Chronic Gastritis and Other Conditions: Relations to Incident Cardiovascular Disease and Dementia
    Open this publication in new window or tab >>Homocysteine Levels in Chronic Gastritis and Other Conditions: Relations to Incident Cardiovascular Disease and Dementia
    Show others...
    2010 (English)In: DIGESTIVE DISEASES AND SCIENCES, ISSN 0163-2116, Vol. 55, no 2, p. 351-358Article in journal (Refereed) Published
    Abstract [en]

    Background Homocysteine levels in circulation are determined by several factors and hyperhomocysteinemia is reportedly associated with cardiovascular diseases and dementia. The aim of this study is to determine the relation of chronic gastritis and other conditions to homocysteine levels and their relation to incident cardiovascular diseases and dementia. Methods An adult population-based cohort (N = 488) was screened for H. pylori infection, gastro-duodenitis ( endoscopic biopsies), disease history, and lifestyle factors. Blood samples were analyzed for pepsinogen I and II ( gastric function), vitamin B12, folate, homocysteine, and cystatin C ( renal function). The methylenetetrahydrofolate reductase C677T polymorphism reportedly associated with hyperhomocysteinemia was analyzed by pyrosequencing. Incident cardiovascular diseases and dementia were monitored during a median follow-up interval of 10 years. Results At baseline, there was a positive relation of S-homocysteine to male gender, age, S-cystatin C, methylenetetrahydrofolate reductase 677TT genotype and atrophic gastritis. During follow-up, cardiovascular diseases occurred in 101/438 and dementia in 25/488 participants, respectively. Logistic regression analysis ( adjusting for gender, age at baseline, follow-up interval, BMI, smoking, alcohol consumption, NSAID use, P-cholesterol, and P-triglycerides) showed an association of S-homocysteine higher than 14.5 mu mol/l to cardiovascular diseases (OR 2.05 [95% c.i. 1.14-3.70]), but not to dementia overall. Conclusions Gender, age, vitamin B12, folate, renal function, atrophic gastritis and the methylenetetrahydrofolate 677TT genotype were significant determinants of homocysteine levels, which were positively related to incident cardiovascular diseases.

    Keywords
    Atrophic gastritis, Cardiovascular disease, Cohort, Cystatin C, Dementia, Folate, Gastritis, Homocysteine, H. pylori, Pepsinogen, Vitamin B12
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-53694 (URN)10.1007/s10620-009-0761-0 (DOI)
    Available from: 2010-02-01 Created: 2010-02-01 Last updated: 2019-06-27
    3. Natural history of chronic gastritis in a population-based cohort
    Open this publication in new window or tab >>Natural history of chronic gastritis in a population-based cohort
    Show others...
    2010 (English)In: SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, ISSN 0036-5521, Vol. 45, no 5, p. 540-549Article in journal (Refereed) Published
    Abstract [en]

    Objective. To describe and explore the natural history of Helicobacter pylori infection and chronic gastritis in terms of gastric mucosal atrophy and ulcer development over time in a population-based cohort. Material and methods. A population-based cohort of 314 volunteers was re-screened (median follow-up interval of 8.4 years) with gastroduodenoscopy with biopsy, assessment of H. pylori status, analysis of pepsinogens, and monitoring of a nonsteroidal anti-inflammatory drug (NSAID) use and alcohol and smoking habits. Results. The incidence of duodenal or prepyloric ulcer was 0.45 per 100 person years and was associated with weekly NSAID use (odds ratios, OR 27.8), weekly alcohol consumption (OR 19.4) and smoking (OR 31.0), but not with H. pylori status. De novo infection with H. pylori was not observed, and the infection had disappeared in 11 of 113 subjects. Among subjects with chronic gastritis, the incidence of atrophy of the corpus mucosa was 1.4 per 100 person years. Atrophy development was related to age (OR 1.23) and to the severity of chronic inflammation in the corpus mucosa at baseline (OR 8.98). Substituting atrophy for subnormal S-pepsinogen I/S-pepsingen II gave similar results. Conclusions. In this cohort, the minimum incidence of ulcer was 0.45 per 100 person years. Smoking, alcohol, and NSAIDs, but not H. pylori infection were significant risk factors. The incidence of atrophy of the corpus mucosa was 1.4 per 100 person years with a positive relation to age and to the degree of chronic inflammation at baseline. Atrophy was stationary in advanced stages.

    Place, publisher, year, edition, pages
    Taylor and Francis, 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-56293 (URN)10.3109/00365521003624151 (DOI)000276897600005 ()
    Note
    This is an electronic version of an article published in: Stefan Redéen, Fredrik Petersson, Stergios Kechagias, Erik Mårdh and Kurt Borch, Natural history of chronic gastritis in a population-based cohort, 2010, SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, (45), 5, 540-549. SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY is available online at informaworldTM: http://dx.doi.org/10.3109/00365521003624151 Copyright: Taylor and Francis http://www.tandf.co.uk/journals/default.asp Available from: 2010-05-07 Created: 2010-05-07 Last updated: 2010-05-29
    4. Reliability of diagnostic tests for Helicobacter pylori infection
    Open this publication in new window or tab >>Reliability of diagnostic tests for Helicobacter pylori infection
    Show others...
    2011 (English)In: Gastroenterology Research and Practice, ISSN 1687-6121, E-ISSN 1687-630X, Vol. 2011, no 940650Article in journal (Refereed) Published
    Abstract [en]

    Introduction: Helicobacter pylori (H.pylori) infection is very common worldwide. A reliable diagnosis is crucial for patients with H.pylori related diseases. At follow-up it is important to confirm that eradication therapy has been successful. There is no established gold standard for the diagnosis of H.pylori infection.

    Material and Methods: A sample of 304 volunteers from the general population was screened for H.pylori infection with serology, 13C-urea breath test (UBT), rapid urease test (RUT) on fresh biopsy, culture from biopsy and histological examination. Each method was tested against the other methods (except serology) taken together as gold standard.

    Result: The sensitivity was 0.99 for serology 0.92 for UBT, 0.96 for RUT, 0.99 for culture and 0.95 for histological examination. Corresponding specificities were 0.82, 0.94, 0.93, 0.90 and 0.92, respectively. The accuracy was 0.86 for serology, 0.94 for UBT, 0.94 for RUT, 0.93 for culture and 0.93 for histology. There was a strong correlation between the results of UBT and histological scores for H.pylori colonization as well as between the results of UBT and the scores of RUT.

    Conclusion: There were only minor differences in accuracy between three invasive tests for H.pylori infection in this population. RUT may be recommended as first choice since a result is obtained within hours. The accuracy of UBT was comparable to the invasive tests and it is recommended for situations when endoscopy is not needed.

    Place, publisher, year, edition, pages
    Hindawi, 2011
    Keywords
    Accuracy, diagnosis, diagnostic test, gold standard, H. pylori, sinsitivity, specificity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-56574 (URN)10.1155/2011/940650 (DOI)000295641000001 ()
    Note
    Funding agencies|Swedish Cancer Society||Research Council in the South East of Sweden (FORSS)||Available from: 2010-05-25 Created: 2010-05-25 Last updated: 2017-12-12
  • 222.
    Redéen, Stefan
    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.
    Petersson, Fredrik
    National University Health System, Singapore.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Mårdh, Erik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. 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.
    Natural history of chronic gastritis in a population-based cohort2010In: SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, ISSN 0036-5521, Vol. 45, no 5, p. 540-549Article in journal (Refereed)
    Abstract [en]

    Objective. To describe and explore the natural history of Helicobacter pylori infection and chronic gastritis in terms of gastric mucosal atrophy and ulcer development over time in a population-based cohort. Material and methods. A population-based cohort of 314 volunteers was re-screened (median follow-up interval of 8.4 years) with gastroduodenoscopy with biopsy, assessment of H. pylori status, analysis of pepsinogens, and monitoring of a nonsteroidal anti-inflammatory drug (NSAID) use and alcohol and smoking habits. Results. The incidence of duodenal or prepyloric ulcer was 0.45 per 100 person years and was associated with weekly NSAID use (odds ratios, OR 27.8), weekly alcohol consumption (OR 19.4) and smoking (OR 31.0), but not with H. pylori status. De novo infection with H. pylori was not observed, and the infection had disappeared in 11 of 113 subjects. Among subjects with chronic gastritis, the incidence of atrophy of the corpus mucosa was 1.4 per 100 person years. Atrophy development was related to age (OR 1.23) and to the severity of chronic inflammation in the corpus mucosa at baseline (OR 8.98). Substituting atrophy for subnormal S-pepsinogen I/S-pepsingen II gave similar results. Conclusions. In this cohort, the minimum incidence of ulcer was 0.45 per 100 person years. Smoking, alcohol, and NSAIDs, but not H. pylori infection were significant risk factors. The incidence of atrophy of the corpus mucosa was 1.4 per 100 person years with a positive relation to age and to the degree of chronic inflammation at baseline. Atrophy was stationary in advanced stages.

  • 223.
    Redéen, Stefan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Petersson, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Törnkrantz, E.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery.
    Levander, H.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery.
    Mårdh, Erik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. 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 for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Reliability of diagnostic tests for Helicobacter pylori infection2011In: Gastroenterology Research and Practice, ISSN 1687-6121, E-ISSN 1687-630X, Vol. 2011, no 940650Article in journal (Refereed)
    Abstract [en]

    Introduction: Helicobacter pylori (H.pylori) infection is very common worldwide. A reliable diagnosis is crucial for patients with H.pylori related diseases. At follow-up it is important to confirm that eradication therapy has been successful. There is no established gold standard for the diagnosis of H.pylori infection.

    Material and Methods: A sample of 304 volunteers from the general population was screened for H.pylori infection with serology, 13C-urea breath test (UBT), rapid urease test (RUT) on fresh biopsy, culture from biopsy and histological examination. Each method was tested against the other methods (except serology) taken together as gold standard.

    Result: The sensitivity was 0.99 for serology 0.92 for UBT, 0.96 for RUT, 0.99 for culture and 0.95 for histological examination. Corresponding specificities were 0.82, 0.94, 0.93, 0.90 and 0.92, respectively. The accuracy was 0.86 for serology, 0.94 for UBT, 0.94 for RUT, 0.93 for culture and 0.93 for histology. There was a strong correlation between the results of UBT and histological scores for H.pylori colonization as well as between the results of UBT and the scores of RUT.

    Conclusion: There were only minor differences in accuracy between three invasive tests for H.pylori infection in this population. RUT may be recommended as first choice since a result is obtained within hours. The accuracy of UBT was comparable to the invasive tests and it is recommended for situations when endoscopy is not needed.

  • 224.
    Redéen, Stefan
    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.
    Ryberg, Anna
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Petersson, Fredrik
    Ryhov Hospital.
    Eriksson, Olle
    Linköping University, Department of Computer and Information Science, Statistics. Linköping University, Faculty of Arts and Sciences.
    Nägga, Katarina
    Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    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.
    Homocysteine Levels in Chronic Gastritis and Other Conditions: Relations to Incident Cardiovascular Disease and Dementia2010In: DIGESTIVE DISEASES AND SCIENCES, ISSN 0163-2116, Vol. 55, no 2, p. 351-358Article in journal (Refereed)
    Abstract [en]

    Background Homocysteine levels in circulation are determined by several factors and hyperhomocysteinemia is reportedly associated with cardiovascular diseases and dementia. The aim of this study is to determine the relation of chronic gastritis and other conditions to homocysteine levels and their relation to incident cardiovascular diseases and dementia. Methods An adult population-based cohort (N = 488) was screened for H. pylori infection, gastro-duodenitis ( endoscopic biopsies), disease history, and lifestyle factors. Blood samples were analyzed for pepsinogen I and II ( gastric function), vitamin B12, folate, homocysteine, and cystatin C ( renal function). The methylenetetrahydrofolate reductase C677T polymorphism reportedly associated with hyperhomocysteinemia was analyzed by pyrosequencing. Incident cardiovascular diseases and dementia were monitored during a median follow-up interval of 10 years. Results At baseline, there was a positive relation of S-homocysteine to male gender, age, S-cystatin C, methylenetetrahydrofolate reductase 677TT genotype and atrophic gastritis. During follow-up, cardiovascular diseases occurred in 101/438 and dementia in 25/488 participants, respectively. Logistic regression analysis ( adjusting for gender, age at baseline, follow-up interval, BMI, smoking, alcohol consumption, NSAID use, P-cholesterol, and P-triglycerides) showed an association of S-homocysteine higher than 14.5 mu mol/l to cardiovascular diseases (OR 2.05 [95% c.i. 1.14-3.70]), but not to dementia overall. Conclusions Gender, age, vitamin B12, folate, renal function, atrophic gastritis and the methylenetetrahydrofolate 677TT genotype were significant determinants of homocysteine levels, which were positively related to incident cardiovascular diseases.

