A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.

Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.

HHV-6 antigen and HHV-6 DNA expression in sporadic adenomatous polyps of the colon.

BACKGROUND. Human herpesvirus-6B (HHV-6B) antigens are commonly found in the intestinal mucosa of patients with immunosuppression. In a series of immunocompetent patients with adenomatous, polyp HHV-6B antigen expression from mucosal biopsies was more intense than in biopsies taken from patients receiving immunosuppressive drugs because of kidney transplantation or inflammatory bowel disease. METHODS. HHV-6B and cytomegalovirus (CMV) antigen expression was determined from mucosal biopsy samples by immunohistochemistry. HHV-6-DNA content was studied in adenomatous polyps (seven tubular adenomas and one tubulovillous adenoma) taken from eight immunocompetent patients and in three mucosal biopsy samples taken from immunocompetent patients without adenomas using in situ hybridization (ISH) method. RESULTS. HHV-6B antigen expression on mucosal biopsies was strongly positive in five of eight patients with adenomas and negative in all patients without adenoma. CMV antigen expression on mucosal biopsies was faintly positive in three of adenoma patients. HHV-6 ISH was positive in seven of eight adenomatous polyps, most intense in the tubulovillous adenoma and negative in all three mucosal biopsies of patients without adenomas. CONCLUSION. Intensive HHV-6-DNA expression was found in adenomatous polyps of the colon. Further studies on involvement of HHV-6 in the development of gastrointestinal polyps are warranted.

HHV-6B is frequently found in the gastrointestinal tract in kidney transplantation patients.

In immunosuppressed patients human herpesvirus 6 (HHV-6) reactivations are common. The aim of the study was to determine to which extent HHV-6 can be found in the gastrointestinal tract in kidney transplant recipients and in patients on chronic dialysis. The HHV-6 and cytomegalovirus (CMV) examinations were performed on gastro duodenal and colon biopsy specimens obtained from 81 kidney transplant recipients and on 46 chronic dialysis patients. The HHV-6 and CMV were demonstrated by immunohistochemistry detecting both HHV-6A and HHV-6B, and CMV-specific antigens. The HHV-6B-positive cells, were found in gastroduodenal biopsy specimens from 34% of the transplant recipients and 28% of the patients on chronic dialysis, CMV-positive cells were found in specimens from 53% of the transplant recipients and 28% of the patients on chronic dialysis. The HHV-6B positive cells were found in the colonic mucosa specimens from 36% of the transplant recipients and 22% of the patients on chronic dialysis, CMV-positive cells were found in specimens from 36% of the transplant recipients and 17% of the patients on chronic dialysis. The HHV-6B positive cells were found equally often in the gastroduodenal as in the colorectal mucosa. The HHV-6B positive cells as well as CMV positive cells were simultaneously found in every fifth of transplant recipients.

Biliary dysplasia in patients with primary sclerosing cholangitis: additional value of DNA ploidity.

BACKGROUND: Detection of biliary dysplasia in PSC is essential for proper timing of liver transplantation to prevent the development of cholangiocancer, which is considered a contraindication for liver transplantation in most centres. In patients with PSC, differential diagnosis of benign, premalignant and malignant biliary strictures is difficult. AIMS: This prospective study aimed to evaluate the role of DNA analysis in combination with brush cytology, scored ERCP findings, and tumour markers to detect hepatobiliary dysplasia and malignancy. MATERIAL AND METHODS: Brush samples for cytology and for evaluation of DNA content analysed with flow cytometry came from 102 consecutive PSC patients referred for ERCP. Symptoms, serum Ca19-9 and CEA were determined at the time of index biliary examination. ERCP findings were scored for intra- and extrahepatic changes. The end-points were liver transplantation or diagnosis of malignancy or dysplasia. RESULTS: Most of the patients were asymptomatic at the time of ERCP: 73% had no symptoms, and 12% had only mild symptoms. An aneuploid DNA content was evident in 20 (20%) patients, and cells suspected for malignancy in 22 (21%). Seven patients had both aneuploidity and cytology (7%) suspicious for malignancy. An end-point, diagnosis of malignancy or liver transplantation was achieved in 42 patients. Combining DNA ploidity and cytology in patients at the end-point, sensitivity was 72%, specificity 82%, positive predictive value 86% and negative predictive value 67%. DISCUSSION AND CONCLUSION: In this mostly asymptomatic PSC-patient population, 33% demonstrated abnormal brush cytology or aneuploidity. Determining DNA ploidy and brush cytology during ERCP offers a useful tool for identifying those PSC patients who are at high risk of developing cholangiocancer.

