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  • 1.
    Alfonsson, Sven
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Weineland-Strandskov, Sandra
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Self-Reported Hedonism Predicts 12-Month Weight Loss After Roux-en-Y Gastric Bypass2017In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 27, no 8, 2073-2078 p.Article in journal (Refereed)
    Abstract [en]

    Introduction Research regarding psychological risk factors for reduced weight loss after bariatric surgery has yielded mixed results, especially for variables measured prior to surgery. More profound personality factors have shown better promise and one such factor that may be relevant in this context is time perspective, i.e., the tendency to focus on present or future consequences. The aim of this study was to investigate the predictive value of time perspective for 12-month weight loss after Roux-en-Y gastric bypass surgery.

    Methods A total of 158 patients were included and completed self-report instruments prior to surgery. Weight loss was measured after 12 months by medical staff. Background variables as well as self-reported disordered eating, psychological distress, and time perspective were analyzed with regression analysis to identify significant predictors for 12-month weight loss.

    Results The mean BMI loss at 12 months was 14 units, from 45 to 30 kg/m(2). Age, sex, and time perspective could significantly predict weight loss but only male sex and self-reported hedonism were independent risk factors for reduced weight loss in the final regression model.

    Conclusion In this study, self-reported hedonistic time perspective proved to be a better predictor for 12-month weight loss than symptoms of disordered eating and psychological distress. It is possible that a hedonistic tendency of focusing on immediate consequences and rewards is analogous to the impaired delay discounting seen in previous studies of bariatric surgery candidates. Further studies are needed to identify whether these patients may benefit from extended care and support after surgery.

  • 2.
    Amcoff, Karin
    et al.
    Univ Orebro, Fac Med & Hlth, Dept Gastroenterol, SE-70182 Orebro, Sweden..
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Lampinen, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Magnuson, Anders
    Univ Orebro, Sch Med Sci, Clin Epidemiol & Biostat, Orebro, Sweden..
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Halfvarson, Jonas
    Univ Orebro, Fac Med & Hlth, Dept Gastroenterol, SE-70182 Orebro, Sweden..
    Clinical implications of assay specific differences in f-calprotectin when monitoring inflammatory bowel disease activity over time2017In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 52, no 3, 344-350 p.Article in journal (Refereed)
    Abstract [en]

    Objective: With several faecal calprotectin (FC) assays on the market, it has been difficult to define a uniform threshold for discriminating between remission and active disease in patients with inflammatory bowel disease (IBD). We aimed to compare the results of different FC-assays in IBD patients, followed over time.Material and methods: IBD patients provided faecal samples and reported clinical activity every third month prospectively over a two year period. FC was measured with two ELISA - (Buhlmann and Immunodiagnostik) and one automated fluoroimmunoassay (Phadia).Results: In total, 13 patients provided 91 faecal samples. The median (IQR) concentration of FC was higher at active disease than at remission for all assays: Buhlmann 845 (1061-226) g/g versus 62 (224-39) g/g, Phadia 369 (975-122) g/g versus 11 (52-11) g/g, and Immundiagnostik 135 (302-69) g/g versus 8 (56-4) g/g. The Buhlmann assay produced the largest absolute difference but the corresponding relative difference seemed to be more pronounced when analysed by the Phadia - (ratio of means 8.5; 95% CI 3.3-21.9) or the Immundiagnostik assay (ratio of means 7.4; 95% CI 3.1-17.6) than by the Buhlmann assay (ratio of means 5.3; 95% CI 2.7-10.6). Consequently, the specificity for discriminating active disease from remission varied between assays (34-75%) when the cut-off 50g/g was used, whereas the differences in sensitivity were less pronounced.Conclusions: Cross-comparisons revealed overall poor agreement between the assays as well as differences in the dynamics of FC. These findings suggest that standardisation of the method is needed to implement FC as a disease monitoring tool at large-scale.

  • 3.
    Angelison, L.
    et al.
    Helsingborg Hosp, Dept Med, Charlotte Yhlens Gata 10, S-25187 Helsingborg, Sweden..
    Almer, S.
    Karolinska Inst, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Eriksson, A.
    Sahlgrenska Univ Hospital Ostra, Dept Gastroenterol, Gothenburg, Sweden..
    Karling, P.
    Umea Univ, Dept Publ Hlth & Clin Med, Div Med, Umea, Sweden..
    Fagerberg, U.
    Vastmanlands Hosp, Clin Res Ctr, Vasteras, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Halfvarson, J.
    Univ Orebro, Dept Gastroenterol, Fac Med & Hlth, Orebro, Sweden..
    Thörn, Mari
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Björk, J.
    Karolinska Inst, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Hindorf, U.
    Lund Univ, Div Gastroenterol, Dept Clin Sci, Lund, Sweden..
    Löfberg, R.
    Karolinska Inst, Dept Med, IBD Unit, Stockholm Gastro Ctr, Stockholm, Sweden. Sodra Alvsborgs Sjukhus, Dept Med, Boras, Sweden..
    Bajor, A.
    Hjortswang, H.
    Linkoping Univ, Dept Gastroenterol, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Hammarlund, P.
    Angelholm Hosp, Dept Med, Angelholm, Sweden..
    Grip, O.
    Skane Univ Hosp, Dept Gastroenterol, Malmo, Sweden..
    Torp, J.
    Kristianstad Cent Hosp, Dept Med, Kristianstad, Sweden..
    Marsal, J.
    Hertervig, E.
    Skane Univ Hosp, Dept Gastroenterol, Lund, Sweden..
    Long-term outcome of infliximab treatment in chronic active ulcerative colitis: a Swedish multicentre study of 250 patients2017In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 45, no 4, 519-532 p.Article in journal (Refereed)
    Abstract [en]

    Background Real-life long-term data on infliximab treatment in ulcerative colitis are limited. Aim To study the long-term efficacy and safety of infliximab in chronic active ulcerative colitis and possible predictors of colectomy and response were also examined. Methods A retrospective multi-centre study of infliximab treatment in 250 patients with chronic active ulcerative colitis with inclusion criteria: age 18 years, ambulatory treated, steroid-dependent or intolerant and/or immunomodulator refractory or intolerant. Results Steroid-free clinical remission was achieved by 123/250 patients (49.2%) at 12 months and in 126/250 patients at a median follow-up of 2.9 years (50.4%). Primary response at 3 months was achieved by 190/250 (76.0%) patients and associated with a high probability of response 168/190 (88.4%) at 12 months and 143/190 (75.3%) at follow-up. Long-term rate of colectomy in primary responders was 6/190 (3.2%) at 12 months and 27/190 (14.2%) at last follow-up. Failure to achieve response at 3 months was associated with a high risk of subsequent colectomy, 29/60 (48.3%) at 12 months and 41/60 (68.3%) at follow-up. Response at 12 months was associated with a low risk of subsequent colectomy, 14/181 (7.7%) compared with non-response 19/34 (55.9%) (P < 0.0001). Non-response at 3 months was an independent predictor of subsequent colectomy (HR = 9.40, 95% CI = 5.10-17.35, P < 0.001). Concomitant azathioprine therapy did not influence outcome in terms of colectomy. Conclusions Long-term efficacy of infliximab treatment in chronic active ulcerative colitis is excellent especially in patients who respond to induction treatment. Conversely, non-response at 3 months predicts a poor outcome, with a high risk of subsequent colectomy.

  • 4.
    Anthony, Lowell
    et al.
    Univ Kentucky, Lexington, KY USA..
    Hoersch, Dieter
    Zentralklin Bad Berka, Bad Berka, Germany..
    Ervin, Claire
    RTI Hlth Solut, Res Triangle Pk, NC USA..
    Kulke, Matthew H.
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Pavel, Marianne
    Charite, D-13353 Berlin, Germany..
    Bergsland, Emily
    UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA..
    Caplin, Martyn
    Royal Free Hosp, Pond St, London NW3 2QG, England..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Warner, Richard
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA..
    Kunz, Pamela
    Stanford Univ, Palo Alto, CA 94304 USA..
    Metz, David C.
    Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA..
    Pasieka, Janice
    Tom Baker Canc Ctr Calgary, Calgary, AB, Canada..
    Pavlakis, Nick
    Royal N Shore Hosp, St Leonards, NSW 2065, Australia..
    DiBenedetti, Dana
    RTI Hlth Solut, Res Triangle Pk, NC USA..
    Haydysch, Emily
    RTI Hlth Solut, Res Triangle Pk, NC USA..
    Yang, Qi Melissa
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Jackson, Shanna
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Arnold, Karie
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Law, Linda
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Lapuerta, Pablo
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Assessing Treatment Benefit of Telotristat Etiprate in Patients with Carcinoid Syndrome: Patient Exit Interviews2016In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 45, no 3, 470-470 p.Article in journal (Other academic)
  • 5.
    Antonodimitrakis, Pantelis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tsolakis, Apostolos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kozlovacki, Gordana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gastric carcinoid in a patient infected with Helicobacter pylori: A new entity?2011In: World Journal of Gastroenterology, ISSN 1007-9327, Vol. 17, no 25, 3066-3068 p.Article in journal (Refereed)
    Abstract [en]

    There are four types of gastric carcinoid tumors, classified according to their histology and malignant potential. Only a few cases of carcinoid tumors in patients infected with Helicobacter pylori (H. pylon) have been reported so far. We report a patient infected with H. pylori presenting with a small solitary gastric carcinoid tumor with very low proliferative rate and normal gastrin levels. The tumor was endoscopically removed and the patient received an eradication therapy against H. pylori. No signs of metastatic disease have been found so far during more than 3 year of follow-up. Infection with H. pylon may cause chronic gastritis with normal or elevated gastrin levels, leading to the development of gastric carcinoids by mechanisms unrelated to gastrin. Enterochromaffin-like cell tumors related to a chronic H. pylori infection may be considered as a distinct type of gastric carcinoid tumors.

  • 6.
    Anvari, Ebrahim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Fred, Rikard G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Welsh, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    The H-1-Receptor Antagonist Cetirizine Protects Partially Against Cytokine- and Hydrogen Peroxide-Induced beta-TC6 Cell Death In Vitro2014In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 43, no 4, 624-629 p.Article in journal (Refereed)
    Abstract [en]

    Objective It has been proposed that the histamine 1 (H-1) receptor not only promotes allergic reactions but also modulates autoimmune diseases, such as type 1 diabetes. In line with this, it has recently been reported that the H-1-receptor antagonist cetirizine can counteract the activation of signals/factors pertinent to the pathogenesis of type 1 diabetes and cytokine-induced beta-cell destruction. Therefore, the overall aim of this study was to determine whether H-1-receptor antagonists affect cytokine-induced beta-cell death and signaling in vitro. Methods The insulin-producing cell line beta-TC6 was exposed to the proinflammatory cytokines interleukin 1 beta(+) interferon gamma, or hydrogen peroxide. The H-1-receptor antagonists desloratadine and cetirizine were added to the cell cultures and cell viability; macrophage inhibitory factor levels, c-Jun N-terminal kinase phosphorylation, c-Jun expression, and beta-catenin levels were analyzed by flow cytometry, real-time polymerase chain reaction, and immunoblotting. Results Cetirizine protected partially against both cytokine- and hydrogen peroxide-induced cell death. This effect was paralleled by an inhibition of cytokine-induced c-Jun N-terminal kinase phosphorylation, c-Jun induction, and a restoration of macrophage inhibitory factor contents. Cetirizine also increased the beta-TC6 cell contents of beta-catenin at basal conditions. Conclusions Our results indicate a protective effect of a specific H-1-receptor antagonist.

  • 7.
    Ardesjö Lundgren, Brita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Portela-Gomes, Guida M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Identification of complement C3 as an autoantigen in inflammatory bowel disease2010In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 22, no 4, 429-436 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Autoantibodies against goblet cells in the gastrointestinal mucosa have been described in patients with inflammatory bowel disease (IBD) but a corresponding autoantigen has not yet been identified. The aim of this study was to identify such an antigen. METHODS: First, 10 candidate autoantigens were discarded based on double stainings of appendiceal sections and a mucin-producing cell line (HT29-mtx). Second, an appendiceal cDNA library was immunoscreened with IBD sera. RESULTS: Three out of 48 positive clones were identified as complement C3. Using immunoprecipitation of in vitro transcribed and translated C3, seven of 17 primary sclerosing cholangitis patient sera, 15 of 65 IBD sera, and none out of 54 sera from healthy blood donors showed C3 immunoreactivity. The results were confirmed using western blot and an enzyme-linked immunosorbent assay with alternative sources of C3 protein. CONCLUSION: In conclusion, we have identified complement C3 as a potential autoantigen in IBD and primary sclerosing cholangitis.

  • 8. Benno, Peter
    et al.
    Bark, Johan
    Collinder, Eje
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Midtvedt, Tore
    Norin, Elisabeth
    Major alterations in metabolic activity of intestinal microflora in Crohn's disease2012In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, Vol. 47, no 2, 251-252 p.Article in journal (Refereed)
  • 9. Beyder, A.
    et al.
    Strege, P.
    Rainey, J.
    Bernard, C.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kashyap, P.
    Farrugia, G.
    Shear sensitivity of the voltage-gated sodium selective ion channels (NaV) in the neuroendocrine cell line QGP-12014In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 26, no S1, 26-26 p.Article in journal (Other academic)
  • 10. Bonfiglio, F
    et al.
    Hysi, P G
    Ek, Weronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karhunen, V
    Rivera, N V
    Männikkö, M
    Nordenstedt, H
    Zucchelli, M
    Bresso, F
    Williams, F
    Tornblom, H
    Magnusson, P K
    Pedersen, N L
    Ronkainen, J
    Schmidt, P T
    D'Amato, M
    A meta-analysis of reflux genome-wide association studies in 6750 Northern Europeans from the general population2017In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 29, no 2, e12923Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Gastroesophageal reflux disease (GERD), the regurgitation of gastric acids often accompanied by heartburn, affects up to 20% of the general population. Genetic predisposition is suspected from twin and family studies but gene-hunting efforts have so far been scarce and no conclusive genome-wide study has been reported. We exploited data available from general population samples, and studied self-reported reflux symptoms in relation to genome-wide single nucleotide polymorphism (SNP) genotypes.