  • 225.
    Ringberg, A.
    et al.
    Department of Plastic Surgery, Malmö University Hospital, Malmö, Sweden.
    Nordgren, H.
    Department of Pathology, University Hospital, Uppsala, Sweden.
    Thorstensson, S.
    Department of Pathology, Central Hospital, Kalmar, Sweden.
    Idvall, I.
    Department of Pathology, Malmö University Hospital, Malmö, Sweden.
    Garmo, H.
    Regional Oncologic Center, University Hospital, Uppsala, Sweden.
    Granstrand, B.
    Department of Surgery, Norrland University Hospital, Umeå, Sweden.
    Arnesson, Lars-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.
    Sandelin, K.
    Department of Surgery, Karolinska Hospital, Stockholm, Sweden.
    Wallgren, A.
    Department of Oncology, Sahlgenska University Hospital, Gothenburg, Sweden.
    Anderson, H.
    Regional Oncologic Center, University Hospital, Lund, Sweden.
    Emdin, S.
    Department of Surgery, Norrland University Hospital, Umeå, Sweden.
    Holmberg, L.
    Regional Oncologic Center, University Hospital, Uppsala, Sweden.
    Histopathological risk factors for ipsilateral breast events after breast conserving treatment for ductal carcinoma in situ of the breast - Results from the Swedish randomised trial2007In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 43, no 2, p. 291-298Article in journal (Refereed)
    Abstract [en]

    Aim: The primary aims were to study risk factors for an ipsilateral breast event (IBE) after sector resection for ductal carcinoma in situ of the breast (DCIS) in a trial comparing adjuvant radiotherapy to no therapy and to assess predictive factors for response to radiotherapy. Secondary aims were to analyse reproducibility of the histopathological evaluation and to estimate correctness of diagnosis in the trial. Setting: A randomised trial in Sweden (the SweDCIS trial), including 1046 women with a median of 5.2 years of follow-up in a population, offered routine mammographic screening. Methods: A case-cohort design with a total of 161 cases of IBE (42 of those being members of the subcohort) and 284 sampled for the sub-cohort. Ninety five percent of the participants' slides could be retrieved and were re-evaluated by three experienced pathologists. Results: Low nuclear grade (NG 1-2) and absence of necrosis halves the risk of IBE in both irradiated and non-irradiated patients. Lesion size, margins of excision and age at diagnosis did not modify these associations. The presence of necrosis modified the effect of radiotherapy: relative risk was 0.40 with necrosis present and 0.07 with necrosis absent (p-value for interaction 0.068). In all subsets of prognostic factors, radiotherapy conferred a substantial benefit. The risk factors for in situ and invasive IBE were similar. The agreement between pathologists was moderate (? = 0.486). Correctness of diagnosis in the subcohort of SweDCIS was 84.8%. Conclusion: Although nuclear grade and necrosis carry prognostic information, we could not define a group with very low risk after sector resection alone. Radiotherapy has a protective effect in all substrata of risk factors studied. The interaction between the presence of necrosis and radiotherapy is a clinically and biologically relevant research area. © 2006 Elsevier Ltd. All rights reserved.

  • 226.
    Roberts, Carol L
    et al.
    University of Liverpool.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Duncan, Sylvia H
    University of Aberdeen.
    O'Kennedy, Niamh
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Dabrosin Söderholm, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Rhodes, Jonathan M
    University of Liverpool.
    Campbell, Barry J
    University of Liverpool.
    Translocation of Crohns disease Escherichia coli across M-cells: contrasting effects of soluble plant fibres and emulsifiers2010In: GUT, ISSN 0017-5749, Vol. 59, no 10, p. 1331-1339Article in journal (Refereed)
    Abstract [en]

    Background Crohns disease is common in developed nations where the typical diet is low in fibre and high in processed food. Primary lesions overlie Peyers patches and colonic lymphoid follicles where bacterial invasion through M-cells occurs. We have assessed the effect of soluble non-starch polysaccharide (NSP) and food emulsifiers on translocation of Escherichia coli across M-cells. Methods To assess effects of soluble plant fibres and food emulsifiers on translocation of mucosa-associated E coli isolates from Crohns disease patients and from non-Crohns controls, we used M-cell monolayers, generated by co-culture of Caco2-cl1 and Raji B cells, and human Peyers patches mounted in Ussing chambers. Results E coli translocation increased across M-cells compared to parent Caco2-cl1 monocultures; 15.8-fold (IQR 6.2-32.0) for Crohns disease E coli (N=8) and 6.7-fold (IQR 3.7-21.0) for control isolates (N=5). Electronmicroscopy confirmed E coli within M-cells. Plantain and broccoli NSP markedly reduced E coli translocation across M-cells at 5 mg/ml (range 45.3-82.6% inhibition, pandlt;0.01); apple and leek NSP had no significant effect. Polysorbate-80, 0.01% vol/vol, increased E coli translocation through Caco2-cl1 monolayers 59-fold (pandlt;0.05) and, at higher concentrations, increased translocation across M-cells. Similarly, E coli translocation across human Peyers patches was reduced 45+/-7% by soluble plantain NSP (5 mg/ml) and increased 2-fold by polysorbate-80 (0.1% vol/vol). Conclusions Translocation of E coli across M-cells is reduced by soluble plant fibres, particularly plantain and broccoli, but increased by the emulsifier Polysorbate-80. These effects occur at relevant concentrations and may contribute to the impact of dietary factors on Crohns disease pathogenesis.

  • 227. Roberts, Carol L.
    et al.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Parsons, Bryony N.
    University of Liverpool, England .
    Prorok-Hamon, Maelle
    University of Liverpool, England .
    Knight, Paul
    University of Liverpool, England .
    Winstanley, Craig
    University of Liverpool, England .
    O´Kennedy, Niamh
    Provexis Plc, Aberdeen, UK.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Rhodes, Jonathan M.
    University of Liverpool, England .
    Campbell, Barry J.
    University of Liverpool, England .
    Soluble plantain fibre blocks adhesion and M-cell translocation of intestinal pathogens2013In: Journal of Nutritional Biochemistry, ISSN 0955-2863, E-ISSN 1873-4847, Vol. 24, no 1, p. 97-103Article in journal (Refereed)
    Abstract [en]

    Dietary fibres may have prebiotic effects mediated by promotion of beneficial bacteria. This study explores the possibility that soluble plant fibre may also improve health by inhibiting epithelial adhesion and translocation by pathogenic bacteria. We have focussed on soluble non-starch polysaccharide (NSP) from plantain bananas (Musa spp.) which previous studies showed to be particularly effective at blocking Escherichia coli epithelial adherence. In vitro and ex vivo studies assessed the ability of plantain NSP to inhibit epithelial cell adhesion and invasion of various bacterial pathogens, and to inhibit their translocation through microfold (M)-cells and human Peyers patches mounted in Ussing chambers. Plantain NSP showed dose-related inhibition of epithelial adhesion and M-cell translocation by a range of pathogens. At 5 mg/ml, a concentration readily achievable in the gut lumen, plantain NSP inhibited adhesion to Caco2 cells by Salmonella Typhimurium (85.0 +/- 8.2%, Pandlt;.01), Shigella sonnei (46.6 +/- 29.3%. Pandlt;.01), enterotoxigenic E.coli (56.1 +/- 23.7%, Pandlt;.05) and Clostridium difficile (67.6 +/- 12.3%, Pandlt;.001), but did not inhibit adhesion by enteropathogenic E.coli. Plantain NSP also inhibited invasion of Caco2 cells by S. Typhimurium (80.2 +/- 9.7%) and Sh. sonnei (46.7 +/- 13.4%); Pandlt;.01. Plantain NSP, 5 mg/ml, also inhibited translocation of S. Typhimurium and Sh. sonnei across M-cells by 73.3 +/- 5.2% and 46.4 +/- 7.7% respectively (Pandlt;.05). Similarly, S. Typhimurium translocation across Peyers patches was reduced 65.9 +/- 8.1% by plantain NSP (Pandlt;.01). Soluble plantain fibre can block epithelial adhesion and M-cell translocation of intestinal pathogens. This represents an important novel mechanism by which soluble dietary fibres can promote intestinal health and prevent infective diarrhoea. Crown Copyright

  • 228. Roberts, CT
    et al.
    Kind, KL
    Earl, RA
    Grant, PA
    Robinson, JS
    Sohlström, Annica
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Owens, PC
    Owens, JA
    Circulating insulin-like growth factor (IGF)-I and IGF binding proteins-1 and-3 and placental development in the guinea-pig2002In: Placenta, ISSN 0143-4004, E-ISSN 1532-3102, Vol. 23, no 10, p. 763-770Article in journal (Refereed)
    Abstract [en]

    Restricting maternal nutrition before and throughout pregnancy in the guinea-pig restricts foetal growth in part by altering placental structural determinants of substrate transfer function. The insulin-like growth factors ha c been implicated in mediating these changes. To assess the role of IGF-I in placental adaptation to maternal undernutrition, we examined the associations of circulating IGF-I and IGF binding proteins - 1, -3 and -4 in the mother with placental structural development. In both mid- and late pregnancy, maternal food restriction reduced maternal plasma IGF-I by 56 per cent (P<0.0005) and 50 per cent (P<0.0005) respectively, and plasma IGFBP-3 by 47 per cent (P=0.03) and 55 per cent (P=0.002), respectively. Maternal plasma IGFBP-4 was reduced by 45 per cent (P=0.041) in food restricted guinea-pigs in mid-pregnancy but not late in pregnancy, while IGFBP-I was unaltered at both stages. Late in pregnancy, food restriction reduced the ratio of maternal circulating IGF-I to IGFBP-I by 52 per cent (P=0.011) and increased the ratio of IGF-I to IGFBP-3 in maternal plasma by 10 per cent (P=0.011). The relationships between the maternal IGF axis and structural correlates of placental function were assessed using pooled data from both ad libitum fed and food restricted animals. In mid-pregnancy, the volume density of the maternal blood space in the placental labyrinth correlated positively with both maternal plasma IGF-1 and IGFBP-3, while maternal blood space volume correlated negatively with maternal plasma IGF-I and IGFBP-3, while maternal blood spacevolume correlated positively with both maternal plasma negatively with maternal plasma IGFBP-1. In late preg IGF-1 and IGFBP-4, while the surface area of syncytiotrophoblast and weight of trophoblast correlated positively, and mean syncytiotrophoblast thickness negatively, with maternal plasma IGF-I. Late in pregnancy, the volume density and weight of svncytrotrophoblast, the surface density and total surface area of trophoblast and the volume of the maternal blood space each correlated positively, and syncytiotrophoblast)last thickness correlated negatively with maternal plasma IGFBP-3. Concomitantly, placental weight, placental diameter, placental volume, volume density and weight of syncytiotrophoblast, weight of foetal capillaries, syncytiotrophoblast surface density and total syncytiotrophoblast surface area in the placental labyrinth, each correlated positively with the ratio of IGF-I to IGFBP-1 in maternal plasma, while syncytiotrophoblast thickness correlated negatively with this ratio. In late pregnancy therefore, increased trophoblast abundance and placental vascularity, and a reduced barrier to diffusion between maternal and foetal blood, occurs in association with increased abundance of IGF-I and its major carrier, IGFBP-3, and a reduction in that of IGFBP-I in maternal blood in the guinea-pig. This suggests that systemic IGF-I and modulation of its bioavailability by IGFBPs -1 and -3 N within the mother may influence placental growth and differentiation in an endocrine fashion, particularly when nutrition is limited. (C) 2002 Elsevier Science Ltd. All rights reserved.

