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  • 1.
    Agreus, Lars
    et al.
    Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Talley, Nicholas J.
    Univ Newcastle, Fac Hlth & Med, Newcastle, NSW, Australia..
    Wallner, Bengt
    Umea Univ, Dept Surg, Umea, Sweden..
    Forsberg, Anna
    Karolinska Inst, Mol Med & Surg, Stockholm, Sweden..
    Vieth, Michael
    Klinikum Bayreuth, Inst Pathol, Bayreuth, Germany..
    Veits, Lothar
    Klinikum Bayreuth, Inst Pathol, Bayreuth, Germany..
    Björkegren, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Engstrand, Lars
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Andreasson, Anna
    Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.;Stockholm Univ, Stress Res Inst, Stockholm, Sweden..
    Towards a healthy stomach?: Helicobacter pylori prevalence has dramatically decreased over 23 years in adults in a Swedish community2016In: United European Gastroenterology journal, ISSN 2050-6406, E-ISSN 2050-6414, Vol. 4, no 5, 686-696 p.Article in journal (Refereed)
    Abstract [en]

    Background In Western countries the prevalence of Helicobacter pylori (H. pylori) infection may be declining but there is a lack of recent longitudinal population studies. We evaluated the changing epidemiology over a 23-year period in Sweden.

    Materials and methods In 1989, the validated Abdominal Symptom Questionnaire (ASQ) was mailed to a random sample of inhabitants (ages 22-80 years) in a Swedish community, and 1097 (87%) responded. H. pylori serology was analysed in a representative subsample (n=145). Twenty-three years later, the ASQ was mailed again using similar selection criteria, and 388 out of 1036 responders had an upper endoscopy with assessment of H. pylori and corpus atrophy status.

    Results The prevalence of positive H. pylori serology decreased from 37.9% (1989) to 15.8% (2012), corresponding to a decrease in odds of 75% per decade (odds ratio (OR): 0.25; 95% confidence interval (CI): 0.11-0.59, p=0.001) independent of age, gender, body mass index (BMI) and level of education, with a pattern consistent with a birth cohort effect. The prevalence increased with increasing age (p=0.001). The prevalence of H. pylori on histology in 2012 was 11.4% (95% CI 8.6-15.0). The prevalence of corpus atrophy on serology and/or histology in 2012 was 3.2% (95% CI 1.8-5.5); all cases were 57 years old.

    Conclusion The stomach is healthier in 2012 compared with 1989. H. pylori prevalence in adults has decreased over the last two decades to a level where clinical management might be affected.

  • 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. Bergquist, Henrik
    et al.
    Agreus, Lars
    Tillander, Lotta
    Johnsson, Folke
    Sorngard, Helene
    Sjostedt, Svante
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Structured Diagnostic and Treatment Approach Versus the Usual Primary Care Approach in Patients With Gastroesophageal Reflux Disease: A Cluster-randomized Multicenter Study2013In: Journal of Clinical Gastroenterology, ISSN 0192-0790, E-ISSN 1539-2031, Vol. 47, no 7, E65-E73 p.Article in journal (Refereed)
    Abstract [en]

    Goals: To compare the clinical outcomes of gastroesophageal reflux disease (GERD) patients treated with an implemented new structured pathway (NSP) or according to existing local clinical practices [old clinical pathway (OCP)]. Background: GERD is a major challenge at the primary care level. Study: Primary care centers (n=24) were cluster randomized to handle patients suffering from symptoms suggestive of GERD according to the NSP (n=97) or the OCP (n=134). In the NSP, the GerdQ questionnaire score was used both for diagnosis and management including treatment. We used validated questionnaires to evaluate disease symptoms, quality of life, and costs at inclusion and at follow-up 2 to 6 months later. Results: On the basis of the Reflux Disease Questionnaire, 56% of the patients treated with the NSP reported total symptom relief at the follow-up compared with 33% in the OCP group (P=0.0013). The reflux symptoms after treatment affected daily activities to a lesser extent in the patients in the NSP group compared with the OCP group (10% vs. 13%, respectively, P=0.01). The utility score of the EuroQoL-5D questionnaire improved more in the NSP group than in the OCP group (0.05 vs. 0.02, respectively, P<0.001). The patients in the NSP group had an approximately 50% lower average total cost for GERD-related health care resources compared with the OCP group [301 Swedish Kronor (SEK) vs. 588 SEK, respectively, NS]. Conclusions: The management of GERD patients in primary care centers using a structured clinical pathway and the results of the GerdQ improves the clinical outcome compared with prevailing local routines (NCT00842387).

  • 5.
    Biglarnia, Alireza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Yamamoto, Shinji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Drachenberg, Cinthia
    Univ Maryland Hosp, Dept Pathol, Baltimore, MD 21201 USA..
    Wagner, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sund, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    von Zur-Muehlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Impact of duodenal cuff inflammation on outcome after clinical pancreas transplantation - a survey of a comprehensive follow-up strategy including serial protocol biopsy of the duodenal cuff2015In: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 22, S15-S15 p.Article in journal (Other academic)
  • 6.
    Biglarnia, AliReza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Yamamoto, Shinji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Drachenberg, Cinthia
    Univ Maryland Hosp, Dept Pathol, Baltimore, MD 21201 USA..
    Wagner, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sund, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    von Zur-Mühlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Impact Of Duodenal Cuff Inflammation On Outcome After Clinical Pancreas Transplantation - A Survey Of A Comprehensive Follow-Up Strategy Including Serial Protocol Biopsy Of The Duodenal Cuff.2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 11, S24-S24 p.Article in journal (Other academic)
  • 7.
    Blom, Kristin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Rubin, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Halfvarson, Jonas
    Torkvist, Leif
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Lordal, Mikael
    Jönsson, Ulla-Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Sjöqvist, Urban
    Håkansson, Lena Douhan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Eosinophil associated genes in the inflammatory bowel disease 4 region: Correlation to inflammatory bowel disease revealed2012In: World Journal of Gastroenterology, ISSN 1007-9327, Vol. 18, no 44, 6409-6419 p.Article in journal (Refereed)
    Abstract [en]

    AIM: To study the association between inflammatory bowel disease (IBD) and genetic variations in eosinophil protein X (EPX) and eosinophil cationic protein (ECP). METHODS: DNA was extracted from ethylene diamine tetraacetic acid blood of 587 patients with Crohn's disease (CD), 592 with ulcerative colitis (UC) and 300 healthy subjects. The EPX405 (G > C, rs2013109), ECP434 (G > C, rs2073342) and ECP562 (G > C, rs2233860) gene polymorphisms were analysed, by the 5'-nuclease allelic discrimination assay. For determination of intracellular content of EPX and ECP in granulocytes, 39 blood samples was collected and extracted with a buffer containing cetyltrimethylammonium bromide. The intracellular content of EPX was analysed using an enzyme-linked immunosorbent assay. The intracellular content of ECP was analysed with the UniCAP (R) system as described by the manufacturer. Statistical tests for calculations of results were chi(2) test, Fisher's exact test, ANOVA, Student-Newman-Keuls test, and Kaplan-Meier survival curve with Log-rank test for trend, the probability values of P < 0.05 were considered statistically significant. RESULTS: The genotype frequency for males with UC and with an age of disease onset of >= 45 years (n = 57) was for ECP434 and ECP562, GG = 37%, GC = 60%, CC = 4% and GG = 51%, GC = 49%, CC = 0% respectively. This was significantly different from the healthy subject's genotype frequencies of ECP434 (GG = 57%, GC = 38%, CC = 5%; P = 0.010) and ECP562 (GG = 68%, GC = 29 /0,CC = 3%; P = 0.009). The genotype frequencies for females, with an age of disease onset of >= 45 years with CD (n = 62), was for the ECP434 and ECP562 genotypes GG = 37%, GC = 52%, CC = 11% and GG = 48%, GC = 47% and CC = 5% respectively. This was also statistically different from healthy controls for both ECP434 (P = 0.010) and ECP562 (P = 0.013). The intracellular protein concentration of EPX and ECP was calculated in mu g/10(6) eosinophils and then correlated to the EPX 405 genotypes. The protein content of EPX was highest in the patients with the CC genotype of EPX405 (GG = 4.65, GC = 5.93, and CC = 6.57) and for ECP in the patients with the GG genotype of EPX405 (GG = 2.70, GC = 2.47 and CC = 1.90). ANOVA test demonstrated a difference in intracellular protein content for EPX (P = 0.009) and ECP (P = 0.022). The age of disease onset was linked to haplotypes of the EPX405, ECP434 and ECP562 genotypes. Kaplan Maier curve showed a difference between haplotype distributions for the females with CD (P = 0.003). The highest age of disease onset was seen in females with the EPX405CC, ECP434GC, ECP562CC haplotype (34 years) and the lowest in females with the EPX405GC, ECP434GC, ECP562GG haplotype (21 years). For males with UC there was also a difference between the highest and lowest age of the disease onset (EPX405CC, ECP434CC, ECP562CC, mean 24 years vs EPX405GC, ECP434GC, ECP562GG, mean 34 years, P = 0.0009). The relative risk for UC patients with ECP434 or ECP562-GC/CC genotypes to develop dysplasia/cancer was 2.5 (95%CI: 1.2-5.4, P = 0.01) and 2.5 (95%CI: 1.1-5.4, P = 0.02) respectively, compared to patients carrying the GG-genotypes. CONCLUSION: Polymorphisms of EPX and ECP are associated to IBD in an age and gender dependent manner, suggesting an essential role of eosinophils in the pathophysiology of IBD.