Human herpesvirus 6 and cytomegalovirus in ileocolonic mucosa in inflammatory bowel disease.

OBJECTIVES: Reactivation of a latent cytomegalovirus (CMV) may occur in inflammatory bowel disease (IBD). Data of human herpesvirus 6 (HHV-6)--a close relative to CMV--in active IBD are scarce. The aim of this study was to detect HHV-6 and CMV antigens in the mucosa of active and inactive IBD. MATERIAL AND METHODS: 79 IBD patients (47 ulcerative colitis (UC) and 32 Crohn's disease (CD)) were recruited and endoscopic and histological disease activity was scored. Control group consisted of 15 non-IBD patients with normal colonoscopy. Immunohistochemical stainings for HHV-6B and CMV antigens were performed on biopsy specimens from the ileum and colorectum. The intensity of HHV-6B and CMV expression was graded as negative, mild, moderate, or intense. RESULTS: HHV-6B antigen was positive in 35 (44%) and CMV in 64 (81%). Of controls, 6 (40%) were mildly positive for HHV-6 and 6 (40%) for CMV. In IBD, both CMV and HHV-6B intensity correlated with endoscopic disease severity (CMV p = 0.010 and HHV-6 p = 0.048). Simultaneous HHV-6B and CMV antigen expression occurred in 29 (37%) and associated with endoscopic activity (p = 0.006) and to a number of immunosuppressives (p = 0.033). A significant difference in HHV-6B positivity was found between endoscopically active and inactive UC (p = 0.040). Both CMV and HHV-6B intensity correlated with histological severity in the rectal biopsy specimens (for CMV p = 0.040 and for HHV-6B p = 0.027). CONCLUSIONS: Both viruses occurred ubiquitously in the IBD mucosa. Coexistence of viruses was common and associated with disease activity and use of immunosuppressives. HHV-6B intensity correlated with endoscopic severity in UC.

Intragraft immunological events associated with EBV DNAemia in liver transplant patients.

Epstein-Barr virus (EBV) may cause post-transplant lymphoproliferative disorder, but most EBV infections after liver transplantation (Ltx) are clinically silent reactivations. In this study, we investigated the intragraft immunological events associated with EBV DNAemia. Altogether, 105 adult Ltx patients were monitored for EBV DNAemia. Fourteen (13%) patients developed EBV DNAemia during the first year after transplantation. Liver biopsies obtained associated with EBV DNAemia, without evidence of other herpes or hepatitis viruses or rejection, were available from five patients. The numbers of lymphocytes positive for B-cell marker (CD20), T-cell markers (CD3, CD4 and CD8) and IL-2R, adhesion molecules (ICAM-1, VCAM-1 and ELAM-1) and their ligands [lymphocyte function-associated antigen-1 (LFA-1), very late antigen (VLA-4) and Sialyl Lewis X (sLeX)] were demonstrated in liver biopsies by immunohistochemistry, and zero-biopsies from donor livers were used as controls. EBV DNAemia was associated with increased number of CD20-positive (22±30, p=0.09) and significantly increased numbers of CD3 (80±16, p=0.001)-, CD4 (23±8, p=0.009)- and CD8 (38±8, p=0.001)-positive lymphocytes in the graft. ICAM-1, but not VCAM-1 or ELAM-1, was strongly expressed and the number of LFA-1-positive cells was significantly increased (48±10, p=0.0002). Low-level EBV DNAemia was associated with B- and especially T-cell infiltration of the graft, as well as an increase in ICAM-1 and the number of LFA-1-positive cells. However, EBV DNAemia or these immunological events did not have any effect on the liver transplant.

