| 1. |
- Andersson, Magnus V., et al.
(författare)
-
Kirurgi – omistligt komplement till medicinsk behandling
- 2009
-
Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 106:45, s. 3003-9
-
Tidskriftsartikel (refereegranskat)abstract
- Kirurgi på rätt indikation och vid rätt tidpunkt är ett omistligt komplement till medicinsk behandling vid inflammatorisk tarmsjukdom, som förebygger sjukdomskomplikationer, förbättrar patienternas livskvalitet och ibland är livräddande. Kirurgi för ulcerös kolit görs oftast som ett tvåstegsförfarande: först kolektomi plus ileostomi med rektum lämnad intakt och i senare skede, med optimerad patient, tarmrekonstruktion anpassad efter patientens individuella livssituation. Kirurgi vid Crohns sjukdom korrigerar komplikationer (stenoser och fistlar) och sparar tarm genom begränsade resektioner och strikturplastiker. Laparoskopisk kirurgi verkar ha viktiga fördelar vid primära tarmresektioner. Modern medicinsk behandling har förändrat indikationerna men ännu inte minskat behovet av kirurgi. Pågående antiinflammatorisk och immunmodulerande behandling är viktig att beakta i samband med kirurgi. Ett nära samspel mellan gastroenterolog och kolorektalkirurg är nödvändigt för att uppnå bästa möjliga långtidsprognos för de individer som lever med IBD.
|
|
| 2. |
|
|
| 3. |
- Assadi, Ghazaleh, et al.
(författare)
-
Functional Analyses of the Crohn's Disease Risk Gene LACC1
- 2016
-
Ingår i: PLOS ONE. - San Francisco, USA : Public Library of Science. - 1932-6203. ; 11:12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Genetic variation in the Laccase (multicopper oxidoreductase) domain-containing 1 (LACC1) gene has been shown to affect the risk of Crohn's disease, leprosy and, more recently, ulcerative colitis and juvenile idiopathic arthritis. LACC1 function appears to promote fatty-acid oxidation, with concomitant inflammasome activation, reactive oxygen species production, and anti-bacterial responses in macrophages. We sought to contribute to elucidating LACC1 biological function by extensive characterization of its expression in human tissues and cells, and through preliminary analyses of the regulatory mechanisms driving such expression.Methods: We implemented Western blot, quantitative real-time PCR, immunofluorescence microscopy, and flow cytometry analyses to investigate fatty acid metabolism-immune nexus (FAMIN; the LACC1 encoded protein) expression in subcellular compartments, cell lines and relevant human tissues. Gene-set enrichment analyses were performed to initially investigate modulatory mechanisms of LACC1 expression. A small-interference RNA knockdown in vitro model system was used to study the effect of FAMIN depletion on peroxisome function.Results: FAMIN expression was detected in macrophage-differentiated THP-1 cells and several human tissues, being highest in neutrophils, monocytes/macrophages, myeloid and plasmacytoid dendritic cells among peripheral blood cells. Subcellular co-localization was exclusively confined to peroxisomes, with some additional positivity for organelle endomembrane structures. LACC1 co-expression signatures were enriched for genes involved in peroxisome proliferator-activated receptors (PPAR) signaling pathways, and PPAR ligands downregulated FAMIN expression in in vitro model systems.Conclusion: FAMIN is a peroxisome-associated protein with primary role(s) in macrophages and other immune cells, where its metabolic functions may be modulated by PPAR signaling events. However, the precise molecular mechanisms through which FAMIN exerts its biological effects in immune cells remain to be elucidated.
|
|
| 4. |
- Fransén, Karin, 1973-, et al.