  • 8. Borssen, A. Danielsson
    et al.
    Lindgren, S.
    Bergquist, A.
    Almer, S.
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Werner, M.
    Risk For Hepatocellular Carcinoma In Autoimmune Hepatitis - Is There An Indication For Surveillance?2013In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 58, no Suppl. 1, S382-S383 p.Article in journal (Other academic)
  • 9. 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.

  • 10.
    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.

  • 11. Bryant, Eleanor J.
    et al.
    King, Neil A.
    Falken, Ylva
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hoist, Jens Juul
    Blundell, John E.
    Naslund, Erik
    Relationships among tonic and episodic aspects of motivation to eat, gut peptides, and weight before and after bariatric surgery2013In: Surgery for Obesity and Related Diseases, ISSN 1550-7289, Vol. 9, no 5, 802-808 p.Article in journal (Refereed)
    Abstract [en]

    Background: The interaction between motivation to eat, eating behavior traits, and gut peptides after Roux-en-Y gastric bypass (RYGB) surgery is not fully understood. Methods: Appetite and hormone responses to a fixed liquid preload were assessed in 12 obese (body mass index 45 +/- 1.9 kg/m(2)) participants immediately before and 3 days, 2 months, and 1 year after RYGB surgery. Subjective appetite and plasma levels of ghrelin, leptin, insulin, and glucagon-like peptide-1 (GLP-1) were measured for a 3-hour postprandial period. Eating behavior traits were also measured using the Three Factor Eating Questionnaire 18 (TFEQR18). Results: There was a decrease in TFEQR18 emotional eating (EE) and uncontrolled eating (UE) from presurgery to 1 year postsurgery but no significant change in cognitive restraint (CR). These changes occurred independently of change in weight. In addition, there was a reduction in subjective appetite ratings and alterations in appetite peptides favoring an anorectic response. Presurgery EE was significantly related to fasting and area under the curve (AUC) ghrelin; UE was associated with AUC desire to eat, and there was a significant association between fasting desire to eat and ghrelin (fasting and AUC). One year postsurgery, UE was positively related to fasting insulin, and CR was negatively associated with GLP-1. UE and subjective hunger were positively correlated, while the relationship between desire to eat and ghrelin remained. onclusion: The relationships among subjective appetite ratings, eating behavior traits, and appetite peptides in obese patients both before and at 1 year after RYGB surgery may contribute to the reduction in a propensity to overeat (as measured by TFEQR18 factors) and weight loss. 

  • 12. Caudwell, P.
    et al.
    Gibbons, C.
    Hopkins, M.
    Näslund, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Finlayson, G.
    Blundell, J.
    Separating Satiety And Satiation In Appetite Control: Effect Of Exercise In Overweight And Obese Adults2013In: Annals of Nutrition and Metabolism, ISSN 0250-6807, E-ISSN 1421-9697, Vol. 63, no Suppl. 1, 1053-1053 p.Article in journal (Other academic)
  • 13. 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)
  • 14.
    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.

  • 15. Costabel, Ulrich
    et al.
    Bendstrup, Elisabeth
    Cottin, Vincent
    Dewint, Pieter
    Egan, Jim J. J.
    Ferguson, James
    Groves, Richard
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Kreuter, Michael
    Maher, Toby M.
    Molina-Molina, Maria
    Nordlind, Klas
    Sarafidis, Alexandre
    Vancheri, Carlo
    Pirfenidone in Idiopathic Pulmonary Fibrosis: Expert Panel Discussion on the Management of Drug-Related Adverse Events2014In: Advances in Therapy, ISSN 0741-238X, E-ISSN 1865-8652, Vol. 31, no 4, 375-391 p.Article, review/survey (Refereed)
    Abstract [en]

    Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.

  • 16.
    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.

  • 17. Ejskjaer, N.
    et al.
    Wo, J.
    Esfandyari, T.
    Jamal, M.
    Dimcevski, G.
    Tarnow, L.
    Malik, R.
    Hellstrom, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Mondou, E.
    Quinn, J.
    Rousseau, F.
    Richard, M.
    Gastric emptying, glycaemia, and upper GI symptoms are independent factors in diabetic gastroparesis2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, S493-S493 p.Article in journal (Other academic)
  • 18. Ejskjaer, N.
    et al.
    Wo, J. M.
    Esfandyari, T.
    Mazen Jamal, M.
    Dimcevski, G.
    Tarnow, L.
    Malik, R. A.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Mondou, E.
    Quinn, J.
    Rousseau, F.
    Mccallum, R. W.
    A phase 2a, randomized, double-blind 28-day study of TZP-102 a ghrelin receptor agonist for diabetic gastroparesis2013In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 25, no 2, e140-e150 p.Article in journal (Refereed)
    Abstract [en]

    Background Gastroparesis causes significant morbidity and treatment options are limited. TZP-102 a novel, macrocyclic, selective, oral ghrelin receptor agonist, was evaluated in a randomized, double-blind, placebo-controlled trial in patients with diabetic gastroparesis. Methods A total of 92 outpatients were randomized to once-daily administrations of 10-mg (n=22), 20-mg (n=21), 40-mg (n=23) TZP-102 or placebo (n=26). The primary endpoint was the change from baseline in gastric half-emptying time (T1/2) utilizing 13C-breath test methodology and secondary endpoints included symptom improvement using patient-reported gastroparesis symptom scores (PAGI-SYM questionnaire) and patient and physician overall treatment evaluations (OTE). Key Results Gastric T1/2 changes were not statistically significant between TZP-102 and placebo after 28days of treatment at any dose. Clinical improvements (-1.0 to -1.4 point mean decrease in symptom severity) occurred in the Gastroparesis Cardinal Symptom Index (GCSI) component of the PAGI-SYM, which was significant vs placebo for all TZP-102 doses combined. Improvements became evident after 1week of treatment. Significantly, more patients given TZP-102 (any dose) had a 50% reduction in baseline GCSI score (28.8%vs 7.7% placebo). Safety profiles were similar across groups. All TZP-102 doses were well-tolerated with no adverse cardiac, weight, or glucose control outcomes. Conclusions &amp; Inferences TZP-102 for 28days, at doses of 10-40mg once daily, was well-tolerated and resulted in a reduction in symptoms of gastroparesis. The lack of correlation between symptom improvement and gastric emptying change is consistent with previous studies in diabetic gastroparesis, and emphasizes the value of patient-defined outcomes in determining therapeutic benefit.

  • 19.
    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.

  • 20. Falken, Y.
    et al.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Abraham-Nordling, M.
    Kressner, U.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Naslund, E.
    Intravenous ghrelin accelerates postoperative gastric emptying and time to first bowel movement in humans2013In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 25, no 6, 474-480 p.Article in journal (Refereed)
    Abstract [en]

    Background Ghrelin has been shown to stimulate gastric emptying in healthy humans and patients with delayed gastric emptying. The aim of this study is to assess the effect of ghrelin on gastric emptying on day 2 after open colorectal surgery. Methods Twenty-four patients (mean age 69.2 +/- 1.4, BMI 25.8 +/- 0.8kgm2) were randomized to saline or ghrelin infusion (15pmolkg1min1) during 3h before and on day 2 after open colorectal surgery. Of these, 20 were assessed both before and after surgery. At start of infusion, a liquid meal (480kcal, 200mL) was administered together with 1.5g acetaminophen. Plasma was obtained at regular intervals together with visual analogue scales for hunger, satiety and nausea. Acetaminophen was analyzed as a marker of gastric emptying. Plasma glucose, insulin, acyl-ghrelin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinoptrophic peptide (GIP), pancreatic polypeptide and peptide YY (PYY) were analyzed. Key Results Gastric emptying was faster during ghrelin infusion compared to saline before and after surgery (P<0.02). In addition, plasma glucose was increased (P<0.05). With ghrelin infusion, plasma insulin was unchanged except for lower values postoperatively (P<0.05). Ghrelin did not alter plasma concentrations of gut peptides. After surgery, ghrelin shortened the time to first bowel movement compared to saline (2.1 +/- 0.3 vs 3.5 +/- 0.4days, P=0.02). Conclusions & Inferences A 3-h ghrelin infusion increased the gastric emptying rate and hastened the time to first bowel movement after surgery. Ghrelin/ghrelin receptor agonists have a therapeutic potential in postoperative ileus; Karolinska Clinical Trial Registry nr CT20110084.

