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Söderholm, Johan D
Alternative names
Publications (10 of 101) Show all publications
Yakymenko, O., Schoultz, I., Gullberg, E., Ström, M., Almer, S., Wallon, C., . . . Söderholm, J. D. (2018). Infliximab restores colonic barrier to adherent-invasive E. coli in Crohn's disease via effects on epithelial lipid rafts. Scandinavian Journal of Gastroenterology, 1-8
Open this publication in new window or tab >>Infliximab restores colonic barrier to adherent-invasive E. coli in Crohn's disease via effects on epithelial lipid rafts
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2018 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, p. 1-8Article in journal (Refereed) Published
Abstract [en]

Objective: Infliximab is important in the therapeutic arsenal of Crohn’s disease (CD). However, its effect on mucosal barrier function is not fully understood. Adherent-invasive Escherichia coli (AIEC) are important in CD pathophysiology, but the transmucosal uptake routes are partly unknown. We investigated effects of infliximab on uptake of colon-specific AIEC HM427 across CD colonic mucosa.

Materials and methods: Endoscopic biopsies from non-inflamed colon of seven patients with CD, before and after two infliximab infusions, and eight non-inflammation controls, were mounted in Ussing chambers. Paracellular permeability (51Cr-EDTA) and transmucosal passage of GFP-expressing HM427 were studied. Mechanisms of HM427 transepithelial transport were investigated in Caco-2 monolayers treated with TNF, in the presence of infliximab and/or endocytosis inhibitors.

Results: Before infliximab treatment, colonic passage of HM427 [CD: 2475 CFU (450–3000); controls 1163(225–1950)] and 51Cr-EDTA permeability were increased in CD (p < .05), but were restored to control levels by infliximab (CD: 150 (18.8–1069)). In TNF-exposed Caco-2 monolayers HM427 transport and lipid rafts/HM427 co-localization was decreased by infliximab. The lipid raft inhibitor methyl-β-cyclodextrin decreased HM427 transport.

Conclusion: Infliximab restored the colonic barrier to AIEC in CD; an effect partially mediated by blocking lipid rafts in epithelial cells. This ability likely contributes to infliximab’s clinical efficacy in colonic CD.

Place, publisher, year, edition, pages
Taylor & Francis, 2018
Keyword
Inflammatory bowel disease, microbiology, large intestine, intestinal barrier function, adherent invasive E. coli
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-147615 (URN)10.1080/00365521.2018.1458146 (DOI)
Available from: 2018-04-27 Created: 2018-04-27 Last updated: 2018-04-27Bibliographically approved
Gerdin, L., Eriksson, A. S., Olaison, G., Sjödahl, R., Ström, M., Söderholm, J. D. & Myrelid, P. (2016). The Swedish Crohn Trial: A Prematurely Terminated Randomized Controlled Trial of Thiopurines or Open Surgery for Primary Treatment of Ileocaecal Crohns Disease. Journal of Crohn's & Colitis, 10(1), 50-54
Open this publication in new window or tab >>The Swedish Crohn Trial: A Prematurely Terminated Randomized Controlled Trial of Thiopurines or Open Surgery for Primary Treatment of Ileocaecal Crohns Disease
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2016 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 10, no 1, p. 50-54Article in journal (Refereed) Published
Abstract [en]

Background and aims: The importance of efficient and safe treatment of Crohns disease is highlighted by its chronicity. Both medical and surgical treatments have shown good results in the symptomatic control of limited ileocaecal Crohns disease. The aim of this study was to compare medical treatment with surgical treatment of ileocaecal Crohns disease. Methods: Thirty-six patients from seven hospitals with primary ileocaecal Crohns disease were randomized to either medical or surgical treatment. The medical treatment was induction of remission with budesonide and thereafter maintenance treatment with azathioprine. The surgical treatment was open ileocaecal resection. Crohns disease activity index over time, expressed as area under the curve at 1, 3 and 5 years, was the primary endpoint. Subjective health measured with the 36-item Short Form Survey Instrument (SF36) and a visual analogue scale (VAS) were secondary endpoints. Results: There were no differences between the treatment groups in Crohns disease activity index over time. General health, measured as SF36 score, was higher in patients receiving surgical treatment than in those receiving medical treatment at 1 year, but there was no corresponding difference in VAS. Due to the slow inclusion rate and changes in clinical practice, the study was t = erminated prematurely. Conclusion: The study ended up being underpowered and should be interpreted with caution, but there was no clinically significant difference between the two treatment arms. Further studies are needed to address this important clinical question.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2016
Keyword
Surgery; clinical trials; quality of life; socio-economical and psychological endpoints
National Category
Clinical Medicine Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-126143 (URN)10.1093/ecco-jcc/jjv184 (DOI)000370275900010 ()26507858 (PubMedID)
Available from: 2016-03-15 Created: 2016-03-15 Last updated: 2018-03-21
Myrelid, P., Salim, S., Darby, T., Almer, S., Melgar, S., Andersson, P. & Söderholm, J. D. (2015). Effects of anti-inflammatory therapy on bursting pressure of colonic anastomosis in murine dextran sulfate sodium induced colitis. Scandinavian Journal of Gastroenterology, 50(8), 991-1001
Open this publication in new window or tab >>Effects of anti-inflammatory therapy on bursting pressure of colonic anastomosis in murine dextran sulfate sodium induced colitis
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2015 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 50, no 8, p. 991-1001Article in journal (Refereed) Published
Abstract [en]

