ABSTRACT
Homozygosity for a nonsense mutation in the fucosyltransferase 2 (FUT2) gene (rs601338G>A) leads to the absence of ABH blood groups (FUT2 non-secretor status) in body fluids. As the secretor status has been shown to be a major determinant for the gut microbial spectrum, assumed to be important in the gut immune homeostasis, we studied the association of rs601338-FUT2 with celiac disease (CelD) and inflammatory bowel disease (IBD) in the Finnish population. Rs601338 was genotyped in CelD (n = 909), dermatitis herpetiformis (DH) (n = 116), ulcerative colitis (UC) (n = 496) and Crohn's disease (CD) (n = 280) patients and healthy controls (n = 2738). CelD showed significant genotypic [P = 0.0074, odds ratio (OR): 1.28] and recessive (P = 0.015, OR: 1.28) association with the rs601338-AA genotype. This was also found in the combined CelD+DH dataset (genotype association: P = 0.0060, OR: 1.28; recessive association: P < 0.011, OR: 1.28). The A allele of rs601338 showed nominal association with dominant protection from UC (P = 0.044, OR: 0.82) and UC+CD (P = 0.035, OR: 0.84). The frequency of non-secretors (rs601338-GG) in controls, CelD, DH, UC and CD datasets was 14.7%, 18%, 18.1%, 14.3% and 16.1%, respectively. No association was evident in the DH or CD datasets alone. In conclusion, FUT2 non-secretor status is associated with CelD susceptibility and FUT2 secretor status may also play a role in IBD in the Finnish population.
Subject(s)
Celiac Disease/enzymology , Celiac Disease/genetics , Fucosyltransferases/genetics , Inflammatory Bowel Diseases/enzymology , Inflammatory Bowel Diseases/genetics , Alleles , Base Sequence , Case-Control Studies , Colitis, Ulcerative/enzymology , Colitis, Ulcerative/genetics , Crohn Disease/enzymology , Crohn Disease/genetics , DNA Primers/genetics , Dermatitis Herpetiformis/enzymology , Dermatitis Herpetiformis/genetics , Finland , Genes, Recessive , Genetic Association Studies , Genotype , Humans , Polymorphism, Single Nucleotide , Risk Factors , Galactoside 2-alpha-L-fucosyltransferaseABSTRACT
Some genetic loci may affect susceptibility to multiple immune system-related diseases. In the current study, we investigated whether the known susceptibility loci for celiac disease (CelD) also associate with Crohn's disease (CD) and/or ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), in Finnish patients. A total of 45 genetic markers were genotyped in a Finnish data set comprising 699 IBD patients and 2482 controls. Single-marker association with IBD and its subphenotypes was tested. A meta-analysis with a Swedish UC data set was also performed. A total of 12 single-nucleotide polymorphisms associated with CD and/or UC (P<0.05). In the subphenotype analysis, rs6974491-ELMO1 (P=0.0002, odds ratio (OR): 2.20) and rs2298428-UBE2L3 (P=5.44 × 10(-5), OR: 2.59) associated with pediatric UC and CD, respectively. In the meta-analysis, rs4819388-ICOSLG (P=0.00042, OR: 0.79) associated with UC. In the subphenotype meta-analysis, rs1738074-TAGAP (P=7.40 × 10(-5), OR: 0.61), rs6974491-ELMO1 (P=0.00052, OR: 1.73) and rs4819388-ICOSLG (P=0.00019, OR: 0.75) associated with familial UC, pediatric UC and sporadic UC, respectively. Multiple CelD risk loci also confer susceptibility for CD and/or UC in the Finnish and Swedish populations. Certain genetic risk variants may furthermore predispose an individual for developing a particular disease phenotype.