  • 21. Farmer, Adam D
    et al.
    Ban, Vin F
    Coen, Steven J
    Sanger, Gareth J
    Barker, Gareth J
    Gresty, Michael A
    Giampietro, Vincent P
    Williams, Steven C
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Andrews, Paul L R
    Aziz, Qasim
    Visually induced nausea causes characteristic changes in cerebral, autonomic and endocrine function in humans2015In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 593, no 5, 1183-1196 p.Article in journal (Refereed)
    Abstract [en]

    UNLABELLED: Nausea is a highly individual and variable experience. The reasons for this variability are incompletely understood although psychophysiological factors have been proposed. Herein we describe objective psychophysiological changes induced by the subjective sensation of motion sickness. In comparison to subjects who did not develop nausea, nausea-sensitive subjects demonstrated electrogastrographic and autonomic changes, which included an increase in sympathetic nervous system activity with a concomitant reduction in parasympathetic activity. Furthermore, differences were also evident in plasma ghrelin, and subcortical and cortical activity. These data have a number of important implications for future research examining the physiological mechanisms that underlie nausea: ○The physiological, hormonal and cortical patterns identified herein represent potential biomarkers of the physiological mechanisms of nausea. ○Reverse translation of the physiological factors identified may facilitate refinement of animal models used to investigate novel anti-emetic agents and emetic liability of candidate drugs, increasing their validity and translation of finding to humans.

    ABSTRACT: An integrated understanding of the physiological mechanisms involved in the genesis of nausea remains lacking. We aimed to describe the psychophysiological changes accompanying visually induced motion sickness, using a motion video, hypothesizing that differences would be evident between subjects who developed nausea in comparison to those who did not. A motion, or a control, stimulus was presented to 98 healthy subjects in a randomized crossover design. Validated questionnaires and a visual analogue scale (VAS) were used for the assessment of anxiety and nausea. Autonomic and electrogastrographic activity were measured at baseline and continuously thereafter. Plasma vasopressin and ghrelin were measured in response to the motion video. Subjects were stratified into quartiles based on VAS nausea scores, with the upper and lower quartiles considered to be nausea sensitive and resistant, respectively. Twenty-eight subjects were exposed to the motion video during functional neuroimaging. During the motion video, nausea-sensitive subjects had lower normogastria/tachygastria ratio and cardiac vagal tone but higher cardiac sympathetic index in comparison to the control video. Furthermore, nausea-sensitive subjects had decreased plasma ghrelin and demonstrated increased activity of the left anterior cingulate cortex. Nausea VAS scores correlated positively with plasma vasopressin and left inferior frontal and middle occipital gyri activity and correlated negatively with plasma ghrelin and brain activity in the right cerebellar tonsil, declive, culmen, lingual gyrus and cuneus. This study demonstrates that the subjective sensation of nausea is associated with objective changes in autonomic, endocrine and brain networks, and thus identifies potential objective biomarkers and targets for therapeutic interventions.

  • 22.
    Franck-Larsson, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Graf, Wilhelm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Edebol Eeg-Olofsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Axelson, Hans W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Physiological and structural anorectal abnormalities in patients with systemic sclerosis and fecal incontinence2014In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 49, no 9, 1073-1083 p.Article in journal (Refereed)
    Abstract [en]

    Objective

    Fecal incontinence is common in systemic sclerosis (SSc), but the underlying mechanisms are not fully understood. The objectives of this study were to characterize anorectal physiological and morphological defects in SSc patients and to correlate the results with incontinence symptoms.

    Materials and methods

    Twenty-five SSc patients underwent anorectal neurophysiological investigations, anal manometry, and ultrasound.

    Results

    Eleven patients (44%) reported incontinence to solid or liquid feces, but no patient reported diarrhea. Increased fiber density (FD) was recorded in 78% of patients with and in 86% of patients without fecal incontinence not significant (NS). Incontinent patients had lower squeeze pressure (SP; median 49.5 mm Hg) in the high-pressure zone (HPZ) than continent patients (median 72 mm Hg; p = 0.01). In two of the incontinent patients, sonographic abnormalities of the internal anal sphincter (IAS) and the external anal sphincter (EAS) were present, whereas in another two patients isolated IAS abnormalities were seen. These four individuals had lower resting pressure at 1 cm and in the HPZ, and lower SP at 2 cm than patients with normal anorectal sonographic findings (p < 0.05).

    Conclusion

    Lower voluntary SP in incontinent patients and EAS sonographic abnormalities only in patients with incontinence suggest that the EAS is more important in maintaining fecal continence in SSc patients than has previously been reported. The finding of increased FD in most patients further supports involvement of the EAS function in SSc and could indicate previous nerve injury with consequent incomplete reinnervation.

  • 23.
    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)
  • 24. 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)
  • 25. Gibbons, C.
    et al.
    Caudwell, P.
    Finlayson, G.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Naslund, E.
    Blundell, J.
    Gastrointestinal Peptide Response To Fat And Carbohydrate: Implications For Satiety Control2013In: Annals of Nutrition and Metabolism, ISSN 0250-6807, E-ISSN 1421-9697, Vol. 63, no Suppl. 1, 458-458 p.Article in journal (Other academic)
  • 26. Gibbons, Catherine
    et al.
    Caudwell, Phillipa
    Finlayson, Graham
    Naslund, Erik
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellstrom, Per M.
    Blundell, John E.
    Susceptibility And Resistance To Exercise-induced Weight Loss Mediated By Physiological And Psychological Components Of Appetite2013In: Medicine & Science in Sports & Exercise, ISSN 0195-9131, E-ISSN 1530-0315, Vol. 45, no 5, 708-708 p.Article in journal (Other academic)
  • 27. Gibbons, Catherine
    et al.
    Caudwell, Phillipa
    Finlayson, Graham
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Naslund, Erik
    Blundell, John E.
    Comparison of Postprandial Profiles of Ghrelin, Active GLP-1, and Total PYY to Meals Varying in Fat and Carbohydrate and Their Association With Hunger and the Phases of Satiety2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 5, E847-E855 p.Article in journal (Refereed)
    Abstract [en]

    Context: The relationship between postprandial peptides at circulating physiological levels and short-term appetite control is not well understood. Objective: The purpose of this study was first to compare the postprandial profiles of ghrelin, glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) after isoenergetic meals differing in fat and carbohydrate content and second to examine the relationships between ghrelin, GLP-1, and PYY with hunger, fullness, and energy intake. Design: Plasma was collected before and periodically after the meals for 180 minutes, after which time ad libitum food was provided. Simultaneous ratings of hunger and fullness were tracked for 180 minutes through phases identified as early (0-60 minutes) and late (60-180 minutes) satiety. Setting: This study was conducted at the Psychobiology and Energy Balance Research Unit, University of Leeds. Participants: The participants were 16 healthy overweight/obese adults. Main Outcome Measures: Changes in hunger and fullness and metabolic markers were indicators of the impact of the meals on satiety. Results: Ghrelin was influenced similarly by the 2 meals [F-(1,F- 12) = 0.658, P = .433] and was significantly associated with changes in hunger (P < .05), which in turn correlated with food intake (P < .05). GLP-1 and PYY increased more by the high-fat meal [F-(1,F- 15) = 5.099 and F-(1,F- 14) = 5.226, P < .05]. GLP-1 was negatively associated with hunger in the late satiety phase and with energy intake (P < .05), but the PYY profile was not associated with hunger or fullness, nor was PYY associated with food intake. Conclusions: The results demonstrate that under these conditions, these peptides respond differently to ingested nutrients. Ghrelin and GLP-1, but not PYY, were associated with short-term control of appetite over the measurement period.

  • 28. Gibbons, Catherine
    et al.
    Finlayson, Graham
    Caudwell, Phillipa
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Näslund, Erik
    Blundell, John E
    Postprandial profiles of CCK after high fat and high carbohydrate meals and the relationship to satiety in humans2016In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 77, 3-8 p.Article in journal (Refereed)
    Abstract [en]

    CONTEXT: CCK is understood to play a major role in appetite regulation. Difficulties in measuring CCK have limited the potential to assess its profile in relation to food-induced satiety. Improvements in methodology and progress in theoretical understanding of satiety/satiation make it timely for this to be revisited.