[Update on current care guidelines. Prevention and treatment of acute kidney injury in adults]. / Aikuisten akuutin munuaisvaurion ehkäisy ja hoito.

Acute kidney injury (AKI) is associated with significant morbidity and mortality. Its prevalence is increasing. Risk factors are older age, diabetes, atherosclerosis, medications, heart failure, male sex, and even mild chronic renal failure. Early detection of AKI is essential, as is the prevention of AKI related to hypovolaemia, contrast agents and nephrotoxic medications. No medication is available for developed AKI, the only therapeutic option being renal replacement therapy. Thus, prevention by adequate fluid therapy, optimisation of renal perfusion pressure and exclusion of post-renal causes of AKI are crucial. To date, the long-term outcome in AKI is unsatisfactory and the costs are high.

CMV findings in the gastrointestinal tract in kidney transplantation patients, patients with end-stage kidney disease and immunocompetent patients.

AIM: Cytomegalovirus (CMV) is the most common viral pathogen affecting organ transplant recipients. The objective was to determine to what extent CMV can be found in the gastrointestinal tract in kidney transplant recipients and to compare them with patients in dialysis and randomly chosen otherwise healthy patients who were referred for oesophagogastroduodenoscopy (OEGD) or colonoscopy. PATIENTS AND METHODS: Biopsies for CMV examinations were obtained from 130 oesophagogastroduodenoscopies and 54 colonoscopies performed on 82 kidney transplant recipients, 49 dialysis patients with chronic end-stage kidney disease and 53 immunocompetent patients because of clinical indications. CMV was demonstrated by immunohistochemistry, both in frozen sections using a monoclonal antibody against CMV-specific antigens (pp65 matrix protein) and in paraffin sections by means of a monoclonal antibody against the delayed early protein (p52). RESULTS: CMV-positive cells were found in the gastroduodenal mucosa in 46 (68%) out of 82 kidney transplant recipients, in 9 (31%) of 49 dialysis patients and in 15 (45%) of 53 immunocompetent patients, in the colorectal mucosa in 7 (50%), in 6 (30%) and in 9 (45%) of the patient groups, respectively. In the transplant recipient group, 4 patients had severe and 10 patients moderate CMV infection in the gastroduodenal mucosa. CMV disease was diagnosed in two patients with severe infection and in one patient with moderate infection. All dialysis and immunocompetent patients had only moderate or mild CMV involvement. CONCLUSION: It appears that CMV-positive cells were present in all groups studied, suggesting that CMV-infected cells alone are not sufficient to make the diagnosis of CMV disease in the transplanted host. Moreover, the clinical symptoms and the intensity of the histologic CMV findings did not correlate with the symptoms the patients were having. In kidney transplant recipients, it emerges that CMV is activated more easily in the upper rather than in the lower gastrointestinal tract.

Vascular deposition of complement C4d is increased in liver allografts with chronic rejection.

BACKGROUND: Complement protein C4d has been used as a marker of antibody mediated rejection in kidney allografts. C4d has been shown to be deposited also in chronic kidney allograft rejection, and frequently in acute liver allograft rejection. In chronic liver allograft rejection there is limited data of C4d positivity. METHODS: 7 liver allografts explanted at retransplantation due to chronic rejection were examined for expression of C4d. Immunoperoxidase technique on frozen sections was used. The "zero" biopsies of the same livers at the first transplantation served as controls. RESULTS: Expression of C4d was significantly increased in portal and central veins as well as in the portal stroma of the grafts with chronic rejection when compared to the expression at implantation of the graft. CONCLUSION: The complement system and anti-donor antibodies may contribute to the process of chronic allograft rejection in the liver.

PepT1 oligopeptide transporter (SLC15A1) gene polymorphism in inflammatory bowel disease.