  • 229.
    Rubér, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Immunopathogenic aspects of resolving and progressing appendicitis2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Appendicitis is one of the most common diseases requiringemergency surgical intervention. There are several indications that the diagnosisappendicitis harbours two different entities, one progressing to gangrene and perforation(advanced) and one that resolves spontaneously (phlegmonous). An immunologically drivenpathogenesis in appendicitis has been suggested on the basis of an inverse relationshipbetween appendicitis and ulcerative colitis, a positive association with Crohn’s disease, anda decreased incidence during pregnancy, generating the hypothesis that theimmunopathogenesis in advanced appendicitis is characterized by a Th1 inflammatoryresponse. The aim of this thesis was to test this hypothesis and investigate the immuneresponse in advanced and phlegmonous appendicitis.

    Material and Methods: The immunologic response was investigated in appendicitis tissue and compared to the immunological response in peripheral blood, analysed by enzyme-linked immunospot assay (ELISPOT). The response pattern was also investigated in patients with an actual appendicitis in the peripheral plasma and peripheral serum before surgery, analysed with Luminex. The immunological response pattern was investigated in peripheral blood several months to years after an appendectomy using ELISPOT and enzyme-linked immunosorbent assay (ELISA).

    Results: The local immune response in the appendiceal tissue in appendicitis was similar to the response in peripheral blood. Patients with actual advanced appendicitis had increased levels of IL-6, CCL20, CCL2, TGF-β, IL-17, IFN-γ, IL-12p70, IL-10, IL-1ra, IL-4, MMP-8, MMP-9 and MPO compared with those with phlegmonous appendicitis. Sex, age or duration of symptoms could not explain the differences between the groups. Individuals with a history of advanced appendicitis had increased secretion of IFN-γ months to years after the appendectomy compared with individuals with a history of phlegmonous appendicitis.

    Conclusions: The local immune response in the appendiceal tissue is mirrored in the blood, which justifies the use of peripheral blood in studies on appendicitis. The immunological response pattern in peripheral blood suggests Th1/Th17- induced inflammation in advanced appendicitis that is present at an early stage. Individuals with a history of advanced appendicitis have stronger Th1 responses than individuals with a history of phlegmonous appendicitis. This may reflect constitutional differences between patients with different outcomes of appendicitis. The increased inflammatory response observed early in advanced appendicitis suggests a more violent inflammation and supports the hypothesis of different immune pathogeneses, where excessive induction of Th1/Th17 immunity and/or deficiencies in down-regulatory feedback mechanisms may explain the excessive inflammation in advanced appendicitis, where the inflammation eventuates in gangrene and perforation.

    List of papers
    1. Different cytokine profiles in patients with a history of gangrenous or phlegmonous appendicitis
    Open this publication in new window or tab >>Different cytokine profiles in patients with a history of gangrenous or phlegmonous appendicitis
    Show others...
    2006 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 143, no 1, p. 117-124Article in journal (Refereed) Published
    Abstract [en]

    Appendicitis is one of the most common and costly acute abdominal states of illnesses. Previous studies suggest two types of appendicitis which may be different entities, one which may resolve spontaneously and another that progresses to gangrene and perforation. Gangrenous appendicitis has a positive association to states of Th1 mediated immunity whereas Th2 associated immune states are associated with lower risk of appendicitis. This study investigated the inflammatory response pattern in patients previously appendicectomized for gangrenous (n = 7), or phlegmonous appendicitis (n = 8) and those with a non-inflamed appendix (n = 5). Peripheral blood mononuclear cells were analysed with ELISPOT analysis for number of spontaneous or antigen/mitogen stimulated IFN-γ, IL-4, IL-10 and IL-12 secreting cells or with ELISA for concentration of spontaneous or antigen/mitogen stimulated IFN-γ, IL-5 and IL-10. Spontaneously IL-10 secreting cells/100 000 lymphocytes were increased in the gangrenous group compared to the phlegmonous group (P = 0.015). The median concentration of IL-10 secreted after Tetanus toxoid (TT)-stimulation were higher in the gangrenous group and the control group, than the phlegmonous group (P = 0.048 and P = 0.027, respectively). The median concentration of TT induced IFN-γ secretion was higher for the gangrenous group compared to both the phlegmonous group and the control group (P = 0.037 and P = 0.003). Individuals with a history of gangrenous appendicitis demonstrated ability to increased IL-10 and IFN-γ production. The increased IFN-γ may support the notion of gangrenous appendicitis as an uncontrolled Th1 mediated inflammatory response and increased IL-10 may speculatively indicate the involvement of cytotoxic cells in the progression to perforation. © 2005 British Society for Immunology.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-37618 (URN)10.1111/j.1365-2249.2005.02957.x (DOI)36747 (Local ID)36747 (Archive number)36747 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
    2. Systemic Th17-like cytokine pattern in gangrenous appendicitis but not in phlegmonous appendicitis
    Open this publication in new window or tab >>Systemic Th17-like cytokine pattern in gangrenous appendicitis but not in phlegmonous appendicitis
    Show others...
    2010 (English)In: SURGERY, ISSN 0039-6060, Vol. 147, no 3, p. 366-372Article in journal (Refereed) Published
    Abstract [en]

    Background. Increasing circumstantial evidence suggests that not all patients with appendicitis will progress to perforation and that appendicitis that resolves may be a common event. Based on this theory and on indications of aberrant regulation of inflammation in gangrenous appendicitis, we hypothesized that. phlegmonous and gangrenous appendicitis are different entities with divergent immunoregulation. Methods. Blood samples were collected from patients with gangrenous appendicitis (n = 16), phlegmonous appendicitis (n = 21), and nonspecific abdominal pain (n = 42). Using multiplex bead arrays, we analyzed a range of inflammatory markers, such as interleukin (IL)-1ra, IL-1r beta, IL-2 IL-6, IL-10, IL-12p70, IL-15, and IL-17; interferon-gamma; tumor necrosis factor; CXCL8; CCL2; CCL3; and matrix metalloproteinase (MMP)-1 MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, and MMP-13 in blood. Results. Compared with patients with phlegmonous appendicitis and nonspecific abdominal pain, the patients With gangrenous appendicitis had increased levels of the proinflammatory markers IL-6, CCL2, IL-17, MMP-8, and MMP-9 (P andlt;= .04 each) accompanied by increased levels of the anti-inflammatory cytokines IL-1ra and IL-10 (P andlt;= .02). Patients with phlegmonous appendicitis had increased levels of IL-10 only. Conclusion. The finding of a pattern inflammatory markers compatible with the highly inflammatory A 17 subset in sera from, patients with gangrenous appendicitis, but not in phlegmonous appendicitis, supports the hypothesis that gangrenous and phlegmonous appendicitis are different entities with diver gent immune regulation. Additional studies of the differential immunopathogenesis of phlegmonous and gangrenous appendicitis are warranted, as this may have important implications in the diagnosis and management of patients with suspicion of appendicitis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-54601 (URN)10.1016/j.surg.2009.09.039 (DOI)000275350700007 ()
    Available from: 2010-03-26 Created: 2010-03-26 Last updated: 2013-08-29
    3. Dysregulated Th1/Th17 response in advanced appendicitis
    Open this publication in new window or tab >>Dysregulated Th1/Th17 response in advanced appendicitis
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: The pathogenesis of appendicitis, the most common abdominal emergency for surgical intervention, is still unknown. Epidemiological differences between perforated and nonperforated appendicitis, polymorphism in the interleukin (IL)-6 gene associated with severity of appendicitis and a more pronounced Th1/Th17-like deviation in advanced compared to phlegmonous appendicitis has been reported. Altogether these findings may indicate that appendicitis harbours two different entities with different immuno-pathogenesis, one progressing to gangrene and perforation and one resolving. In this study we aimed to further investigate systemic cytokine profiles in a large sample of patients, with advanced and phlegmonous appendicitis from a Th1, Th2, Th17 and innate perspective, and also clarify if time as duration of symptoms could explain the differences.

    Methods: Blood samples were preoperatively collected from patients with advanced (n=61) and phlegmonous appendicitis (n=108). The Th1-associated (IFN-γ, IL-12p70), Th2-associated (IL-4, IL-5), Th17-associated (IL-17, IL-6, CCL20, CCL2) and innate-associated (IL-1β, IL-6, MPO, CXCL8, GM-CSF), markers were analyzed in plasma using multiplex bead assay.

    Results: Patients with advanced appendicitis had increased levels of IL-6 (P=0.0001), CCL2 (P=0.001), MPO (P=0.039), IL-12p70 (P=0.010) and CCL20 (P=0.002) as compared to phlegmonous appendicitis and age, sex or duration of symptoms at sampling could not explain the differences.

    Conclusion: The findings suggest a dysregulated Th1/Th17 type inflammation in advanced appendicitis, already early in the disease course, that eventuates in gangrene and perforation and gives further support to the notion of appendicitis as two entities.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-80373 (URN)
    Available from: 2012-08-24 Created: 2012-08-24 Last updated: 2012-08-24Bibliographically approved
    4. Local and systemic cytokine secretion in advanced and phlegmonous appendicitis
    Open this publication in new window or tab >>Local and systemic cytokine secretion in advanced and phlegmonous appendicitis
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Appendicitis is the most common abdominal emergency for surgery, but its underlying pathogenesis is still unknown. Appendicitis most likely harbors two different entities with different pathogenesis, one progressing to gangrene and perforation and one resolving. Previous studies on cytokines in peripheral blood points to different immunopathogenesis in advanced and resolving appendicitis. The relation of the peripheral blood analyzes to the local immune response in appendix is unclear. This study investigated local immune response in the appendix compared to blood, utilizing enzyme linked immunospot essay (ELISpot) which allows detection of low grade cytokine secretion from single cells.

    Methods: Appendiceal tissue and blood samples were collected from patients with advanced (gangrenous or perforated) (n=11) and phlegmonous appendicitis (n=7). Mononuclear cells were analyzed with ELISpot for number of spontaneous and PHA stimulated IFN-γ-, IL-12p70-(both Th1), IL-4-(Th2), IL-17-(Th17), TGF-β-(anti-inflammatory/Th17) and IL-10-(anti-inflammatory/Th1) secreting cells.

    Results: In appendix, the number of IL-4-(P=0.042) and IL-10-(P=0.042) secreting cells was increased in advanced appendicitis as compared to phlegmonous and a trend for increase was observed for IL-12p70 (P=0.055) and TGF-β (P=0.067). In blood the number of IL-4-(P=0.045), TGF-β-(P=0.007) and IFN-γ-(P=0.019), secreting cells were increased in patients with advanced appendicitis and a trend for increase was observed for IL-12p70 (P=0.068)

    Conclusion: Present findings are in line with previous studies demonstrating an increased inflammatory response in advanced as compared to phlegmonous appendicitis. The local immune response in the appendiceal tissue is mirrored in the blood, which justifies the use of analyzes on peripheral blood when investigating immune response in appendicitis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-80374 (URN)
    Available from: 2012-08-24 Created: 2012-08-24 Last updated: 2012-08-24Bibliographically approved
  • 230.
    Rubér, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Andersson, Manne
    Unit for Autoimmunity and Immune regulation, County hospital Ryhov, Jönköping, Sweden.
    Olaison, Gunnar
    Copenhagen University, Faculty of Health Sciences, Department of Surgery, Hospital Nord, Holbæk, Denmark.
    Andersson, Roland E
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Ekerfelt, Christina
    Unit for Autoimmunity and Immune regulation, County hospital Ryhov, Jönköping, Sweden.
    Dysregulated Th1/Th17 response in advanced appendicitisManuscript (preprint) (Other academic)
    Abstract [en]

    Background: The pathogenesis of appendicitis, the most common abdominal emergency for surgical intervention, is still unknown. Epidemiological differences between perforated and nonperforated appendicitis, polymorphism in the interleukin (IL)-6 gene associated with severity of appendicitis and a more pronounced Th1/Th17-like deviation in advanced compared to phlegmonous appendicitis has been reported. Altogether these findings may indicate that appendicitis harbours two different entities with different immuno-pathogenesis, one progressing to gangrene and perforation and one resolving. In this study we aimed to further investigate systemic cytokine profiles in a large sample of patients, with advanced and phlegmonous appendicitis from a Th1, Th2, Th17 and innate perspective, and also clarify if time as duration of symptoms could explain the differences.