    OBJECTIVE: First, examine how physiologically relevant postprandial CCK8/33(s) profiles are influenced by fat (HF) or carbohydrate (HCHO) meals. Second, to examine relationships between postprandial CCK and profiles of satiety (hunger/fullness) and satiation (meal size).

    PARTICIPANTS AND DESIGN: Sixteen overweight/obese adults (11 females/5 males) participated in a randomised-crossover study (46 years, 29.8kg/m(2)) in a university research centre. Plasma was collected preprandially and for 180min postprandially. Simultaneously, ratings of hunger/fullness were tracked for 180min before an ad libitum lunch was provided.

    RESULTS: CCK8/33(s) levels increased more rapidly and reached a higher peak following HF compared to HCHO breakfast (F(1,15)=14.737, p<0.01). Profiles of hunger/fullness did not differ between conditions (F(1,15)=0.505, p=0.488; F(1,15)=2.277, p=0.152). There was no difference in energy intake from the ad libitum meal (HF-3958 versus HCHO-3925kJ; t(14)=0.201, p=0.844). CCK8/33(s) profiles were not associated with subjective appetite during early and late phases of satiety; nor was there an association between CCK8/33(s) and meal size.

    CONCLUSIONS: These results demonstrate CCK levels were higher after HF meal compared to HCHO isocaloric meal. There was no association between CCK levels and intensity of satiety, or with meal size. Under these circumstances, CCK does not appear to play a unique independent role in satiety/satiation. CCK probably acts in conjunction with other peptides and the action of the stomach.

  • 29. Gillberg, L.
    et al.
    Berg, S.
    de Verdier, P. J.
    Lindbom, L.
    Werr, J.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Effective treatment of mouse experimental colitis by alpha 2 integrin antibody: comparison with alpha 4 antibody and conventional therapy2013In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 207, no 2, 326-336 p.Article in journal (Refereed)
    Abstract [en]

    Aim To compare the therapeutic effect of a2 and a4 integrin-blocking antibodies to conventional inflammatory bowel disease drugs methotrexate, 5-aminosalicylic acid and azathioprine in the dextran sulphate sodium mouse colitis model. Methods Colitis was induced in balb/c mice with 2.53.0% dextran sulphate sodium. Treatment was given daily for 7 days after the onset of colitis, by rectal installation. Clinical signs of disease were assessed daily using a disease activity index. After 19 days, all animals were killed and colon samples collected for histological grading and mRNA/protein analysis. All treatment groups were compared with an untreated control group and a treatment group receiving dextran sulphate sodium alone to monitor the potential degree of clinical remission. Results Treatment with anti-a2 antibodies and methotrexate reduced the body weight loss. At the end of treatment, anti-a2 antibodies reduced rectal bleeding, while methotrexate reduced the disease activity index score. Histological evaluation showed that anti-a2 antibodies, methotrexate, 5-aminosalicylic acid and azathioprine treatment reduced the acute inflammation; methotrexate was the only treatment with effect on the crypt score. Compared with the dextran sulphate sodium alone group, the methotrexate group showed down-regulation of IL-1 beta at the mRNA level, while the anti-a2 antibody group displayed decreased protein expression of iNOS and IL-1 beta. Conclusions Specific blocking of extravascular trafficking of leucocytes with a2-antibodies could be a new beneficial drug target in inflammatory bowel disease.

  • 30. Gillberg, L.
    et al.
    Varsanyi, M.
    Sjöström, M.
    Lördal, M.
    Lindholm, J.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nitric oxide pathway-related gene alterations in inflammatory bowel disease2012In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, Vol. 47, no 11, 1283-1297 p.Article in journal (Refereed)
    Abstract [en]

    Objective: To reveal specific gene activation in nitric oxide (NO)-related inflammation we studied differential gene expression in inflammatory bowel disease (IBD). Methods. Total RNA was isolated from 20 biopsies of inflamed mucosa from Crohn's disease (CD) and ulcerative colitis (UC) patients each as well as from six controls, labeled with 32P-dCTP and hybridized to a human NO gene array. Significant genes were analyzed for functional gene interactions and heatmaps generated by hierarchical clustering. A selection of differentially expressed genes was further evaluated with immunohistochemical staining. Results. Significant gene expression differences were found for 19 genes in CD and 23 genes in UC compared to controls, both diseases with high expression of ICAM1 and IL-8. Correlation between microarray expression and corresponding protein expression was significant (r 0.47, p 0.002). Clustering analysis together with functional gene interaction analysis revealed clusters of coregulation and coexpression in CD and UC: transcripts involved in angiogenesis, inflammatory response mediated by the transcription factor hypoxia-inducible factor 1, and tissue fibrosis. Also, a fourth cluster with transcripts regulated by the transcription factor Sp1 was found in UC. Conclusions. Expression analysis in CD and UC revealed disease-specific regulation of NO-related genes, which might be involved in perpetuating inflammatory disease activity in IBD.

  • 31.
    Hagforsen, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Paivandy, Aida
    Lampinen, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Weström, Simone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Calounova, Gabriela
    Melo, Fabio R.
    Rollman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ablation of human skin mast cells in situ by lysosomotropic agents2015In: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 24, no 7, 516-521 p.Article in journal (Refereed)
    Abstract [en]

    Mast cells are known to have a detrimental impact on numerous types of inflammatory skin diseases such as contact dermatitis, atopic eczema and cutaneous mastocytosis. Regimens that dampen skin mast cell-mediated activities can thus offer an attractive therapeutic option under such circumstances. As mast cells are known to secrete a large array of potentially pathogenic compounds, both from preformed stores in secretory lysosomes (granules) and after de novo synthesis, mere inhibition of degranulation or interference with individual mast cell mediators may not be sufficient to provide an effective blockade of harmful mast cell activities. An alternative strategy may therefore be to locally reduce skin mast cell numbers. Here, we explored the possibility of using lysosomotropic agents for this purpose, appreciating the fact that mast cell granules contain bioactive compounds prone to trigger apoptosis if released into the cytosolic compartment. Based on this principle, we show that incubation of human skin punch biopsies with the lysosomotropic agents siramesine or Leu-Leu methyl ester preferably ablated the mast cell population, without causing any gross adverse effects on the skin morphology. Subsequent analysis revealed that mast cells treated with lysosomotropic agents predominantly underwent apoptotic rather than necrotic cell death. In summary, this study raises the possibility of using lysosomotropic agents as a novel approach to targeting deleterious mast cell populations in cutaneous mastocytosis and other skin disorders negatively influenced by mast cells.

  • 32.
    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)
  • 33.
    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.

  • 34.
    Halim, M. Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gillberg, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Boghus, Sandy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellstrom, Per. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nitric oxide regulation of migrating motor complex: randomized trial of N-G-monomethyl-L-arginine effects in relation to muscarinic and serotonergic receptor blockade2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, no 2, 105-118 p.Article in journal (Refereed)
    Abstract [en]

    Aim: The migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using N-G-monomethyl-L-arginine (L-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron. Methods: Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor L-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using L-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry. Results: L-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. L-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated by L-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells. Conclusion: Nitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.

  • 35.
    Halim, Md. Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Gut peptides in gastrointestinal motility and mucosal permeability2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Gut regulatory peptides, such as neuropeptides and incretins, play important roles in hunger, satiety and gastrointestinal motility, and possibly mucosal permeability. Many peptides secreted by myenteric nerves that regulate motor control are also produced in mucosal epithelial cells. Derangements in motility and mucosal permeability occur in many diseases. Current knowledge is fragmentary regarding gut peptide actions and mechanisms in motility and permeability.

    This thesis aimed to 1) develop probes and methods for gut permeability testing, 2) elucidate the role of neuropeptide S (NPS) in motility and permeability, 3) characterize nitrergic muscle relaxation and 4) characterize mechanisms of glucagon-like peptide 1 (GLP-1) and the drug ROSE-010 (GLP-1 analog) in motility inhibition.

    A rapid fluorescent permeability test was developed using riboflavin as a transcellular transport probe and the bisboronic acid 4,4'oBBV coupled to the fluorophore HPTS as a sensor for lactulose, a paracellular permeability probe. This yielded a lactulose:riboflavin ratio test.

    NPS induced muscle relaxation and increased permeability through NO-dependent mechanisms. Organ bath studies revealed that NPS induced NO-dependent muscle relaxation that was tetrodotoxin (TTX) sensitive. In addition to the epithelium, NPS and its receptor NPSR1 localized at myenteric nerves. Circulating NPS was too low to activate NPSR1, indicating NPS uses local autocrine/paracrine mechanisms.