Subject(s)
Celiac Disease/genetics , Celiac Disease/immunology , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/immunology , Adult , Case-Control Studies , Child , Colitis, Ulcerative/genetics , Colitis, Ulcerative/immunology , Crohn Disease/genetics , Crohn Disease/immunology , Finland , Genetic Association Studies , Genetic Markers , Genetic Predisposition to Disease , Humans , Polymorphism, Single Nucleotide , Risk Factors , SwedenABSTRACT
We explored whether episodes stimulating leucocytes in vivo could be tracked from whole blood samples by monitoring activation of STAT1 by flow cytometry. The method was tested in hepatitis C patients (n = 9) that were on interferon (IFN)alpha regimen. CD14+ monocytes responded strongly to IFNalpha/gamma being sensitive indicators for recent immune activation. At 45 min after s.c. IFNalpha 91% of monocytes were phosphorylated STAT1+. The frequency of responding cells decreased to a base level within 6 h. Monocytes, however, had a long-term deficient phosphorylated STAT1 response to IFNalphain vitro that in patients on standard IFNalpha regimen lasted for 48 h. In patients on pegylated IFNalpha the phosphorylated STAT1 response was completely absent. We conclude that whole blood analysis of STAT1 activation by flow cytometry is applicable to monitor immune cells in patient material.
Subject(s)
Flow Cytometry/methods , Interferon-alpha/therapeutic use , Monitoring, Immunologic , Monocytes/metabolism , STAT1 Transcription Factor/metabolism , Adult , Animals , Female , Hepatitis C/immunology , Hepatitis C/metabolism , Hepatitis C/therapy , Humans , Male , Mice , Middle Aged , Monitoring, Immunologic/methods , Monocytes/immunology , Phosphorylation , STAT1 Transcription Factor/bloodABSTRACT
BACKGROUND: We studied the complications of gallstone disease in kidney transplantation patients and evaluated whether the screening and treatment of gallstones before acceptance to the kidney waiting list is relevant. METHODS: Complications of gallstone disease were evaluated in 1608 kidney transplantation patients on cyclosporine and long-term steroid treatment with median age 45.5 years, transplanted between 1990 and 2000. To evaluate the prevalence of cholecystolithiasis after kidney transplantation an abdominal ultrasound examination was cross-sectionally performed to a subgroup of 304 patients and the results were correlated to their serum lipid values, changes in BMI and use of statins. RESULTS: Pre-transplant cholecystectomy due to cholecystolithiasis (prerequisite for acceptance to kidney waiting list) had been performed on 71 (4%) of the patients. Thirty (15%) patients with diagnosed post-transplant gallstones and four without gallstones developed biliary complications. There were 25 cases of cholecystitis of which three resulted in gallbladder perforations. Seventeen patients (50%) with biliary complications required urgent surgery and one (3%) patient died of post-operative complications. In the subgroup of ultrasound examination patients (median 7 years post-transplant follow-up) 81% of the patients had no gallstones and 9% of the patients had gallstones had developed after transplantation. Patients with pre-transplant gallstones were older (P < 0.01) and patients with post-transplant gallstones gained the most weight during the follow-up. No differences in lipid values were found. CONCLUSION: In transplantation patients, the complications of gallstone disease may be severe. Screening and treatment of pre- and post-transplantation gallstone disease are recommended.
Subject(s)
Cholecystitis/etiology , Cholecystolithiasis/etiology , Gallstones/complications , Kidney Diseases/surgery , Kidney Transplantation/adverse effects , Adolescent , Adult , Aged , Cholecystectomy , Cholecystitis/epidemiology , Cholecystitis/surgery , Cholecystolithiasis/epidemiology , Cholecystolithiasis/surgery , Female , Finland/epidemiology , Follow-Up Studies , Gallstones/diagnostic imaging , Humans , Male , Middle Aged , Prevalence , Prognosis , Retrospective Studies , Severity of Illness Index , UltrasonographyABSTRACT
The most common organ-specific manifestation of cytomegalovirus (CMV) infection after liver transplantation is hepatitis. Here we retrospectively describe the detailed virological, histological, immunological, and clinical findings associated with CMV infection in 229 consecutive adult liver transplantation patients. CMV infection was diagnosed by pp65 antigenemia. From 439 liver biopsies, CMV antigens were demonstrated by immunohistochemistry and CMV DNA by hybridization. The Banff criteria were used for histology. The expression of various adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], endothelial leukocyte adhesion molecule-1 [ELAM-1]), their ligands (leukocyte function antigen-1 [LFA-1], very late antigen-4 [VLA-4], Sialyl-LewisX-molecule [SLeX]), and lymphoid activation markers (major histocompatibility complex [MHC] Class II, interleukin-2-receptor [IL-2R]) was demonstrated by immunohistochemistry. CMV infection of the transplant occurred in 26 patients (11% of all 229 patients and 17% of the 151 patients with liver biopsy). The incidence was higher among seronegative (26%) than in seropositive recipients (9%), but most cases 18/26 (70%) were reactivations. The CMV pp65 antigenemia levels were usually high in primary infections (893+/-1069, range 50-3000 pp65+cells), but varied widely in reactivations (388+/-740, range 3-3000). The histological Banff score was slightly increased (2.3+/-0.9). Microabscesses, lymphocytic infiltration, Kupffer cell reaction, and parenchymal alterations were common but viral inclusions rare. CMV significantly (P<0.05) increased ICAM-1 and VCAM-1 expression and the number of LFA-1, VLA-4, and Class II-positive lymphocytes in the graft. All CMV infections were successfully treated with antivirals. Intragraft CMV infection had no influence on the long-term outcome, but biliary complications were common. In conclusion, CMV infection of the liver transplant occurred both in primary infection and in reactivation, and also in the cases with low pp65 antigenemia levels. Microabscesses and other histological alterations were common but viral inclusions rare. Increased adhesion molecule expression was associated with lymphocyte infiltration. Successfully treated CMV hepatitis had no influence on the long-term clinical outcome.