    METHODS: We performed a GWAS meta-analysis of three independent population-based cohorts from Sweden, Finland, and UK. GERD cases (n=2247) and asymptomatic controls (n=4503) were identified using questionnaire-derived symptom data. Upon stringent quality controls, genotype data for more than 2.5M markers were used for association testing. Bioinformatic characterization of genomic regions associated with GERD included gene-set enrichment analysis (GSEA), in silico prediction of genetic risk effects on gene expression, and computational analysis of drug-induced gene expression signatures using Connectivity Map (cMap).

    KEY RESULTS: We identified 30 GERD suggestive risk loci (P≤5×10(-5) ), with concordant risk effects in all cohorts, and predicted functional effects on gene expression in relevant tissues. GSEA revealed involvement of GERD risk genes in biological processes associated with the regulation of ion channel and cell adhesion. From cMap analysis, omeprazole had significant effects on GERD risk gene expression, while antituberculosis and anti-inflammatory drugs scored highest among the repurposed compounds.

    CONCLUSIONS: We report a large-scale genetic study of GERD, and highlight genes and pathways that contribute to further our understanding of its pathogenesis and therapeutic opportunities.

  • 11. Borssen, Asa Danielsson
    et al.
    Almer, Sven
    Prytz, Hanne
    Wallerstedt, Sven
    Friis-Liby, Inga-Lill
    Bergquist, Annika
    Nyhlin, Nils
    Hultcrantz, Rolf
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Weiland, Ola
    Lindgren, Stefan
    Verbaan, Hans
    Werner, Marten
    Hepatocellular and extrahepatic cancer in patients with autoimmune hepatitis - a long-term follow-up study in 634 Swedish patients2015In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, Vol. 50, no 2, 217-223 p.Article in journal (Refereed)
    Abstract [en]

    Objectives. Cirrhosis is a well-known risk factor for hepatocellular cancer, but the true risk in autoimmune hepatitis (AIH) is scarcely studied. Other cancers may arise after prolonged use of immune-modulating drugs. The aim of this study was to investigate the cancer risk in a large cohort of AIH patients. Material and methods. Six hundred and thirty-four Swedish patients in a well-defined cohort were matched to the Cause of Death Registry and the Cancer Registry. Standard incidence ratios were calculated by relating the incidences in the cohort to an age-matched material from the Swedish background population. Results. A higher overall incidence of malignancies than the background population was found, counting from the date of diagnosis (standard incidence ratio (SIR) 2.08, 95% CI 1.68-2.55). The highest risk was found for hepatocellular carcinoma (HCC). We found 10 cases (4.0%) in 248 patients with cirrhosis, which gives an incidence rate of 0.3%. Standard incidence ratio for developing hepatobiliary cancer was 54.55 (95% CI 19.92-99.99). HCC only occurred in cirrhotic patients. There was also an increased risk for non-melanoma skin cancer (SIR 9.87, 95% CI 6.26-14.81). Conclusion. A slightly enhanced risk for malignancies in general compared to the background population was found. The risk of hepatobiliary cancer was increased, but the annual risk over the observational period was well under the postulated 1.5% when surveillance in cirrhotic patients is considered to be cost-effective.

  • 12.
    Borssen, Åsa Danielsson
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Marschall, Hanns-Ulrich
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden..
    Bergquist, Annika
    Karolinska Univ Hosp Huddinge, Karolinska Inst, Sect Hepatol & Gastroenterol, Dept Med, Stockholm, Sweden..
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Weiland, Ola
    Karolinska Univ Hosp Huddinge, Karolinska Inst, Div Infect Dis, Dept Med, Stockholm, Sweden..
    Kechagias, Stergios
    Univ Hosp, Dept Gastroenterol & Hepatol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Nyhlin, Nils
    Orebro Univ, Fac Med & Hlth, Dept Gastroenterol, Orebro, Sweden..
    Verbaan, Hans
    Lund Univ, Univ Hosp Skane, Div Gastroenterol, Dept Clin Sci, Malmo, Sweden..
    Nilsson, Emma
    Lund Univ, Univ Hosp Skane, Div Gastroenterol, Dept Clin Sci, Lund, Sweden..
    Werner, Mårten
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Epidemiology and causes of death in a Swedish cohort of patients with autoimmune hepatitis2017In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 52, no 9, 1022-1028 p.Article in journal (Refereed)
    Abstract [en]

    Background: Epidemiological studies of autoimmune hepatitis (AIH) show varying figures on prevalence and incidence, and data on the long-term prognosis are scarce.Objective To investigate the epidemiology, long-term prognosis and causes of death in a Swedish AIH cohort.Material and methods: Data collected from 634 AIH patients were matched to the Cause of Death Registry, and survival analyses were made. Prevalence and incidence were calculated for university hospitals with full coverage of cases and compared to the County of Vasterbotten in Northern Sweden.Results: AIH point prevalence was 17.3/100,000 inhabitants in 2009, and the yearly incidence 1990-2009 was 1.2/100,000 inhabitants and year. The time between diagnosis and end of follow-up, liver transplantation or death was in median 11.3 years (range 0-51.5 years). Men were diagnosed earlier (p<.001) and died younger than women (p=.002). No gender differences were found concerning transplant-free, overall survival and liver-related death. Cirrhosis at diagnosis was linked to an inferior survival (p<.001). Liver-related death was the most common cause of death (32.7%). The relative survival started to diverge from the general population 4 years after diagnosis but a distinct decline was not observed until after more than 10 years.Conclusions: Long-term survival was reduced in patients with AIH. No gender difference regarding prognosis was seen but men died younger, probably as a result of earlier onset of disease. Cirrhosis at diagnosis was a risk factor for poor prognosis and the overall risk of liver-related death was increased.

  • 13. Bucinskaite, V
    et al.
    Tolessa, T
    Pedersen, J
    Rydqvist, B
    Zerihun, L
    Holst, J J
    Hellström, Per M.
    Receptor-mediated activation of gastric vagal afferents by glucagon-like peptide-1 in the rat2009In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 21, no 9, 978-e78 p.Article in journal (Refereed)
    Abstract [en]

    The vagus nerve plays a role in mediating effects of the two glucagon-like peptides GLP-1 and GLP-2 on gastrointestinal growth, functions and eating behaviour. To obtain electrophysiological and molecular evidence for the contribution of afferent pathways in chemoreception from the gastrointestinal tract, afferent mass activity in the ventral gastric branch of the vagus nerve and gene expression of GLP-1 receptors and GLP-2 receptors in the nodose ganglion were examined in Sprague–Dawley rats. Intravenous administration of GLP-1 (30–1000 pmol kg−1), reaching high physiological plasma concentrations, increased vagal afferent mass activity peaking (13–52% above basal level, < 0.05) 3–5 min after injection. Repeated administration of GLP-1 (1000 pmol kg−1; five times, 15 min intervals) elicited similar responses. Pretreatment with GLP-1 receptor antagonist exendin(9-39)amide (500 pmol kg−1) abolished the GLP-1 response to doses 30–300 pmol kg−1 but had no effect on the vagal response to gastric distension. For comparison, GLP-2 (1000 pmol kg−1) had no effect on vagal afferent activity. Vagal chemoreception of GLP-1 is supported by expression of the GLP-1 receptor gene in the nodose ganglion. However, the GLP-2 receptor was also expressed. To conclude, our results show that peripherally administered GLP-1, differently from GLP-2, activates vagal afferents, with no evidence of desensitisation. The GLP-1 effect was blocked by exendin(9-39)amide, suggesting that GLP-1 receptors on vagal afferent nerves mediate sensory input from the gastrointestinal tract or pancreas; either directly or indirectly via the release of another mediator. GLP-2 receptors appear not be functionally expressed on vagal afferents.

  • 14. Cesarini, M.
    et al.
    Collins, G.
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Santos, A.
    Sjöberg, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Parkes, M.
    Keshav, S.
    Travis, S.
    Predicting the risk of acute severe colitis (ASC) at diagnosis of Ulcerative Colitis (UC): external validation2015In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 9, no S1, S117-S118 p.Article in journal (Other academic)
  • 15.
    Cesarini, Monica
    et al.
    Oxford Univ Hosp, Translat Gastroenterol Unit, Oxford, England.;Sapienza Univ Rome, Dipartimento Med Interna & Specialita Med, Rome, Italy..
    Collins, Gary S.
    Univ Oxford, Ctr Stat Med, Oxford, England..
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Santos, Antonieta
    Cambridge Univ Hosp, Gastroenterol Unit, Cambridge, England.;Hosp Amato Lusitano, Gastroenterol Unit, Castelo Branco, Portugal..
    Wang, Lai Mun
    Oxford Univ Hosp, Dept Cellular Pathol, Oxford, England..
    Sjöberg, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Parkes, Miles
    Oxford Univ Hosp, Translat Gastroenterol Unit, Oxford, England..
    Keshav, Satish
    Oxford Univ Hosp, Translat Gastroenterol Unit, Oxford, England..
    Travis, Simon P. L.
    Oxford Univ Hosp, Translat Gastroenterol Unit, Oxford, England..
    Predicting the Individual Risk of Acute Severe Colitis at Diagnosis2017In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 11, no 3, 335-341 p.Article in journal (Refereed)
    Abstract [en]

    Background and Aims: Acute severe colitis [ASC] is associated with major morbidity. We aimed to develop and externally validate an index that predicted ASC within 3 years of diagnosis. Methods: The development cohort included patients aged 16-89 years, diagnosed with ulcerative colitis [UC] in Oxford and followed for 3 years. Primary outcome was hospitalization for ASC, excluding patients admitted within 1 month of diagnosis. Multivariable logistic regression examined the adjusted association of seven risk factors with ASC. Backwards elimination produced a parsimonious model that was simplified to create an easy-to-use index. External validation occurred in separate cohorts from Cambridge, UK, and Uppsala, Sweden. Results: The development cohort [Oxford] included 34/111 patients who developed ASC within a median 14 months [range 1-29]. The final model applied the sum of 1 point each for extensive disease, C-reactive protein [CRP] >10 mg/l, or haemoglobin < 12 g/dl F or < 14 g/dl M at diagnosis, to give a score from 0/3 to 3/3. This predicted a 70% risk of developing ASC within 3 years [score 3/3]. Validation cohorts included different proportions with ASC [Cambridge = 25/96; Uppsala = 18/298]. Of those scoring 3/3 at diagnosis, 18/18 [Cambridge] and 12/13 [Uppsala] subsequently developed ASC. Discriminant ability [c-index, where 1.0 = perfect discrimination] was 0.81 [Oxford], 0.95 [Cambridge], 0.97 [Uppsala]. Internal validation using bootstrapping showed good calibration, with similar predicted risk across all cohorts. A nomogram predicted individual risk. Conclusions: An index applied at diagnosis reliably predicts the risk of ASC within 3 years in different populations. Patients with a score 3/3 at diagnosis may merit early immunomodulator therapy.

  • 16.
    Cui, Tao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Novel Circulating and Tissue Biomarkers for Small Intestine Neuroendocrine Tumors and Lung Carcinoids2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Small intestine neuroendocrine tumors (SI-NETs) and lung carcinoids (LCs) are relatively indolent tumors, which originate from neuroendocrine (NE) cells of the diffuse NE system. Metastases can spread before diagnosis. Thus, potential cures become unavailable, which entitles new biomarker development. Indeed, we aimed at developing Ma2 autoantibodies and olfactory receptor 51E1 (OR51E1) as potential novel biomarkers and exploring other candidate protein markers in patients’ serum.

    First, we established a sensitive, specific and reliable anti-Ma2 indirect ELISA to distinguish SI-NET patients from healthy controls. We detected longer progression-free and recurrence-free survivals in patients expressing low anti-Ma2 titers. Moreover, a high anti-Ma2 titer was more sensitive than chromogranin A for the risk of recurrence after radical operation of SI-NET patients.

    We then investigated OR51E1 expression in SI-NETs and LCs. OR51E1 mRNA expression, analyzed by quantitative real-time PCR, was high in microdissected SI-NET cells, in LC cell lines and in frozen LC specimens. Immunohistochemistry (IHC) showed abundant OR51E1 protein expression in SI-NETs. OR51E1 co-expressed with vesicular-monoamine-transporter-1 in the majority of normal and neoplastic enterochromaffin cells.

    Furthermore, the study on LCs revealed that OR51E1, somatostatin receptor (SSTR) 2, SSTR3, and SSTR5 are expressed in 85%, 71%, 25% and 39% of typical carcinoids (TCs), whereas in 86%, 79%, 43% and 36% of atypical carcinoids (ACs). Based on the proposed IHC scoring system, in the LC cases, where all SSTR subtypes were absent, membrane OR51E1 expression was detected in 10 out of 17 TCs and 1 out of 2 ACs. Moreover, higher OR51E1 scores were detected in 5 out of 6 OctreoScan-negative LC lesions.

    In addition, the last presented study used a novel suspension bead array, which targeted 124 unique proteins, by using Human Protein Atlas antibodies, to profile biotinylated serum samples from SI-NET patients and healthy controls. We showed 9 proteins, IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP as significant contributors to tumor classification.