    Nitrergic signaling inhibition by nitric oxide synthase inhibitor L-NMMA elicited premature duodenojejunal phase III contractions in migrating motility complex (MMC) in humans. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. Intestinal contractions were stimulated by L-NMMA, but not TTX. NOS immunoreactivity was detected in the myenteric plexus but not smooth muscle.

    Food-intake increased motility of human antrum, duodenum and jejunum. GLP-1 and ROSE-010 relaxed bethanechol-induced contractions in muscle strips. Relaxation was blocked by GLP-1 receptor antagonist exendin(9-39) amide, L-NMMA, adenylate cyclase inhibitor 2´5´-dideoxyadenosine or TTX. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle.

    In conclusion, rapid chemistries for permeability were developed while physiological mechanisms of NPS, nitrergic and GLP-1 and ROSE-010 signaling were revealed. In the case of NPS, a tight synchrony between motility and permeability was found.

     

    List of papers
    1. Rapid small intestinal permeability assay based on riboflavin and lactulose detected by bis-boronic acid appended benzyl viologens
    Open this publication in new window or tab >>Rapid small intestinal permeability assay based on riboflavin and lactulose detected by bis-boronic acid appended benzyl viologens
    Show others...
    2015 (English)In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 439, 115-121 p.Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Although organoboronic acids are efficient high-throughput sugar sensors, they have not been pursued for gut permeability studies. A modification of the lactulose/mannitol assay is described by which small intestinal permeability is assessed at the time of urine collection using a lactulose/riboflavin ratio.

    METHODS: Volunteers ingested 50mg riboflavin and either 5g mannitol or 10g lactulose. Urine was collected for 6hrs. Riboflavin was assayed by autofluorescence. Riboflavin was removed by C18 solid phase extraction. Lactulose and mannitol were then assayed using 1,1'-bis(2-boronobenzyl)-4,4'-bipyridinium (4,4'oBBV) coupled to the fluorophore HPTS.

    RESULTS: The temporal profile over 6hrs for riboflavin paralleled mannitol. Riboflavin recovery in urine was 11.1±1.9 % (mean±SEM, n=7), similar to mannitol. There was selective binding of 4,4'oBBV to lactulose, likely involving cooperativity between the fructose and galactose moieties. Lower limits of detection and quantification were 90 and 364μM. The lactulose assay was insensitive to other permeability probes (e.g., sucrose, sucralose) while tolerating glucose or lactose. This assay can be adapted to automated systems. Stability of 4,4'oBBV exceeds 4years.

    CONCLUSIONS: Riboflavin measured by autofluorescence combined with lactulose measured with 4,4'oBBV represents a useful new chemistry for rapid measurement of intestinal permeability with excellent stability, cost and throughput benefits.

    Keyword
    Intestinal permeability, Organoborane, Gastroenterology, Lactulose, Mannitol, Riboflavin
    National Category
    Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:uu:diva-236349 (URN)10.1016/j.cca.2014.09.031 (DOI)000347499700021 ()25300228 (PubMedID)
    Note

    De två första författarna delar första författarskapet.

    Available from: 2014-11-18 Created: 2014-11-18 Last updated: 2016-05-25Bibliographically approved
    2. Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide
    Open this publication in new window or tab >>Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide
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    2015 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 309, no 8, G625-G634 p.Article in journal (Refereed) Published
    Abstract [en]

    Neuropeptide S (NPS) receptor (NPSR1) polymorphisms are associated with enteral dysmotility and inflammatory bowel disease (IBD). This study investigated the role of NPS in conjunction with nitrergic mechanisms in the regulation of intestinal motility and mucosal permeability. In rats, small intestinal myoelectric activity and luminal pressure changes in small intestine and colon, along with duodenal permeability were studied. In human intestine, NPS and NPSR1 were localized by immunostaining. Pre- and postprandial plasma NPS was measured by ELISA in healthy and active IBD humans. Effects and mechanisms of NPS were studied in human intestinal muscle strips. In rats, NPS 100-4000 pmol/kg·min had effects on the small intestine and colon. Low doses of NPS increased myoelectric spiking (p<0.05). Higher doses reduced spiking and prolonged the cycle length of the migrating myoelectric complex, reduced intraluminal pressures (p<0.05-0.01) and increased permeability (p<0.01) through NO-dependent mechanisms. In human intestine, NPS localized at myenteric nerve cell bodies and fibers. NPSR1 was confined to nerve cell bodies. Circulating NPS in humans was tenfold below the ~0.3 nmol/l dissociation constant (Kd) of NPSR1, with no difference between healthy and IBD subjects. In human intestinal muscle strips pre-contracted by bethanechol, NPS 1-1000 nmol/l induced NO-dependent muscle relaxation (p<0.05) that was sensitive also to tetrodotoxin (p<0.01). In conclusion, NPS inhibits motility and increases permeability in neurocrine fashion acting through NO in the myenteric plexus in rats and humans. Aberrant signaling and up-regulation of NPSR1 could potentially exacerbate dysmotility and hyperpermeability by local mechanisms in gastrointestinal functional and inflammatory reactions.

    Keyword
    inflammation; inflammatory bowel disease; migrating motor complex; NO; peristalsis
    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-264766 (URN)10.1152/ajpgi.00104.2015 (DOI)000364068300002 ()26206857 (PubMedID)
    Funder
    The Swedish Medical Association, SLS-176671Swedish Research Council, 7916Swedish Society of Medicine, SLS-176671Swedish National Board of Health and Welfare, SLS-176671
    Note

    Shared first name: Wan Salman Wan Saudi and Md. Abdul Halim.

    Shared last name: Dominic-Luc Webb, Markus Sjöblom and Per M. Hellström.

    Available from: 2015-10-16 Created: 2015-10-16 Last updated: 2017-01-25Bibliographically approved
    3. Nitric oxide regulation of migrating motor complex: randomised trial of L-NMMA effects in relation to muscarinic and serotonergic receptor blockade
    Open this publication in new window or tab >>Nitric oxide regulation of migrating motor complex: randomised trial of L-NMMA effects in relation to muscarinic and serotonergic receptor blockade
    Show others...
    2015 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, no 2, 105-118 p.Article in journal (Refereed) Published
    Abstract [en]

    Aim

    The migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using NG-monomethyl-l-arginine (l-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron.

    Methods

    Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor l-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using l-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry.

    Results

    l-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. l-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. l-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated byl-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells.

    Conclusion

    Nitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.

    Keyword
    motility, myenteric plexus, NG-monomethyl-l-arginine, nitric oxide, nitric oxide synthase
    National Category
    Gastroenterology and Hepatology
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-259469 (URN)DOI:10.1111/apha.12554 (DOI)
    Funder
    Swedish Research Council, 7916
    Note

    De 2 första författarna delar förstaförfattarskapet.

    The study was supported by Swedish Research Council (7916), Uppsala University (540113) and the Erik, Karin och Gösta Selander Fund (14-03-07)

    Available from: 2015-08-04 Created: 2015-08-04 Last updated: 2017-01-25Bibliographically approved
    4. GLP-1 acts at myenteric neurons to inhibit motility in humans: results of in vivo motility studies and in vitro characterization of responses to GLP-1 and ROSE-010: GLP-1 and digestive motility
    Open this publication in new window or tab >>GLP-1 acts at myenteric neurons to inhibit motility in humans: results of in vivo motility studies and in vitro characterization of responses to GLP-1 and ROSE-010: GLP-1 and digestive motility
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Glucagon-like peptide-1 (GLP-1) is secreted from L-cells after nutrient ingestion, inhibiting motility. Aims: To clarify whether infused GLP-1 inhibits in vivo prandial motility response and determine the likeliest target cell type and mechanism of action of GLP-1 and its analogue ROSE-010 using in vitro human gut muscle strips. Methods: Sixteen healthy volunteers underwent antroduodenojejunal manometry. Recordings of 1 hour infusion of saline or GLP-1 (0.7 or 1.2 pmol/kg/min) were compared. Plasma GLP-1 and GLP-2 were measured by RIA. Gastrointestinal muscle strips from surgical re-sections, pre-contracted with bethanechol or electric field stimulation (EFS), were investigated for GLP-1 or ROSE-010 induced relaxation. Receptors for GLP-1 and GLP-2 (GLP-1R, GLP-2R) were visualized by immunohistochemistry. Mechanisms were studied employing exendin(9-39) amide, Lw-nitro-monomethyl arginine (L-NMMA), 2´5´-dideoxyadenosine (DDA) and tetrodotoxin (TTX). Results: Food-intake increased motility index from 4.0±0.5 to 6.4±0.3 (antrum), 4.2±0.4 to 5.7±0.4 (duodenum) and 4.6±0.3 to 5.9±0.2 (jejunum) ln(Σ(mmHg·s·min-1)). GLP-1 at 0.7 pmol/kg/minwas sufficient to suppress these indexes from 6.2±0.4 to 3.8±0.7, 5.6±0.6 to 3.9±0.6 and 5.8±0.1 to 4.6±0.4 ln(Σ(mmHg·s·min-1)). Both GLP-1 doses raised plasma GLP-1, but not GLP-2. GLP-1 (EC50 40 nM) and ROSE-010 (EC50 50 nM) relaxed bethanechol-induced contractions in muscle strips. Inhibitory responses were blocked by exendin(9-39) amide, L-NMMA, DDA or TTX pre-treatment. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle. Conclusions: GLP-1 and ROSE-010 inhibit motility through GLP-1R at myenteric neurons, which also possess GLP-2 receptors. GLP-1 increases more than GLP-2 with meals and does not increase plasma GLP-2. GLP-1 and ROSE-010 relaxations are cAMP and NO dependent.