    Methods: Blood samples were preoperatively collected from patients with advanced (n=61) and phlegmonous appendicitis (n=108). The Th1-associated (IFN-γ, IL-12p70), Th2-associated (IL-4, IL-5), Th17-associated (IL-17, IL-6, CCL20, CCL2) and innate-associated (IL-1β, IL-6, MPO, CXCL8, GM-CSF), markers were analyzed in plasma using multiplex bead assay.

    Results: Patients with advanced appendicitis had increased levels of IL-6 (P=0.0001), CCL2 (P=0.001), MPO (P=0.039), IL-12p70 (P=0.010) and CCL20 (P=0.002) as compared to phlegmonous appendicitis and age, sex or duration of symptoms at sampling could not explain the differences.

    Conclusion: The findings suggest a dysregulated Th1/Th17 type inflammation in advanced appendicitis, already early in the disease course, that eventuates in gangrene and perforation and gives further support to the notion of appendicitis as two entities.

  • 231.
    Rubér, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Andersson, Manne
    County Hospital Ryhov.
    Petersson, B Fredrik
    Karolinska University Hospital.
    Olaison, Gunnar
    University of Copenhagen.
    Andersson, Roland
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Ekerfelt, Christina
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Systemic Th17-like cytokine pattern in gangrenous appendicitis but not in phlegmonous appendicitis2010In: SURGERY, ISSN 0039-6060, Vol. 147, no 3, p. 366-372Article in journal (Refereed)
    Abstract [en]

    Background. Increasing circumstantial evidence suggests that not all patients with appendicitis will progress to perforation and that appendicitis that resolves may be a common event. Based on this theory and on indications of aberrant regulation of inflammation in gangrenous appendicitis, we hypothesized that. phlegmonous and gangrenous appendicitis are different entities with divergent immunoregulation. Methods. Blood samples were collected from patients with gangrenous appendicitis (n = 16), phlegmonous appendicitis (n = 21), and nonspecific abdominal pain (n = 42). Using multiplex bead arrays, we analyzed a range of inflammatory markers, such as interleukin (IL)-1ra, IL-1r beta, IL-2 IL-6, IL-10, IL-12p70, IL-15, and IL-17; interferon-gamma; tumor necrosis factor; CXCL8; CCL2; CCL3; and matrix metalloproteinase (MMP)-1 MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, and MMP-13 in blood. Results. Compared with patients with phlegmonous appendicitis and nonspecific abdominal pain, the patients With gangrenous appendicitis had increased levels of the proinflammatory markers IL-6, CCL2, IL-17, MMP-8, and MMP-9 (P andlt;= .04 each) accompanied by increased levels of the anti-inflammatory cytokines IL-1ra and IL-10 (P andlt;= .02). Patients with phlegmonous appendicitis had increased levels of IL-10 only. Conclusion. The finding of a pattern inflammatory markers compatible with the highly inflammatory A 17 subset in sera from, patients with gangrenous appendicitis, but not in phlegmonous appendicitis, supports the hypothesis that gangrenous and phlegmonous appendicitis are different entities with diver gent immune regulation. Additional studies of the differential immunopathogenesis of phlegmonous and gangrenous appendicitis are warranted, as this may have important implications in the diagnosis and management of patients with suspicion of appendicitis.

  • 232.
    Rubér, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Ekerfelt, Christina
    Unit for Autoimmunity and Immune regulation, County hospital Ryhov, Jönköping, Sweden.
    Andersson, Roland E
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Olaison, Gunnar
    Copenhagen University, Faculty of Health Sciences, Department of Surgery, Hospital Nord, Holbæk, Denmark.
    Local and systemic cytokine secretion in advanced and phlegmonous appendicitisManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Appendicitis is the most common abdominal emergency for surgery, but its underlying pathogenesis is still unknown. Appendicitis most likely harbors two different entities with different pathogenesis, one progressing to gangrene and perforation and one resolving. Previous studies on cytokines in peripheral blood points to different immunopathogenesis in advanced and resolving appendicitis. The relation of the peripheral blood analyzes to the local immune response in appendix is unclear. This study investigated local immune response in the appendix compared to blood, utilizing enzyme linked immunospot essay (ELISpot) which allows detection of low grade cytokine secretion from single cells.

    Methods: Appendiceal tissue and blood samples were collected from patients with advanced (gangrenous or perforated) (n=11) and phlegmonous appendicitis (n=7). Mononuclear cells were analyzed with ELISpot for number of spontaneous and PHA stimulated IFN-γ-, IL-12p70-(both Th1), IL-4-(Th2), IL-17-(Th17), TGF-β-(anti-inflammatory/Th17) and IL-10-(anti-inflammatory/Th1) secreting cells.

    Results: In appendix, the number of IL-4-(P=0.042) and IL-10-(P=0.042) secreting cells was increased in advanced appendicitis as compared to phlegmonous and a trend for increase was observed for IL-12p70 (P=0.055) and TGF-β (P=0.067). In blood the number of IL-4-(P=0.045), TGF-β-(P=0.007) and IFN-γ-(P=0.019), secreting cells were increased in patients with advanced appendicitis and a trend for increase was observed for IL-12p70 (P=0.068)

    Conclusion: Present findings are in line with previous studies demonstrating an increased inflammatory response in advanced as compared to phlegmonous appendicitis. The local immune response in the appendiceal tissue is mirrored in the blood, which justifies the use of analyzes on peripheral blood when investigating immune response in appendicitis.

  • 233.
    Ryberg, Anna
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Monstein, Hans-Jürg
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Microbiology.
    Expression of multiple forms of 3'-end variant CCK2 receptor mRNAs in human pancreatic adenocarcinoma2011In: BMC research notes, ISSN 1756-0500, Vol. 4, p. 131-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Two main types of receptors for gastrin and cholecystokinin (CCK) have been cloned and identified. CCK1 (CCK-A) receptors are expressed in the pancreas, the gallbladder, and parts of the brain, while CCK2 (CCK-B/gastrin) receptors (CCK2R) are expressed in gastric glands and in most of the brain. A splice variant of the CCK2R designated CCKRi4sv (CCK-C), which is constitutively expressed in human pancreatic cancer cells, has also been described. The purpose of the present investigation was to study CCK2R, CCK2i4svR, and gastrin mRNA expression in human pancreatic adenocarcinoma on the assumption that co-expression of CCK2R and gastrin or constitutive CCK2i4svR mRNA expression plays a pivotal role in the progression of pancreatic cancer.

    FINDINGS: PCR amplification using CCK2R specific primer-pairs, followed by ethidium-bromide stained agarose gel electrophoresis revealed the expression of wild-type CCK2R mRNA in 12 of 17 biopsy specimens. A CCK2R intron 4 specific nested PCR assay revealed that CCK2i4svR mRNA was expressed in only one of the biopsy specimen. The authenticity of PCR amplicons was confirmed by cloning of selected amplicons and DNA sequence analysis. Moreover, we found that hitherto undescribed multiple forms of 3'-end variant CCK2R mRNAs with various deletions in the retained intron 4 and exon 5, tentatively generating truncated proteins, were expressed in the pancreatic adenocarcinomas.

    CONCLUSION: Cloning and DNA sequencing of selected amplicons revealed that CCK2R and multiple CCK2i4svR-like mRNAs are expressed in human pancreatic adenocarcinoma. The originally described CCK2i4svR mRNA was only expressed in one of 17 tumours and appears to be rarely expressed in pancreatic adenocarcinoma. We report that CCK2R- and gastrin mRNA co-expression may play a role in a portion, but not in all of these tumours, and that aberrant splicing takes places in these tissues generating multiple forms of 3'-end variant CCK2R mRNAs.

  • 234.
    Ryberg, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    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.
    Sun, Yi-Qian
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Monstein, Hans-Jürg
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology .
    Concurrent genotyping of Helicobacter pylori virulence genes and human cytokine SNP sites using whole genome amplified DNA derived from minute amounts of gastric biopsy specimen DNA2008In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 8, p. 175-Article in journal (Refereed)
    Abstract [en]

    Background: Bacterial and cellular genotyping is becoming increasingly important in the diagnosis of infectious diseases. However, difficulties in obtaining sufficient amount of bacterial and cellular DNA extracted from the same human biopsy specimens is often a limiting factor. In this study, total DNA (host and bacterial DNA) was isolated from minute amounts of gastric biopsy specimens and amplified by means of whole genome amplification using the multiple displacement amplification (MDA) technique. Subsequently, MDA-DNA was used for concurrent Helicobacter pylori and human host cellular DNA genotyping analysis using PCR-based methods.

    Results: Total DNA was isolated from gastric biopsy specimens of 12 subjects with gastritis and 16 control subjects having a normal mucosa. The DNA was amplified using a multiple displacement amplification (MDA) kit. Next, concurrent genotyping was performed using H. pylori-specific virulence gene PCR amplification assays, pyrosequencing of bacterial 16S rDNA and PCR characterisation of various host genes. This includes Interleukin 1-beta (IL1B) and Interferon-gamma receptor (IFNGR1) SNP analysis, and Interleukin-1 receptor antagonist (IL1RN) variable tandem repeats (VNTR) in intron 2. Finally, regions of the vacA-gene were PCR amplified using M13-sequence tagged primers which allowed for direct DNA sequencing, omitting cloning of PCR amplicons. H. pylori specific multiplex PCR assays revealed the presence of H. pylori cagA and vacA genotypic variations in 11 of 12 gastritis biopsy specimens. Using pyrosequencing, 16S rDNA variable V3 region signatures of H. pylori were found in 11 of 12 individuals with gastritis, but in none of the control subjects. Similarly, IL1B and IFNGR1-SNP and IL1RN-VNTR patterns could be established in all individuals. Furthermore, sequencing of M13-sequence tagged vacA-PCR amplicons revealed the presence of highly diverse H. pylori vacA-s/i/m regions.

    Conclusion: The PCR-based molecular typing methods applied, using MDA-amplified DNA derived from small amounts of gastric biopsy specimens, enabled a rapid and concurrent molecular analysis of bacterial and host genes in the same biopsy specimen. The principles and technologies used in this study could also be applied to any situation in which human host and microbial genes of interest in microbial-host interactions would need to be sequenced.

  • 235.
    Salim, Sa'ad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Silva, Manuel A
    McMaster University.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Andersson, Peter
    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.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Perdue, Mary H
    McMaster University.
    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.
    CD83(+)CCR7(-) Dendritic Cells Accumulate in the Subepithelial Dome and Internalize Translocated Escherichia coli HB101 in the Peyers Patches of Heal Crohns Disease2009In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 174, no 1, p. 82-90Article in journal (Refereed)
    Abstract [en]

    Recurrent Crohns disease originates with small erosions in the follicle-associated epithelium overlying the Peyers patches. Animal studies have illustrated mucosal immune regulation by dendritic cells located in the subepithelial dome. The aim of this study was to characterize the dendritic cells at this specific site in patients with Crohns disease. Heal tissues were obtained after surgery performed on Crohns patients; ileal samples from noninflammatory bowel disease and ulcerative colitis served as standard and inflammatory controls, respectively. Flow cytometry of isolated intestinal mononuclear cells showed a larger subset of dendritic cells in Crohns samples compared with controls. This finding was corroborated by confocal microscopy, showing enhanced infiltrates of cells positive for the dendritic cell markers, DC-SIGN(+) and CD83(+), in the subepithelial dome. Moreover, the CD83(+) cells in Crohns tissues showed reduced expression of the lymph node migratory receptor, CCR7, possibly contributing to the high numbers of dendritic cells. After exposure to nonpathogenic Escherichia coli in Ussing chambers, dendritic cells in the subepithelial dome of Crohns disease demonstrated increased co-localization with translocated bacteria. Immunohistochemical results revealed that DC-SIGN(+) cells in Crohns tissues were found to express toll-like receptor 4 and produce tumor necrosis factor-a. In conclusion, nonmigrating dendritic cells that accumulate in the subepithelial dome and internalize nonpathogenic bacteria may be important for the onset and perpetuation of mucosal inflammation in Crohns disease.