    In conclusion, we proposed Ma2 autoantibodies as a sensitive circulating marker for SI-NET recurrence; OR51E1 as a candidate therapeutic target for SI-NETs; whereas as a novel diagnostic marker for LCs and 9 serum proteins as novel potential SI-NET markers.

    List of papers
    1. Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors
    Open this publication in new window or tab >>Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors
    Show others...
    2010 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 5, no 12, e16010- p.Article in journal (Refereed) Published
    Abstract [en]

    Background: Small intestine neuroendocrine tumors (SI-NETs) belong to a rare group of cancers. Most patients have developed metastatic disease at the time of diagnosis, for which there is currently no cure. The delay in diagnosis is a major issue in the clinical management of the patients and new markers are urgently needed. We have previously identified paraneoplastic antigen Ma2 (PNMA2) as a novel SI-NET tissue biomarker. Therefore, we evaluated whether Ma2 autoantibodies detection in the blood stream is useful for the clinical diagnosis and recurrence of SI-NETs. Methodology/Principal Findings: A novel indirect ELISA was set up to detect Ma2 autoantibodies in blood samples of patients with SI-NET at different stages of disease. The analysis was extended to include typical and atypical lung carcinoids (TLC and ALC), to evaluate whether Ma2 autoantibodies in the blood stream become a general biomarker for NETs. In total, 124 blood samples of SI-NET patients at different stages of disease were included in the study. The novel Ma2 autoantibody ELISA showed high sensitivity, specificity and accuracy with ROC curve analysis underlying an area between 0.734 and 0.816. Ma2 autoantibodies in the blood from SI-NET patients were verified by western blot and sequential immunoprecipitation. Serum antibodies of patients stain Ma2 in the tumor tissue and neurons. We observed that SI-NET patients expressing Ma2 autoantibody levels below the cutoff had a longer progression and recurrence-free survival compared to those with higher titer. We also detected higher levels of Ma2 autoantibodies in blood samples from TLC and ALC patients than from healthy controls, as previously shown in small cell lung carcinoma samples. Conclusion: Here we show that high Ma2 autoantibody titer in the blood of SI-NET patients is a sensitive and specific biomarker, superior to chromogranin A (CgA) for the risk of recurrence after radical operation of these tumors.

     

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-140192 (URN)10.1371/journal.pone.0016010 (DOI)000285793600058 ()21209860 (PubMedID)
    Available from: 2011-01-04 Created: 2011-01-04 Last updated: 2014-01-23Bibliographically approved
    2. Olfactory receptor 51E1 protein as a potential novel tissue biomarker for small intestine neuroendocrine carcinomas
    Open this publication in new window or tab >>Olfactory receptor 51E1 protein as a potential novel tissue biomarker for small intestine neuroendocrine carcinomas
    Show others...
    2013 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 168, no 2, 253-261 p.Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: Late diagnosis hinders proper management of small intestine neuroendocrine carcinoma (SI-NEC) patients. The olfactory receptor, family 51, subfamily E, member 1 (OR51E1) has been reported as a potential novel SI-NEC marker, without protein expression recognition. Thus, we further studied whether the encoded protein may be a novel SI-NEC clinical biomarker.

    DESIGN: OR51E1 coding sequence was cloned using total RNA from SI-NEC patient specimens. Quantitative real-time PCR analysis explored OR51E1 expression in laser capture microdissected SI-NEC cells and adjacent microenvironment cells. Moreover, immunohistochemistry investigated OR51E1 protein expression on operation and biopsy material from primary SI-NECs, mesentery, and liver metastases from 70 patients. Furthermore, double immunofluorescence studies explored the potential co-localization of the vesicular monoamine transporter 1 (SLC18A1, generally referred to as VMAT1) and OR51E1 in the neoplastic cells and in the intestinal mucosa adjacent to the tumor.

    RESULTS: OR51E1 coding sequence analysis showed absence of mutation in SI-NEC patients at different stages of disease. OR51E1 expression was higher in microdissected SI-NEC cells than in the adjacent microenvironment cells. Furthermore, both membranous and cytoplasmic OR51E1 immunostaining patterns were detected in both primary SI-NECs and metastases. Briefly, 18/43 primary tumors, 7/28 mesentery metastases, and 6/18 liver metastases were 'positive' for OR51E1 in more than 50% of the tumor cells. In addition, co-localization studies showed that OR51E1 was expressed in >50% of the VMAT1 immunoreactive tumor cells and of the enterochromaffin cells in the intestinal mucosa adjacent to the tumor.

    CONCLUSION: OR51E1 protein is a potential novel clinical tissue biomarker for SI-NECs. Moreover, we suggest its potential therapeutic molecular target development using solid tumor radioimmunotherapy.

    National Category
    Cell and Molecular Biology Cancer and Oncology Endocrinology and Diabetes Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:uu:diva-205136 (URN)10.1530/EJE-12-0814 (DOI)000315577400023 ()23184910 (PubMedID)
    Available from: 2013-08-14 Created: 2013-08-14 Last updated: 2015-03-23Bibliographically approved
    3. Olfactory Receptor 51E1 as a Novel Target for Diagnosis in Somatostatin Receptor Negative Lung Carcinoids
    Open this publication in new window or tab >>Olfactory Receptor 51E1 as a Novel Target for Diagnosis in Somatostatin Receptor Negative Lung Carcinoids
    Show others...
    2013 (English)In: Journal of Molecular Endocrinology, ISSN 0952-5041, Vol. 51, 277-286 p.Article in journal (Refereed) Published
    Abstract [en]

    Somatostatin receptors (SSTRs) may be used in lung carcinoids (LCs) for diagnosis and therapy, although additional targets are clearly warranted. This study aimed to investigate whether olfactory receptor 51E1 (OR51E1) may be a potential target for LCs. OR51E1 coding sequence was analyzed in LC cell lines, NCI-H727 and NCI-H720. OR51E1 transcript expression was investigated in LC cell lines and frozen specimens by quantitative real-time PCR. OR51E1, SSTR2, SSTR3, and SSTR5 expression was evaluated by immunohistochemistry on paraffin-embedded sections of 73 typical carcinoids (TCs), 14 atypical carcinoids (ACs) and 11 regional/distant metastases, and compared to OctreoScan data. Immunohistochemistry results were rendered semiquantitatively on a scale from 0 to 3+, taking into account the cellular compartmentalization (membrane vs. cytoplasm) and the percentage of tumor cells (<50% vs. >50%). Our results showed that wild-type OR51E1 transcript was expressed in both LC cell lines. OR51E1 mRNA was expressed in 9/12 TCs and 7/9 ACs (p=NS). Immunohistochemically, OR51E1, SSTR2, SSTR3 and SSTR5 were detected in 85%, 71%, 25% and 39% of TCs, and in 86%, 79%, 43% and 36% of ACs, respectively. OR51E1 immunohistochemical scores were higher or equal compared to SSTRs in 79% of TCs and 86% of ACs. Furthermore, in the LC cases where all SSTR subtypes were lacking, membrane OR51E1 expression was detected in 10/17 TCs and 1/2 ACs. Moreover, higher OR51E1 immunohistochemical scores were detected in 5/6 OctreoScan-negative LC lesions. Therefore, the high expression of OR51E1 in LCs makes it a potential novel diagnostic target in SSTR-negative tumors.

    Keyword
    Olfactory receptor 51E1, lung carcinoids, novel target for diagnosis, somatostatin receptors, OctreoScan
    National Category
    Cell and Molecular Biology Cancer and Oncology Endocrinology and Diabetes
    Research subject
    Endocrinology and Diabetology; Lung Medicine; Molecular Biology; Oncology
    Identifiers
    urn:nbn:se:uu:diva-205526 (URN)10.1530/JME-13-0144 (DOI)000329207100012 ()23969981 (PubMedID)
    Note

    De två första författarna delar första författarskapet.

    Available from: 2013-08-29 Created: 2013-08-19 Last updated: 2014-02-05Bibliographically approved
    4. Identification of Candidate Serum Proteins for Classifying Well-Differentiated Small Intestinal Neuroendocrine Tumors
    Open this publication in new window or tab >>Identification of Candidate Serum Proteins for Classifying Well-Differentiated Small Intestinal Neuroendocrine Tumors
    Show others...
    2013 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 8, no 11, e81712- p.Article in journal (Refereed) Published
    Abstract [en]

    Background

    Patients with well-differentiated small intestine neuroendocrine tumors (WD-SI-NET) are most often diagnosed at a metastatic stage of disease, which reduces possibilities for a curative treatment. Thus new approaches for earlier detection and improved monitoring of the disease are required.

    Materials and methods

    Suspension bead arrays targeting 124 unique proteins with antibodies from the Human Protein Atlas were used to profile biotinylated serum samples. Discoveries from a cohort of 77 individuals were followed up in a cohort of 132 individuals both including healthy controls as well as patients with untreated primary WD-SI-NETs, lymph node metastases and liver metastases.

    Results

    A set of 20 antibodies suggested promising proteins for further verification based on technically verified statistical significance. Proceeding, we assessed the classification performance in an independent cohort of patient serum, achieving, classification accuracy of up to 85% with different subsets of antibodies in respective pairwise group comparisons. The protein profiles of nine targets, namely IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP were verified as significant contributors to tumor classification.

    Conclusions

    We propose new potential protein biomarker candidates for classifying WD-SI-NET at different stage of disease. Further evaluation of these proteins in larger sample sets and with alternative approaches is needed in order to further improve our understanding of their functional relation to WD-SI-NET and their eventual use in diagnostics.

    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell and Molecular Biology Cancer and Oncology Endocrinology and Diabetes Gastroenterology and Hepatology
    Research subject
    Endocrinology and Diabetology; Molecular Biology; Molecular Biotechnology; Oncology
    Identifiers
    urn:nbn:se:uu:diva-205549 (URN)10.1371/journal.pone.0081712 (DOI)000327543500120 ()
    Available from: 2013-08-29 Created: 2013-08-19 Last updated: 2014-01-23Bibliographically approved
  • 17.
    Cui, Tao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Tsolakis, Apostolos V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Li, Su-Chen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Cunningham, Janet L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Lind, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olfactory receptor 51E1 protein as a potential novel tissue biomarker for small intestine neuroendocrine carcinomas2013In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 168, no 2, 253-261 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Late diagnosis hinders proper management of small intestine neuroendocrine carcinoma (SI-NEC) patients. The olfactory receptor, family 51, subfamily E, member 1 (OR51E1) has been reported as a potential novel SI-NEC marker, without protein expression recognition. Thus, we further studied whether the encoded protein may be a novel SI-NEC clinical biomarker.

    DESIGN: OR51E1 coding sequence was cloned using total RNA from SI-NEC patient specimens. Quantitative real-time PCR analysis explored OR51E1 expression in laser capture microdissected SI-NEC cells and adjacent microenvironment cells. Moreover, immunohistochemistry investigated OR51E1 protein expression on operation and biopsy material from primary SI-NECs, mesentery, and liver metastases from 70 patients. Furthermore, double immunofluorescence studies explored the potential co-localization of the vesicular monoamine transporter 1 (SLC18A1, generally referred to as VMAT1) and OR51E1 in the neoplastic cells and in the intestinal mucosa adjacent to the tumor.

    RESULTS: OR51E1 coding sequence analysis showed absence of mutation in SI-NEC patients at different stages of disease. OR51E1 expression was higher in microdissected SI-NEC cells than in the adjacent microenvironment cells. Furthermore, both membranous and cytoplasmic OR51E1 immunostaining patterns were detected in both primary SI-NECs and metastases. Briefly, 18/43 primary tumors, 7/28 mesentery metastases, and 6/18 liver metastases were 'positive' for OR51E1 in more than 50% of the tumor cells. In addition, co-localization studies showed that OR51E1 was expressed in >50% of the VMAT1 immunoreactive tumor cells and of the enterochromaffin cells in the intestinal mucosa adjacent to the tumor.

    CONCLUSION: OR51E1 protein is a potential novel clinical tissue biomarker for SI-NECs. Moreover, we suggest its potential therapeutic molecular target development using solid tumor radioimmunotherapy.

  • 18.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundqvist, Anders
    AstraZeneca R&D, Gothenburg, Sweden..
    Abrahamsson, Bertil
    AstraZeneca R&D, Gothenburg, Sweden..
    Tannergren, Christer
    AstraZeneca R&D, Gothenburg, Sweden..
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Regional Intestinal Permeability of Three Model Drugs in Human2016In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, no 9, 3013-3021 p.Article in journal (Refereed)
    Abstract [en]

    Currently there are only a limited number of determinations of human P-eff in the distal small intestine and none in the large intestine. This has hindered the validation of preclinical models with regard to absorption in the distal parts of the intestinal tract, which can be substantial for BCS class II-IV drugs, and drugs formulated into modified-release (MR) dosage forms. To meet this demand, three model drugs (atenolol, metoprolol, and ketoprofen) were dosed in solution intravenously, and into the jejunum, ileum, and colon of 14 healthy volunteers. The P-eff of each model drug was then calculated using a validated deconvolution method. The median P-eff of atenolol in the jejunum, ileum, and colon was 0.45, 0.15, and 0.013 X 10(-4) cm/s, respectively. The corresponding values for metoprolol were 1.72, 0.72, and 1.30 X 10(-4) cm/s, and for ketoprofen 8.85, 6.53, and 3.37 X 10(-4) cm/s, respectively. This is the first study where the human Peff of model drugs has been determined in all parts of the human intestinal tract in the same subjects. The jejunal values were similar to directly determined values using intestinal single-pass perfusion, indicating that the deconvolution method is a valid approach for determining regional P-eff. The values from this study will be highly useful in the validation of preclinical regional absorption models and in silico tools.