    Keyword
    Antroduodenojejunal motility, Glucagon-like peptides, Peptide hormones, ROSE-010, exendin(9-39) amide
    National Category
    Medical and Health Sciences
    Research subject
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-294388 (URN)
    Available from: 2016-05-19 Created: 2016-05-19 Last updated: 2016-05-25
  • 36.
    Halim, Md Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gillberg, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Boghus, Sandy
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Dominic-Luc, Webb
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    M. Hellström, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nitric oxide regulation of migrating motor complex: randomised trial of L-NMMA effects in relation to muscarinic and serotonergic receptor blockade2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, no 2, 105-118 p.Article in journal (Refereed)
    Abstract [en]

    Aim

    The migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using NG-monomethyl-l-arginine (l-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron.

    Methods

    Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor l-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using l-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry.

    Results

    l-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. l-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. l-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated byl-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells.

    Conclusion

    Nitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.

  • 37.
    Halim, Md. Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Marie, Degerblad
    Karolinska Institutet.
    Dominic-Luc, Webb
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Magnus, Sundbom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery. Uppsala University.
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    GLP-1 Inhibits Prandial Antro-Duodeno-Jejunal Motility in Humans: Native GLP-1 Compared With Analogue ROSE-010 In Vitro2016In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 150, no 4, suppl. 1, S97-S98 p.Article in journal (Refereed)
    Abstract [en]

    Background: Glucagon-like peptide-1 (GLP-1) is secreted from L-cells after nutrient ingestion, inhibiting motility. Aims: To clarify whether infused GLP-1 inhibits in vivo prandial motility response and determine the likeliest target cell type and mechanism of action of GLP-1 and its analogue ROSE-010 using in vitro human gut muscle strips. Methods: Sixteen healthy volunteers underwent antroduodenojejunal manometry. Recordings of 1 hour infusion of saline or GLP-1 (0.7 or 1.2 pmol/kg/min) were compared. Plasma GLP-1 and GLP-2 were measured by RIA. Gastrointestinal muscle strips from surgical re-sections, pre-contracted with bethanechol or electric field stimulation (EFS), were investigated for GLP-1 or ROSE-010 induced relaxation. GLP-1, GLP-2 and receptors for GLP-1 and GLP-2 (GLP-1R, GLP-2R) were visualized by immunohistochemistry. Mechanisms were studied employing exendin(9-39) amide, Lw-nitro-monomethyl arginine (L-NMMA), 2´5´-dideoxyadenosine (DDA) and tetrodotoxin (TTX). Results: Food-intake increased motility index from 4.0±0.5 to 6.4±0.3 (antrum), 4.2±0.4 to 5.7±0.4 (duodenum) and 4.6±0.3 to 5.9±0.2 (jejunum) ln(Σ(mmHg·s·min-1)). GLP-1 at 0.7 pmol/kg/minwas sufficient to suppress these indexes from 6.2±0.4 to 3.8±0.7, 5.6±0.6 to 3.9±0.6 and 5.8±0.1 to 4.6±0.4 ln(Σ(mmHg·s·min-1)). Both GLP-1 doses raised plasma GLP-1, but not GLP-2. GLP-1 (EC50 40 nM) and ROSE-010 (EC50 50 nM) relaxed bethanechol-induced contractions in muscle strips. Inhibitory responses were blocked by exendin(9-39) amide, L-NMMA, DDA or TTX pre-treatment. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle. Conclusions: GLP-1 and ROSE-010 inhibit motility through GLP-1R at myenteric neurons, which also possess GLP-2 receptors. GLP-1 increases more than GLP-2 with meals and does not increase plasma GLP-2. GLP-1 and ROSE-010 relaxations are cAMP and NO dependent.

  • 38.
    Halim, Mohammed Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    D-erythro-Sphingosine and Pregnenolonesulphate activate TRPM3 channels synergistically in INS-1E cells2017In: Bangladesh Journal of Medical Science, ISSN 2223-4721, E-ISSN 2076-0299, Vol. 16, no 1, 98-106 p.Article in journal (Refereed)
    Abstract [en]

    Background: A group of ion channels have recently been studied to understand the pathogenesis of diabetes. The transient receptor potential (TRP) channels are thought to be involved in many cellular functions. TRPM3, a member of the melastatin-like transient receptor is mainly expressed in human kidney and brain. It is also expressed in human pancreas. Therefore, it is desirable to find compounds able to induce an increase of intracellular calcium([Ca2+](i)) in pancreatic beta cells thereby trigger insulin secretion. Aims: The aim of the study was to confirm whether D-erythroSphingosine and Pregnenolonesulphate activates TRPM3. Another aim was to investigate whether pancreatic beta cells express TRPM3-channels. INS-1E cells were used as a model of beta-cells for [Ca2+](i) measurement. Results: Application of endogenous neurosteroidpregnenolonesulphate (35 mu M) led to a rapid Ca2+ influx in INS-1E cells and pancreatic beta cells. When PS was applied in the absence of extracellular Ca2+ the [Ca2+](i) response to PS was completely lost. The increase in [Ca2+](i) induced by PS was inhibited by cholesterol. Western blot data identified a protein reacting specifically with polyclonal antibodies for TRPM3. Conclusion: Our results demonstrate that both pancreatic beta-cells and INS-1E cells express functional TRPM3-channels and both SPH and PS are TRPM3 agonists.

  • 39. Hallén, Karin
    et al.
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nilsson, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Wanders, Alkwin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Vanishing bile duct-like syndrome in a patient with Hodgkin lymphoma: pathological development and restitution2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 9, 1271-1275 p.Article in journal (Refereed)
  • 40.
    Hansdotter, Ida
    et al.
    Umea Univ Hosp, Dept Surg & Perioperat Sci, Surg, S-90185 Umea, Sweden..
    Björ, Ove
    Umea Univ, Dept Radiat Sci, Oncol, Umea, Sweden..
    Andreasson, Anna
    Karolinska Inst, Div Family Med, Huddinge, Sweden.;Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden..
    Agreus, Lars
    Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden..
    Hellström, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Forsberg, Anna
    Karolinska Inst, Mol Med & Surg, Stockholm, Sweden..
    Talley, Nicholas J.
    Univ Newcastle, Fac Med, Newcastle, NSW 2300, Australia..
    Vieth, Michael
    Klinikum Bayreuth, Inst Pathol, Bayreuth, Germany..
    Wallner, Bengt
    Umea Univ Hosp, Dept Surg & Perioperat Sci, Surg, S-90185 Umea, Sweden..
    Hill classification is superior to the axial length of a hiatal hernia for assessment of the mechanical anti-reflux barrier at the gastroesophageal junction2016In: ENDOSCOPY INTERNATIONAL OPEN, ISSN 2364-3722, Vol. 4, no 3, E311-E317 p.Article in journal (Refereed)
    Abstract [en]

    Background and study aims: The pathogenesis of gastroesophageal reflux disease (GERD) is multifactorial, including the mechanical anti-reflux barrier of the gastroesophageal junction. This barrier can be evaluated endoscopically in two ways: by measuring the axial length of any hiatal hernia present or by assessing the gastroesophageal flap valve. The endoscopic measurement of axial length is troublesome because of the physiological dynamics in the area. Grading the gastroesophageal flap valve is easier and has proven reproducible. The aim of the present study was to compare the two endoscopic grading methods with regard to associations with GERD. Patients and methods: Population-based subjects underwent endoscopic examination assessing the axial length of hiatus hernia, the gastroesophageal flap valve using the Hill classification, esophagitis using the Los Angeles (LA) classification, and columnar metaplasia using the Z-line appearance (ZAP) classification. Biopsies were taken from the squamocolumnar junction to assess the presence of intestinal metaplasia. Symptoms were recorded with the validated Abdominal Symptom Questionnaire. GERD was defined according to the Montreal definition. Results: In total, 334 subjects were included in the study and underwent endoscopy; 86 subjects suffered from GERD and 211 presented no symptoms or signs of GERD. Based on logistic regression, the estimated area under the curve statistic (AUC) for Hill (0.65 [95 % CI 0.59-0.72]) was higher than the corresponding estimate for the axial length of a hiatal hernia (0.61 [95 % CI 0.54-0.68]), although the difference was not statistically significant (P=0.225). Conclusion: From our data, and in terms of association with GERD, the Hill classification was slightly stronger compared to the axial length of a hiatal hernia, but we could not verify that the Hill classification was superior as a predictor. The Hill classification may replace the axial length of a hiatal hernia in the endoscopic assessment of the mechanical anti-reflux barrier of the gastroesophageal junction.