Subject(s)
Antigens, Viral/blood , Cytomegalovirus Infections/pathology , Cytomegalovirus/immunology , DNA, Viral/analysis , Gene Expression Regulation, Viral , Immunohistochemistry/methods , Liver Transplantation , Adult , Biopsy , Cell Adhesion Molecules/analysis , Cytomegalovirus/genetics , Cytomegalovirus Infections/complications , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/virology , Histocompatibility Antigens Class II/analysis , Humans , In Situ Hybridization , Intercellular Adhesion Molecule-1/analysis , Liver Transplantation/adverse effects , Retrospective Studies , Vascular Cell Adhesion Molecule-1/analysisABSTRACT
An association between cytomegalovirus (CMV) infection and alloresponse has been suggested. CMV increases inflammation and adhesion molecule expression in graft, and induces cytokines and growth factors, linked with transplant vasculopathy and chronic rejection. We have investigated the gene expression of various inflammatory factors in the CMV-associated immune response and compared this with the immune response of acute rejection in liver transplants by using DNA microarray technology. Gene expression was studied at mRNA level in biopsies from liver transplant patients experiencing CMV infection or acute rejection. RNA extracted from liver grafts after reperfusion was used as control material. Among the strongly upregulated genes in the specimens obtained from liver transplants during CMV infection were IFN-gamma, caspases 1 and 3, granzymes A and B, TGF-beta receptors II and III, IL-10 receptor alpha, VCAM-1, TNF receptor, IL-4, TNF-alpha, IL-10, IL-2 receptor beta, IL-1beta, PDGF-receptor beta, vascular adhesion protein-1, TGF-beta2, and ICAM-1. In biopsies with acute liver allograft rejection, the most significantly upregulated genes were MHC class II, IFN-gamma, caspases 1 and 3, IL-2R beta and gamma, granzymes A and B, VLA-4, L-selectin, E-selectin, VCAM-1, and IL-1beta. Upregulated genes common for CMV and alloresponse were granzyme A and B, E-selection, IFN-gamma, VCAM-1, VLA-4, TNF, caspases 1, 3, and 8, and PDGF. Microarray analysis defined different entities in the immune responses of CMV infection and acute rejection. The differences and similarities of the gene expression profiles related to those in CMV infection and rejection may help to understand the intragraft immunologic events.