  • 236.
    Salim, Sa´ad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    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.
    Importance of Disrupted Intestinal Barrier in Inflammatory Bowel Diseases2011In: INFLAMMATORY BOWEL DISEASES, ISSN 1078-0998, Vol. 17, no 1, p. 362-381Article, review/survey (Refereed)
    Abstract [en]

    The current paradigm of inflammatory bowel diseases (IBD), both Crohns disease (CD) and ulcerative colitis (UC), involves the interaction between environmental factors in the intestinal lumen and inappropriate host immune responses in genetically predisposed individuals. The intestinal mucosal barrier has evolved to maintain a delicate balance between absorbing essential nutrients while preventing the entry and responding to harmful contents. In IBD, disruptions of essential elements of the intestinal barrier lead to permeability defects. These barrier defects exacerbate the underlying immune system, subsequently resulting in tissue damage. The epithelial phenotype in active IBD is very similar in CD and UC. It is characterized by increased secretion of chloride and water, leading to diarrhea, increased permeability via both the transcellular and paracellular routes, and increased apoptosis of epithelial cells. The main cytokine that seems to drive these changes is tumor necrosis factor alpha in CD, whereas interleukin (IL)-13 may be more important in UC. Therapeutic restoration of the mucosal barrier would provide protection and prevent antigenic overload due to intestinal "leakiness. Here we give an overview of the key players of the intestinal mucosal barrier and review the current literature from studies in humans and human systems on mechanisms underlying mucosal barrier dysfunction in IBD.

  • 237.
    Salim, Sa'ad Yislam
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Mucosal dendritic cells in inflammatory bowel disease2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Crohn's disease, a chronic inflammation of the bowel, is a multi-factorial condition where uncontrolled immune responses to luminal bacteria occur in genetically predisposed individuals. The first observable clinical signs are small ulcers that form at a specialised form of epithelium, follicle-associated epithelium (FAB). The FAB covers immune inductive sites, Peyer's patches, which function primarily as sensory areas that sample the externaI gut environment. Dendritic cells are one of the key cells that are involved in sensing luminal contents and orchestrating the gut immune system.

    The main aim of this thesis was to determine whether the barrier of the FAB is breached in Crohn's disease and if dysfunctional immune regulators, namely dendritic cells, playaroIe in initiating and/or maintaining the chronic intestinal inflammation.

    Using biopsies and surgical specimens, we were able to show that in Crohn's disease, there was an increased transmucosaI transport of Escherichia coli compared to specimens from ulcerative colitis and non-inflammatory bowel disease (IBD) controIs. Dendritic cells internalised a higher percentage of bacteria that had translocated across the FAB in the Crohn's samples. Furthermore, significantly higher concentrations of TNF-u was released upon bacterial stimulation by tissues from patients with Crohn's disease than in controIs.

    We went on to characterise the dendritic cells present in the Peyer's patches of patients with Crohn's disease. We found an accumulation of both immature and mature dendritic cells beneath the FAB, in the sub-epithelial dome (SED). Normally, mature dendritic cells migrate towards T cell-rich areas. However, we observed mature dendritic cells accumulating in the SED because they lacked the CCR7 migratory receptor. Furthermore, they were more prone to take-up bacteria, and produced TNF.

    To study the function of mucosal dendritic cells, we performed isolation experiments and mixed Iymphocyte reactions. Dendritic cells from both the ileum and blood of patients with active Crohn's had reduced capacity for inducing T cell proliferation than non-IBD controIs. Blood dendritic cells of patients in remission had normalised function that was similar to dendritic cells from healthy controls.

    The SAMPl/YitFc mice, considered an appropriate murine model for Crohn's disease, had an inherent permeability defect that increased with the chronicity of intestinaI inflammation. However unlike in human Crohn's disease, dendritic cells did not seem to playaroIe in murine ileitis.

    This thesis highlights the accumulation of the actively surveying dendritic cells that are prone to bacterial internalisation, and points to their possible different functional roles in active versus in-active disease; thereby confirming dendritic cells as one ofthe key components in the pathogenesis ofCrohn's disease.

    List of papers
    1. Increased uptake of non-pathogenic E. coli via the follicle-associated epithelium in longstanding ileal Crohn's disease
    Open this publication in new window or tab >>Increased uptake of non-pathogenic E. coli via the follicle-associated epithelium in longstanding ileal Crohn's disease
    Show others...
    2008 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 215, no 2, p. 135-144Article in journal (Refereed) Published
    Abstract [en]

    In Crohn's disease (CD), inflammation is driven by luminal commensal micro-organisms, however, mechanisms of early phases of inflammation need further clarification. The earliest observable lesions of recurrent CD are microscopic erosions at the specialized follicle-associated epithelium (FAE), which lines the Peyer's patches. Therefore, our aim was to investigate the mucosal barrier to non-pathogenic bacteria in FAE of CD. The FAE of macroscopically normal ileum from patients with longstanding CD, ulcerative colitis, and controls was studied in Ussing chambers regarding electrophysiology and permeability to 51Cr-EDTA, horseradish peroxidase, and non-pathogenic E. coli strains. Transepithelial passage routes and uptake into dendritic cells were studied by confocal and electron microscopy. FAE of CD showed increased numbers of adherent bacteria, after E. coli exposure in Ussing chambers, as well as spontaneously in non-exposed archival surgical tissues. Further, we found increased uptake of fluorescent E. coli K-12 and HB101 across FAE of CD, but not in ulcerative colitis. Microscopy demonstrated intercellular and transcellular uptake of E. coli in CD, but only transcellular in controls. FAE exposed to E. coli demonstrated changes in conductance and 51Cr-EDTA permeability, suggesting that bacteria affected the paracellular pathway in CD mucosa. Following bacterial uptake, CD mucosa also demonstrated an increased percentage of E. coli co-localizing with dendritic cells, and augmented tissue release of TNF-α. Our data present novel insights into the pathophysiology of CD by demonstrating a previously unrecognized defect of FAE barrier to bacteria in ileal CD, leading to increased load of commensal bacteria to the inductive sites of mucosal immunity. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    Keywords
    Adult Aged Bacterial Adhesion *Bacterial Translocation Case-Control Studies Colitis, Ulcerative/immunology/microbiology Crohn Disease/genetics/immunology/*microbiology Dendritic Cells/microbiology Escherichia coli/*physiology Female Humans *Ileum Immunoen
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-43367 (URN)10.1002/path.2337 (DOI)73653 (Local ID)73653 (Archive number)73653 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
    2. CD83(+)CCR7(-) Dendritic Cells Accumulate in the Subepithelial Dome and Internalize Translocated Escherichia coli HB101 in the Peyers Patches of Heal Crohns Disease
    Open this publication in new window or tab >>CD83(+)CCR7(-) Dendritic Cells Accumulate in the Subepithelial Dome and Internalize Translocated Escherichia coli HB101 in the Peyers Patches of Heal Crohns Disease
    Show others...
    2009 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 174, no 1, p. 82-90Article in journal (Refereed) Published
    Abstract [en]

    Recurrent Crohns disease originates with small erosions in the follicle-associated epithelium overlying the Peyers patches. Animal studies have illustrated mucosal immune regulation by dendritic cells located in the subepithelial dome. The aim of this study was to characterize the dendritic cells at this specific site in patients with Crohns disease. Heal tissues were obtained after surgery performed on Crohns patients; ileal samples from noninflammatory bowel disease and ulcerative colitis served as standard and inflammatory controls, respectively. Flow cytometry of isolated intestinal mononuclear cells showed a larger subset of dendritic cells in Crohns samples compared with controls. This finding was corroborated by confocal microscopy, showing enhanced infiltrates of cells positive for the dendritic cell markers, DC-SIGN(+) and CD83(+), in the subepithelial dome. Moreover, the CD83(+) cells in Crohns tissues showed reduced expression of the lymph node migratory receptor, CCR7, possibly contributing to the high numbers of dendritic cells. After exposure to nonpathogenic Escherichia coli in Ussing chambers, dendritic cells in the subepithelial dome of Crohns disease demonstrated increased co-localization with translocated bacteria. Immunohistochemical results revealed that DC-SIGN(+) cells in Crohns tissues were found to express toll-like receptor 4 and produce tumor necrosis factor-a. In conclusion, nonmigrating dendritic cells that accumulate in the subepithelial dome and internalize nonpathogenic bacteria may be important for the onset and perpetuation of mucosal inflammation in Crohns disease.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16424 (URN)10.2353/ajpath.2009.080273 (DOI)
    Available from: 2009-01-23 Created: 2009-01-23 Last updated: 2017-12-14Bibliographically approved
    3. T-cell expansion capacity of Dendritic cells isolated from patients wiht Chron's disease
    Open this publication in new window or tab >>T-cell expansion capacity of Dendritic cells isolated from patients wiht Chron's disease
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Aphtoid lesions at the follicle-associated epithelium (FAE) are one of the earliest observable signs of recurrent ileal Crohn’s disease (CD). In an earlier study, we found an abnormal accumulation of dendritic cells (DCs) situated beneath the FAE, in the sub-epithelial dome (SED) of patients with CD. These DCs were prone to E.coli uptake. The aim here was to isolate and characterise DCs from patients with CD and determine their functional properties in T-cell expansion. Initially, DCs were isolated from eleal mucosa and blood of 5 CD patients and 5 patients with non-IBD disorders, via magnetic bead separation. DCs were also isolated from blood of 5 patients in long-term remission and 5 healthy volunteers, via FACS sorting and separation. Mixed lymphocyte reaction was performed on the isolated DCs and expansion of T-cells was recorded. DCs that were isolated from blood were also characterised via FACS analysis. DCs from patients with active CD had the tendency of having lower T-cell expansion capacity than DCs from non-IBD controls. The capacity to stimulate T-cells proliferation was restored to similar levels as healthy controls in DCs isolated from patients in remission. However, there was more than 10-fold increase in myeloid (CD11c+) DCs present in the peripheral blood mononuclear cells of CD than in healthy controls. The myeloid DCs were primarily immature (CD83-) and expressed the lymph node migratory receptor CCR7. This population of DCs may be responsible for inducing a tolerogenic or regulatory effect. Our results hint to a complex immune-regulatory mechanism where DCs at different stages of chronic inflammation exert different immune-modulatory effects.

    Keywords
    Blood, E.coli LF82, FACS, IBD, ileum, mixed lymphhocyte reaction
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-52228 (URN)
    Available from: 2009-12-11 Created: 2009-12-11 Last updated: 2009-12-11Bibliographically approved
    4. Barrier defect in the follicle-associated epithelium of SAMP1/YitFc mice demonstrates vulnerability to adherent-invasive Escherichia coli LF82
    Open this publication in new window or tab >>Barrier defect in the follicle-associated epithelium of SAMP1/YitFc mice demonstrates vulnerability to adherent-invasive Escherichia coli LF82
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    SAMP1/YitFc mice are a unique murine model for Crohn’s disease (CD) as they develop spontaneous intestinal inflammation without chemical or genetic manipulations. Inflammation is primarily located in the distal ileum, which is the hallmark location for CD. It is at the distal ileum of CD where small erosions that develop at the follicle-associated epithelium (FAE) and are one of the earliest observable lesions in recurrent ileitis. In the report, we studied the intestinal permeability defect and examined the role of dendritic cells (DCs) in the SAMP1/YitFc mice ileitis. Segments of FAE and VE from 11 and 27 weeks old SAMP1/YitFc mice and AKR control background stains were mounted on Ussing chambers. Electrical conductivity and permeability to 51Cr-EDTA, horseradish peroxidise (HRP) and E.coli HB101 and LF82 were recorded. There was ileal permeability to 51Cr-EDTA and HRP in the 27 weeks old SAMP1/YitFc mice. Both E.coli HB101 and LF82 increased conductance by two-folds in FAE and VE of SAMP1/YitFc mice. Furthermore, both bacterial strains increased tissue conductance and 51Cr-EDTA passage. There was greater passage of E.coli LF82 in the 27 week old DAMP1/YitFc mice than in controls. Confocal microscopy revealed a high number of CD11c+ DCs in the sub-epithelial dome (SED) area, though there was no difference between the SAMP1/YitFc mice than the AKR controls. Immunofluorescence characterisation also did not reveal any phenotypic difference in DCs between the mice strains. These results show that SAMP1/YitFc mice have a barrier defect, which was more pronounced in the FAE of older mice, and demonstrate a mucosal sensitivity bacteria. It also confirms that this model of chronic ileitis is primarily a defect in permeability defect and not DCs.