  • 41.
    Hellstrom, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Satiety signals and obesity2013In: Current Opinion in Gastroenterology, ISSN 0267-1379, E-ISSN 1531-7056, Vol. 29, no 2, 222-227 p.Article, review/survey (Refereed)
    Abstract [en]

    Purpose of review The obesity epidemic over the world has called to attention different ways to manage this development. As bariatric surgery today is the only manner by which rapid and sustained weight control can be achieved, new ways of treating obesity are under investigation. This review focuses on today's knowledge on satiety signaling as a means to combat obesity. Recent findings The combined knowledge achieved from obesity surgery with gastric bypass and duodenal switch together with the pharmacological treatment of type 2 diabetes have given us some clues of how to manage obesity. The basis for our understanding is the present research focusing on the gut peptide hormones that are released in response to food intake, and the paucity of satiety signaling seems to prevail in obesity. This means that obese patients experience less activation of higher brain centers in association with a meal and therefore compensate with increased meal size or frequent food intake. Summary Altered satiety signaling primarily emanating from the gastrointestinal tract seems to lead to the development of obesity and type 2 diabetes. Pharmacological tools that enhance the gut hormone signaling are in focus for the upcoming venues of treatment.

  • 42.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Obesity research in adolescence: moving object-hard to target2013In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 98, no 5, 1147-1148 p.Article in journal (Other academic)
  • 43.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Al-Saffar, K. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Diaz, Hetzel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Ram, G. V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Intestinal fatty acid binding protein parallels temporal changes in Harvey-Bradshaw Index and TNF alpha in response to infliximab in Crohn's disease2017In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 11, S389-S389 p.Article in journal (Other academic)
  • 44.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Diaz, Hetzel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Lönnkvist, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Befrits, R.
    Fecal calprotectin and serum C-reactive protein predict outcome of infliximab induction therapy in inflammatory bowel disease2015In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 9, no S1, S287-S288 p.Article in journal (Other academic)
  • 45.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Halim, Md Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Tryggve, Ljung
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University.
    Holst, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Karolinska Institutet.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Luminal Nitric Oxide and Plasma Nitrite/Nitrate As Predictors of Colectomy in Corticosteroid-Treated Acute Colitis2015In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 148, no 4, suppl. 1, Sul 231Article in journal (Refereed)
    Abstract [en]

    Background: Nitric oxide (NO) is known to be up-regulated by the induction of induciblenitric oxide synthase (iNOS) in inflammatory conditions. NO gas can be used as a markerof inflammatory activity in hollow organs. In parallel, plasma nitrite + nitrate (NOx) canreflect the ongoing inflammatory activity. We analyzed rectal NO before and after threedays, as well as plasma NOx in patients on glucocorticosteroid (GC) therapy in hospitalizedpatients. The aim of the study was to evaluate the relationship of rectal luminal NO andcirculating plasma NOx in acute fulminant colitis to the outcome as therapeutic responseor colectomy.

    Methods: 50 patients with median age 41 (range 20-78) years were hospitalizeddue to acute fulminant colitis and received treatment with high-dose GCs. Luminal nitricoxide was analyzed with chemiluminescence before therapy onset of therapy with GC andon day 3 of treatment. NOx was measured by nitrite/nitrate colorimetric assay. NO levelsand plasma NOx were compared to clinical disease activity index and C-reactive protein(CRP).

    Results: 32 responded to GC treatment and 18 did not, resulting in colectomy.The responders had higher luminal NO than non-responders (day 1: 12525±2600, day 3:15590±4157 ppb) vs non-responders (day 1: 2874±1283, day 3: 1137±297 ppb) (p<0.0114).Using an optimal cut-off NO level of 2250 ppb, sensitivity and specificity was 86% and81% for colectomy (p<0.0001). The area under the curve was 0.88 and likelihood ratio4.8. Similarly, plasma NOx was higher in responders vs non-responders (day 1: 6.2±0.3 vs3.9±0.4 umol/L) (p<0.0001). Using plasma NOx, we found a corresponding cut-off at 5umol/L with sensitivity 87% and specificity 87%. The area under the curve was 0.88 andlikelihood ratio 6.7. Luminal NO was also correlated to plasma NOx (r=0.33, p=0.0205).In the responder group, CRP levels decreased (day 1: 22.31±2.95, day 3: 15.69±3.57mg/L), whereas among non-responders CRP levels increased (day 1: 45.83±11.10, day 3:76.35±16.96 mg/L) (p<0.0167). Kaplan-Meier analysis showed that patients with baselineNO levels lower than 2250 ppb were at a significantly higher risk of colectomy within onemonth from onset of GCS treatment (p<0.0001). Twelve out of 18 (67%) in patients withday 1 NO <2250 ppb were colectomized, the corresponding number of patients with NO>2250 ppb was 3 out of 32 (9%). In a similar manner, using plasma NOx <5 uml/L foranalysis, we found 13 (72%) to be colectomized, and with >5 umol/L only two (6%).

    Conclusion: NO and its oxidation product NOx are markers of inflammatory activity in thegut. However, with more intense inflammation and mucosal damage, the less NO is produced.Luminal NO as well as plasma NOx can be used as a sensitive biomarker to predict colectomyin the outcome of acute fulminant colitis

  • 46.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hendolin, Panu
    Biohit Oyj, Clin Sci, Helsinki, Finland..
    Kaihovaara, Pertti
    Biohit Oyj, Clin Sci, Helsinki, Finland.;Univ Helsinki, Res Unit Acetaldehyde & Canc, Helsinki, Finland..
    Kronberg, Leif
    Abo Akad Univ, Johan Gadolin Proc Chem Ctr, Lab Organ Chem, Turku, Finland..
    Meierjohann, Axel
    Abo Akad Univ, Johan Gadolin Proc Chem Ctr, Lab Organ Chem, Turku, Finland..
    Millerhovf, Anders
    Univ Uppsala Hosp, Clin Trial Consultants, Uppsala, Sweden..
    Paloheimo, Lea
    Biohit Oyj, Clin Sci, Helsinki, Finland..
    Sundelin, Heidi
    Abo Akad Univ, Johan Gadolin Proc Chem Ctr, Lab Organ Chem, Turku, Finland..
    Syrjanen, Kari
    Biohit Oyj, Clin Sci, Helsinki, Finland..
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Salaspuro, Mikko
    Univ Helsinki, Res Unit Acetaldehyde & Canc, Helsinki, Finland..
    Slow-release L-cysteine capsule prevents gastric mucosa exposure to carcinogenic acetaldehyde: results of a randomised single-blinded, cross-over study of Helicobacter-associated atrophic gastritis2017In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 52, no 2, 230-237 p.Article in journal (Refereed)
    Abstract [en]

    Introduction: Helicobacter-induced atrophic gastritis with a hypochlorhydric milieu is a risk factor for gastric cancer. Microbes colonising acid-free stomach oxidise ethanol to acetaldehyde, a recognised group 1 carcinogen. Objective: To assess gastric production of acetaldehyde and its inert condensation product, non-toxic 2-methyl-1,3-thiazolidine-4-carboxylic acid (MTCA), after alcohol intake under treatment with slow-release L-cysteine or placebo. Methods: Seven patients with biopsy-confirmed atrophic gastritis, low serum pepsinogen and high gastrin-17 were studied in a cross-over single-blinded design. On separate days, patients randomly received 200 mg slow-release L-cysteine or placebo with intragastric instillation of 15% (0.3 g/kg) ethanol. After intake, gastric concentrations of ethanol, acetaldehyde, L-cysteine and MTCA were analysed. Results: Administration of L-cysteine increased MTCA (p < .0004) and decreased gastric acetaldehyde concentrations by 68% (p < .0001). The peak L-cysteine level was 7552 +/- 2687 mu mol/L at 40 min and peak MTCA level 196 +/- 98 mu mol/L at 80 min after intake. Gastric L-cysteine and MTCA concentrations were maintained for 3 h. The AUC for MTCA was 11-fold higher than acetaldehyde, indicating gastric first-pass metabolism of ethanol. With placebo, acetaldehyde remained elevated also at low ethanol concentrations representing 'non-alcoholic' beverages and food items. Conclusions: After gastric ethanol instillation, slow-release L-cysteine eliminates acetaldehyde to form inactive MTCA, which remains in gastric juice for up to 3 h. High acetaldehyde levels indicate a marked gastric first-pass metabolism of ethanol resulting in gastric accumulation of carcinogenic acetaldehyde. Local exposure of the gastric mucosa to acetaldehyde can be mitigated by slow-release L-cysteine capsules.