(författare)
-
Polymorphism in the retinoic acid metabolizing enzyme CYP26B1 and the development of Crohn's disease
- 2013
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8, s. e72739-
-
Tidskriftsartikel (refereegranskat)abstract
- Several studies suggest that Vitamin A may be involved in the pathogenesis of inflammatory bowel disease (IBD), but the mechanism is still unknown. Cytochrome P450 26 B1 (CYP26B1) is involved in the degradation of retinoic acid and the polymorphism rs2241057 has an elevated catabolic function of retinoic acid, why we hypothesized that the rs2241057 polymorphism may affect the risk of Crohn's disease (CD) and Ulcerative Colitis (UC). DNA from 1378 IBD patients, divided into 871 patients with CD and 507 with UC, and 1205 healthy controls collected at Örebro University Hospital and Karolinska University Hospital were analyzed for the CYP26B1 rs2241057 polymorphism with TaqMan® SNP Genotyping Assay followed by allelic discrimination analysis. A higher frequency of patients homozygous for the major (T) allele was associated with CD but not UC compared to the frequency found in healthy controls. A significant association between the major allele and non-stricturing, non-penetrating phenotype was evident for CD. However, the observed associations reached borderline significance only, after correcting for multiple testing. We suggest that homozygous carriers of the major (T) allele, relative to homozygous carriers of the minor (C) allele, of the CYP26B1 polymorphism rs2241057 may have an increased risk for the development of CD, which possibly may be due to elevated levels of retinoic acid. Our data may support the role of Vitamin A in the pathophysiology of CD, but the exact mechanisms remain to be elucidated.
|
|
| 5. |
- Li, Dalin, et al.
(författare)
-
A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition
- 2016
-
Ingår i: Gastroenterology. - : Saunders Elsevier. - 0016-5085 .- 1528-0012. ; 151:4, s. 724-732
-
Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA).Methods: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing.Results: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)).Conclusions: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.
|
|
| 6. |
- McGovern, Dermot P B, et al.
(författare)
-
Genome-wide association identifies multiple ulcerative colitis susceptibility loci
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:4, s. 332-337
-
Tidskriftsartikel (refereegranskat)abstract
- Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.
|
|
| 7. |
|
|
| 8. |
- Schoultz, Ida, et al.
(författare)
-
Combined polymorphisms in genes encoding the inflammasome components NALP3 and CARD8 confer susceptibility to Crohn's disease in Swedish men
- 2009
-
Ingår i: American Journal of Gastroenterology. - : Wolters Kluwer. - 0002-9270 .- 1572-0241. ; 104:5, s. 1180-1188
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Crohn's disease (CD) is characterized by overproduction of proinflammatory cytokines like interleukin (IL)-1beta. Production of mature IL-1beta is dependent on a caspase-1-activating protein complex called the NALP3 inflammasome, composed of NALP3, ASC, and CARD8. NALP3 shares structural similarities with Nod2, and both of these proteins are required for bacteria-induced IL-1beta secretion. The combination of the polymorphisms CARD8 (C10X)and NALP3 (Q705K) was recently shown to be associated with rheumatoid arthritis.Our aim was to investigate whether these combined polymorphisms play a role in the susceptibility to CD. METHODS: The study included 498 CD patients in two cohorts from different regions and 742 control individuals from a Swedish population. DNA was isolated from whole blood. Polymorphisms of (Q705K) NALP3 and (C10X) CARD8, as well as the Nod2 variants, R702W and G908R, were genotyped using the Taqman single nucleotide polymorphism assay. The Nod2 frameshift mutation, L1007fs, was detected by Megabace SNuPe genotyping. RESULTS: Our results show that men who have both the C10X and Q705K alleles in CARD8 and NALP3, and who express wild-type alleles of Nod2 are at an increased risk of developing CD (odds ratio, OR: 3.40 range: 1.32-8.76); P = 0.011). No association with these polymorphisms was found in women (OR: 0.89 (range: 0.44-1.77); P = 0.74). CONCLUSIONS: We suggest a role for combined polymorphisms in CARD8 and NALP3 in the development of CD in men, with obvious sex differences in the genetic susceptibility pattern. These findings give further support to the importance of innate immune responses in CD.