  • 19.
    Darmanis, Spyros
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cui, Tao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Drobin, Kimi
    KTH - Royal Institute of Technology, Stockholm, Sweden.
    Li, Su-Chen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH - Royal Institute of Technology, Stockholm, Sweden.
    Schwenk, Jochen M.
    KTH - Royal Institute of Technology, Stockholm, Sweden.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Identification of Candidate Serum Proteins for Classifying Well-Differentiated Small Intestinal Neuroendocrine Tumors2013In: PLoS ONE, ISSN 1932-6203, Vol. 8, no 11, e81712- p.Article in journal (Refereed)
    Abstract [en]

    Background

    Patients with well-differentiated small intestine neuroendocrine tumors (WD-SI-NET) are most often diagnosed at a metastatic stage of disease, which reduces possibilities for a curative treatment. Thus new approaches for earlier detection and improved monitoring of the disease are required.

    Materials and methods

    Suspension bead arrays targeting 124 unique proteins with antibodies from the Human Protein Atlas were used to profile biotinylated serum samples. Discoveries from a cohort of 77 individuals were followed up in a cohort of 132 individuals both including healthy controls as well as patients with untreated primary WD-SI-NETs, lymph node metastases and liver metastases.

    Results

    A set of 20 antibodies suggested promising proteins for further verification based on technically verified statistical significance. Proceeding, we assessed the classification performance in an independent cohort of patient serum, achieving, classification accuracy of up to 85% with different subsets of antibodies in respective pairwise group comparisons. The protein profiles of nine targets, namely IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP were verified as significant contributors to tumor classification.

    Conclusions

    We propose new potential protein biomarker candidates for classifying WD-SI-NET at different stage of disease. Further evaluation of these proteins in larger sample sets and with alternative approaches is needed in order to further improve our understanding of their functional relation to WD-SI-NET and their eventual use in diagnostics.

  • 20. de Miranda, Noel F. C. C.
    et al.
    van Dinther, Maarten
    van den Akker, Brendy E. W. M.
    van Wezel, Tom
    ten Dijke, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Morreau, Hans
    Transforming Growth Factor beta Signaling in Colorectal Cancer Cells With Microsatellite Instability Despite Biallelic Mutations in TGFBR22015In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 148, no 7, 1427-1437.e8 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: Most colorectal cancer (CRC) cells with high levels of microsatellite instability (MSI-H) accumulate mutations at a microsatellite sequence in the gene encoding transforming growth factor beta receptor II (TGFBR2). TGF beta signaling therefore is believed to be defective in these tumors, although CRC cells with TGFBR2 mutations have been reported to remain sensitive to TGF beta. We investigated how TGF beta signaling might continue in MSI-H CRC cells. METHODS: We sequenced the 10-adenines microsatellite sequence in the TGFBR2 gene of 32 MSI-H colon cancer tissues and 6 cell lines (HCT116, LS180, LS411N, RKO, SW48, and SW837). Activation of TGF beta signaling was detected by SMAD2 phosphorylation and through use of a TGF beta-responsive reporter construct in all CRC cell lines. Transcripts of TGFBR2 were knocked-down in CRC cells using short hairpin RNA. Full-length and mutant forms of TGFBR2 were expressed in LS411N cells, which do not respond to TGF beta, and their activities were measured. RESULTS: SMAD2 was phosphorylated in most MSI-H CRC tissues (strong detection in 44% and weak detection in 34% of MSI-H tumors). Phosphorylation of SMAD2 in MSI-H cells required TGFBR2-even the form encoding a frameshift mutation. Transcription and translation of TGFBR2 with a 1-nucleotide deletion at its microsatellite sequence still produced a full-length TGFBR2 protein. However, protein expression required preservation of the TGFBR2 microsatellite sequence; cells in which this sequence was replaced with a synonymous nonmicrosatellite sequence did not produce functional TGFBR2 protein. CONCLUSION: TGF beta signaling remains active in some MSI-H CRC cells despite the presence of frameshift mutations in the TGFBR2 gene because the mutated gene still expresses a functional protein. Strategies to reactivate TGF beta signaling in colorectal tumors might not be warranted, and the functional effects of mutations at other regions of microsatellite instability should be evaluated.

  • 21. de Ridder, Lissy
    et al.
    Turner, Dan
    Wilson, David C.
    Koletzko, Sibylle
    Martin-de-Carpi, Javier
    Fagerberg, Ulrika L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Spray, Christine
    Sladek, Malgorzata
    Shaoul, Ron
    Roma-Giannikou, Eleftheria
    Bronsky, Jiri
    Serban, Daniela E.
    Cucchiara, Salvatore
    Veres, Gabor
    Ruemmele, Frank M.
    Hojsak, Iva
    Kolho, Kaija L.
    Davies, Ieuan H.
    Aloi, Marina
    Lionetti, Paolo
    Veereman-Wauters, Gigi
    Braegger, Christian P.
    Trindade, Eunice
    Wewer, Anne V.
    Hauer, Almuthe
    Levine, Arie
    Malignancy and Mortality in Pediatric Patients with Inflammatory Bowel Disease: A Multinational Study from the Porto Pediatric IBD Group2014In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 20, no 2, 291-300 p.Article in journal (Refereed)
    Abstract [en]

    Background: The combination of the severity of pediatric-onset inflammatory bowel disease (IBD) phenotypes and the need for intense medical treatment may increase the risk of malignancy and mortality, but evidence regarding the extent of the problem is scarce. Therefore, the Porto Pediatric IBD working group of ESPGHAN conducted a multinational-based survey of cancer and mortality in pediatric IBD. Methods: A survey among pediatric gastroenterologists of 20 European countries and Israel on cancer and/or mortality in the pediatric patient population with IBD was undertaken. One representative from each country repeatedly contacted all pediatric gastroenterologists from each country for reporting retrospectively cancer and/or mortality of pediatric patients with IBD after IBD onset, during 2006-2011. Results: We identified 18 cases of cancers and/or 31 deaths in 44 children (26 males) who were diagnosed with IBD (ulcerative colitis, n = 21) at a median age of 10.0 years (inter quartile range, 3.0-14.0). Causes of mortality were infectious (n = 14), cancer (n = 5), uncontrolled disease activity of IBD (n = 4), procedure-related (n = 3), other non-IBD related diseases (n = 3), and unknown (n = 2). The most common malignancies were hematopoietic tumors (n = 11), of which 3 were hepatosplenic T-cell lymphoma and 3 Ebstein-Barr virus-associated lymphomas. Conclusions: Cancer and mortality in pediatric IBD are rare, but cumulative rates are not insignificant. Mortality is primarily related to infections, particularly in patients with 2 or more immunosuppressive agents, followed by cancer and uncontrolled disease. At least 6 lymphomas were likely treatment-associated by virtue of their phenotype.

  • 22. Degraeuwe, Pieter L J
    et al.
    Beld, Monique P A
    Ashorn, Merja
    Canani, Roberto Berni
    Day, Andrew S
    Diamanti, Antonella
    Fagerberg, Ulrika L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Henderson, Paul
    Kolho, Kaija-Leena
    Van de Vijver, Els
    van Rheenen, Patrick F
    Wilson, David C
    Kessels, Alfons G H
    Faecal calprotectin in suspected paediatric inflammatory bowel disease.2015In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 60, no 3, 339-346 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The diagnostic accuracy of faecal calprotectin (FC) concentration for paediatric inflammatory bowel disease (IBD) is well described at the population level, but not at the individual level. We reassessed the diagnostic accuracy of FC in children with suspected IBD and developed an individual risk prediction rule using individual patient data.

    METHODS: MEDLINE, EMBASE, DARE, and MEDION databases were searched to identify cohort studies evaluating the diagnostic performance of FC in paediatric patients suspected of having IBD. A standard study-level meta-analysis was performed. In an individual patient data meta-analysis, we reanalysed the diagnostic accuracy on a merged patient dataset. Using logistic regression analysis we investigated whether and how the FC value and patient characteristics influence the diagnostic precision. A prediction rule was derived for use in clinical practice and implemented in a spreadsheet calculator.

    RESULTS: According to the study-level meta-analysis (9 studies, describing 853 patients), FC has a high overall sensitivity of 0.97 (95% confidence interval [CI] 0.92-0.99) and a specificity of 0.70 (0.59-0.79) for diagnosing IBD. In the patient-level pooled analysis of 742 patients from 8 diagnostic accuracy studies, we calculated that at an FC cutoff level of 50 μg/g there would be 17% (95% CI 15-20) false-positive and 2% (1-3) false-negative results. The final logistic regression model was based on individual data of 545 patients and included both FC level and age. The area under the receiver operating characteristic curve of this derived prediction model was 0.92 (95% CI 0.89-0.94).

    CONCLUSIONS: In high-prevalence circumstances, FC can be used as a noninvasive biomarker of paediatric IBD with only a small risk of missing cases. To quantify the individual patients' risk, we developed a simple prediction model based on FC concentration and age. Although the derived prediction rule cannot substitute the clinical diagnostic process, it can help in selecting patients for endoscopic evaluation.

  • 23. D'Hoore, A.
    et al.
    Albert, M. R.
    Cohen, S. M.
    Herbst, F.
    Matter, I.
    Van der Speeten, K.
    Dominguez, J.
    Rutten, H.
    Muldoon, J. P.
    Bardakcioglu, O.
    Senagore, A. J.
    Ruppert, R.
    Mills, S.
    Stamos, M. J.
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Choman, E.
    Wexner, S. D.
    COMPRES: a prospective postmarketing evaluation of the compression anastomosis ring CAR 27/ColonRing2015In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 17, no 6, 522-529 p.Article in journal (Refereed)
    Abstract [en]

    AimPreclinical studies have suggested that nitinol-based compression anastomosis might be a viable solution to anastomotic leak following low anterior resection. A prospective multicentre open label study was therefore designed to evaluate the performance of the ColonRing in (low) colorectal anastomosis. MethodThe primary outcome measure was anastomotic leakage. Patients were recruited at 13 different colorectal surgical units in Europe, the United States and Israel. Institutional review board approval was obtained. ResultsBetween 21 March 2010 and 3 August 2011, 266 patients completed the study protocol. The overall anastomotic leakage rate was 5.3% for all anastomoses, including a rate of 3.1% for low anastomoses. Septic anastomotic complications occurred in 8.3% of all anastomoses and 8.2% of low anastomoses. ConclusionNitinol compression anastomosis is safe, effective and easy to use and may offer an advantage for low colorectal anastomosis. A prospective randomized trial comparing ColonRing with conventional stapling is needed.

  • 24.
    Edholm, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Gastric Bypass: Facilitating the Procedure and Long-term Results2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Gastric bypass achieves weight loss in the morbidly obese. Preoperative weight loss is used to reduce the enlarged fatty liver that otherwise reduces visibility during surgery. The purpose of gastric bypass is to provide patients with long-term weight loss. The aim of this thesis was to investigate the result of preoperative low calorie diet on liver volume and to evaluate the long-term result of gastric bypass.

    Paper I showed that four weeks of low calorie diet reduces intrahepatic fat by 40% and facilitates surgery mainly through improved visualisation. Paper II demonstrated that all of the reduction of liver volume occurs during the first two weeks of treatment with low calorie diet.  In paper I liver volume was reduced by 12% and in paper II by 18%. Paper III focused on long-term results and showed that gastric bypass achieves a mean 63% excess body mass index loss in obese patients after 11 years. However, of these 40% undergo abdominoplasty and 2% require additional bariatric surgery. Only 24% adhere to the lifelong recommendation on multivitamins and 72% to Vitamin B12 recommendations. Paper IV evaluated gastric bypass as a revisional procedure after earlier restrictive surgery had failed. Similar weight results as after primary gastric bypass are attained. No patient taking vitamin B12 supplementation was deficient at follow-up, regardless of whether the vitamin was taken as a pill or as intramuscular injections.

    List of papers
    1. Preoperative 4-week low-calorie diet reduces liver volume and intrahepatic fat, and facilitates laparoscopic gastric bypass in morbidly obese
    Open this publication in new window or tab >>Preoperative 4-week low-calorie diet reduces liver volume and intrahepatic fat, and facilitates laparoscopic gastric bypass in morbidly obese
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    2011 (English)In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 21, no 3, 345-350 p.Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: The aim of this study was to explore changes in liver volume and intrahepatic fat in morbidly obese patients during 4 weeks of low-calorie diet (LCD) before surgery and to investigate if these changes would facilitate the following laparoscopic gastric bypass.

    METHODS: Fifteen female patients (121.3 kg, BMI 42.9) were treated preoperatively in an open study with LCD (800-1,100 kcal/day) during 4 weeks. Liver volume and fat content were assessed by magnetic resonance imaging and spectroscopy before and after the LCD treatment.

    RESULTS: Liver appearance and the complexity of the surgery were scored at the operation. Eighteen control patients (114.4 kg, BMI 40.8), without LCD were scored similarly. Average weight loss in the LCD group was 7.5 kg, giving a mean weight of 113.9 kg at surgery. Liver volume decreased by 12% (p < 0.001) and intrahepatic fat by 40% (p < 0.001). According to the preoperative scoring, the size of the left liver lobe, sharpness of the liver edge, and exposure of the hiatal region were improved in the LCD group compared to the controls (all p < 0.05).