Background. The aim of this study was to examine the effect of colitis and anti-inflammatory therapies on the healing of colonic anastomoses in mice. Methods. Female C57BL/6 mice were randomized into eight groups; four groups receiving plain tap-water and four groups receiving dextran sulfate sodium. Intra-peritoneal treatment was given therapeutically for 14 days with placebo, prednisolone, azathioprine, or infliximab (IFX). Colonic anastomoses were performed and bursting pressure (BP) measurements were recorded and the inflammation evaluated with histology and zymography. Results. The mice with colitis had a more active inflammation based on histology and bowel weight compared with the tap water group, 8.3 (7.6-9.5) mg/mm and 5.5 (4.8-6.2) mg/mm respectively (p less than 0.0001). Similarly mice with colitis receiving placebo had a more active inflammation, 12.8 (10.6-15.0) mg/mm, which differed significantly from all the other therapy arms among the colitic mice; prednisolone 8.1 (7.5-9.1) mg/mm (p = 0.014), azathioprine 8.2 (7.0-8.5) mg/mm (p = 0.0046), IFX 6.7 (6.4-7.9) mg/mm (p = 0.0055). BP for the placebo group was 90.0 (71.5-102.8) mmHg and did not differ from azathioprine or IFX groups, 84.4 (70.5-112.5) and 92.3 (75.8-122.3) mmHg respectively. In contrast BP for the prednisolone group was significantly decreased compared to placebo, 55.5 (42.8-73.0) mmHg (p = 0.0004). Conclusions. All therapies had a beneficial effect on the colitis. An impaired BP of colonic anastomoses was noted after preoperative steroids but not after azathioprine or IFX in this model.

Place, publisher, year, edition, pages
TAYLOR and FRANCIS LTD, 2015
Keyword
anastomosis; colitis; dextran sulfate sodium; inflammatory bowel disease; postoperative complications; surgical
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-121927 (URN)10.3109/00365521.2014.964760 (DOI)000361323200008 ()25861827 (PubMedID)
Note

Funding Agencies|Science Foundation Ireland (SFI) by SFI [02/CE/B124, 07/CE/B1368]

Available from: 2015-10-13 Created: 2015-10-12 Last updated: 2017-12-01
Söderholm, J. D. (2015). Gut immunology: Nanoparticles ferry gut antigens. Nature Nanotechnology, 10(4), 298-299
Open this publication in new window or tab >>Gut immunology: Nanoparticles ferry gut antigens
2015 (English)In: Nature Nanotechnology, ISSN 1748-3387, E-ISSN 1748-3395, Vol. 10, no 4, p. 298-299Article in journal, Editorial material (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-118062 (URN)000353365600007 ()
Available from: 2015-05-20 Created: 2015-05-20 Last updated: 2017-12-04
Vicario, M., Gonzalez-Castro, A. M., Martinez, C., Lobo, B., Pigrau, M., Guilarte, M., . . . Santos, J. (2015). Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations. Gut, 64(9), 1379-1388
Open this publication in new window or tab >>Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations
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2015 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 64, no 9, p. 1379-1388Article in journal (Refereed) Published
Abstract [en]