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
- Törkvist, Leif
(författare)
-
Surgical trauma, inflammation and tissue injury
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Surgical tissue trauma is a strong stimulus for local inflammation, including leukocyte recruitment. While such a response may be of importance for the defense against microorganisms, it is also clear that inflammation may contribute to further tissue injury. After skin flap surgery, both decreased blood perfusion and inflammation may contribute to necrosis formation in flap tissue. In this thesis, based on an experimental skin flap model in the rat, the potential negative effects of the inflammatory response on tissue viability were examined, with special reference to the role of neutrophils in the development of post-surgical skin necrosis. We found that the survival rate and degree of inflammation in rat skin flaps varied significantly with the time lag between transportation of the animals from the supplier and flap surgery, apparently in relation to the level of environmental stress. Thus, as compared to acclimatized rat, flap survival was increased and neutrophil recruitment decreased in recently transported animals. Moreover, plasma corticosterone levels were elevated during the first days of acclimatization, and treatment of rats accustomed to their new environment with the glucocorticoid dexamethasone increased flap survival and decreased neutrophil accumulation to levels near those observed in animals operated on arrival. Treatment with leukotriene-synthesis inhibitors significantly increased skin flap survival, while a cysteinyl-leukotriene receptor antagonist did not. These findings suggest that leukotrienes are involved in the development of necrosis in surgical skin flaps in the rat, possibly via leukotriene B4-induced neutrophil recruitment. Survival of rat skin flaps was significantly increased by i.v. treatment with a monoclonal antibody blocking rat leukocyte CD18 function. This antibody also significantly inhibited accumulation of neutrophils in the flap tissue, strongly suggesting that neutrophil recruitment plays an important role in the development tissue necrosis in this experimental flap model. Systemic perioperative treatment with heparin significantly increased the viability of skin flaps in the rat. This effect of heparin appeared to correlate with its ability to prolong clotting time, but not with the degree of total flap blood flow or surgery-induced neutrophil accumulation in the flap. Similar effects on flap viability were observed with the low molecular weight heparin dalteparin, which had minor effects on clotting time and significantly reduced flap neutrophil recruitment without affecting leukocyte rolling. While treatment with heparins may be useful as prophylaxis or for salvage of threatened surgical flaps, their mechanism(s) of action need further investigation. Very low doses of calcitonin-gene related peptide i.p. significantly improved the survival of rat skin flaps. This beneficial effect by CGRP appeared to be related to a reduction in the surgically induced neutrophil recruitment into the flap, and not to hemodynamic changes. Taken together, while being an important host-defence mechanism, surgically induced inflammation, and in particular neutrophil recruitment, appears to be detrimental to skin flap survival. Thus, in efforts to improve skin flap viability, it may be of value to consider anti-inflammatory treatment in addition to agents that increase tissue blood flow.
|
|
| 12. |
- Westerlind, Helga, et al.
(författare)
-
Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis.
- 2017
-
Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 66:3, s. 421-428
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Collagenous colitis (CC) is a major cause of chronic non-bloody diarrhoea, particularly in the elderly female population. The aetiology of CC is unknown, and still poor is the understanding of its pathogenesis. This possibly involves dysregulated inflammation and immune-mediated reactions in genetically predisposed individuals, but the contribution of genetic factors to CC is underinvestigated. We systematically tested immune-related genes known to impact the risk of several autoimmune diseases for their potential CC-predisposing role.DESIGN: Three independent cohorts of histologically confirmed CC cases (N=314) and controls (N=4299) from Sweden and Germany were included in a 2-step association analysis. Immunochip and targeted single nucleotide polymorphism (SNP) genotype data were produced, respectively, for discovery and replication purposes. Classical human leucocyte antigen (HLA) variants at 2-digit and 4-digit resolution were obtained via imputation from single marker genotypes. SNPs and HLA variants passing quality control filters were tested for association with CC with logistic regression adjusting for age, sex and country of origin.RESULTS: Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2×10(-10) for SNP rs4143332). Among the HLA variants, most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5, which was targeted and confirmed in the replication data set (p=2.3×10(-11); OR=2.06; 95% CI (1.67 to 2.55) in the combined analysis).CONCLUSIONS: HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis.
|
|
| 13. |
- Zucchelli, Marco, et al.
(författare)
-
Association of TNFSF15 polymorphism with irritable bowel syndrome.
- 2011
-
Ingår i: Gut. - London : BMJ. - 1468-3288 .- 0017-5749. ; 60:12, s. 1671-7
-
Tidskriftsartikel (refereegranskat)abstract
- Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder, affecting more than 10% of the general population worldwide. Although a genetic component is suspected, unambiguous susceptibility genes have so far not been identified. This study tested the hypothesis that genes contributing to epithelial barrier integrity, control of mucosal immune responses and interactions with bacteria in the gut are associated with IBS.
|
|