Subject(s)
Cytomegalovirus Infections/genetics , Gene Expression Profiling , Gene Expression Regulation , Graft Rejection/genetics , Liver Transplantation/physiology , Oligonucleotide Array Sequence Analysis , Biopsy , Growth Substances/genetics , Histocompatibility Antigens Class II/genetics , Humans , Inflammation/genetics , Interleukins/genetics , Liver Transplantation/immunology , RNA, Messenger/geneticsABSTRACT
In addition to cytomegalovirus (CMV), activation of other betaherpesviruses, especially human herpesvirus 6 (HHV-6), has been reported in liver transplant patients. The purpose of this study was to investigate the posttransplant HHV-6-DNAemia in relation to CMV-DNAemia in liver transplant patients. Thirty-one adult liver allograft recipients were regularly monitored for CMV and HHV-6 during the first 3 months after transplantation. For the diagnosis of CMV infections, pp65-antigenemia assay and quantitative DNA-PCR were used. HHV-6 was demonstrated by using quantitative DNA-PCR and HHV-6 antigenemia test. Altogether 253 blood specimens of 31 recipients were analyzed. In addition, CMV and HHV-6 specific antigens were demonstrated by immunohistochemistry in liver biopsy specimens in the case of graft dysfunction. Thirteen patients (40%) developed a clinically significant CMV infection, at a mean of 33 days (range 5 to 62 days) after transplantation and were treated with intravenous ganciclovir. The peak viral loads of these symptomatic CMV infections were high (CMV-DNA 34210 +/- 37557 copies/mL plasma). Six additional asymptomatic patients demonstrated significantly lower CMV-DNAemia levels (1020 +/- 1008 copies/mL, P < .05), and were not treated. Concurrently with CMV, HHV-6 DNAemia and antigenemia were detected in 17 of 19 patients, mean 11 days (range 6 to 24 days) after transplantation. HHV-6 appeared prior to CMV in most cases (12 of 17). However, the peak viral loads were low (HHV-6-DNA <1500 copies/mL blood), even in the five patients who demonstrated HHV-6 antigens on liver biopsy. All CMV infections were successfully treated with ganciclovir and the CMV DNAemia/antigenemia subsided. HHV-6 also responded to the antiviral treatment, but more slowly and less clearly. In conclusion, HHV-6 activations were common and usually associated with CMV infection in liver transplant patients. Further investigation of the clinical significance of HHV-6 DNAemia/antigenemia is necessary.
Subject(s)
Cytomegalovirus Infections/epidemiology , Cytomegalovirus/genetics , DNA, Viral/blood , Herpesvirus 6, Human/genetics , Liver Transplantation/physiology , Postoperative Complications/virology , Adult , DNA, Viral/genetics , Follow-Up Studies , Humans , Polymerase Chain Reaction , Postoperative Period , Roseolovirus Infections/epidemiology , Time Factors , Transplantation, HomologousABSTRACT
OBJECTIVES: To determine whether inflammation in the gut associated immune system is activated in rheumatoid arthritis (RA). The expression of chemokine receptor- (CCR4, CCR5) and cytokine- (interleukin (IL)2, IL10, interferon gamma (IFNgamma), tumour necrosis factor alpha (TNFalpha), and transforming growth factor beta (TGFbeta)) specific mRNA in intestinal biopsy samples from patients with RA was examined. METHODS: Duodenal biopsy samples from 13 patients with RA and 15 control subjects were studied. The mRNA expression of CCR4, CCR5, IL2, IL10, IFNgamma, TNFalpha, and TGFbeta in intestinal biopsy samples was demonstrated by real time quantitative reverse transcriptase-polymerase chain reaction. RESULTS: The mRNA expression of CCR4, CCR5, and IL10 in intestinal biopsy samples was increased in patients with RA in comparison with control subjects (p = 0.001, p = 0.046, p = 0.019). No difference in the expression levels of IL2, IFNgamma, TNFalpha, or TGFbeta was seen between patients with RA and controls. CONCLUSIONS: The increased intestinal mRNA expression of IL10, CCR5, and CCR4 suggests that gut associated immune cells are activated in patients with RA.