Background and aims Altered intestinal barrier is associated with immune activation and clinical symptoms in diarrhoea-predominant IBS (IBS-D). Increased mucosal antigen load may induce specific responses; however, local antibody production and its contribution to IBS aetiopathogenesis remain undefined. This study evaluated the role of humoral activity in IBS-D. Methods A single mucosal jejunal biopsy, luminal content and blood were obtained from healthy volunteers (H; n = 30) and IBS-D (n = 49; Rome III criteria) participants. Intraepithelial lymphocytes, mast cells, B lymphocytes and plasma cells were studied by imaging techniques. Differential gene expression and pathway analysis were assessed by microarray and PCR techniques. Blood and luminal immunoglobulins (Igs) were quantified. Gastrointestinal symptoms, respiratory atopy and stress and depression were also recorded. Results Patients with IBS-D showed a higher number and activation of mucosal B lymphocytes and plasma cells (p less than 0.05). Mast cell density was increased in patients with IBS-D (non-atopic) and in close proximity to plasma cells (p less than 0.05). Microarray profiling identified differential humoral activity in IBS-D, involving proliferation and activation of B lymphocytes and Igs production (p less than 0.001). Mucosal humoral activity was higher in IBS-D, with upregulation of germline transcripts and Ig genes (1.3-fold-1.7-fold increase; p less than 0.05), and increased IgG(+) cells and luminal IgG compared with H (p less than 0.05), with no differences in blood. Biological markers of humoral activity correlated positively with bowel movements, stool form and depression. Conclusions Enhanced small bowel humoral immunity is a distinctive feature of IBS-D. Mucosal Ig production contributes to local inflammation and clinical manifestations in IBS-D.

Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-121427 (URN)10.1136/gutjnl-2013-306236 (DOI)000360389800006 ()25209656 (PubMedID)
Note

Funding Agencies|Fondo de Investigacion Sanitaria; CIBERehd, Instituto de Salud Carlos III, Subdireccion General de Investigacion Sanitaria, Ministerio de Economia y Competitividad [CP10/00502, PI13/00935, CM08/00229, CM10/00155, FI12/00254, PI12/00314, EII2011-0035, PI11/00716]; Ministerio de Educacion, Direccion General de Investigacion [SAF 2009-07416]; Agencia de Gestio dAjuts Universitaris i de Recerca, de la Generalitat de Catalunya [2009 SGR 219, 2011 BP/A00099]; Rome Foundation; Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas [CB06/04/0021]

Available from: 2015-09-18 Created: 2015-09-18 Last updated: 2017-12-04Bibliographically approved
Parsons, B. N., Wigley, P., Simpson, H. L., Williams, J. M., Humphrey, S., Salisbury, A.-M., . . . Campbell, B. J. (2014). Dietary Supplementation with Soluble Plantain Non-Starch Polysaccharides Inhibits Intestinal Invasion of Salmonella Typhimurium in the Chicken. PLoS ONE, 9(2), 87658
Open this publication in new window or tab >>Dietary Supplementation with Soluble Plantain Non-Starch Polysaccharides Inhibits Intestinal Invasion of Salmonella Typhimurium in the Chicken
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. 87658-Article in journal (Refereed) Published
Abstract [en]

Soluble fibres (non-starch polysaccharides, NSP) from edible plants but particularly plantain banana (Musa spp.), have been shown in vitro and ex vivo to prevent various enteric pathogens from adhering to, or translocating across, the human intestinal epithelium, a property that we have termed contrabiotic. Here we report that dietary plantain fibre prevents invasion of the chicken intestinal mucosa by Salmonella. In vivo experiments were performed with chicks fed from hatch on a pellet diet containing soluble plantain NSP (0 to 200 mg/d) and orally infected with S. Typhimurium 4/74 at 8 d of age. Birds were sacrificed 3, 6 and 10 d post-infection. Bacteria were enumerated from liver, spleen and caecal contents. In vitro studies were performed using chicken caecal crypts and porcine intestinal epithelial cells infected with Salmonella enterica serovars following pre-treatment separately with soluble plantain NSP and acidic or neutral polysaccharide fractions of plantain NSP, each compared with saline vehicle. Bacterial adherence and invasion were assessed by gentamicin protection assay. In vivo dietary supplementation with plantain NSP 50 mg/d reduced invasion by S. Typhimurium, as reflected by viable bacterial counts from splenic tissue, by 98.9% (95% CI, 98.1-99.7; Pless than0.0001). In vitro studies confirmed that plantain NSP (5-10 mg/ml) inhibited adhesion of S. Typhimurium 4/74 to a porcine epithelial cell-line (73% mean inhibition (95% CI, 64-81); Pless than0.001) and to primary chick caecal crypts (82% mean inhibition (95% CI, 75-90); Pless than0.001). Adherence inhibition was shown to be mediated via an effect on the epithelial cells and Ussing chamber experiments with ex-vivo human ileal mucosa showed that this effect was associated with increased short circuit current but no change in electrical resistance. The inhibitory activity of plantain NSP lay mainly within the acidic/pectic (homogalacturonan-rich) component. Supplementation of chick feed with plantain NSP was well tolerated and shows promise as a simple approach for reducing invasive salmonellosis.