    Keywords
    52Cr-EDTA, dentric cells, E.coli, HRP, permeability, Ussing chanbers
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-52233 (URN)
    Available from: 2009-12-11 Created: 2009-12-11 Last updated: 2009-12-11Bibliographically approved
  • 238.
    Salim, Sa'ad Yislam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Fru Che, Karlhans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Söderholm, Johan
    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 Östergötland.
    T-cell expansion capacity of Dendritic cells isolated from patients wiht Chron's diseaseManuscript (preprint) (Other academic)
    Abstract [en]

    Aphtoid lesions at the follicle-associated epithelium (FAE) are one of the earliest observable signs of recurrent ileal Crohn’s disease (CD). In an earlier study, we found an abnormal accumulation of dendritic cells (DCs) situated beneath the FAE, in the sub-epithelial dome (SED) of patients with CD. These DCs were prone to E.coli uptake. The aim here was to isolate and characterise DCs from patients with CD and determine their functional properties in T-cell expansion. Initially, DCs were isolated from eleal mucosa and blood of 5 CD patients and 5 patients with non-IBD disorders, via magnetic bead separation. DCs were also isolated from blood of 5 patients in long-term remission and 5 healthy volunteers, via FACS sorting and separation. Mixed lymphocyte reaction was performed on the isolated DCs and expansion of T-cells was recorded. DCs that were isolated from blood were also characterised via FACS analysis. DCs from patients with active CD had the tendency of having lower T-cell expansion capacity than DCs from non-IBD controls. The capacity to stimulate T-cells proliferation was restored to similar levels as healthy controls in DCs isolated from patients in remission. However, there was more than 10-fold increase in myeloid (CD11c+) DCs present in the peripheral blood mononuclear cells of CD than in healthy controls. The myeloid DCs were primarily immature (CD83-) and expressed the lymph node migratory receptor CCR7. This population of DCs may be responsible for inducing a tolerogenic or regulatory effect. Our results hint to a complex immune-regulatory mechanism where DCs at different stages of chronic inflammation exert different immune-modulatory effects.

  • 239.
    Salim, Sa'ad Yislam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Myrelid, Pär
    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 Östergötland.
    Darfeuille-Michaud, Arlette
    Pathogénie Bactérienne Intestinale Laboratoire de Bactériologie, CBRV, Université d'Auvergne, Clermont-Ferrand, France.
    Pizzaro, Theresa T.
    Digestive Health Center of Excellence, University of Virginia Health System, Charlottesville, VA, USA.
    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 Östergötland.
    Barrier defect in the follicle-associated epithelium of SAMP1/YitFc mice demonstrates vulnerability to adherent-invasive Escherichia coli LF82Manuscript (preprint) (Other academic)
    Abstract [en]

    SAMP1/YitFc mice are a unique murine model for Crohn’s disease (CD) as they develop spontaneous intestinal inflammation without chemical or genetic manipulations. Inflammation is primarily located in the distal ileum, which is the hallmark location for CD. It is at the distal ileum of CD where small erosions that develop at the follicle-associated epithelium (FAE) and are one of the earliest observable lesions in recurrent ileitis. In the report, we studied the intestinal permeability defect and examined the role of dendritic cells (DCs) in the SAMP1/YitFc mice ileitis. Segments of FAE and VE from 11 and 27 weeks old SAMP1/YitFc mice and AKR control background stains were mounted on Ussing chambers. Electrical conductivity and permeability to 51Cr-EDTA, horseradish peroxidise (HRP) and E.coli HB101 and LF82 were recorded. There was ileal permeability to 51Cr-EDTA and HRP in the 27 weeks old SAMP1/YitFc mice. Both E.coli HB101 and LF82 increased conductance by two-folds in FAE and VE of SAMP1/YitFc mice. Furthermore, both bacterial strains increased tissue conductance and 51Cr-EDTA passage. There was greater passage of E.coli LF82 in the 27 week old DAMP1/YitFc mice than in controls. Confocal microscopy revealed a high number of CD11c+ DCs in the sub-epithelial dome (SED) area, though there was no difference between the SAMP1/YitFc mice than the AKR controls. Immunofluorescence characterisation also did not reveal any phenotypic difference in DCs between the mice strains. These results show that SAMP1/YitFc mice have a barrier defect, which was more pronounced in the FAE of older mice, and demonstrate a mucosal sensitivity bacteria. It also confirms that this model of chronic ileitis is primarily a defect in permeability defect and not DCs.

  • 240.
    Samuelsson, Anders
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Anesthesiology . Östergötlands Läns Landsting, Anaesthesiology and Surgical Centre, Department of Intensive Care UHL.
    Abdiu, Avni
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
    Wackenfors, Angelica
    Department of Hand and Plastic Surgery Linköpings Universitet.
    Sjöberg, Folke
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Burn Unit . Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
    Serotonin kinetics in patients with burn injuries: A comparison between the local and systemic responses measured by microdialysis-A pilot study2008In: Burns, ISSN 0305-4179, E-ISSN 1879-1409, Vol. 34, no 5, p. 617-622Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate serotonin (5HT) locally in burned and uninjured skin (intracutaneous) by microdialysis, and simultaneously record urinary and blood values in the same subjects. For comparison, serotonin values were also measured in skin of healthy controls. Design and setting: An experimental study in burned patients with of more than 25% TBSA (total burn surface area) % in an 8-bed tertiary burns unit, serving about 3.5 million persons. Patients and methods: Six subjects with a median TBSA% of 59% (range 33.5-90), and five healthy controls were examined by intracutaneous microdialysis of the skin. Results: 5HT was increased in burned patients, compared with controls. This increase was tenfold in skin and was noted both in uninjured and burned skin. The highest values were recorded on day 1 (median 16.1 nmol in uninjured and 9.5 nmol in burned skin) and day 2 (15.6 nmol in uninjured and 13.4 nmol in burned skin). A rapid reduction was noted on day 3 (4.9 nmol in uninjured and 3.8 nmol in burned skin). The corresponding value for control subjects was 1.3 nmol. The 5HT in blood was twice normal on day 2, and gradually reduced on days 3 and 4 (3189, 3035 and 2573 nmol, respectively). Urinary 5HT concentrations were increased only on day 2 at 1755 nmol and thereafter returned to the normal range on days 3 and 4 (1248 and 1344 nmol, respectively). Conclusions: We showed that microdialysis may be used in the critical care of burns, and local skin serotonin concentrations examined continuously for several days. The findings of significantly raised tissue serotonin concentrations, compared to that in blood and urine, suggests that serotonin may be important in local vascular control and formation of oedema. © 2007 Elsevier Ltd and ISBI.

  • 241.
    Samuelsson, Anders
    et al.
    Linköping University, Department of Medicine and Health Sciences, Anesthesiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthesiology and Surgical Centre.
    Farnebo, Simon
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Magnusson, Beatrice
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences.
    Anderson, Chris
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Dermatology and Venerology in Östergötland.
    Tesselaar, Erik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Burn Unit . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
    Implications for critical care of a new in vivo human vascular microdosing technique for giving noradrenaline and nitroglycerine by microdialysisManuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: Skin has a large dynamic capacity for alterations in blood flow, and is therefore often used for recruitment of blood during states of hypoperfusion. Little is known, however, about the metabolic consequences seen in skin secondary to hyporperfusion, particularly when the effects of vasoactive drugs are involved. The aims of this study were: to develop an in vivo, human microdosing model based on microdialysis in skin; and to investigate the effects on blood flow and metabolism of administering noradrenaline and nitroglycerine locally.

    Method: Nine healthy volunteers each had two or three microdialysis catheters placed intradermally in the volar surface of the lower arm. After a stabilisation period, the catheters were perfused with buffers containing noradrenaline 0.5 or 5 μg/ml for 60 minutes, and after a second period of equilibrium of 60 minutes, all catheters were perfused with buffer containing nitroglycerine (0.5mg/ml). Changes in the blood flow in the skin were measured by laser Doppler imaging urea and ethanol clearance. Simultaneous changes in tissue glucose, lactate, and pyruvate concentrations were recorded.

    Results: Perfusing skin with noradrenaline and nitroglycerine induced appreciable changes in all variables studied, depending on time and dose. The changes in glucose and lactate concentrations correlated with the change in blood flow assessed by either laser Doppler imaging or urea clearance. The changes in glucose and lactate that were induced by vasoconstriction (noradrenaline) continued until vasodilatation was induced by nitroglycerine.

    Conclusion: Noradrenaline given by microdialysis in healthy volunteers induced reproducible and dose-dependent hypoperfusion and ischaemia with simultaneous metabolic consequences. Among these, we particularly note that: tissue glucose concentrations responded rapidly to hypoperfusion but remained considerably higher than zero, which suggests an energy-dependent deficiency in cellular uptake; and vasoconstriction remained after cessation of the noradrenaline perfusion, implicating vasospasm and a lack of autoregulatory (recovery) capacity in skin. These findings are particularly interesting from the critical care perspective, where noradrenaline is used extensively for circulatory support. The metabolic consequences may be underestimated and our results suggest that further investigations are warranted.

  • 242.
    Samuelsson, Anders
    et al.
    Linköping University, Department of Medical and Health Sciences, Anesthesiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Intensive Care UHL.
    Farnebo, Simon
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Plastic Surgery, Hand surgery UHL.
    Magnusson, Beatrice
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Anderson, Chris
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Dermatology and Venerology in Östergötland.
    Tesselaar, Erik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Zettersten, Erik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Burn Center. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Plastic Surgery, Hand surgery UHL. Östergötlands Läns Landsting, Sinnescentrum, Department of Anaesthesiology and Surgery UHL.
    Implications for burn shock resuscitation of a new in vivo human vascular microdosing technique (microdialysis) for dermal administration of noradrenaline2012In: Burns, ISSN 0305-4179, E-ISSN 1879-1409, Vol. 38, no 7, p. 975-983Article in journal (Refereed)
    Abstract [en]

    Introduction: Skin has a large dynamic capacity for alterations in blood flow, and is therefore often used for recruitment of blood during states of hypoperfusion such as during burn shock resuscitation. However, little is known about the blood flow and metabolic consequences seen in the dermis secondary to the use vasoactive drugs (i.e. noradrenaline) for circulatory support. The aims of this study were therefore: to develop an in vivo, human microdosing model based on dermal microdialysis; and in this model to investigate effects on blood flow and metabolism by local application of noradrenaline and nitroglycerin by the microdialysis system simulating drug induced circulatory support. less thanbrgreater than less thanbrgreater thanMethod: Nine healthy volunteers had microdialysis catheters placed intradermally in the volar surface of the lower arm. The catheters were perfused with noradrenaline 3 or 30 mmol/L and after an equilibrium period all catheters were perfused with nitroglycerine (2.2 mmol/L). Dermal blood flow was measured by the urea clearance technique and by laser Doppler imaging. Simultaneously changes in dermal glucose, lactate, and pyruvate concentrations were recorded. less thanbrgreater than less thanbrgreater thanResults: Noradrenaline and nitroglycerine delivered to the dermis by the microdialysis probes induced large time- and dose-dependent changes in all variables. We particularly noted that tissue glucose concentrations responded rapidly to hypoperfusion but remained higher than zero. Furthermore, vasoconstriction remained after the noradrenaline administration implicating vasospasm and an attenuated dermal autoregulatory capacity. The changes in glucose and lactate by vasoconstriction (noradrenaline) remained until vasodilatation was actively induced by nitroglycerine. less thanbrgreater than less thanbrgreater thanConclusion: These findings, i.e., compromised dermal blood flow and metabolism are particularly interesting from the burn shock resuscitation perspective where noradrenaline is commonly used for circulatory support. The importance and clinical value of the results obtained in this in vivo dermal model in healthy volunteers needs to be further explored in burn-injured patients.