Subject(s)
Arthritis, Rheumatoid/immunology , Duodenum/immunology , Adult , Aged , Aged, 80 and over , Arthritis, Rheumatoid/pathology , Biopsy , Cytokines/biosynthesis , Cytokines/genetics , Duodenum/pathology , Female , Gastroscopy , Gene Expression , Humans , Interleukin-10/biosynthesis , Interleukin-10/genetics , Male , Middle Aged , RNA, Messenger/genetics , Receptors, CCR4 , Receptors, CCR5/biosynthesis , Receptors, CCR5/genetics , Receptors, Chemokine/biosynthesis , Receptors, Chemokine/genetics , Reverse Transcriptase Polymerase Chain Reaction , Stomach/pathologyABSTRACT
BACKGROUND: Mutations in the caspase-activating recruitment domain 15 (CARD15) gene are associated with Crohn disease (CD). CARD15 is an intracellular receptor for bacterial lipopolysaccharides (LPS). LPS-induced activation of transfectants containing the frameshift mutation (1007fs) of CARD15 is impaired. The aim of this study was to investigate whether the presence of CARD15 1007fs affects activation of CD patients' own cells. Patients (4 homozygotes, 6 heterozygotes, and 6 wild-type) were matched according to clinical picture and medication. METHODS: Immune inflammatory status was evaluated by measuring monocyte HLA-DR and CD11b densities and the proportion of CD14dimCD16+ monocytes, and was found to be comparable in the three groups. Blood mononuclear cells were cultured overnight in serum-free medium alone, or the medium supplemented with LPS (0.1-10.0 ng/mL), a combination of IFN-gamma (100 IU/mL) and granulocyte-macrophage colony stimulating factor (GM-CSF) (5 ng/mL), or both. TNF and IL-10 levels in the culture supernatant were determined. RESULTS: LPS 0.1 or 1.0 ng/mL alone did not increase TNF levels. IFN-gamma/GM-CSF induced TNF release, and co-culture with LPS 1.0 or 10.0 ng/mL was strongly synergistic. CARD15 1007fs mutation was linked in a gene-dose-dependent manner to low TNF release induced by IFN-gamma/GM-CSF (P value for linear trend = 0.001). The degree of synergism in co-culture was normal or high, suggesting that 1007fs did not depress responses to LPS. IL-10 levels were not related to CARD15 1007fs. CONCLUSIONS: In CD patients, CARD15 1007fs is associated in a gene-dose-dependent manner to low mononuclear cell TNF release by IFN-gamma/GM-CSF but does not impair TNF release by LPS. This type of immune dysregulation may influence susceptibility to and/or phenotype of CD.
Subject(s)
Crohn Disease/genetics , Crohn Disease/immunology , Frameshift Mutation , Intracellular Signaling Peptides and Proteins/genetics , Leukocytes, Mononuclear/physiology , Adult , Case-Control Studies , Cell Culture Techniques , Female , Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Humans , Interferon-gamma/physiology , Interleukin-10/metabolism , Leukocytes, Mononuclear/drug effects , Lipopolysaccharides/pharmacology , Male , Middle Aged , Nod2 Signaling Adaptor Protein , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Helicobacter pylori has been found to be only a minor risk factor for gastroduodenal complications in kidney transplantation patients. The aim of the study was to follow up the course of H. pylori infection in a group of immunosuppressed kidney transplantation patients. METHODS: After a median follow-up of 6.8 years, control serum samples were taken from 93 originally seropositive and 88 originally seronegative kidney transplant recipients. H. pylori antibodies of the IgG and IgA classes and serum pepsinogen I levels were measured from pretransplant and follow-up samples in parallel. In addition, CagA antibodies were measured from the baseline samples of the seropositive patients. RESULTS: 83 of the 93 seropositive patients were also cagA-positive. In addition to the 10 patients who received H. pylori eradication therapy, 27 (29%) of the 92 patients with originally elevated H. pylori IgG antibody titres showed IgG titres at normal level or levels decreased by more than 70% and below 2000 (regarded as seroreverters) after the follow-up. One of the originally seronegative patients seroconverted during the study period. After transplantation, the decrease of serum pepsinogen I values was in accordance with improved kidney function. Patients with lower serum pepsinogen I levels before the transplantation seroreverted more easily. CONCLUSIONS: A spontaneous H. pylori seroreversion occurred in 29% of the immunosuppressed kidney transplantation patients. After a successful kidney transplantation, serum pepsinogen I values declined significantly.