    CONCLUSIONS: The overall complexity of the surgery was perceived lower in the LCD group (p < 0.05), due to improved exposure and reduced psychological stress (both p < 0.05). Four weeks of preoperative LCD resulted in a significant decrease in liver volume and intrahepatic fat content, and facilitated the subsequent laparoscopic gastric bypass as scored by the surgeon

    Keyword
    Gastric bypass, Laparoscopy, Low-calorie diet, Magnetic resonance, Morbid obesity
    National Category
    Medical and Health Sciences
    Research subject
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-142256 (URN)10.1007/s11695-010-0337-2 (DOI)000287523200013 ()21181291 (PubMedID)
    Available from: 2011-01-13 Created: 2011-01-13 Last updated: 2014-02-10Bibliographically approved
    2. Low calorie diet during four weeks prior to laparoscopic gastric bypass – no further reduction in liver volume after two weeks
    Open this publication in new window or tab >>Low calorie diet during four weeks prior to laparoscopic gastric bypass – no further reduction in liver volume after two weeks
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Surgery
    Research subject
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-213789 (URN)
    Available from: 2014-01-03 Created: 2014-01-03 Last updated: 2014-02-10
    3. Long-term results 11 years after primary gastric bypass in 384 patients
    Open this publication in new window or tab >>Long-term results 11 years after primary gastric bypass in 384 patients
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    2013 (English)In: Surgery for Obesity and Related Diseases, ISSN 1550-7289, Vol. 9, no 5, 708-713 p.Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Roux-en-Y gastric bypass surgery (RYGB) as treatment of morbid obesity results in substantial weight loss. Most published long-term studies have included few patients at the last follow-up point. The aim of the present study was to explore long-term results in a large cohort of patients 7-17 years after gastric bypass.

    METHODS:

    All 539 patients who had undergone primary RYGB from 1993 to 2003 at Uppsala and Örebro University Hospitals received a questionnaire regarding their postoperative status. Blood samples were obtained and the medical charts studied.

    RESULTS: 

    Of the 539 patients, 384 responded (71.2% response rate, mean age 37.9 yr, body mass index 44.5 kg/m2 at surgery, 317 women, and 67 men). At a mean follow-up of 11.4 years (range 7-17), the body mass index had decreased to 32.5 kg/m2, corresponding to an excess body mass index loss of 63.3%. Similar weight loss was observed, regardless of the length of follow-up. Orally treated diabetes resolved in 72% and sleep apnea and hyperlipidemia were improved. Revisional bariatric surgery had been performed in 2.1% and abdominoplasty in 40.2%. The gastrointestinal symptoms were considered tolerable. The overall result was satisfactory for 79% of the patients and 92% would recommend Roux-en-Y gastric bypass to a friend. Attendance to the annual checkups was 37%. Vitamin B12 supplements were taken by 72% and multivitamins by 24%.

    CONCLUSION:

    At 11 years, substantial weight loss was maintained and revisional surgery was rare. Surprisingly few patients were compliant with the recommendation of lifelong supplements and yearly evaluations; however, patient satisfaction was high.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-181684 (URN)10.1016/j.soard.2012.02.011 (DOI)000325782900023 ()22551577 (PubMedID)
    Available from: 2012-09-27 Created: 2012-09-27 Last updated: 2014-02-10Bibliographically approved
    4. Twelve-year results for revisional gastric bypass after failed restrictive surgery in 131 patients
    Open this publication in new window or tab >>Twelve-year results for revisional gastric bypass after failed restrictive surgery in 131 patients
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    2014 (English)In: Surgery for Obesity and Related Diseases, ISSN 1550-7289, Vol. 10, no 1, 44-48 p.Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Gastric banding (GB) and vertical banded gastroplasty (VBG) may result in unsatisfactory weight loss or intolerable side effects. Such outcomes are potential indications for additional bariatric surgery, and Roux-en-Y gastric bypass is frequently used at such revisions (rRYGB). The present study examined long-term results of rRYGB.

    METHODS: In total, 175 patients who had undergone rRYGB between 1993 and 2003 at 2 university hospitals received a questionnaire regarding their current status. The questionnaire was returned by 131 patients (75% follow-up rate, 66 VBG and 65 GB patients). Blood samples were obtained and medical charts studied. The reason for conversion was mainly unsatisfactory weight loss among the VBG patients and intolerable side effects among GB patients.

    RESULTS: The 131 patients (112 women), mean age 41.8 years at rRYGB, were evaluated at mean 11.9 years (range 7-17) after rRYGB. Mean body mass index of those with prior unsatisfactory weight loss was reduced from 40.1 kg/m(2) (range 28.7-52.2) to 32.6 kg/m(2) (range 19.1-50.2) (P<.01). Only 2 patients (2%) underwent additional bariatric surgery after rRYGB. The overall result was satisfactory for 74% of the patients. Only 21% of the patients adhered to the recommendation of lifelong multivitamin supplements while 76% took vitamin B12. Anemia was present in 18%.

    CONCLUSIONS: rRYGB results in sustained weight loss and satisfied patients when VBG or GB have failed. Subsequent bariatric surgery was rare but micronutrient deficiencies were frequent.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-213784 (URN)10.1016/j.soard.2013.05.011 (DOI)000331773800007 ()24094870 (PubMedID)
    Available from: 2014-01-03 Created: 2014-01-03 Last updated: 2014-04-04Bibliographically approved
  • 25. Edholm, T
    et al.
    Cejvan, Kenan
    Abdel-Halim, S M
    Efendic, S
    Schmidt, P T
    Hellström, Per M.
    The incretin hormones GIP and GLP-1 in diabetic rats: effects on insulin secretion and small bowel motility2009In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 21, no 3, 313-321 p.Article in journal (Refereed)
    Abstract [en]

    Incretin hormones often display inhibitory actions on gut motility. The aim of this study was to investigate if altered responsiveness to glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) as regards insulin release and small bowel motility could bring further clarity to the pathophysiology of diabetes in the Goto-Kakizaki (GK) rat. The isolated perfused pancreas was studied in male GK and Wistar rats (controls) under euglycemic and hyperglycemic conditions. Glucose-dependent insulinotropic peptide (10 nmol L−1) or GLP-1 (10 nmol L−1) were added to the medium and perfusate was collected and analysed for insulin. Moreover, GK and Wistar rats were supplied with bipolar electrodes in the small bowel and myoelectric activity was recorded during intravenous administration of GIP (1–400 pmol kg−1 min−1) or GLP-1 (0.1–20 pmol kg−1 min−1). Finally, tissue was collected from GK and Wistar rats for RNA extraction. Under euglycemia, GIP and GLP-1 stimulated the initial insulin response by 10-fold in GK rats (P < 0.05). At later hyperglycemia, the insulin response to GIP and GLP-1 was blunted to about one-third compared with controls (P < 0.05). In the bowel GLP-1 was about 2.6–16.7 times more potent than GIP in abolishing the migrating myoelectric complex in the GK and control rats. Polymerase chain reaction (PCR) showed GIP and GLP-1 receptor gene expression in pancreatic islets and in small bowel. The initially high, but later low insulin responsiveness to stimulation with GIP and GLP-1 along with inhibition of small bowel motility in the GK rat indicates a preserved incretin response on motility in diabetes type 2.

  • 26. Edholm, T.
    et al.
    Degerblad, M.
    Grybäck, P.
    Hilsted, L.
    Holst, J. J.
    Jacobsson, H.
    Efendic, S.
    Schmidt, P. T.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and insulin-glucose homeostasis2010In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 22, no 11, 1191-e315 p.Article in journal (Refereed)
    Abstract [en]

    Background 

    Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are major incretins with important effects on glucoregulatory functions. The aim of this study was to investigate effects of GIP and GLP-1 on gastric emptying and appetite after a mixed meal, and effects on insulin secretion and glucose disposal in humans.

    Methods 

    Randomized crossover single-blind study in 17 healthy volunteers receiving GIP (2 or 5 pmol kg−1 min−1, n = 8), GLP-1 (0.75 pmol kg−1 min−1, n = 9) or NaCl for 180 min with a radionuclide-labeled omelette and fruit punch (370 kcal). Outcome measures were gastric emptying rate, insulinogenic index, hunger, satiety, desire to eat, and prospective food consumption. Blood was analyzed for GIP, GLP-1, glucagon, C-peptide, peptide YY (PYY) and ghrelin.

    Key Results 

    Glucose-dependent insulinotropic polypeptide 2 and 5 pmol kg−1 min−1 decreased gastric half-emptying time from 128.5 ± 34.0 min in controls to 93.3 ± 6.3 and 85.2 ± 11.0 min (P < 0.05). Glucose-dependent insulinotropic polypeptide 5 pmol kg−1 min−1 decreased postprandial glucose (P < 0.001) and insulin (P < 0.05) with increased insulinogenic index. Glucose-dependent insulinotropic polypeptide had no effects on hunger, desire to eat, satiety or prospective consumption. Glucagon-like peptide-1 0.75 pmol kg−1 min−1 increased half-emptying time from 76.6 ± 7.6 min to 329.4 ± 71.6 (P < 0.01). Glucagon-like peptide-1 decreased plasma glucose and insulin (both P < 0.05–0.001), and increased insulinogenic index markedly. Hunger, desire to eat and prospective consumption were decreased (P < 0.05), and satiety borderline increased (P < 0.06).

    Conclusion & Inferences 

    The incretin effect of GIP and GLP-1 differs as GLP-1 exerts a strong glucoregulatory incretin through inhibition of gastric emptying, which GIP does not. Thus, GLP-1 as incretin mimetic may offer unique benefits in terms of weight loss in treatment of type 2 diabetes.

  • 27. Egenvall, M.
    et al.
    Morner, M.
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Gunnarsson, U.
    Degree of blood loss during surgery for rectal cancer: a population-based epidemiologic study of surgical complications and survival2014In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 16, no 9, 696-702 p.Article in journal (Refereed)
    Abstract [en]

    Aim The hypothesis tested in this study was that major blood loss during surgery for rectal cancer increases the risk for surgical complications and for small bowel obstruction (SBO) as a result of adhesions or tumour recurrence, and reduces overall survival. Method Data were retrieved from the Uppsala/Orebro Regional Rectal Cancer Registry for all patients undergoing radical resection for rectal cancer during 1997-2003 (n = 1843) and were matched against the Swedish National Patient Registry regarding surgery and admission for SBO. These patient records were scrutinized to determine the etiology of surgery for SBO. The registry was scrutinized for blood loss and other surgical complications associated with surgery. Uni- and multivariate Cox analysis and logistic regression were used. Results Ninety-four (5.1%) patients underwent surgery for SBO > 30 days after the index operation: 82 for adhesions and 12 for tumour recurrence. The volume of blood lost did not influence the risk of surgery for SBO as a result of adhesions, but blood loss above the median (>= 800 ml) increased the risk for surgery for SBO caused by tumour recurrence (hazard ratio = 10.52; 95% CI: 1.36-81.51). Increased blood loss increased the risk of surgical complications (OR = 1.78; 95% CI: 1.35-2.35 with blood loss of >= 450 ml) but did not reduce overall survival. Irradiation before surgery increased blood loss, complications and admission for SBO. Conclusion Major blood loss during surgery for rectal cancer increases the risk of later surgery for SBO caused by tumour recurrence and surgical complications, but overall survival is not affected.

  • 28. Ehrsson, Ylva Tiblom
    et al.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Brismar, Kerstin
    Sharp, Lena
    Langius-Eklöf, Ann
    Laurell, Göran
    Explorative study on the predictive value of systematic inflammatory and metabolic markers on weight loss in head and neck cancer patients undergoing radiotherapy2010In: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 18, no 11, 1385-1391 p.Article in journal (Refereed)
    Abstract [en]

    Purpose

    This study aimed to explore the predictive value of systematic inflammatory and metabolic markers in head and neck (H&N) cancer patients during radiotherapy (RT).

    Methods

    Twenty-seven patients were evaluated. The protocol included serial blood tests [highly sensitive C-reactive protein (hsCRP), albumin, insulin-like growth factor 1 (IGF-1), IGF binding protein 1 (IGFBP-1) and ghrelin], measurements of body weight and assessment of oral mucositis.

    Results

    The mean nadir of weight loss was observed at the end of RT. At the time of diagnosis, mean hsCRP was 5.2 +/- 1.0 mg/L. HsCRP significantly increased during RT and decreased during the post-RT period. Mean maximum hsCRP was 35.8 +/- 8.5 mg/L, with seven patients reaching >40 mg/L. A numerical decrease of albumin (by 18.2%) and only small changes in IGF-1, IGFBP-1 and ghrelin levels were observed. None of the metabolic parameters was significantly associated with weight loss.

    Conclusions

    HsCRP increased in response to RT for H&N cancer as a sign of irradiation-induced inflammation. Weight loss was not preceded by changes of the metabolic parameters, indicating that assessment of the blood markers used in this study is of little value. Regular body weight measurement and assessment of oral mucositis are feasible, cheap and important procedures to control the metabolic homeostasis during RT.

  • 29. Ejskjaer, N.
    et al.
    Dimcevski, G.
    Wo, J.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gormsen, L. C.
    Sarosiek, I.
    Softeland, E.
    Nowak, T.
    Pezzullo, J. C.
    Shaughnessy, L.
    Kosutic, G.
    McCallum, R.
    Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study2010In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 22, no 10, 1069-1077 p.Article in journal (Refereed)
    Abstract [en]

    Background 

    Gastroparesis, a chronic disorder of abnormal gastric motility, is common in patients with diabetes mellitus. A synthetic, selective ghrelin receptor agonist, TZP-101, is in clinical development for treatment of gastroparesis. This double-blind, randomized, placebo-controlled study evaluated the safety and efficacy of multiple TZP-101 doses in patients with moderate to severe symptomatic diabetic gastroparesis.

    Methods 

    Patients were admitted to the hospital and adaptively randomized to receive a single 30-min intravenous infusion of 20, 40, 80, 160, 320, or 600 μg kg−1 TZP-101, (n = 57) or placebo, (n = 19) for four consecutive days. Symptoms were evaluated daily with the patient-rated Gastroparesis Cardinal Symptom Index (GCSI) and Gastroparesis Symptom Assessment (GSA). Clinicians rated gastroparesis symptoms on treatment day 4.

