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1.
Scand J Gastroenterol ; 48(12): 1423-7, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24099308

RESUMO

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.


Assuntos
Pólipos Adenomatosos/virologia , Antígenos Virais/metabolismo , Colo/virologia , Neoplasias do Colo/virologia , DNA Viral/análise , Herpesvirus Humano 6/imunologia , Mucosa Intestinal/virologia , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patologia , Biomarcadores/análise , Biópsia , Estudos de Casos e Controles , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Citomegalovirus/imunologia , Herpesvirus Humano 6/genética , Humanos , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia
2.
Liver Int ; 32(5): 783-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22098817

RESUMO

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.


Assuntos
Neoplasias do Sistema Biliar/genética , Colangiocarcinoma/genética , Colangite Esclerosante/complicações , DNA de Neoplasias/análise , Ploidias , Adulto , Neoplasias do Sistema Biliar/diagnóstico , Biomarcadores Tumorais/sangue , Biópsia/métodos , Antígeno CA-19-9/sangue , Colangiocarcinoma/diagnóstico , Colangiopancreatografia Retrógrada Endoscópica , Citometria de Fluxo , Humanos , Estudos Prospectivos
3.
Transpl Int ; 25(7): 776-82, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22616807

RESUMO

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.


Assuntos
Trato Gastrointestinal/virologia , Herpesvirus Humano 6/metabolismo , Transplante de Rim/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/farmacologia , Endoscopia/métodos , Feminino , Humanos , Imunossupressores/efeitos adversos , Mucosa Intestinal/metabolismo , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Diálise Renal/métodos , Insuficiência Renal/terapia
4.
Scand J Gastroenterol ; 46(11): 1324-33, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21879802

RESUMO

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.


Assuntos
Colite Ulcerativa/virologia , Doença de Crohn/virologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Infecções por Herpesviridae/imunologia , Herpesvirus Humano 6/imunologia , Mucosa Intestinal/virologia , Adulto , Idoso , Antígenos Virais/análise , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo/virologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/patologia , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/complicações , Feminino , Infecções por Herpesviridae/complicações , Herpesvirus Humano 6/isolamento & purificação , Humanos , Íleo/virologia , Hospedeiro Imunocomprometido/imunologia , Imuno-Histoquímica , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Adulto Jovem
5.
BMC Med Genet ; 10: 8, 2009 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-19175939

RESUMO

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.


Assuntos
Doença Celíaca/genética , Colite Ulcerativa/genética , Doença de Crohn/genética , Psoríase/genética , Receptores de Interleucina/genética , Estudos de Casos e Controles , Doença Celíaca/complicações , Colite Ulcerativa/complicações , Doença de Crohn/complicações , Finlândia , Marcadores Genéticos , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Hungria , Itália , Desequilíbrio de Ligação , Psoríase/complicações , Suécia
6.
Nephrol Dial Transplant ; 24(11): 3533-9, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19675062

RESUMO

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.


Assuntos
Citomegalovirus/isolamento & purificação , Trato Gastrointestinal/virologia , Falência Renal Crônica/virologia , Transplante de Rim , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Virais/sangue , Endoscopia , Feminino , Mucosa Gástrica/patologia , Humanos , Imunocompetência , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade
7.
Duodecim ; 125(20): 2236-7, 2009.
Artigo em Fi | MEDLINE | ID: mdl-19998761

RESUMO

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.


Assuntos
Injúria Renal Aguda/terapia , Injúria Renal Aguda/diagnóstico , Adulto , Humanos , Diálise Renal , Fatores de Risco
8.
Clin Infect Dis ; 46(3): 434-9, 2008 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-18181741

RESUMO

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.


Assuntos
Mucosa Gástrica/virologia , Herpesvirus Humano 6/isolamento & purificação , Mucosa Intestinal/virologia , Transplante de Fígado , Infecções por Roseolovirus/virologia , Adulto , Citomegalovirus/isolamento & purificação , Dispepsia/virologia , Endoscopia Gastrointestinal , Mucosa Gástrica/patologia , Humanos , Imunocompetência , Hospedeiro Imunocomprometido , Imuno-Histoquímica , Mucosa Intestinal/patologia , Infecções por Roseolovirus/imunologia , Infecções por Roseolovirus/patologia
9.
Inflamm Bowel Dis ; 14(2): 176-85, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17941079

RESUMO

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.


Assuntos
Doença de Crohn/epidemiologia , Doença de Crohn/genética , Mutação , Proteína Adaptadora de Sinalização NOD2/genética , População Branca/genética , Estudos de Casos e Controles , Feminino , Finlândia/epidemiologia , Efeito Fundador , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo
10.
APMIS ; 116(2): 99-106, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18321360

RESUMO

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.