Subject(s)
Helicobacter Infections/etiology , Helicobacter pylori/isolation & purification , Kidney Transplantation/adverse effects , Adolescent , Adult , Aged , Anti-Ulcer Agents/therapeutic use , Antibodies, Bacterial/blood , Breath Tests , Female , Follow-Up Studies , Graft Survival/drug effects , Helicobacter Infections/drug therapy , Helicobacter Infections/immunology , Helicobacter pylori/immunology , Humans , Immunoglobulin A/analysis , Immunoglobulin G/analysis , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Pepsinogen A/bloodABSTRACT
BACKGROUND: Variants of the caspase activating recruitment domain 15/nucleotide oligomerisation domain 2 (CARD15/NOD2) gene have been associated with susceptibility to Crohn's disease (CD). AIM: Our aim was to evaluate the allele frequencies of the CARD15 variants R702W, G908R, and 1007fs in Finnish inflammatory bowel disease (IBD) patients and to search for possible associations between CARD15 variants and occurrence of familial forms of IBD or complicated forms of CD. PATIENTS AND METHODS: We investigated 198 sporadic CD patients, 46 probands with familial CD, 27 CD probands from mixed IBD families, 99 unrelated patients with ulcerative colitis (UC), and 300 control individuals for the occurrence of the CARD15 gene variants R702W, G908R, and 1007fs. RESULTS: In CD patients, the allele frequencies for the rare variants of these polymorphisms were 3.3%, 0.6%, and 4.8% (total 8.7%), and the corresponding frequencies in healthy controls were 1.8%, 0%, and 1.7% (total 3.5%) (8.7% v 3.5%; p<0.01). In UC patients allele frequencies were comparable with those in controls. The frequency of the 1007fs polymorphism variant allele was significantly higher among all CD patients than in controls (4.8% v 1.7%; p<0.01) but there was no significant difference in allele frequencies between the CD and UC groups. The 1007fs allele frequency was higher in familial CD than in non-familial cases with CD (10.9% v 3.5%; p<0.01). There were no significant differences in the allele frequencies of the R702W and G908R polymorphisms between CD patients, UC patients, and controls. We found that 15.5% of CD patients, 9.1% of UC patients, and 6.7% of controls carried at least one of the CARD15 variants. In CD patients carrying at least one of the three NOD2 variants, the ileum was affected more often than in non-carrier CD patients (90% v 73%; p<0.05), they had stricturing or penetrating disease more often than non-carriers (88% v 56%; p<0.01), and they had an increased need for bowel surgery. CONCLUSIONS: The frequency of NOD2 gene variants was lower in genetically homogenous Finns than in other populations. The 1007fs variant was associated with CD. The occurrence of CARD15 variants predicted ileal location as well as stricturing and penetrating forms of CD.
Subject(s)
Carrier Proteins/genetics , Crohn Disease/genetics , Genetic Predisposition to Disease , Intracellular Signaling Peptides and Proteins , Adolescent , Adult , Age of Onset , Aged , Child , Colitis, Ulcerative/genetics , Crohn Disease/complications , Crohn Disease/pathology , Female , Gene Frequency , Genetic Variation , Heterozygote , Homozygote , Humans , Male , Middle Aged , Nod2 Signaling Adaptor Protein , Phenotype , Retrospective StudiesABSTRACT
BACKGROUND: The familial occurrence of inflammatory bowel disease (IBD) and the clinical features of familial and sporadic IBD in the genetically homogeneous Finnish population are evaluated. METHODS: 257 patients with Crohn disease (CD) and 436 with ulcerative colitis (UC) participated in the study. They were asked whether IBD was present (familial IBD) or absent (sporadic IBD) in their first-degree relatives. Data on the clinical course of the disease were collected from the patient records. Antibodies to Saccharomyces cerevisiae (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA) were determined from serum samples. RESULTS: Affected first-degree relatives were found in 15.6% of patients with CD and in 13.8% of patients with UC. In familial cases CD was more often located in the ileum (38% versus 21%) and less often in the ileocolon (35% versus 50%) (P< 0.05) than in sporadic cases. A greater percentage of CD patients than UC patients were smokers (47% versus 13%; P < 0.01). An elevated level of IgA and/or IgG antibodies for ASCA was found more often in CD patients than in UC patients (59% versus 14%; P < 0.01), while pANCA were found more often in UC than in CD patients (48% versus 12%; P < 0.01). The combination of pANCA-ASCA+ yielded a sensitivity, specificity and positive predictive value of 48%, 92% and 90%, respectively, for CD, and the combination of pANCA + ASCA- of 55%, 94% and 90%, respectively, for UC. CONCLUSIONS: The percentage of familial IBD cases in Finland is comparable to that reported elsewhere in Europe. No important clinical differences between patients with familial and sporadic forms of the disease were found. ASCA is associated with both familial and sporadic CD and pANCA with UC, but low sensitivity diminishes their value as a serological marker of IBD or as a differential diagnostic test between CD and UC.