    Key Results 

    The 80 μg kg−1 dose was identified as the most effective dose. On day 4, there was statistically significant improvement compared with placebo in the severity of GCSI Loss of Appetite and Vomiting scores for that dose group (P = 0.034 and P = 0.006). In addition, at the 80 μg kg−1 dose, the proportion of patients with at least 50% improvement in vomiting score was significantly different (P = 0.019) compared with placebo. Meal-related GSA scores for Postprandial fullness were significantly improved in the 80 μg kg−1 TZP-101 group compared with placebo (P = 0.012). Clinicians rated the 80 μg kg−1 group better improved than placebo for overall symptom assessment (P = 0.047). Safety profiles were similar in the placebo and TZP-101 groups and all doses were well-tolerated.

  • 30. Ejskjaer, N
    et al.
    Vestergaard, E T
    Hellström, Per M.
    Gormsen, L C
    Madsbad, S
    Madsen, J L
    Jensen, T A
    Pezzullo, J C
    Christiansen, J S
    Shaughnessy, L
    Kosutic, G
    Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis2009In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 29, no 11, 1179-1187 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    TZP-101 is a synthetic, selective ghrelin agonist in development for gastroparesis.

    AIM:

    To assess safety and effects of TZP-101 in diabetes patients with symptomatic gastroparesis.

    METHODS:

    Adults with type 1 or type 2 diabetes mellitus received placebo and TZP-101 (80, 160, 320 or 600 microg/kg) infusions in a cross-over manner following a radiolabelled meal. Blood glucose levels were stabilized using a hyperinsulinemic-euglycemic clamp. Primary endpoints were gastric half emptying and latency times. Secondary measures included assessment of gastroparesis symptoms and endocrine responses.

    RESULTS:

    Ten patients with type 1 (n = 7) or 2 (n = 3) diabetes, moderate-to-severe gastroparesis symptoms and > or =29% retention 4 h after a radiolabelled solid meal were enrolled. TZP-101 produced significant reductions in solid meal half-emptying (20%, P = 0.043) and latency (34%, P = 0.037) times vs. placebo. Reductions in overall postmeal symptom intensity (24%) and postprandial fullness (37%) following TZP-101 infusion were not statistically significant. Most adverse events were mild and self-limiting and there were no identifiable differences in numbers or types of adverse events between TZP-101 and placebo.

    CONCLUSIONS:

    This proof-of-concept study demonstrates that the ghrelin agonist TZP-101 is well-tolerated in diabetes patients with moderate-to-severe chronic gastroparesis and shows statistically significant improvements in gastric emptying.

  • 31.
    Emilsson, Louise
    et al.
    Vardcentralen Varmlands Nysater, Primary Care Res Unit, Varmland County, Sweden.;Univ Oslo, Inst Hlth & Soc, Dept Hlth Management & Hlth Econ, Oslo, Norway..
    Lebwohl, Benjamin
    Columbia Univ Coll Phys & Surg, Dept Med, Celiac Dis Ctr, New York, NY 10032 USA.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ludvigsson, Jonas F.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Orebro Univ Hosp, Dept Pediat, Orebro, Sweden..
    Cardiovascular disease in patients with coeliac disease: A systematic review and meta-analysis2015In: Digestive and Liver Disease, ISSN 1590-8658, E-ISSN 1878-3562, Vol. 47, no 10, 847-852 p.Article in journal (Refereed)
    Abstract [en]

    Background: Coeliac disease has been associated with an increased risk of cardiovascular disease in some studies, whereas other studies have shown no association. We performed a systematic review and meta-analysis of cardiovascular disease in celiac disease. Methods: Pubmed, Cinahl, EMBASE and Medline via Ovid were searched for relevant articles published until January 5, 2015. English-language articles on studies with more than 20 patients were included, and were quality rated using the GRADE risk of bias tool. We used random-effects models and assessed heterogeneity using the I-2 statistic. Results: Ten studies were relevant, reporting the risk of myocardial infarction, cardiovascular death and stroke in 33,128/32,903/32,466 coeliac disease patients respectively. Only one study examined celiac disease and a composite measure of cardiovascular disease and this study found a hazard ratio of 1.10 (95% CI 1.03-1.28). In a meta-analysis, we observed an increased risk of stroke (OR 1.11; 95% CI 1.02-1.20). The risks of myocardial infarction (OR 1.12; 95% CI 0.83-1.40) and cardiovascular death (OR 1.12; 95% CI 0.96-1.29) were similar but were estimated with less certainty. Heterogeneity was low for all outcomes except for myocardial infarction where it was moderate. Conclusion: Coeliac disease was associated with a modestly increased risk of cardiovascular disease, but the evidence base is limited.

  • 32.
    Emilsson, Össur Ingi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Univ Iceland, Fac Med, Reykjavik, Iceland.;Landspitali Univ Hosp, Dept Resp Med & Sleep, Reykjavik, Iceland..
    Benediktsdottir, Bryndis
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Landspitali Univ Hosp, Dept Resp Med & Sleep, Reykjavik, Iceland..
    Olafsson, Isleifur
    Landspitali Univ Hosp, Dept Clin Biochem, Reykjavik, Iceland..
    Cook, Elizabeth
    Landspitali Univ Hosp, Dept Clin Biochem, Reykjavik, Iceland..
    Juliusson, Sigurdur
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Landspitali Univ Hosp, Dept Ear Nose & Throat, Reykjavik, Iceland..
    Berg, Sören
    Lund Univ, Dept Otolaryngol & Head & Neck Surg, Lund, Sweden..
    Nordang, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Björnsson, Einar Stefan
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Landspitali Univ Hosp, Dept Gastroenterol, Reykjavik, Iceland..
    Gudlaugsdottir, Sunna
    Landspitali Univ Hosp, Dept Gastroenterol, Reykjavik, Iceland..
    Gudmundsdottir, Anna Soffia
    Landspitali Univ Hosp, Dept Gastroenterol, Reykjavik, Iceland..
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gislason, Thorarinn
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Landspitali Univ Hosp, Dept Resp Med & Sleep, Reykjavik, Iceland..
    Definition of nocturnal gastroesophageal reflux for studies on respiratory diseases2016In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 51, no 5, 524-530 p.Article in journal (Refereed)
    Abstract [en]

    Objective Nocturnal gastroesophageal reflux (nGER) has been associated with respiratory diseases. Our aim was to study a questionnaire method to identify nGER subjects with respiratory involvement in a general population. Material and methods A subgroup of Icelandic participants in the European Community Respiratory Health Survey III (ECRHS III) reporting symptoms of nGER (n =48) as well as age and gender paired controls (n =42) were studied further by a structured interview, questionnaires, laryngeal fibrescopy, and exhaled breath condensate. A subgroup underwent 24-h oesophageal pH impedance (24-h MII-pH) measurements. Symptoms of nGER were assessed with a modified version of the reflux disease questionnaire (RDQ), where symptoms were divided into daytime and nocturnal. A report of nGER both at baseline and at follow-up was defined as persistent nGER. Results Participants reporting persistent nGER had significantly more signs of laryngopharyngeal reflux according to the reflux finding score than those without nGER (Mean +/- SD: 5.1 +/- 2.3 vs. 3.9 +/- 2.2, p =0.02). Of the 16 persistent nGER subjects that underwent 24-h MII-pH, 11 had abnormal gastroesophageal reflux, but none of three control subjects (69% vs. 0%). Pepsin was more commonly found in exhaled breath condensate in the nGER group (67% vs. 45%, p =0.04). Conclusions Participants with nGER symptoms at least once a month, reported on two occasions, had a high level of positive 24-h MII-pH measurements, laryngeal inflammation and pepsin in exhaled breath condensate. This nGER definition identified a representable group for studies on nGER and respiratory diseases in a general population.

  • 33.
    Engstrand Lilja, Helene
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wefer, Hugo
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17177 Stockholm, Sweden.;Karolinska Inst, Sci Life Lab, S-17177 Stockholm, Sweden..
    Nyström, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Finkel, Yigael
    Karolinska Inst, Dept Clin Sci & Educ, S-11883 Stockholm, Sweden.;Sachs Childrens & Youth Hosp, S-11883 Stockholm, Sweden..
    Engstrand, Lars
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17177 Stockholm, Sweden.;Karolinska Inst, Sci Life Lab, S-17177 Stockholm, Sweden.;Sci Life Lab, Clin Genom Facil, S-17165 Solna, Sweden..
    Intestinal dysbiosis in children with short bowel syndrome is associated with impaired outcome2015In: Microbiome, ISSN 0026-2633, E-ISSN 2049-2618, Vol. 3, UNSP 18Article in journal (Refereed)
    Abstract [en]

    Background: The composition of the intestinal microbiota seems to be an important factor in determining the clinical outcome in children with short bowel syndrome (SBS). Alterations in the microbiota may result in serious complications such as small bowel bacterial overgrowth (SBBO) and intestinal mucosal inflammation that lead to prolonged parenteral nutrition (PN) dependency with subsequently increased risk of liver failure and sepsis. To date, there are no reported mappings of the intestinal microbiome in children with SBS. Here, we present the first report on the intestinal microbial community profile in children with SBS. Findings: The study includes children diagnosed with SBS in the neonatal period. Healthy siblings served as controls. Fecal samples were collected, and microbial profiles were analyzed by using 16S rRNA gene sequencing on the Illumina MiSeq platform. We observed a pronounced microbial dysbiosis in children with SBS on PN treatment with an increased and totally dominating relative abundance of Enterobacteriacae in four out of five children compared to children with SBS weaned from PN and healthy siblings. Conclusions: The overall decreased bacterial diversity in children with SBS is consistent with intestinal microbiome mappings in inflammatory bowel diseases such as Crohn's disease and necrotizing enterocolitis in preterm infants. Our findings indicate that intestinal dysbiosis in children with SBS is associated with prolonged PN dependency.

  • 34.
    Eriksson, Carl
    et al.
    Orebro Univ, Dept Gastroenterol, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    Marsal, Jan
    Lund Univ, Immunol Sect, Lund, Sweden.;Skane Univ Hosp, Dept Gastroenterol, Lund, Sweden..
    Bergemalm, Daniel
    Orebro Univ, Dept Gastroenterol, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    Vigren, Lina
    Ystad Hosp, Dept Internal Med, Ystad, Sweden..
    Bjork, Jan
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Digest Dis, Stockholm, Sweden..
    Eberhardson, Michael
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Digest Dis, Stockholm, Sweden..
    Karling, Pontus
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Soderman, Charlotte
    St Goran Hosp, Dept Internal Med, Stockholm, Sweden..
    Myrelid, Par
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.;Linkoping Univ Hosp, Dept Surg, Linkoping, Sweden..
    Cao, Yang
    Orebro Univ, Sch Med Sci, Dept Clin Epidemiol & Biostat, Orebro, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Sjöberg, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Thörn, Mari
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Karlen, Per
    Danderyd Hosp, Dept Internal Med, Stockholm, Sweden..
    Hertervig, Erik
    Skane Univ Hosp, Dept Gastroenterol, Lund, Sweden..
    Strid, Hans
    Sodra Alvsborgs Sjukhus, Dept Internal Med, Boras, Sweden..
    Ludvigsson, Jonas F.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Orebro Univ Hosp, Dept Pediat, Orebro, Sweden..
    Almer, Sven
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Digest Dis, Stockholm, Sweden..
    Halfvarson, Jonas
    Orebro Univ, Dept Gastroenterol, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    Long-term effectiveness of vedolizumab in inflammatory bowel disease: a national study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG)2017In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 52, no 6-7, 722-729 p.Article in journal (Refereed)
    Abstract [en]

    Objectives: Clinical trials have demonstrated the efficacy of vedolizumab in inflammatory bowel disease (IBD). However, these findings may not reflect the clinical practice. Therefore, we aimed to describe a vedolizumab-treated patient population and assess long-term effectiveness.Materials and methods: Patients initiating vedolizumab between 1 June 2014 and 30 May 2015 were identified through the Swedish National Quality Registry for IBD. Prospectively collected data on treatment and disease activity were extracted. Clinical remission was defined as Patient Harvey Bradshaw index<5 in Crohn's disease (CD) and Patient Simple Clinical Colitis Activity index<3 in ulcerative colitis (UC).Results: Two-hundred forty-six patients (147CD, 92 UC and 7 IBD-Unclassified) were included. On study entry, 86% had failed TNF-antagonist and 48% of the CD patients had undergone1 surgical resection. After a median follow-up of 17 (IQR: 14-20) months, 142 (58%) patients remained on vedolizumab. In total, 54% of the CD- and 64% of the UC patients were in clinical remission at the end of follow-up, with the clinical activity decreasing (p<.0001 in both groups). Faecal-calprotectin decreased in CD (p<.0001) and in UC (p=.001), whereas CRP decreased in CD (p=.002) but not in UC (p=.11). Previous anti-TNF exposure (adjusted HR: 4.03; 95% CI: 0.96-16.75) and elevated CRP at baseline (adjusted HR: 2.22; 95% CI: 1.10-4.35) seemed to be associated with discontinuation because of lack of response. Female sex was associated with termination because of intolerance (adjusted HR: 2.75; 95% CI: 1.16-6.48).Conclusion: Vedolizumab-treated patients represent a treatment-refractory group. A long-term effect can be achieved, even beyond 1 year of treatment.