Place, publisher, year, edition, pages
Public Library of Science, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-105237 (URN)10.1371/journal.pone.0087658 (DOI)000330626900093 ()
Available from: 2014-03-14 Created: 2014-03-14 Last updated: 2017-12-05
Andersson, P., Norblad, R., Söderholm, J. D. & Myrelid, P. (2014). Ileorectal anastomosis in comparison with ileal pouch anal anastomosis in reconstructive surgery for ulcerative colitis - a single institution experience. Journal of Crohn's & Colitis, 8(7), 582-589
Open this publication in new window or tab >>Ileorectal anastomosis in comparison with ileal pouch anal anastomosis in reconstructive surgery for ulcerative colitis - a single institution experience
2014 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 8, no 7, p. 582-589Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION:

Ileal pouch anal anastomosis (IPAA) is the standard procedure for reconstruction after colectomy for ulcerative colitis (UC). However, ileorectal anastomosis (IRA) as an alternative has, recently experienced a revival. This study from a single center compares the clinical outcomes of these procedures.

METHODS:

From 1992 to 2006, 253 patients consecutively underwent either IRA (n=105) or IPAA (n=148). Selection to either procedure was determined on the basis of rectal inflammation, presence of dysplasia/cancer or patient preferences. Patient-records were retrospectively evaluated. Mean follow-up time was 5.4 and 6.3 years respectively.

RESULTS:

Major postoperative complications occurred in 12.4% of patients after IRA and in 12.8% after IPAA (ns). Complications of any kind after IRA or IPAA, even including subsequent stoma-closure, occurred in 23.8% and 39.9% respectively (p<0.01). Estimated cumulative failure rates after 5 and 10 years were 10.1% and 24.1% for IRA and 6.1% and 18.6% for IPAA respectively (ns). The most common cause for failure was intractable proctitis (4.8%) and unspecified dysfunction (4.8%) respectively. At follow-up 76.9% of patients with IRA had proctitis and 34.1% with IPAA had pouchitis. Estimated cumulative cancer-risk after 10, 20 and 25 year duration of disease was 0.0%, 2.1% and 8.7% for IRA. Figures for IPAA were 0.7%, 1.8% and 1.8% (ns).

CONCLUSION:

Failure-rates did not significantly differ between patients operated with IRA or IPAA. Patients operated with IPAA had a higher cumulative number of postoperative complications. The high long-term cancer-risk after IRA indicates that this procedure should be an interim solution in younger patients.

Place, publisher, year, edition, pages
Elsevier, 2014
Keyword
Ulcerative colitis; IRA; IPAA; Complications; Failure
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-109174 (URN)10.1016/j.crohns.2013.11.014 (DOI)000337867700003 ()24315777 (PubMedID)
Available from: 2014-08-12 Created: 2014-08-11 Last updated: 2017-12-05
Vanheel, H., Vicario, M., Vanuytsel, T., Van Oudenhove, L., Martinez, C., Keita, Å., . . . Farre, R. (2014). Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia. Gut, 63(2), 262-271
Open this publication in new window or tab >>Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia
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2014 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 63, no 2, p. 262-271Article in journal (Refereed) Published
Abstract [en]

Objective Functional dyspepsia (FD) is an extremely common functional gastrointestinal disorder, the pathophysiology of which is poorly understood. We hypothesised that impaired intestinal barrier function is involved in the onset and persistence of this disorder by inducing low-grade inflammation. Therefore, our aim was to evaluate duodenal mucosal integrity and low-grade inflammation in patients with FD. Design Duodenal biopsy specimens were obtained from 15 patients with FD fulfilling the Rome III criteria and 15 age- and gender-matched healthy volunteers. Transepithelial electrical resistance (TEER) and paracellular permeability were measured in Ussing chambers. Expression of cell-to-cell adhesion proteins was evaluated by real-time PCR, western blot and/or immunofluorescence. Numbers of mast cells, eosinophils and intraepithelial lymphocytes were assessed by immunohistochemistry. Results Patients with FD displayed lower TEER and increased paracellular passage compared with healthy controls, which is indicative of impaired mucosal integrity. In addition, abnormal expression of cell-to-cell adhesion proteins at the level of tight junctions, adherens junctions and desmosomes was shown. Furthermore, patients were characterised by the presence of low-grade inflammation, as demonstrated by increased infiltration of mucosal mast cells and eosinophils. A significant association between the expression level of several cell-to-cell adhesion proteins, the extent of increased permeability and the severity of low-grade inflammation was found. Conclusions These findings challenge the classical paradigm that patients with FD show no structural changes in the gastrointestinal tract. We suggest that impaired intestinal barrier function is a pathophysiological mechanism in FD. Thus, restoration of intestinal barrier integrity may be a potential therapeutic target for treating patients with FD.