Subject(s)
Antibodies, Antineutrophil Cytoplasmic/analysis , Inflammatory Bowel Diseases/epidemiology , Inflammatory Bowel Diseases/genetics , Adolescent , Adult , Age Distribution , Aged , Biomarkers/analysis , Child , Cohort Studies , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/epidemiology , Colitis, Ulcerative/genetics , Crohn Disease/diagnosis , Crohn Disease/epidemiology , Crohn Disease/genetics , Enzyme-Linked Immunosorbent Assay , Female , Finland/epidemiology , Humans , Incidence , Inflammatory Bowel Diseases/diagnosis , Male , Middle Aged , Predictive Value of Tests , Probability , Prognosis , Risk Assessment , Sex DistributionABSTRACT
BACKGROUND: Before the introduction of modern medication for ulcer disease, gastroduodenal complications were often fatal in recipients of kidney transplants. Helicobacter pylori causes gastritis and is an important risk factor for peptic ulcer disease and gastric malignancies. The aim of this study was to evaluate whether H. pylori infection influences the outcomes of kidney transplantation. METHODS: Between 1991 and 1994, serum H. pylori antibodies were determined in samples taken just before transplantation from 500 consecutive recipients of kidney transplants. Clinical data were collected retrospectively by means of questionnaires sent to the patients and from the national kidney transplantation registry. RESULTS: The prevalence of seropositivity of H. pylori was 31% in the 500 renal transplant subjects, and the seropositivity increased with age. There were no differences in patient or graft survival between the seronegative and seropositive patients. During the first 3 months after transplantation, five seronegative and one seropositive patient had gastroduodenal ulcers, with bleeding complications in three of the seronegative ones. After 3 months, there were more ulcers in the seropositive group (6 vs 3%) and more oesophagitis in the seronegative group (9 vs 7%). During the 6-year follow-up, two cases of gastroduodenal malignancies were found in the helicobacter-positive group and none in the seronegative group. CONCLUSIONS: Helicobacter pylori infections did not result in significant postoperative gastric complications. Two of the 155 seropositive patients developed gastroduodenal malignancies.
Subject(s)
Helicobacter Infections/complications , Helicobacter Infections/drug therapy , Helicobacter pylori , Kidney Transplantation/adverse effects , Adolescent , Adult , Aged , Child , Duodenal Neoplasms/etiology , Female , Finland/epidemiology , Graft Survival , Helicobacter Infections/epidemiology , Humans , Kidney Transplantation/physiology , Male , Middle Aged , Peptic Ulcer/etiology , Retrospective Studies , Stomach Neoplasms/etiology , Survival RateABSTRACT
BACKGROUND: The majority of patients with inherited haemochromatosis carry two mutant alleles of the recently discovered HFE gene. Individuals heterozygous for the HFE mutation could be predisposed to end-stage liver disease due to other causes. METHODS: The frequencies of the HFE gene mutations C282Y and H63D were determined in DNA samples obtained from 189 liver transplant patients and 225 healthy Finnish blood donors. RESULTS: 5% of the 189 liver transplant recipients were heterozygotes and 0.5% homozygotes for the C282Y mutation, while 16% were heterozygotes and 0.5% homozygotes for the H63D mutation. These figures were not increased in comparison to controls, of whom 11% were C282Y heterozygotes, 16% H63D heterozygotes and 0.9% H63D homozygotes. Among recipients with acute non-A-E hepatitis (n = 31), the frequency of the H63D allele was higher than in controls (21% versus 9.1%, P < 0.01). Perls' stain for iron in explanted liver specimens was positive in 28% of recipients with alcoholic cirrhosis, 26% of patients with acute non-A-E hepatitis and 14% in the rest of the recipients. The HFE genotypes did not correlate with the iron status. CONCLUSION: Individuals heterozygous for either the C282Y or H63D mutation of the HFE gene are not at increased risk of developing chronic end-stage liver disease. However, subjects heterozygous for the H63D mutation may have an increased risk to develop fulminant non-A-E hepatitis.