BACKGROUND: Human polymorphisms affecting gut epithelial barrier and interactions with bacteria predispose to the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC). The intestinal transporter PepT1, encoded by the SLC15A1 gene, mediates intracellular uptake of bacterial products that can induce inflammation and NF-kappaB activation upon binding to NOD2, a protein often mutated in CD. Hence, we tested SLC15A1 polymorphisms for association with IBD. METHODS: Twelve SLC15A1 single nucleotide polymorphisms (SNPs) were genotyped in 1783 individuals from 2 cohorts of Swedish and Finnish IBD patients and controls. An in vitro system was set up to evaluate the potential impact of SLC15A1 polymorphism on PepT1 transporter function by quantification of NOD2-mediated activation of NF-kappaB. RESULTS: The common allele (C) of a coding polymorphism (rs2297322, Ser117Asn) was associated with CD susceptibility both in Sweden and in Finland, but with genetic effects in opposite directions (risk and protection, respectively). The best evidence of association was found in both populations when the analysis was performed on individuals not carrying NOD2 common risk alleles (Sweden allelic P = 0.0007, OR 1.97, 95% confidence interval [CI] 1.34-2.92; Finland genotype P = 0.0013, OR 0.63, 95% CI 0.44-0.90). The PepT1 variant encoded by the C allele (PepT1-Ser117) was associated with reduced signaling downstream of NOD2 (P < 0.0001 compared to Pept1-Asn117). CONCLUSIONS: A functional polymorphism in the SLC15A1 gene might be of relevance to inflammation and antibacterial responses in IBD. Whether this polymorphism truly contributes to disease susceptibility needs to be further addressed, and should stimulate additional studies in other populations.

IL23R in the Swedish, Finnish, Hungarian and Italian populations: association with IBD and psoriasis, and linkage to celiac disease.

BACKGROUND: Association of the interleukin-23 receptor (IL23R) with inflammatory bowel disease (IBD) has been confirmed in several populations. IL23R also associates with psoriasis, suggesting that the gene may be an important candidate for many chronic inflammatory diseases. METHODS: We studied association of single-nucleotide variants in IL23R with IBD in Swedish patients, in both Crohn's disease (CD) and ulcerative colitis (UC) subsets. The same genetic variants were also studied in Finnish patients with psoriasis or celiac disease, and in Hungarian and Italian patients with celiac disease. RESULTS: Association of IL23R with IBD was replicated in our Swedish patients, and linkage and association of the IL23R region with psoriasis was found in the Finnish population. The IL23R region was also linked to celiac disease in Finnish families, but no association of IL23R variants with celiac disease was found in the Finnish, Hungarian or Italian samples. CONCLUSION: Our study is the first to demonstrate association of IL23R with CD and UC in Swedish patients with IBD. It is also the first study to report linkage and association of the IL23R region with psoriasis in the Finnish population. Importantly, this is the first report of linkage of the IL23R region to celiac disease, a chronic inflammatory condition in which IL23R has not been previously implicated.

Association of IL23R, TNFRSF1A, and HLA-DRB1*0103 allele variants with inflammatory bowel disease phenotypes in the Finnish population.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC), 2 major forms of inflammatory bowel disease (IBD), are complex disorders with significant genetic predisposition. The first CD-associated gene, CARD15/NOD2, was recently identified and since then several reports on novel IBD candidate genes have emerged. We investigated disease phenotype association to genetic variations in IL23R, ATG16L1, DLG5, ABCB1/MDR1, TLR4, TNFRSF1A, chromosome 5 risk haplotype including SLC22A4 and SLC22A5, and HLA-DRB1*0103 allele among Finnish IBD patients. METHODS: A total of 699 IBD patients were genotyped for disease-associated variants by polymerase chain reaction (PCR) and restriction enzyme digestion or Sequenom iPLEX method. RESULTS: Five markers spanning the IL23R gene were associated with CD. The SNP (single nucleotide polymorphism) rs2201841 gave the strongest association (P = 0.002). The rare HLA-DRB1*0103 allele was found to associate with UC (P = 0.008), and the TNFRSF1A A36G variant was associated with familial UC (P = 0.007). Upon phenotypic analysis we detected association between familial UC and rare TNFRSF1A alleles 36G and IVS6+10G (P = 0.001 and P = 0.042, respectively). In addition, IL23R markers were associated with stricturing CD (P = 0.010-0.017), and ileocolonic CD was more prevalent in the carriers of the same 2 TNFRSF1A variants (P = 0.021 and P = 0.028, respectively). Less significant genotype-phenotype associations were observed for the TLR4 and HLA variants. CONCLUSIONS: We were able to replicate the association of the IL23R variants with CD as well as HLA-DRB1*0103 with UC; confirmation of TNFRSF1A association with UC needs additional studies. Our findings also suggest that polymorphisms at IL23R and TNFRSF1A, and possibly HLA and TLR4, loci may account for phenotypic variation in IBD.