  • 243.
    Sandström, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Dahlqvist Leinhard, Olof
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences.
    Dahlström, Nils
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Freij, Anna
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences.
    Kihlberg, Johan
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Brismar, Torkel
    Karolinska University Hospital, Stockholm, Sweden .
    Smedby, Örjan
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Radiology in Linköping.
    Lundberg, Peter
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Upptag i levern av kontrastmedlet Gd-EOB-DTPA påverkas kraftigt av leverfunktionen2009Conference paper (Other academic)
  • 244.
    Sandström, Per
    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.
    Trulsson, Lena
    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.
    Sundqvist, Tommy
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    von Dobeln, U.
    Department of Laboratory Medicine Karolinska University Hospital Huddinge, Stockholm.
    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.
    Serum amino acid profile in patients with acute pancreatitis2008In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 35, no 1, p. 225-231Article in journal (Refereed)
    Abstract [en]

    Patients in the early phase of acute pancreatitis (AP) have reduced serum levels of arginine and citrulline. This may be of patho-biological importance, since arginine is the substrate for nitric oxide, which in turn is involved in normal pancreatic physiology and in the inflammatory process. Serum amino acid spectrum was measured daily for five days and after recovery six weeks later in 19 patients admitted to the hospital for acute pancreatitis. These patients had abnormal levels of most amino acids including arginine, citrulline, glutamine and glutamate. Phenylalanine and glutamate were increased, while arginine, citrulline, ornithine and glutamine were decreased compared to levels after recovery. NO2/NO3 concentration in the urine, but not serum arginase activity, was significantly increased day 1 compared to day 5 after admission. Acute pancreatitis causes a disturbance of the serum amino acid spectrum, with possible implications for the inflammatory process and organ function both in the pancreas and the gut. Supplementation of selected amino acids could possibly be of value in this severe condition. © 2007 Springer-Verlag.

  • 245.
    Schoultz, Ida
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Mechanisms of bacterial-epithelial interaction in Crohn’s disease2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Crohn’s disease (CD) is believed to be initiated when an individual, who has agenetic predisposition either leading to a disturbance in the barrier functionand/or the innate immune system is exposed to triggering environmentalfactors, the most important being intraluminal bacteria. Genetic and functionalstudies have confirmed the Pattern-recognition receptors (PRRs), Nod2, TLR4and NALP3, as important mediators of the inflammatory process associatedwith disease progression. However, the mechanisms that link enteric bacteriaand barrier function in a background of genetic predisposition to CD are justbeginning to emerge. The general aim of this thesis was therefore to morethoroughly investigate the mechanisms of bacterial-epithelial interaction in CD.

    Here we present evidence suggesting that the small bowel is able to inducetranscytosis of antigens after short term exposure to Yersinia pseudotuberculosis. This suggests that small bowel enterocytes are able toattain follicle associated epithelial (FAE) abilities and contribute to the barrierdysfunction observed in CD. Furthermore we report a positive effect of anti-TNFα treatment (infliximab) on the translocation of adherent invasive E.coli (AIEC) across the colonic mucosa of patients suffering from severe CD.

    We also confirm the importance of the Nod-like receptors (NLRs) in thepathogenesis of CD by showing that combined polymorphisms in the genesencoding NALP3 and CARD8 confer susceptibility to CD among Swedish menand in addition to previous published results add a gender aspect on thegenotype-phenotype relationship in CD. Finally, we show that Nod2 is rapidlysubjected to ubiquitination followed by proteasomal degradation, henceproviding important clues about how NLR regulation might occur in the cell,suggesting that the ubiquitin-proteasome pathway is an important factor toconsider in the development of the disease.

    In conclusion we report novel insights into the bacterial-epithelial interactionsoccurring in CD and contribute important clues about the origin of this disease.ISBN: 978-

    List of papers
    1. Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis
    Open this publication in new window or tab >>Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis
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    2008 (English)In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 88, no 11, p. 1215-1226Article in journal (Refereed) Published
    Abstract [en]

    Crohns disease is characterized by a defect in intestinal barrier function, where bacteria are considered the most important inflammation-driving factor. Enteric bacteria, including E. coli and Yersinia spp, affect tight junctions in enterocytes, but little is known about bacterial effects on the transcellular pathway. Our objective was to study the short-term effects of Y. pseudotuberculosis on uptake of nanoparticles across human villus epithelium. Monolayers of human colon epithelium-derived Caco-2 cells and biopsies of normal human ileum were studied after 2 h exposure to Y. pseudotuberculosis expressing (inv+) or lacking (inv-) the bacterial adhesion molecule, invasin. Transepithelial transport of fluorescent nanoparticles (markers of transcytosis) was quantified by flow cytometry, and mechanisms explored by using inhibitors of endocytosis. Epithelial expressions of beta 1-integrin and particle uptake pathways were studied by confocal microscopy. The paracellular pathway was assessed by electrical resistance (TER), mannitol flux, and expression of tight junction proteins occludin and caludin-4 by confocal microscopy. Inv + Y. pseudotuberculosis adhered to the apical surface of epithelial cells and induced transcytosis of exogenous nanoparticles across Caco-2 monolayers (30-fold increase, P < 0.01) and ileal mucosa (268 +/- 47% of control; P < 0.01), whereas inv-bacteria had no effect on transcytosis. The transcytosis was concentration-, particle size-and temperature-dependent, and possibly mediated via macropinocytosis. Y. pseudotuberculosis also induced apical expression of beta 1-integrin on epithelial cells. A slight drop in TER was seen after exposure to inv+ Y. pseudotuberculosis, whereas mannitol flux and tight junction protein expression was unchanged. In summary, Y. pseudotuberculosis induced apical expression of beta 1-integrin and stimulated uptake of nanoparticles via invasin-dependent transcytosis in human intestinal epithelium. Our findings suggest that bacterial factors may initiate transcytosis of luminal exogenous particles across human ileal mucosa, thus presenting a novel mechanism of intestinal barrier dysfunction.

    Keywords
    barrier function, beta 1-integrin, Caco-2 cells, confocal microscopy, Crohns disease, Ussing chambers
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16079 (URN)10.1038/labinvest.2008.86 (DOI)
    Available from: 2009-01-07 Created: 2009-01-07 Last updated: 2017-12-14Bibliographically approved
    2. Infliximab reduces bacterial uptake in mucosal biopsies of Crohn’s colitis viamicrotubule-dependent pathway
    Open this publication in new window or tab >>Infliximab reduces bacterial uptake in mucosal biopsies of Crohn’s colitis viamicrotubule-dependent pathway
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: A defective intestinal barrier, shown by increased paracellular permeability is an importantpathogenic factor in Crohn’s disease (CD). TNFα is a key mediator in the regulation of the intestinal barrierfunction. Treatment with antibodies directed against TNFα, such as infliximab, has been established as animportant part of the therapeutic arsenal in severe Crohn’s disease, but the mechanisms of action have yet tobe elucidated. Part of infliximab’s effect has been suggested to be reduced apoptosis of epithelial cells andthereby reduced paracellular permeability. Our aim was to study how infliximab affects uptake of adherent E.coli across the colonic mucosa in CD.

    Method: Seven patients with active CD colitis were examined before and after a four week treatment withinfliximab. Control biopsies were taken from healthy volunteers (4) and patients undergoing controlexamination for colonic polyps (4), aged 36 (range 25-81), coloscopy. Biopsies were taken from macroscopicallynon-inflamed descending colon and were mounted in Ussing chambers to study barrier function. Transmucosalpassage of green fluorescent protein (GFP) incorporated E. coli HM427, an adherent bacteria isolated from thecolon of a CD patient, was studied by quantifying the translocated fluorescent bacteria using flow cytometry.

    Results: Bacterial passage across the colonic mucosa was increased in CD (2500 ± 300 arb. units) comparedwith controls (960 ± 280; p<0.05), and was reduced to 500 ± 200 units after the infliximab treatment (p<0.05).In biopsies treated with colchicine (a microtubuline inhibitor) uptake of E. coli HM427 was reduced by 2/3compared to non-treated biopsies.

    Conclusion: Patients with active Crohn’s disease showed a defect in the barrier to adherent E. coli, which waspartly mediated through a microtubule dependent uptake. The four week treatment with infliximab improvedthe intestinal barrier to these bacteria. This may constitute an important part of infliximab’s mechanisms ofaction in active colitis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-21097 (URN)
    Available from: 2009-09-29 Created: 2009-09-29 Last updated: 2010-01-14Bibliographically approved
    3. Combined Polymorphisms in Genes Encoding the Inflammasome Components NALP3 and CARD8 Confer Susceptibility to Crohns Disease in Swedish Men
    Open this publication in new window or tab >>Combined Polymorphisms in Genes Encoding the Inflammasome Components NALP3 and CARD8 Confer Susceptibility to Crohns Disease in Swedish Men
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    2009 (English)In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 104, no 5, p. 1180-1188Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES : Crohns disease (CD) is characterized by overproduction of proinflammatory cytokines like interleukin (IL)-1 beta. Production of mature IL-1 beta is dependent on a caspase-1-activating protein complex called the NALP3 inflammasome, composed of NALP3, ASC, and CARD8. NALP3 shares structural similarities with Nod2, and both of these proteins are required for bacteria-induced IL-1 beta secretion. The combination of the polymorphisms CARD8 (C10X) and NALP3 (Q705K) was recently shown to be associated with rheumatoid arthritis. Our aim was to investigate whether these combined polymorphisms play a role in the susceptibility to CD.

    METHODS: The study included 498 CD patients in two cohorts from different regions and 742 control individuals from a Swedish population. DNA was isolated from whole blood. Polymorphisms of (Q705K) NALP3 and (C10X) CARD8, as well as the Nod2 variants, R702W and G908R, were genotyped using the Taqman single nucleotide polymorphism assay. The Nod2 frameshift mutation, L1007fs, was detected by Megabace SNuPe genotyping.

    RESULTS: Our results show that men who have both the C10X and Q705K alleles in CARD8 and NALP3, and who express wild-type alleles of Nod2 are at an increased risk of developing CD (odds ratio, OR: 3.40 range: 1.32-8.76); P = 0.011). No association with these polymorphisms was found in women (OR: 0.89 (range: 0.44-1.77); P = 0.74).

    CONCLUSIONS: We suggest a role for combined polymorphisms in CARD8 and NALP3 in the development of CD in men, with obvious sex differences in the genetic susceptibility pattern. These findings give further support to the importance of innate immune responses in CD.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-18957 (URN)10.1038/ajg.2009.29 (DOI)
    Available from: 2009-06-06 Created: 2009-06-05 Last updated: 2017-12-13Bibliographically approved
    4. Ubiquitination and degradation of the Crohn’s Disease associated protein Nod2involves the E2 enzyme UBE2G2
    Open this publication in new window or tab >>Ubiquitination and degradation of the Crohn’s Disease associated protein Nod2involves the E2 enzyme UBE2G2
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Mutations predisposing to Crohn’s disease (CD) have been mapped to the CARD15/Nod2 locus,which encodes a cytoplasmic receptor hereafter referred to as Nod2, a member of the NACHT-LRR (NLR) familyof pattern recognition receptors. The binding of bacterial muramyl dipeptide (MDP) to Nod2 triggers theactivation of the nuclear factor-κB (NFκB) pathway, thereby inducing a number of pro-inflammatory genes. Themost common variant of Nod2 associated with CD is the frame shift mutation L1007fs, which results in atruncated form of the protein unable to respond to MDP. Despite active research, little is known about howNod2 is regulated. The aim of this study was to investigate if the cellular Nod2 protein level is regulated by theubiquitin-proteasome pathway.