Place, publisher, year, edition, pages
BMJ Publishing Group, 2014
Keyword
FUNCTIONAL DYSPEPSIA; DUODENAL MUCOSA; INFLAMMATION
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-104113 (URN)10.1136/gutjnl-2012-303857 (DOI)000329488100015 ()
Available from: 2014-02-07 Created: 2014-02-07 Last updated: 2017-12-06
Wang, A., Keita, Å. V., Phan, V., McKay, C. M., Schoultz, I., Lee, J., . . . Mckay, D. M. (2014). Targeting Mitochondria-Derived Reactive Oxygen Species to Reduce Epithelial Barrier Dysfunction and Colitis. American Journal of Pathology, 184(9), 2516-2527
Open this publication in new window or tab >>Targeting Mitochondria-Derived Reactive Oxygen Species to Reduce Epithelial Barrier Dysfunction and Colitis
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2014 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 184, no 9, p. 2516-2527Article in journal (Refereed) Published
Abstract [en]

Epithelial permeability is often increased in inflammatory bowel diseases. We hypothesized that perturbed mitochondrial function would cause barrier dysfunction and hence epithelial mitochondria could be targeted to treat intestinal inflammation. Mitochondrial dysfunction was induced in human colon-derived epithelial cell lines or colonic biopsy specimens using dinitrophenol, and barrier function was assessed by transepithelial flux of Escherichia coil with or without mitochondria-targeted antioxidant (MTA) cotreatment. The impact of mitochondria-targeted antioxidants on gut permeability and dextran sodium sulfate (DSS)-induced colitis in mice was tested. Mitochondrial superoxide evoked by dinitrophenol elicited significant internalization and transtocation of E. coil across epithelia and control colonic biopsy specimens, which was more striking in Crohns disease biopsy specimens; the mitochondria-targeted antioxidant, MitoTEMPO, inhibited these barrier defects. Increased gut permeability and reduced epithelial mitochondrial voltage-dependent anion channel expression were observed 3 days after DSS. These changes and the severity of DSS-colitis were reduced by MitoTEMPO treatment. In vitro DSS-stimulated IL-8 production by epithelia was reduced by MitoTEMPO. Metabolic stress evokes significant penetration of commensal bacteria across the epithelium, which is mediated by mitochondria-derived superoxide acting as a signaling, not a cytotoxic, molecule. MitoTEMPO inhibited this barrier dysfunction and suppressed colitis in DSS-colitis, likely via enhancing barrier function and inhibiting proinflammatory cytokine production. These novel findings support consideration of MTAs in the maintenance of epithelial barrier function and the management of inflammatory bowel diseases.

Place, publisher, year, edition, pages
American Society for Investigative Pathology (ASIP), 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-110962 (URN)10.1016/j.ajpath.2014.05.019 (DOI)000341283900016 ()25034594 (PubMedID)
Note

Funding Agencies|Canadian Institutes of Health Research [MPO 126005]; Swedish Medical Research Council

Available from: 2014-10-03 Created: 2014-10-01 Last updated: 2017-12-05
Persborn, M. & Söderholm, J. D. (2013). Editorial Material: Commentary: the effects of probiotics on barrier function and mucosal pouch microbiota during maintenance treatment for severe pouchitis in patients with ulcerative colitis - authors reply. Alimentary Pharmacology and Therapeutics, 38(11-12), 1406-1407
Open this publication in new window or tab >>Editorial Material: Commentary: the effects of probiotics on barrier function and mucosal pouch microbiota during maintenance treatment for severe pouchitis in patients with ulcerative colitis - authors reply
2013 (English)In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 38, no 11-12, p. 1406-1407Article in journal, Editorial material (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-102378 (URN)10.1111/apt.12535 (DOI)000326681400010 ()
Available from: 2013-12-09 Created: 2013-12-09 Last updated: 2017-12-06
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