High frequency of gastroduodenal cytomegalovirus infection in liver transplant patients.

The prevalence and significance of cytomegalovirus (CMV) detected in biopsy specimens from the gastroduodenal mucosa of liver transplant patients, patients with chronic or acute liver failure and immunocompetent patients with dyspeptic symptoms were evaluated. 80 liver transplant patients with upper gastrointestinal symptoms, 132 patients with chronic and 25 with acute liver failure, and 33 immunocompetent, dyspeptic patients underwent oesophagogastroduodenoscopies, with biopsies from the duodenum and stomach. CMV was demonstrated by immunohistochemistry in frozen sections, using a monoclonal antibody against CMV-specific antigens (pp65 matrix protein), and in paraffin sections by a monoclonal antibody against delayed early protein (p52). 71% of the liver transplant patients, 45% of the patients with chronic liver disease, 20% with acute liver failure, and 45% of the immunocompetent, dyspeptic patients had CMV-positive findings in the gastroduodenal mucosa (liver transplant patients vs other groups, p<0.01). Histopathological findings in CMV-positive samples were focal inflammation, including increased inflammation of the lamina propria, infiltrating leukocytes intra-epithelially, regenerative changes in the epithelial cells and inclusion bodies. In conclusion, CMV-positive cells and inclusions are often found in the gastroduodenal mucosa of liver transplant patients, as well as in patients suffering from chronic liver disease or even in otherwise healthy patients with dyspeptic symptoms.

Human herpesvirus 6 infection of the gastroduodenal mucosa.

BACKGROUND: Human herpesvirus 6 (HHV-6) infections are usually asymptomatic reactivations in adult liver transplant recipients, but they may also cause fever or graft dysfunction. HHV-6 infection can also present symptoms of gastroenteritis. In this study, we investigated the presence of HHV-6 in the gastroduodenal mucosa of liver transplant recipients and in immunocompetent patients undergoing gastroscopic examination because of dyspeptic symptoms. METHODS: HHV-6 and cytomegalovirus (CMV) examinations were performed on gastroduodenal biopsy specimens obtained during upper gastrointestinal endoscopic examinations from 90 liver transplant recipients and from 31 immunocompetent patients with upper gastrointestinal symptoms. In the gastroduodenal mucosa, HHV-6 and CMV was demonstrated by immunohistochemistry in frozen sections using monoclonal antibodies against HHV-6- and CMV-specific antigens. RESULTS: HHV-6-positive cells were found in biopsy specimens from 21 (23%) of the liver transplant recipients and 6 (19%) of the immunocompetent patients, CMV-positive cells were found in specimens from 55 (61%) of the transplant recipients and 7 (23%) of the immunocompetent patients, and 12 transplant recipients were found to have both HHV-6 and CMV infection. Fifteen transplant recipients with positive HHV-6 findings in the gastroduodenal mucosa also had HHV-6 antigenemia, whereas 30 patients with HHV-6 antigenemia did not have gastroduodenal involvement. Endoscopic findings in these patients included biliary complications in 10 patients and gastritis in 2 patients. Histopathological findings were nonspecific and included very mild inflammation. A total of 30 (94%) of the transplant recipients with biliary complications also had HHV-6 or CMV detected in the duodenal mucosa. CONCLUSIONS: HHV-6-positive cells and CMV-positive cells were frequently found in the gastroduodenal mucosa of liver transplant recipients and of immunocompetent patients undergoing gastroscopic examination because of dyspeptic symptoms.