  • 47.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Samuelsson, Bodil
    Danderyd Hosp, Div Orthoped, Karolinska Inst, Dept Clin Sci, Stockholm, Sweden.;Sophiahemmet Univ Coll, Stockholm, Sweden..
    Al-Ani, Amer N.
    Karolinska Univ Hosp, Dept Clin Sci & Technol Clintec, Div Orthoped, Karolinska Inst, Huddinge, Sweden..
    Hedström, Margareta
    Karolinska Univ Hosp, Dept Clin Sci & Technol Clintec, Div Orthoped, Karolinska Inst, Huddinge, Sweden..
    Normal gastric emptying time of a carbohydrate-rich drink in elderly patients with acute hip fracture: a pilot study2017In: BMC Anesthesiology, ISSN 1471-2253, E-ISSN 1471-2253, Vol. 17, 23Article in journal (Refereed)
    Abstract [en]

    Background: Guidelines for fasting in elderly patients with acute hip fracture are the same as for other trauma patients, and longer than for elective patients. The reason is assumed stress-induced delayed gastric emptying with possible risk of pulmonary aspiration. Prolonged fasting in elderly patients may have serious negative metabolic consequences. The aim of our study was to investigate whether the preoperative gastric emptying was delayed in elderly women scheduled for surgery due to acute hip fracture. Methods: In a prospective study gastric emptying of 400 ml 12.6% carbohydrate rich drink was investigated in nine elderly women, age 77-97, with acute hip fracture. The emptying time was assessed by the paracetamol absorption technique, and lag phase and gastric half-emptying time was compared with two gender-matched reference groups: ten elective hip replacement patients, age 45-71 and ten healthy volunteers, age 28-55. Results: The mean gastric half-emptying time in the elderly study group was 53 +/- 5 (39-82) minutes with an expected gastric emptying profile. The reference groups had a mean half-emptying time of 58 +/- 4 (41-106) and 59 +/- 5 (33-72) minutes, indicating normal gastric emptying time in elderly with hip fracture. Conclusion: This pilot study in women with an acute hip fracture shows no evidence of delayed gastric emptying after an orally taken carbohydrate-rich beverage during the pre-operative fasting period. This implies no increased risk of pulmonary aspiration in these patients. Therefore, we advocate oral pre-operative management with carbohydrate-rich beverage in order to mitigate fasting-induced additive stress in the elderly with hip fracture.

  • 48.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Smithson, A.
    Stowell, G.
    Greene, S.
    Kenny, E.
    Damico, C.
    Leone-Bay, A.
    Baughman, R.
    Grant, M.
    Richardson, P.
    Receptor-mediated inhibition of small bowel migrating complex by GLP-1 analog ROSE-010 delivered via pulmonary and systemic routes in the conscious rat2012In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 179, no 1-3, 71-76 p.Article in journal (Refereed)
    Abstract [en]

    Background: ROSE-010, a Glucagon-Like Peptide-1 (GLP-1) analog, reduces gastrointestinal motility and relieves acute pain in patients with irritable bowel syndrome (IBS). The rat small bowel migrating myoelectric complex (MMC) is a reliable model of pharmacological effects on gastrointestinal motility. Accordingly, we investigated whether ROSE-010 works through GLP-1 receptors in gut musculature and its effectiveness when administered by pulmonary inhalation. Materials and methods: Rats were implanted with bipolar electrodes at 5, 15 and 25 cm distal to pylorus and myoelectric activity was recorded. First, intravenous or subcutaneous injections of ROSE-010 or GLP-1 (1, 10, 100 mu g/kg) with or without the GLP-1 receptor blocker exendin(9-39)amide (300 mu g/kg.h), were studied. Second, ROSE-010 (100, 200 mu g/kg) Technosphere (R) powder was studied by inhalation. Results: The baseline MMC cycle length was 17.5 +/- 0.8 min. GLP-1 and ROSE-010. administered intravenously or subcutaneously, significantly inhibited myoelectric activity and prolonged MMC cycling; 100 mu g/kg completely inhibited spiking activity for 49.1 +/- 4.2 and 73.3 +/- 7.7 min, while the MMC cycle length increased to 131.1 +/- 11.4 and 149.3 +/- 15.5 min, respectively. Effects of both drugs were inhibited by exendin(9-39) amide. Insufflation of ROSE-010 (100, 200 mu g/kg) powder formulation totally inhibited myoelectric spiking for 52.6 +/- 5.8 and 70.1 +/- 5.4 min, and increased MMC cycle length to 102.6 +/- 18.3 and 105.9 +/- 9.5 min, respectively. Conclusions: Pulmonary delivery of ROSE-010 inhibits gut motility through the GLP-1R similar to natural GLP-1. ROSE-010 causes receptor-mediated inhibition of MMC comparable to that of intravenous or subcutaneous administration. This suggests that ROSE-010 administered as a Technosphere (R) inhalation powder has potential in IBS pain management and treatment.

  • 49.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Stålhammar, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Beydogan, H.
    QuintilesIMS, Real World Evidence Solut & HEOR, Solna, Sweden..
    Huetson, P.
    QuintilesIMS, Real World Evidence Solut & HEOR, Solna, Sweden..
    Skup, M.
    AbbVie Inc, N Chicago, IL USA..
    Agreus, L.
    Karolinska Institute.
    Indirect burden of patients with moderate inflammatory bowel disease in Uppsala County Council, Sweden: a retrospective study using real-world data2017In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 11, S457-S457 p.Article in journal (Other academic)
  • 50.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Tack, Jan
    Univ Leuven, Louvain, Belgium..
    Johnson, Lakshmi Vasist
    GlaxoSmithKline, Res Triangle Pk, NC USA..
    Hacquoil, Kimberley
    GlaxoSmithKline, Stevenage, Herts, England..
    Barton, Matthew E.
    GlaxoSmithKline, Res Triangle Pk, NC USA..
    Richards, Duncan B.
    GlaxoSmithKline, Stevenage, Herts, England..
    Alpers, David H.
    Washington Univ, Sch Med, St Louis, MO USA..
    Sanger, Gareth J.
    Queen Mary Univ London, Barts & London Sch Med & Dent, London, England..
    Dukes, George E.
    GlaxoSmithKline, Res Triangle Pk, NC USA..
    The pharmacodynamics, safety and pharmacokinetics of single doses of the motilin agonist, camicinal, in type 1 diabetes mellitus with slow gastric emptying2016In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 173, no 11, 1768-1777 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE Here we have investigated the pharmacokinetics, pharmacodynamics and safety of single doses of camicinal in type 1 diabetes mellitus (T1DM) patients with a history of slow gastric emptying with symptoms consistent with gastroparesis. EXPERIMENTAL APPROACH In a randomized, double-blind, placebo-controlled, incomplete block, three-period, two-centre crossover study, patients received oral administration of placebo and two of the three possible doses of camicinal (25, 50 or 125 mg). Gastric emptying (C-13-octanoic acid breath test), pharmacokinetics and safety were primary outcomes. KEY RESULTS Nine of the 10 patients enrolled completed the study. Gastric half-emptying time decreased by -95 min (95% CI: -156.8, -34.2) after a single dose of camicinal 125 mg compared with placebo (52 vs. 147 min, P < 0.05), representing a 65% improvement. A decrease of the gastric half-emptying time compared with placebo (approximately 39 min) was observed with camicinal 25 and 50 mg, representing a 27% reduction for both doses (not statistically significant). A positive exposure-response relationship was demonstrated across all doses. The effects of camicinal on gastric half-emptying time were not influenced by fasting glucose levels. Single doses up to 125 mg were well tolerated. Camicinal was well absorbed, exhibiting linear and approximately dose-proportional pharmacokinetic characteristics and a clear exposure-response relationship with gastric emptying. CONCLUSIONS AND IMPLICATIONS Camicinal significantly accelerated gastric emptying of solids in T1DM patients following administration of a single oral dose. Camicinal was well tolerated and exhibited similar pharmacokinetic characteristics in diabetic patients to those previously reported in healthy volunteers.

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