  • 35. Falkén, Y.
    et al.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Holst, J. J.
    Näslund, E.
    Changes in Glucose Homeostasis after Roux-en-Y Gastric Bypass Surgery for Obesity at Day Three, Two Months, and One Year after Surgery: Role of Gut Peptides2011In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 96, no 7, 2227-2235 p.Article in journal (Refereed)
    Abstract [en]

    Context:

    Endocrine effects of gastric bypass (GBP) surgery for obesity on glucose homeostasis are not fully understood.

    Main Objective:

    The main objective of the study was to assess the changes in plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), leptin, somatostatin, glucose-dependent insulinotropic peptide, enteroglucagon, and glucagon early after GBP.

    Method:

    Twelve obese subjects (body mass index 45.3 ± 1.9 kg/m2) were subjected to a liquid meal without lipids before and 3 d, 2 months, and 1 yr after GBP. Plasma concentrations of glucose, insulin, leptin, and gut peptide hormones were assessed before and for 180 min after the meal. Satiety was measured with visual analog scales. The absorption rate of acetaminophen added to the liquid meal was measured. Insulin resistance was measured by the homeostasis model assessment of insulin resistance.

    Results:

    All subjects lost weight (body mass index 30.3 ± 1.8 kg/m2 at 1 yr). Fasting glucose was significantly lower on d 3 (P < 0.05). There was a progressive decrease in the homeostasis model assessment of insulin resistance after 2 months postoperatively. Postprandially, there was a progressive rise of GLP-1 and enteroglucagon and a transient increase in pancreatic glucagon release over the study period. There was a leftward shift of the time course of plasma glucose and insulin. Somatostatin release was lower on d 3 (P < 0.05) but then unchanged. The absorption rate of acetaminophen was twice as fast after GBP compared with before surgery and did not change over time. Satiety scores increased markedly postoperatively.

    Conclusion:

    Both enhanced insulin sensitivity and incretin hormones, such as GLP-1, contribute to the early control of glucose homeostasis. Progressively increasing postprandial levels of enteroglucagon (oxyntomodulin) and GLP-1 facilitate weight loss and enhance insulin effectiveness.

  • 36. Falkén, Y.
    et al.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sanger, G. J.
    Dewit, O.
    Dukes, G.
    Grybäck, P.
    Holst, J. J.
    Näslund, E.
    Actions of prolonged ghrelin infusion on gastrointestinal transit and glucose homeostasis in humans2010In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 22, no 6, e192-e200 p.Article in journal (Refereed)
    Abstract [en]

    Background

    Ghrelin is produced by enteroendocrine cells in the gastric mucosa and stimulates gastric emptying in healthy volunteers and patients with gastroparesis in short-term studies. The aim of this study was to evaluate effects of intravenous ghrelin on gastrointestinal motility and glucose homeostasis during a 6-h infusion in humans.

    Methods

    Ghrelin  (15 pmol kg−1 min−1) or saline was infused intravenously for 360 min after intake of radio-opaque markers, acetaminophen, and lactulose after a standardized breakfast in 12 male volunteers. Gastric emptying, orocecal transit, colonic transit, postprandial plasma concentrations of glucose, insulin, glucagon-like peptide-1 (GLP-1), and peptide YY were assessed. In vitro studies of gastrointestinal muscle contractility were performed.

    Key Results

    The gastric emptying rate was faster for ghrelin compared to saline (P = 0.002) with a shorter half-emptying time (50.3 ± 3.9 vs 59.9 ± 4.4 min, P = 0.004). There was no effect of ghrelin on orocecal or colonic transit. Postprandial elevations of plasma glucose, insulin, and GLP-1 occurred 15 min earlier and were higher with ghrelin. The insulinogenic index did not change during ghrelin infusion. Basal in vitro contractility was unaffected by ghrelin.

    Conclusions & Inferences

    The effect of a 6-h ghrelin infusion on gastrointestinal motility is limited to the stomach without affecting orocecal or colonic transit. Plasma glucose, insulin, and GLP-1 are elevated postprandially, probably as a result of the hastened gastric emptying. Changes in glucose homeostasis as a consequence of stimulated gastric emptying and hormone release, need to be taken into account in the use of pharmacological stimulants for the treatment of motility disorders.

  • 37.
    Fall, Tove
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Mandic-Havelka, Aleksandra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Helmersson-Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Sundstrom, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Reference Intervals for Fecal Calprotectin in Adults Using Two Different Extraction Methods in the Uppsala-SCAPIS Cohort.2017In: Clinical Laboratory, ISSN 1433-6510, Vol. 63, no 9, 1493-1496 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Fecal calprotectin measurement is generally recommended to exclude inflammatory bowel disease (IBD) in patients with suspected IBD. A problem with the fecal calprotectin assays so far has been the rather long test-turnaround times. Recently a particle enhanced turbidimetric immunoassay (PETIA) for fecal calprotectin with assay times of approximately 10 minutes has been introduced on the European market. The aim of this study was to define reference intervals for adults with this new fecal calprotectin PETIA using two different extraction methods.

    METHODS: Samples were collected from 382 healthy individuals from the Swedish CArdioPulmonary bioImage Study (SCAPIS) Uppsala cohort in the age range 50 - 65 years. 202 samples were processed with CALEX® Cap extraction device (BÜHLMANN, Schönenbuch, Switzerland) and 180 samples were extracted using weighed samples. The extracted samples were analyzed on a Mindray BS-380 using the fCal Turbo PETIA reagent (BÜHLMANN).

    RESULTS: The calculated reference values for the Calex device were < 199 µg/g for the whole cohort, < 184 µg/g for females, and < 215 µg/g for males, while the corresponding values for weighed samples were < 153 µg/g for the whole cohort, < 141 µg/g for females, and < 215 µg/g for males. There were no significant statistical differences for calprotectin levels in males and females.

    CONCLUSIONS: The CALEX device yielded slightly higher calprotectin values. As there were no significant gender differences, the study indicates gender independent reference intervals of < 199 µg/g feces for the CALEX device and < 153 µg/g feces for weighed samples in patients in the 50 - 65 year age range.

  • 38. Feodoroff, Benjamin
    et al.
    Ellström, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Hyytiainen, Heidi
    Sarna, Seppo
    Hanninen, Marja-Liisa
    Rautelin, Hilpi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Campylobacter jejuni isolates in Finnish patients differ according to the origin of infection2010In: Gut Pathogens, ISSN 1757-4749, Vol. 2, no 1, 22Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: BACKGROUND: Campylobacter jejuni is a significant cause of bacterial enteritis worldwide. Very little is known about the pathogenicity mechanisms and virulence factors of this important enteropathogen. C. jejuni isolates from 166 Finnish patients, collected from July to December in 2006, were studied for the presence of putative virulence factors and susceptibility to antimicrobials. Isolates were tested for production of gamma-glutamyltransferase (GGT) as well as the presence of genes ceuE, cgtB, ciaB, cj0486, pldA, virB11, wlaN, and the gene cluster cdtABC. Bacterial characteristics were compared to information on foreign travel history as well as information on the course and the symptoms of disease obtained from questionnaires returned by patients. RESULTS: Except for one domestic isolate, antimicrobial resistance was only detected in isolates of foreign origin. Univariate analyses showed association between bloody stools and both GGT production (p=0.025) and the presence of cgtB (p=0.034). Multivariate analysis verified that GGT production was more prevalent in domestic isolates (p<0.0001), while the genes cj0486 (p<0.0001) and ceuE (p<0.0001) were associated with C. jejuni isolates of foreign origin. CONCLUSIONS: The results indicate that imported and domestic C. jejuni isolates differ significantly in several aspects from each other.

  • 39.
    Flemström, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bengtsson, Magnus Wilhelm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Mäkelä, Kari Antero
    Inst. of Biomedicine, Div. of Physiology, Oulu Univ., Oulu, Finland.
    Herzig, Karl-Heinz
    Inst. of Biomedicine, Div. of Physiology, Oulu Univ., Oulu, Finland.
    Effects of short-term food deprivation on orexin-A-induced intestinal bicarbonate secretion in comparison with related secretagogues2010In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 198, no 3, 373-380 p.Article, review/survey (Refereed)
    Abstract [en]

    Studies of gastrointestinal physiology in humans and intact animals are usually conducted after overnight fast. We have compared effects of orexin-A, vasoactive intestinal polypeptide (VIP), melatonin, serotonin, uroguanylin, ghrelin and prostaglandin E2 (PGE2) on duodenal bicarbonate secretion in fed and overnight fasted animals. This review is a summary of our findings. Secretagogues  were administered by intra-arterial infusion or luminally (PGE2) Enterocyte intracellular calcium ([Ca2+]i) signaling was studied by fluorescence imaging. Total RNA was extracted, reverse transcripted to cDNA and expression of orexin receptors measured by quantitative real-time PCR.

    Orexin-A stimulates the duodenal secretion in continuously fed animals but not in food deprived animals. Similarly, short fasting causes a 100-fold decrease  of the amount of the muscarinic agonist bethanechol required for stimulation of secretion. In contrast, fasting does not affect secretory responses to intra-arterial VIP, melatonin, serotonin, uroguanylin and ghrelin, or that to luminal PGE2. Orexin-A induces [Ca2+]i signaling in enterocytes from fed rats but no significant [Ca2+]i responses occurs in enterocytes from fasted animals. In addition, overnight fasting decreases the expression of mucosal and enterocyte orexin receptors.

    Short food deprivation thus decreases duodenal expression of orexin receptors and abolishes the secretory response to orexin-A as well as orexin-A induced [Ca2+]i signaling. Fasting, furthermore, decreases mucosal sensitivity to bethanechol. The absence of declines in secretory responses to other secretagogues tested is strong evidence that short fasting does affect not the secretory capacity of the duodenal mucosa in general. Studies of intestinal secretion require particular evaluation with respect to feeding status.

  • 40.
    Flemström, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Mäkelä, Kari
    University of Oulu, Oulu, Finland.
    Purhonen, Anna-Kaisa
    University of Oulu, Oulu, Finland.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jedstedt, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Walkowiak, Jan
    University of Medical Sciences, Poznan, Poland.
    Herzig, Karl-Heinz
    University of Oulu, Oulu, Finland.
    Apelin stimulation of duodenal bicarbonate secretion: feeding-dependent and mediated via apelin-induced release of enteric cholecystokinin2011In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 201, no 1, 141-150 p.Article in journal (Refereed)
    Abstract [en]

    Aim: Apelin peptides is the endogenous ligand of the G protein-coupled receptor APJ. Proposed actions include involvement in control of cardiovascular functions, appetite and body metabolism. We have investigated effects of apelin peptides on duodenal bicarbonate secretion in vivo and the release of cholecystokinin (CCK) from acutely isolated mucosal cells and the neuroendocrine cell line STC-1. Methods: Lewis x Dark Agouti rats had free access to water and, unless fasted overnight, free access  to food. A segment of proximal duodenum was cannulated in situ in anesthetized animals. Mucosal bicarbonate secretion was titrated (pH stat) and apelin was administered to the duodenum by close intra-arterial infusion. Total RNA was extracted from mucosal specimens, reverse transcripted to cDNA and expression of the APJ receptor measured by quantitative real-time PCR. Apelin-induced release of CCK was measured using (i) cells prepared from proximal small intestine, and (ii) STC-1 cells. Results: Even the lowest dose of apelin-13 (6 pmol kg-1 h-1) caused a significant rise in bicarbonate secretion. Stimulation occurred only in continuously fed animals and even a 100-fold greater dose (600 pmol kg-1 h-1) of apelin was without effect in overnight food deprived animals. Fasting also induced a 8-fold decrease  in the expression of APJ receptor mRNA. Apelin induced significant release of CCK from both mucosal and STC-1 cells, and the CCKA receptor antagonist devazepide abolished bicarbonate secretory responses to apelin. Conclusions: Apelin-induced stimulation of duodenal electrolyte secretion is feeding dependent and mediated by local mucosal release of CCK

     

  • 41.
    Frigstad, S. O.
    et al.
    Vestre Viken Hosp Trust, Dept Med, Baerum Hosp, Drammen, Norway.;Ostfold Hosp Trust, Dept Res, Gralum, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Hammarlund, P.
    Angelholms Hosp, Dept Med, Angelholm, Sweden..
    Bonderup, O.
    Silkeborg Reg Hosp, Dept Gastroenterol, Silkeborg, Denmark..
    Rannem, T.
    Nordsjaelland Hosp, Dept Gastroenterol, Hillerod, Denmark..
    Haaber, A.
    Herlev Gentofte Hosp, Dept Gastroenterol, Hellerup, Denmark..
    Fallingborg, J.
    Aalborg Univ Hosp, Dept Med Gastroenterol, Aalborg, Denmark..
    Blom, H.
    Sunderby Hosp, Dept Med, Lulea, Sweden..
    Bajor, A.
    Sahlgrens Univ Hosp, Dept Internal Med, Gothenburg, Sweden.;SAS, Dept Med, Boras, Sweden..
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Anaemia and iron deficiency in gastroenterology: a Scandinavian prospective, observational study of iron isomaltoside in clinical practice2017In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 11, S351-S351 p.Article in journal (Other academic)
  • 42. Frigstad, S. O.
    et al.
    Rannem, T.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hammarlund, P.
    Bonderup, O.
    A Scandinavian prospective observational study of iron isomaltoside 1000 treatment: Clinical practice and outcomes in iron deficiency anaemia in patients with IBD2015In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 9, no S1, S320-S320 p.Article in journal (Other academic)
  • 43. Fritsch Fredin, Maria
    et al.
    Vidal, Alexander
    Utkovic, Helena
    Götlind, Yu-Yuan
    Willén, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jansson, Liselotte
    Hultgren Hörnquist, Elisabeth
    Melgar, Silvia
    The application and relevance of ex vivo culture systems for assessment of IBD treatment in murine models of colitis2008In: Pharmacological Research, ISSN 1043-6618, E-ISSN 1096-1186, Vol. 58, no 3-4, 222-231 p.Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the relevance of mouse ex vivo cultures as a first screening model for new therapeutic agents of Inflammatory Bowel Disease (IBD). Two murine models (dextran sodium sulphate (DSS)-induced colitis and Galphai2-deficient mice) and two anti-inflammatory agents (methyl-prednisolone and the proteasome inhibitor MG132) were evaluated. The in vivo effects of methyl-prednisolone were assessed in both models. Ex vivo colonic tissue from both mouse models were cultured in the presence or absence of the drugs and TaqMan Low-Density arrays were used to assess the regulation of inflammatory genes before and after drug treatment. Colitis induced a similar inflammatory gene profile in both mouse models in in vivo studies and in ex vivo cultures. The differences encountered reflected the different phases of colitis in the models, e.g. innate cytokine/chemokine profile in the DSS model and T cell related markers in Galphai2-deficient mice. After steroid treatment, a similar pattern of genes was suppressed in the two mouse models. We confirmed the suppression of inflammatory gene expression for IL-1beta, IL-6 and iNOS in ex vivo and in vivo colons from both mouse models by quantitative RT-PCR. Importantly, the inflammatory responses in the murine ex vivo culture system reflected the in vivo response in the inflamed colonic tissue as assessed by changes in inflammatory gene expression, suggesting that the murine culture system can be used for validation of future IBD therapies.