Subject(s)
HLA Antigens/genetics , Hemochromatosis/genetics , Histocompatibility Antigens Class I/genetics , Liver Transplantation , Membrane Proteins , Mutation , Adolescent , Adult , Aged , Case-Control Studies , DNA Mutational Analysis/methods , DNA Primers , Female , Hemochromatosis/pathology , Hemochromatosis Protein , Humans , Liver/pathology , Male , Middle AgedABSTRACT
In inflammatory bowel diseases (IBD), certain chromosomal candidate loci have been repeatedly identified by independent studies in different populations. To investigate the contribution of the loci on chromosomes 1, 3, 7, 12, 14, and 16 to the susceptibility of IBD in Finnish population, where the predominant feature is the excess of ulcerative colitis (UC) families compared to Crohn's disease (CD) families, we carried out linkage analyses using 93 Finnish, multiply-affected IBD families. We observed nominal evidence for linkage to chromosome 3p21, consistent with earlier reports. The lod scores peaked at D3S2432, with a maximum two-point lod score of 1.68 (P=0.0027). In addition, we studied whether risk of IBD is associated with functional variants of two positional candidate genes; the chemokine receptor CCR5 gene on chromosome 3p21 and the interleukin-4 receptor alpha-subunit gene (IL4RA) on chromosome 16. We did not find any significant correlation between a 32-bp deletion variant of CCR5 or a single nucleotide change A1902G (Gln576Arg) of IL4RA, and IBD phenotypes, with the exception that in the UC group homozygosity for the G1902 allele of IL4RA was less frequent (0.019 vs 0.049, P=0.038). In conclusion, our study, carried out in a genetically homogenous population, suggests that chromosome 3 may contain a susceptibility gene for IBD.
Subject(s)
Chromosomes, Human, Pair 3 , Inflammatory Bowel Diseases/genetics , Receptors, CCR5/genetics , Receptors, Interleukin-4/genetics , Alleles , Chromosome Mapping , Chromosomes, Human, Pair 16 , Female , Finland , Genetic Linkage , Genetic Predisposition to Disease , Genetic Testing , Humans , Inflammatory Bowel Diseases/ethnology , Male , Microsatellite Repeats , Middle AgedABSTRACT
We studied the effect of initial graft function and acute rejection on graft survival in 1047 cadaveric renal transplantations during 1991-1997 with a constant policy of donor selection, graft allocation, and immunosuppression. The overall 1- and 5-year patient survival rates were 96 % and 88 %, and the 1- and 5-year graft survival (GS) rates were 92 % and 78 %. Delayed graft function (DGF) occurred in 31 % and there were 1.2 % never-functioning grafts. One-year GS in transplantations with early graft function (EGF) was 95 % compared to 87 % in DGF (P < 0.001). Donor age and cause of death, type of graft perfusion and cold ischemia time, and type and length of dialysis treatment were significant factors in determining the onset of graft function. These factors did not have a significant direct effect on GS. Early ( < 100 days) acute rejection occurred in 25 %. In transplantations without rejection, the 1 and 5-year GS was 93.3 % and 80.8 %. In acute rejection responding to steroids, the GS was equal to that up to 3 years, but after that a significantly worse survival rate was observed (1- and 5-year GS: 93.6 % and 73.4 %). DGF was detrimental to GS both in transplantations without rejection and in all rejection types.
Subject(s)
Graft Rejection , Graft Survival , Kidney Transplantation , Tissue Donors , Adolescent , Adult , Aged , Cadaver , Child , Child, Preschool , Female , Humans , Infant , Kidney/physiopathology , Male , Middle Aged , Transplantation, HomologousABSTRACT
Increased intestinal permeability has been proposed as one aetiological factor for inflammatory bowel diseases (IBD). We have previously found that intestinal permeability of a water-soluble contrast medium, iohexol, correlates with disease activity. The objective was to compare the iohexol test with the lactulose-mannitol ratio, which is a more extensively studied permeability marker, in patients with active IBD. Urinary excretion of iohexol was compared to the lactulose-mannitol ratio in 22 patients with an exacerbation of IBD and in 10 healthy controls. Median intestinal absorption of iohexol was 0.64% (range 0.13-3.8%) in the 22 patients and 0.3% (range 0.15-0.54%) in the controls (p = 0.016), whereas the median lactulose-mannitol ratio was 0.037 (range 0.01-0.260) in patients and 0.03 (range 0.004-0.063) in controls (N.S.). Correlation between urinary excretion of iohexol and lactulose-mannitol ratio was positive (R = +0.41, p = 0.018). The urinary excretion of iohexol correlated positively with endoscopic disease activity (R = +0.74, p < 0.001) and the modified Harvey-Bradshaw index (R = +0.44, p = 0.04). The lactulose-mannitol ratio correlated positively with endoscopic disease activity (R = +0.44, p = 0.05), but correlations with clinical index or c-reactive protein were poor. In conclusion, the iohexol test is a superior activity marker compared to the lactulose-mannitol ratio which probably reflects, instead, some pathogenic property of IBD.