Novel CARD15/NOD2 mutations in Finnish patients with Crohn's disease and their relation to phenotypic variation in vitro and in vivo.

BACKGROUND: Three mutations (R702W, G908R, and 1007fs) of the CARD15/NOD2 gene associate with Crohn's disease (CD). Despite a strong linkage of CD to the inflammatory bowel disease (IBD) 1 region, only 16% of the Finnish CD patients carry 1 of these 3 mutations, pointing to the possibility of yet undetected founder mutations in the genetically isolated Finns. The aim of this study was to screen for CARD15 mutations in Finnish CD patients and to assess their functional consequences and relation to clinical phenotype. METHODS: We performed CARD15 mutation screening in 240 CD probands. For functional studies, blood mononuclear cells were cultured alone or with muramyl dipeptide (MDP) and IL-8 levels were determined. RESULTS: We identified 30 different variants, including 12 new ones. Allele frequencies for the R702W, G908R, and 1007fs mutations were 3.3%, 0.4%, and 4.8%, respectively. The 1007fs variant was the only 1 associated significantly with CD. Five novel variants (R38M, W355X, P727L, W907R, R1019X) were found in 5 patients. The biochemical nature of these new mutations, data obtained by cross-species comparisons, as well as low IL-8 production favors their pathogenic role. All 5 patients with novel mutations presented a complicated form of ileal or ileocolonic disease. CONCLUSIONS: In conclusion, we identified 5 novel CARD15 mutations with an apparent pathophysiological role, but could not identify a putative Finnish founder mutation. It is still possible that regulatory mutations present in the flanking or intronic areas of the CARD15 gene contribute to the genetic susceptibility of CD. Homozygosity or compound heterozygosity for CARD15 gene mutations must be considered especially in complicated CD patients.

Detection of Helicobacter species in chronic liver disease and chronic inflammatory bowel disease.

AIM: To study the association between helicobacters and chronic liver diseases and chronic inflammatory bowel diseases. PATIENTS AND METHODS: Thirty-two patients with various chronic liver diseases and 137 patients with inflammatory bowel disease were enrolled. Antibodies to H. pylori, H. hepaticus, H. bilis, and H. pullorum were measured by enzyme immunoassay (EIA), and sera positive in a non-pylori helicobacter EIA were further examined by immunoblot assay. Detection of Helicobacter DNA in liver biopsies was done by denaturating gradient gel electrophoresis of PCR products (PCR-DGGE) and DNA sequence analysis. RESULTS: Six inflammatory bowel disease patients, four with ulcerative colitis and two with Crohn's disease, and one liver disease patient with autoimmune cholangitis had antibodies to non-pylori helicobacters by an immunoblot assay. Four immunoblot assay-negative patients, three with autoimmune and one with non-autoimmune liver disease, had Helicobacter DNA in liver biopsies; three of the polymerase chain reaction (PCR) products were closely related to non-pylori helicobacters. CONCLUSION: Evidence for non-pylori helicobacters was scant in Finnish patients with inflammatory bowel disease or chronic but not end stage liver disease. We cannot, however, rule out their role in these diseases.

Neuropeptide s receptor 1 gene polymorphism is associated with susceptibility to inflammatory bowel disease.

BACKGROUND & AIMS: The neuropeptide S receptor (NPSR1) gene has been associated recently with asthma and maps in a region of chromosome 7 previously linked also to inflammatory bowel disease (IBD). NPSR1 is expressed on the epithelia of several organs including the intestine, and appears to be up-regulated in inflammation. We tested NPSR1 gene polymorphism for association with IBD and verified whether the expression of its 2 major isoforms (NPSR1-A and NPSR1-B) is altered in the intestine of IBD patients. METHODS: Eight NPSR1 polymorphisms were genotyped in 2490 subjects from 3 cohorts of IBD patients and controls from Italy, Sweden, and Finland. Real-time polymerase chain reaction and immunohistochemistry were used to quantify NPSR1 messenger RNA (mRNA) and protein expression in intestinal biopsy specimens from IBD patients and controls. RESULTS: Global analysis of the whole dataset identified strong association of a NPSR1 haplotype block with IBD (P = .0018) and its 2 major forms: Crohn's disease (CD) (P = .026) and ulcerative colitis (UC) (P = .003). Genetic effects caused by individual haplotypes were identified mainly for the predisposing haplotype H2 in CD (P = .0005) and the protective haplotype H8 in UC (P = .003). NPSR1 mRNA and protein levels were increased in IBD patients compared with controls, and the risk haplotype H2 correlated with higher expression of both NPSR1-A (P = .024) and NPSR1-B (P = .047) mRNAs. CONCLUSIONS: NPSR1 polymorphism is associated with IBD susceptibility. Specific NPSR1 alleles might act as genetic risk factors for chronic inflammatory diseases of the epithelial barrier organs.