  • 44. Gibbons, Catherine
    et al.
    Blundell, John E
    Caudwell, Phillipa
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Näslund, Erik
    Finlayson, Graham
    The Role of Episodic Postprandial Peptides in Exercise-Induced Compensatory Eating.2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 11, 4051-4059 p.Article in journal (Refereed)
    Abstract [en]

    Context: Prolonged physical activity gives rise to variable degrees of body weight and fat loss, and is associated with variability in appetite control. Whether these effects are modulated by postprandial, peptides is unclear. We examined the role of postprandial peptide response in compensatory eating during 12 weeks of aerobic exercise and in response to high-fat, low-carbohydrate (HFLC) and low-fat, high-carbohydrate (LFHC) meals.

    Methods: Of the 32 overweight/obese individuals, 16 completed 12 weeks of aerobic exercise and 16 nonexercising control subjects were matched for age and body mass index. Exercisers were classified as responders or nonresponders depending on net energy balance from observed compared with expected body composition changes from measured energy expenditure. Plasma samples were collected before and after meals to compare profiles of total and acylated ghrelin, insulin, cholecystokinin, glucagon-like peptide 1 (GLP-1), and total peptide YY (PYY) between HFLC and LFHC meals, pre- and postexercise, and between groups.

    Results: No differences between pre- and postintervention peptide release. Responders had greater suppression of acylated ghrelin (P < 0.05) than nonresponders, as well as higher postprandial levels of GLP-1 (P < 0.001) and total PYY (P < 0.001) compared with nonresponders and control subjects.

    Conclusion: No impact on postprandial peptide release was found after 12 weeks of aerobic exercise. Responders to exercise-induced weight loss showed greater suppression of acylated ghrelin and greater release of GLP-1 and total PYY at baseline. Therefore, episodic postprandial peptide profiles appear to form part of the pre-existing physiology of exercise responders and suggest differences in satiety potential may underlie exercise-induced compensatory eating.

  • 45. Gibbons, Catherine
    et al.
    Blundell, John E
    Caudwell, Phillipa
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Näslund, Erik
    Finlayson, Graham
    The Role of Episodic Postprandial Peptides in Exercise-Induced Compensatory Eating.2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 11, 4051-4059 p.Article in journal (Refereed)
    Abstract [en]

    Context: Prolonged physical activity gives rise to variable degrees of body weight and fat loss, and is associated with variability in appetite control. Whether these effects are modulated by postprandial, peptides is unclear. We examined the role of postprandial peptide response in compensatory eating during 12 weeks of aerobic exercise and in response to high-fat, low-carbohydrate (HFLC) and low-fat, high-carbohydrate (LFHC) meals.

    Methods: Of the 32 overweight/obese individuals, 16 completed 12 weeks of aerobic exercise and 16 nonexercising control subjects were matched for age and body mass index. Exercisers were classified as responders or nonresponders depending on net energy balance from observed compared with expected body composition changes from measured energy expenditure. Plasma samples were collected before and after meals to compare profiles of total and acylated ghrelin, insulin, cholecystokinin, glucagon-like peptide 1 (GLP-1), and total peptide YY (PYY) between HFLC and LFHC meals, pre- and postexercise, and between groups.

    Results: No differences between pre- and postintervention peptide release. Responders had greater suppression of acylated ghrelin (P < 0.05) than nonresponders, as well as higher postprandial levels of GLP-1 (P < 0.001) and total PYY (P < 0.001) compared with nonresponders and control subjects.

    Conclusion: No impact on postprandial peptide release was found after 12 weeks of aerobic exercise. Responders to exercise-induced weight loss showed greater suppression of acylated ghrelin and greater release of GLP-1 and total PYY at baseline. Therefore, episodic postprandial peptide profiles appear to form part of the pre-existing physiology of exercise responders and suggest differences in satiety potential may underlie exercise-induced compensatory eating.

  • 46.
    Graf, Wilhelm
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Andersson, Magnus
    Åkerlund, Jan-Erik
    Börjesson, Lars
    Long-term outcome after surgery for Crohn's anal fistula2016In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 18, 80-85 p.Article in journal (Refereed)
    Abstract [en]

    AIM: Treatment of Crohn's anal fistula remains challenging and little is known about factors associated with healing. The aim of this study was to assess the rate of healing after surgical treatment and analyse clinical variables related to healing.

    METHOD: 119 patients (63 female, mean age 36 (±13.7) years with histopathologically verified Crohn's disease underwent a surgical procedure for anal fistula at four main referral centres in Sweden, January 1998 - December 2009. Baseline and treatment-related variables were recorded and analysed for correlation with fistula healing at a final follow-up at a mean 7.2 (median 7.1, 1.0-17.5) years.

    RESULTS: Of the 119 patients 62 (52%) were healed at final follow-up. Fourteen healed after one procedure and the remaining 48 healed after a further median of 4.0 (2-20) procedures. Ten (8%) patients were subjected to a proctectomy. Final healing was more common in patients operated with a procedure aiming at eradicating the fistula (P=0.0001), without proctitis (P=0.02), and a shorter duration of Crohn' disease (P=.0019).

    CONCLUSION: Long-term healing of a Crohn's anal fistula can be expected in about half of the patients, usually after repeated surgical treatment. The probability for cure was higher when a curative operation was performed in a patient without proctitis and a shorter duration of Crohn's disease. An attempt to close a Crohn's anal fistula is thus often worthwhile. This article is protected by copyright. All rights reserved.

  • 47. Gryback, P
    et al.
    Bajc, M
    Granerus, G
    Lyrenas, E
    Hermansson, G
    Beckman, KW
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Olsson, E
    Fernstrom, A
    Jacobsson, H
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Undersökning av ventrikeltömning med gammakamera. Kliniskt användbar, enhetlig metod nu fastställd: [Examination of gastric emptying with gamma camera. Clinically useful,uniform method now established]2000In: Läkartidningen, ISSN 0023-7205, Vol. 97, no 15, 1811-1816 p.Article in journal (Other academic)
    Abstract [en]

    Although more than 30 years have passed since the introduction of scintigraphic testing of gastric emptying there has been no well-defined standard. Eight Swedish hospitals have established a nationally standardized method for scintigraphic testing of gastric emptying of solids. 160 healthy subjects participated. The meal consisted of a 99mTc-labeled omelet (1300 kJ) and 150 ml unlabeled soft drink (290 kJ). There were no differences in calculated variables between the centers. Premenopausal women showed slower emptying than postmenopausals and men of any age, making separate reference values for younger women necessary.

  • 48. Gustavsson, A
    et al.
    Järnerot, G
    Hertervig, E
    Friis-Liby, I
    Blomquist, L
    Karlén, P
    Grännö, C
    Vilien, M
    Ström, M
    Verbaan, H
    Hellström, Per M.
    Magnuson, A
    Halfvarson, J
    Tysk, C
    Clinical trial: colectomy after resue therapy in ulcerative colitis-3-year follow-up of the Swedish-Danish controlled infliximab study2010In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 32, no 8, 984-989 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The long-term efficacy of infliximab as rescue therapy in steroid-refractory ulcerative colitis is not well described.

    AIM:

    To examine the long-term efficacy of infliximab as a rescue therapy through a 3-year follow-up of a previous placebo-controlled trial of infliximab in acute steroid-refractory ulcerative colitis.

    METHOD:

    In the original study, 45 patients were randomized to a single infusion of infliximab 5 mg/kg or placebo, and at 3 months, 7/24 patients given infliximab were operated vs. 14/21 patients given placebo. Three years or later, patients were asked to participate in a clinical follow-up.

    RESULTS:

    Another seven patients underwent colectomy during follow-up: five in the infliximab group and two in the placebo group. After 3 years, a total of 12/24 (50%) patients given infliximab and 16/21 (76%) given placebo (P = 0.012) had a colectomy. None of eight patients in endoscopic remission at 3 months later had a colectomy compared with 7/14 (50%) patients who were not in remission (P=0.02). There was no mortality.

    CONCLUSION:

    The benefit of rescue therapy with infliximab in steroid-refractory acute ulcerative colitis remained after 3 years. The main advantage of infliximab treatment occurred during the first 3 months, whereas subsequent colectomy rates were similar in the two groups. Mucosal healing at 3 months influenced later risk of colectomy.

  • 49.
    Hagström, Hannes
    et al.
    Karolinska Univ Hospital, Dept Med, Ctr Digest Dis, Hepatol Unit, Huddinge, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Nasr, Patrik
    Linkoping Univ, Dept Gastroenterol & Hepatol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Ekstedt, Mattias
    Linkoping Univ, Dept Gastroenterol & Hepatol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Kechagias, Stergios
    Linkoping Univ, Dept Gastroenterol & Hepatol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Onnerhag, Kristina
    Lund Univ, Skane Univ Hosp, Dept Gastroenterol & Hepatol, Lund, Sweden..
    Nilsson, Emma
    Lund Univ, Skane Univ Hosp, Dept Gastroenterol & Hepatol, Lund, Sweden..
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sheikhi, Reza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Marschall, Hanns-Ulrich
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden..
    Stal, Per
    Karolinska Univ Hospital, Dept Med, Ctr Digest Dis, Hepatol Unit, Huddinge, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Hultcrantz, Rolf W.
    Karolinska Univ Hospital, Dept Med, Ctr Digest Dis, Hepatol Unit, Huddinge, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Low to moderate lifetime alcohol consumption is associated with less advanced stages of fibrosis in non-alcoholic fatty liver disease2016In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 63, no 1 SUPP, 18A-19A p.Article in journal (Refereed)
  • 50.
    Hagström, Hannes
    et al.
    Karolinska Univ Hosp, Div Hepatol, Ctr Digest Dis, S-14186 Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Nasr, Patrik
    Linkoping Univ, Dept Gastroenterol & Hepatol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Ekstedt, Mattias
    Linkoping Univ, Dept Gastroenterol & Hepatol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Kechagias, Stergios
    Linkoping Univ, Dept Gastroenterol & Hepatol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Önnerhag, Kristina
    Skane Univ Hosp, Dept Gastroenterol & Hepatol, Malmo, Sweden..
    Nilsson, Emma
    Skane Univ Hosp, Dept Gastroenterol & Hepatol, Malmo, Sweden..
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sheikhi, Reza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Marschall, Hanns-Ulrich
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden..
    Hultcrantz, Rolf
    Karolinska Univ Hosp, Div Hepatol, Ctr Digest Dis, S-14186 Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Stål, Per
    Karolinska Univ Hosp, Div Hepatol, Ctr Digest Dis, S-14186 Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Low to moderate lifetime alcohol consumption is associated with less advanced stages of fibrosis in non-alcoholic fatty liver disease2017In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 52, no 2, 159-165 p.Article in journal (Refereed)
    Abstract [en]

    Background and aim: Moderate alcohol consumption has been associated with a lower risk of disease severity in non-alcoholic fatty liver disease (NAFLD). It is unclear if this reflects current or lifetime drinking, or can be attributed to confounders such as diet and exercise. We evaluated the impact of lifetime alcohol consumption on fibrosis severity in NAFLD. Methods: We prospectively enrolled 120 subjects with biopsy-proven NAFLD and through detailed questionnaires examined lifetime alcohol consumption, diet and physical activity. Main outcome measures were odds ratios (OR) for fibrosis stage, calculated through ordinal regression after adjustment for body mass index, diabetes mellitus type 2, smoking and age at biopsy. A biomarker for recent alcohol consumption, phosphatidyl ethanol (PEth) was sampled. Results: An increase in median weekly alcohol consumption to a maximum of 13 drinks per week was associated with lower fibrosis stage (adjusted OR for each incremental unit, 0.86; 95% CI, 0.76-0.97; p = .017). The lowest risk for fibrosis was found with the lowest odds seen in the top quartile of alcohol consumption (aOR 0.23; 95% CI 0.08-0.66; p = .006). Adding soft drink and coffee consumptions, and physical activity to the model did not change the estimates. Subjects with PEth >= 0.3 mu mol/L had higher ORs for a higher fibrosis stage (aOR 2.77; 95% CI 1.01-7.59; p = .047). Conclusion: Lifetime alcohol consumption with up to 13 units per week is associated with lower fibrosis stage in NAFLD. Elevated PEth is associated with higher stages of fibrosis.

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