    Material and Methods/Results: Nod2 was shown to be subjected to rapid turnover in the colorectal cancer cellline SW480 as measured by immunoprecipitation following inhibition of protein synthesis with cyklohexamide.Immunoprecipitation of Nod2 also revealed co-precipitation of ubiquitin, suggesting that Nod2 wasubiquitinated. In line with this observation, inhibition of the proteasome using MG-132 or lactacystin, resultedin increased levels of Nod2 in the cells. UBE2G2, an E2 enzyme, thus conferring specificity of ubiquitin binding,was identified to have affinity for the CARD domain of Nod2. Activation of Nod2 with MDP enhanced itsubiquitination, and increasing amounts of UBE2G2 in the cells abrogated NFB-activation, suggesting thatubiquitination of Nod2 may be important for the resolution of the inflammatory signal.

    Conclusion: Taken together, our results show that the cellular level of Nod2 protein is regulated via theubiquitin-proteasome pathway, suggesting that Nod2-driven inflammation may be resolved through rapiddegradation of Nod2. Consequently, not only polymorphisms in Nod2 directly, but also in genes regulatingNod2 protein levels may contribute to the susceptibility to Crohn’s disease.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-21099 (URN)
    Available from: 2009-09-29 Created: 2009-09-29 Last updated: 2010-01-14Bibliographically approved
  • 246.
    Schoultz, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Carlsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Gullberg, Elisabet
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Endocrinology and Gastroenterology.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Endocrinology and Gastroenterology.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    McKay, Derek M.
    Department of Physiology and Biophysics, University of Calgary, Calgary, Canada.
    Rhodes, Jonathan M.
    Department of Medicine, Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, University of Liverpool, Liverpool, United Kingdom.
    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.
    Infliximab reduces bacterial uptake in mucosal biopsies of Crohn’s colitis viamicrotubule-dependent pathwayManuscript (preprint) (Other academic)
    Abstract [en]

    Background: A defective intestinal barrier, shown by increased paracellular permeability is an importantpathogenic factor in Crohn’s disease (CD). TNFα is a key mediator in the regulation of the intestinal barrierfunction. Treatment with antibodies directed against TNFα, such as infliximab, has been established as animportant part of the therapeutic arsenal in severe Crohn’s disease, but the mechanisms of action have yet tobe elucidated. Part of infliximab’s effect has been suggested to be reduced apoptosis of epithelial cells andthereby reduced paracellular permeability. Our aim was to study how infliximab affects uptake of adherent E.coli across the colonic mucosa in CD.

    Method: Seven patients with active CD colitis were examined before and after a four week treatment withinfliximab. Control biopsies were taken from healthy volunteers (4) and patients undergoing controlexamination for colonic polyps (4), aged 36 (range 25-81), coloscopy. Biopsies were taken from macroscopicallynon-inflamed descending colon and were mounted in Ussing chambers to study barrier function. Transmucosalpassage of green fluorescent protein (GFP) incorporated E. coli HM427, an adherent bacteria isolated from thecolon of a CD patient, was studied by quantifying the translocated fluorescent bacteria using flow cytometry.

    Results: Bacterial passage across the colonic mucosa was increased in CD (2500 ± 300 arb. units) comparedwith controls (960 ± 280; p<0.05), and was reduced to 500 ± 200 units after the infliximab treatment (p<0.05).In biopsies treated with colchicine (a microtubuline inhibitor) uptake of E. coli HM427 was reduced by 2/3compared to non-treated biopsies.

    Conclusion: Patients with active Crohn’s disease showed a defect in the barrier to adherent E. coli, which waspartly mediated through a microtubule dependent uptake. The four week treatment with infliximab improvedthe intestinal barrier to these bacteria. This may constitute an important part of infliximab’s mechanisms ofaction in active colitis.

  • 247.
    Schoultz, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Kufer, Thomas
    Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Germany.
    Jiang, Tieshan
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Jandu, Narveen
    University of Toronto, Toronto, Canada.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    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.
    Ubiquitination and degradation of the Crohn’s Disease associated protein Nod2involves the E2 enzyme UBE2G2Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Mutations predisposing to Crohn’s disease (CD) have been mapped to the CARD15/Nod2 locus,which encodes a cytoplasmic receptor hereafter referred to as Nod2, a member of the NACHT-LRR (NLR) familyof pattern recognition receptors. The binding of bacterial muramyl dipeptide (MDP) to Nod2 triggers theactivation of the nuclear factor-κB (NFκB) pathway, thereby inducing a number of pro-inflammatory genes. Themost common variant of Nod2 associated with CD is the frame shift mutation L1007fs, which results in atruncated form of the protein unable to respond to MDP. Despite active research, little is known about howNod2 is regulated. The aim of this study was to investigate if the cellular Nod2 protein level is regulated by theubiquitin-proteasome pathway.

    Material and Methods/Results: Nod2 was shown to be subjected to rapid turnover in the colorectal cancer cellline SW480 as measured by immunoprecipitation following inhibition of protein synthesis with cyklohexamide.Immunoprecipitation of Nod2 also revealed co-precipitation of ubiquitin, suggesting that Nod2 wasubiquitinated. In line with this observation, inhibition of the proteasome using MG-132 or lactacystin, resultedin increased levels of Nod2 in the cells. UBE2G2, an E2 enzyme, thus conferring specificity of ubiquitin binding,was identified to have affinity for the CARD domain of Nod2. Activation of Nod2 with MDP enhanced itsubiquitination, and increasing amounts of UBE2G2 in the cells abrogated NFB-activation, suggesting thatubiquitination of Nod2 may be important for the resolution of the inflammatory signal.

    Conclusion: Taken together, our results show that the cellular level of Nod2 protein is regulated via theubiquitin-proteasome pathway, suggesting that Nod2-driven inflammation may be resolved through rapiddegradation of Nod2. Consequently, not only polymorphisms in Nod2 directly, but also in genes regulatingNod2 protein levels may contribute to the susceptibility to Crohn’s disease.

  • 248.
    Schoultz, Ida
    et al.
    University of Calgary, Canada .
    McKay, Catherine M
    University of Calgary, Canada .
    Graepel, Rabea
    University of Calgary, Canada .
    Phan, Van C
    University of Calgary, Canada .
    Wang, Arthur
    University of Calgary, Canada .
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    McKay, Derek M
    University of Calgary, Canada .
    Indomethacin-induced translocation of bacteria across enteric epithelia is reactive oxygen species-dependent and reduced by vitamin C2012In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 303, no 5, p. G536-G545Article in journal (Refereed)
    Abstract [en]

    Schoultz I, McKay CM, Graepel R, Phan VC, Wang A, Soderholm J, McKay DM. Indomethacin-induced translocation of bacteria across enteric epithelia is reactive oxygen species-dependent and reduced by vitamin C. Am J Physiol Gastrointest Liver Physiol 303: G536-G545, 2012. First published June 14, 2012; doi:10.1152/ajpgi.00125.2012.-The enteric epithelium must absorb nutrients and water and act as a barrier to the entry of luminal material into the body; this barrier function is a key component of innate immunity. Nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy occurs via inhibition of prostaglandin synthesis and perturbed epithelial mitochondrial activity. Here, the direct effect of NSAIDs [indomethacin, piroxicam (cyclooxygenase 1 and 2 inhibitors), and SC-560 (a cyclooxygenase 1 inhibitor)] on the barrier function of human T84 epithelial cell line monolayers was assessed by transepithelial electrical resistance (TER) and internalization and translocation of a commensal Escherichia coli. Exposure to E. coli in the presence and absence of drugs for 16 h reduced TER; however, monolayers cotreated with E. coli and indomethacin, but not piroxicam or SC-560, displayed significant increases in internalization and translocation of the bacteria. This was accompanied by increased reactive oxygen species (ROS) production, which was also increased in epithelia treated with E. coli only. Colocalization revealed upregulation of superoxide synthesis by mitochondria in epithelia treated with E. coli + indomethacin. Addition of antioxidants (vitamin C or a green tea polyphenol, epigallocathechin gallate) quenched the ROS and prevented the increase in E. coli internalization and translocation evoked by indomethacin, but not the drop in TER. Evidence of increased apoptosis was not observed in this model. The data implicate epithelial-derived ROS in indomethacin-induced barrier dysfunction and show that a portion of the bacteria likely cross the epithelium via a transcellular pathway. We speculate that addition of antioxidants as dietary supplements to NSAID treatment regimens would reduce the magnitude of decreased barrier function, specifically the transepithelial passage of bacteria.

  • 249.
    Schoultz, Ida
    et al.
    University of Calgary.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    McKay, Derek M
    University of Calgary.
    Is Metabolic Stress a Common Denominator in Inflammatory Bowel Disease?2011In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 17, no 9, p. 2008-2018Article, review/survey (Refereed)
    Abstract [en]

    The enteric epithelium represents the major boundary between the outside world and the body, and in the colon it is the interface between the host and a vast and diverse microbiota. A common feature of inflammatory bowel disease (IBD) is decreased epithelial barrier function, and while a cause-and-effect relationship can be debated, prolonged loss of epithelial barrier function (whether this means the ability to sense bacteria or exclude them) would contribute to inflammation. While there are undoubtedly individual nuances in IBD, we review data in support of metabolic stress-that is, perturbed mitochondrial function-in the enterocyte as a contributing factor to the initiation of inflammation and relapses in IBD. The postulate is presented that metabolic stress, which can arise as a consequence of a variety of stimuli (e.g., infection, bacterial dysbiosis, and inflammation also), will reduce epithelial barrier function and perturb the enterocyte-commensal flora relationship and suggest that means to negate enterocytic metabolic stress should be considered as a prophylactic or adjuvant therapy in IBD.

  • 250.
    Schoultz, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Halfvarsson, Jonas
    Örebro University Hospital.
    Torkvist, Leif
    Karolinska University Hospital.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine . Linköping University, Faculty of Health Sciences.
    Sjoqvist, Urban
    Karolinska University Hospital.
    Lordal, Mikael
    Karolinska University Hospital.
    Tysk, Curt
    Örebro University Hospital.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    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.
    Combined Polymorphisms in Genes Encoding the Inflammasome Components NALP3 and CARD8 Confer Susceptibility to Crohns Disease in Swedish Men2009In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 104, no 5, p. 1180-1188Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES : Crohns disease (CD) is characterized by overproduction of proinflammatory cytokines like interleukin (IL)-1 beta. Production of mature IL-1 beta is dependent on a caspase-1-activating protein complex called the NALP3 inflammasome, composed of NALP3, ASC, and CARD8. NALP3 shares structural similarities with Nod2, and both of these proteins are required for bacteria-induced IL-1 beta secretion. The combination of the polymorphisms CARD8 (C10X) and NALP3 (Q705K) was recently shown to be associated with rheumatoid arthritis. Our aim was to investigate whether these combined polymorphisms play a role in the susceptibility to CD.

    METHODS: The study included 498 CD patients in two cohorts from different regions and 742 control individuals from a Swedish population. DNA was isolated from whole blood. Polymorphisms of (Q705K) NALP3 and (C10X) CARD8, as well as the Nod2 variants, R702W and G908R, were genotyped using the Taqman single nucleotide polymorphism assay. The Nod2 frameshift mutation, L1007fs, was detected by Megabace SNuPe genotyping.

    RESULTS: Our results show that men who have both the C10X and Q705K alleles in CARD8 and NALP3, and who express wild-type alleles of Nod2 are at an increased risk of developing CD (odds ratio, OR: 3.40 range: 1.32-8.76); P = 0.011). No association with these polymorphisms was found in women (OR: 0.89 (range: 0.44-1.77); P = 0.74).

    CONCLUSIONS: We suggest a role for combined polymorphisms in CARD8 and NALP3 in the development of CD in men, with obvious sex differences in the genetic susceptibility pattern. These findings give further support to the importance of innate immune responses in CD.

234567 201 - 250 of 331
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