Enhanced detection of cholangiocarcinoma with serum trypsinogen-2 in patients with severe bile duct strictures.

BACKGROUND/AIMS: Primary sclerosing cholangitis (PSC) is associated with a high risk of cholangiocarcinoma. Our aim was to evaluate the diagnostic value of trypsinogen-1, trypsinogen-2, tumour-associated trypsin inhibitor, human chorionic gonadotropin beta and trypsin-2-alpha(1)-antitrypsin for cholangiocarcinoma and to compare them with CA19-9 and CEA. METHODS: The study consisted of 84 patients with either PSC or cholangiocarcinoma or both referred for liver transplantation or other liver surgery. The serum concentrations were determined by time-resolved immunofluorometric assays. RESULTS: Forty-six patients were transplanted due to PSC; in 3 of the explanted livers cholangiocarcinoma was found incidentally. All transplanted patients had severe biliary strictures together with cirrhosis or pre-cirrhosis. Twenty-nine of 38 patients with cholangiocarcinoma were candidates for intervention. In all, 8 patients had both PSC and cholangiocarcinoma. Receiver-operating characteristics curve analysis showed that serum trypsinogen-2 had the highest accuracy in differentiating between cholangiocarcinoma and PSC. The area under the curve (AUC) value was 0.804 for trypsinogen-2 and 0.613 for CA19-9. Serum trypsinogen-2 also showed the highest accuracy for differentiation between PSC and PSC with simultaneous cholangiocarcinoma with an AUC value of 0.759. CONCLUSIONS: Our results suggest that serum trypsinogen-2 is a most useful marker for diagnosing patients with cholangiocarcinoma, and it is superior to serum CA19-9 and CEA.

Monitoring of EBV-DNAemia by quantitative real-time PCR after adult liver transplantation.

BACKGROUND: Post-transplant lymphoproliferative disease (PTLD) causes significant morbidity and mortality in transplantation. The clinical significance of Epstein-Barr virus (EBV) in the development of PTLD is clear, but not all EBV-reactivations cause PTLD. OBJECTIVES: We retrospectively analyzed EBV-DNAemia in liver transplant patients by a quantitative TaqMan-based real-time plasma PCR. STUDY DESIGN: Altogether 1284 specimens, obtained from 105 patients for frequent monitoring of cytomegalovirus (CMV) and human herpesvirus-6 and -7 (HHV-6, HHV-7) during the post-transplant year, were retrospectively tested for EBV-DNA. RESULTS: Altogether, 14/105 (13%) patients showed EBV-DNAemia, which usually occurred within 3 months after transplantation and subsided within a few weeks. EBV-DNAemia occurred concurrently with CMV in 10/14, with HHV-6 in 11/14, and with all three betaherpesviruses in 4/14 cases. The peak viral loads were relatively low (median 2100 EBV-DNA copies/ml, range 568-6600), except in one patient who first had low-level EBV-DNA (562-3022 copies/ml) in the early post-transplant period, but on day 175 after transplantation developed high-level DNAemia (9851-86,975copies/ml) which continued for 6 months and developed into PTLD at 6 months after transplantation. CONCLUSION: Low-level EBV-DNAemia is common after liver transplantation, often occurring together with betaherpesviruses, but seldom leads to high viral loads or PTLD. However, monitoring of EBV-DNA levels in the patients can be useful.