| 1. |
- Blom, Kristin, et al.
(författare)
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Eosinophil associated genes in the inflammatory bowel disease 4 region : Correlation to inflammatory bowel disease revealed
- 2012
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Ingår i: World Journal of Gastroenterology. - : Baishideng Publishing Group Inc.. - 1007-9327 .- 2219-2840. ; 18:44, s. 6409-6419
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Hertervig, Erik, et al.
(författare)
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[Colitis cancer--myth or reality?]
- 2009
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Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 106:45, s. 3000-3002
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Forskningsöversikt (refereegranskat)abstract
- Det finns specifika grupper av patienter med ulcerös kolit och crohnkolit som har ökad risk för att utveckla kolorektal cancer. Mycket tyder dock på att risken har reducerats under senare tid. Prognosen vid manifest kolorektal cancer har också förbättrats. Inflammation i sig har visat sig vara en oberoende riskfaktor för kolorektal cancer. Den förbättrade antiinflammatoriska terapin med framför allt 5-aminosalicylsyra har visat sig vara en plausibel förklaring till den minskade risken. Koloskopisk övervakning och förbättrad terapi vid manifest kolorektal cancer är faktorer som sannolikt ligger bakom en kraftigt förbättrad prognos.
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| 3. |
- Hertervig, Erik, et al.
(författare)
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Kolitcancer - mer myt än verklighet?
- 2009
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Ingår i: Läkartidningen. - 0023-7205. ; 106:45, s. 3000-3002
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Tidskriftsartikel (refereegranskat)abstract
- Patients with ulcerative colitis (UC) and Crohn´s colitis are at increased of developing colorectal cancer (CRC). However, recent studies suggest that the risk is now less than previously thought. Well established risk factors include extent and duration of disease, primary sclerosing cholangitis (PSC) and a family history of CRC. Recently inflammation (both microscopic and macroscopic) has been shown to represent an important independent risk factor for CRC development. Thus one likely explanation for the decreased risk of CRC observed in UC patients is the use of agents that inhibit the inflammatory process, particularly 5-ASA. Ursodeoxycholic acid has been found to be chemopreventive in UC patients with PSC. Evidence from case series and case-control studies suggest that surveillance colonoscopy also reduces the risk of CRC. Prospective randomized controlled trials will never be done because of ethical and logistical concerns. Thus, in the absence of these studies, our knowledge will have to rely on biologic and observational studies
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| 4. |
- Schoultz, Ida, et al.
(författare)
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Combined polymorphisms in genes encoding the inflammasome components NALP3 and CARD8 confer susceptibility to Crohn's disease in Swedish men
- 2009
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Ingår i: American Journal of Gastroenterology. - : Wolters Kluwer. - 0002-9270 .- 1572-0241. ; 104:5, s. 1180-1188
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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.
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| 5. |
- Sjöqvist, Urban
(författare)
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Malignant transformation of the colorectal mucosa in inflammatory bowel disease
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ulcerative colitis (UC) and Crohn's disease (CD) are disorders of unknown etiology, often referred to as inflammatory bowel diseases (IBD). The increased risk of colorectal cancer (CRC) in patients with longstanding, extensive colonic IBD is an important clinical problem. Colonoscopic surveillance, annually or every second year, with multiple biopsies for histopathological detection of dysplasia, is now used to manage this increased risk at many centers for IBD. Dysplasia is a useful prognostic marker for subsequent cancer development but has limitations including substantial inter- and intra-observer variability among pathologists. Furthermore, concomitant active inflammation makes assessment and interpretation of dysplasia difficult. There is a need for more accurate and more objective markers for neoplastic transformation of the colorectal mucosa in high-risk individuals. Although long-term treatment with 5-ASA compounds seems to lower the risk of CRC in IBD, no studies using primarily preventive drugs have been performed. The aims of this thesis were to assess the utility of other markers for malignant transformation of the colorectal mucosa and also to explore any potential chemo-preventive properties of long-term oral therapy with ursodeoxycholic acid in high-risk patients with IBD. By using monoclonal antibodies, the expression of the proliferative antigens Ki-67 and PCNA was assessed in biopsy specimens with various degrees of epithelial dysplasia and inflammatory changes. Increased staining with MIB-1 and PCNA correlated with increased severity of dysplasia but also with increased inflammation. In the absence of inflammation, immunostaining with these two antibodies may complement dysplasia, especially in the indefinite changes category. Alkaline sphingomyelinase (SMase) hydrolyses sphingomyelin (SM) generating ceramide which is important in the regulation of cell growth. The activity of alkaline SMase activity is decreased in CRC and premalignant conditions and was also found to be decreased in IBD-patients. There was also an age-dependent decrease of alkaline SMase both in IBD- patients and controls. Flow cytometric DNA-analyses of biopsy specimen can detect gross chromosomal aberrations and also have the ability to correctly estimate the number of cells in proliferation (S-phase). In normal colorectal mucosa it was found that the S-phase increased linearly with age and decreased from the right colon over the transverse colon to the left colon. The fraction of G2cells increased significantly with increased S-phase fraction. No aneuploidy was detected. In 324 UC-patients undergoing colonoscopic surveillance, the S-phase of aneuploid samples was significantly increased compared to diploid, but significantly lowered in comparison with sporadic CRC. An increase in S-phase fraction in patients with IBD without active inflammation may be an additional marker for neoplastic potential in the colorectal mucosa. Ursodeoxycholic acid, a natural bile salt, has been associated with regression of experimentally induced neoplasia in rats. In a two year prospective, double blind randomized pilot study in high-risk IBD-patients, none of the ten patients in the treatment group had progression of dysplasia, while two of the nine patients in the placebo group were refered for colectomy due to progression of dysplasia. UDCA may exert chemo-preventive action(s) in patients with longstanding IBD in the colon, but further studies are needed in order to determine optimal selection of patients, UDCA-dose and treatment time.
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