Assuntos
Infecções por Citomegalovirus/virologia , Citomegalovirus/imunologia , Gastroenteropatias/virologia , Transplante de Fígado , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/química , Antígenos Virais/análise , Antivirais/uso terapêutico , Biópsia , Infecções por Citomegalovirus/tratamento farmacológico , Feminino , Ganciclovir/uso terapêutico , Mucosa Gástrica/virologia , Gastroenteropatias/tratamento farmacológico , Humanos , Proteínas Imediatamente Precoces/análise , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade
11.
J Clin Virol ; 37 Suppl 1: S76-81, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17276374

RESUMO

BACKGROUND: Human herpesvirus-6 (HHV-6) infections have been reported after liver transplantation. In this study, the detection of HHV-6 DNA in peripheral blood mononuclear cells (PBMC) was compared with HHV-6 antigenemia in liver transplant patients. OBJECTIVES: Forty-three adult liver recipients were frequently monitored by HHV-6 antigenemia test, which detects the viral antigens in PBMC, but is rather qualitative than quantitative. STUDY DESIGN: From the same PBMC specimens HHV-6 DNA was demonstrated by in situ hybridization using a biotinylated probe and quantified as positive cells/10, 000 PBMC. Altogether 330 blood specimens were analyzed. RESULTS: During the first 6 months (mean 12 days) after transplantation, 35/43 patients developed HHV-6 antigenemia. Concurrently, HHV-6 DNA-positive cells with mean peak number of 661(+/-574)/10, 000 were detected in 33/35 patients. Seven patients received ganciclovir treatment because of concurrent CMV infection with mean peak number of HHV-6 DNA-positive cells 381(+/-336) before and 34(+/-59)/10, 000 after the treatment (p = 0.03). All CMV infections responded to ganciclovir, but HHV-6 DNAemia disappeared slowly, within 79 days (mean 36 days). Without antivirals, HHV-6 DNAemia/antigenemia lasted usually longer. CONCLUSIONS: Detection of HHV-6 DNA in PBMC correlated well with HHV-6 antigenemia, and may be used in the monitoring of transplant patients.


Assuntos
Herpesvirus Humano 6/isolamento & purificação , Leucócitos Mononucleares/virologia , Falência Hepática/complicações , Transplante de Fígado , Infecções por Roseolovirus/virologia , Antígenos Virais/análise , Infecções por Citomegalovirus/tratamento farmacológico , DNA Viral/análise , Ganciclovir/uso terapêutico , Humanos , Hibridização In Situ , Falência Hepática/cirurgia
12.
J Clin Virol ; 37(2): 104-8, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16931140

RESUMO

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.


Assuntos
DNA Viral/sangue , Herpesvirus Humano 4/isolamento & purificação , Transplante de Fígado/efeitos adversos , Reação em Cadeia da Polimerase/métodos , Adulto , Herpesvirus Humano 4/genética , Humanos , Transtornos Linfoproliferativos/etiologia , Carga Viral
13.
World J Gastroenterol ; 12(23): 3668-72, 2006 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-16773682

RESUMO

Studies examining the inheritance of inflammatory bowel disease (IBD) within different family groups have been the basis for recent molecular advances in the genetics of IBD. The derived heritability in Crohn's disease (CD) is higher than in many other complex diseases. The risk of IBD is highest in first-degree relatives of a CD proband, but first-degree relatives of a proband suffering from ulcerative colitis (UC) and more distant relatives are also at increased risk. Disease concordance rates in IBD have been examined in multiplex families and in three large European twin studies.


Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Doenças em Gêmeos/genética , Predisposição Genética para Doença/genética , Estudos em Gêmeos como Assunto , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/etiologia , Doença de Crohn/epidemiologia , Doença de Crohn/etiologia , Doenças em Gêmeos/epidemiologia , Doenças em Gêmeos/etiologia , Europa (Continente)/epidemiologia , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/etiologia , Humanos , Padrões de Herança , Linhagem , Fenótipo , Fatores de Risco
14.
Nat Commun ; 7: 12342, 2016 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-27503255

RESUMO

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.


Assuntos
Colite Ulcerativa/genética , Colite Ulcerativa/prevenção & controle , Mutação/genética , Ubiquitina-Proteína Ligases/genética , Alelos , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Análise de Sequência de DNA
15.
J Clin Endocrinol Metab ; 88(10): 4602-8, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14557429

RESUMO

In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, hypoparathyroidism (HP) is the most common endocrine component. It occurs in most (but not all) patients. Determinants of its occurrence are unknown, and there is no proof for its autoimmune nature. Recently, the Ca(2+)-sensing receptor (CaSR) was reported to be an autoantigen in HP. With our group of 90 patients, we aimed at identifying the determinants and pathomechanism of HP. For the determinants, we evaluated gender and the HLA class II. For the pathomechanism, we searched for parathyroid autoantibodies, including antibodies against CaSR and PTH. Also, we studied whether AIRE is expressed in the human parathyroid, because its absence could be a pathogenetic factor. We found a clear gender linkage with lower and later incidence in males. Of the 14 patients who had escaped HP, 13 were males. This was associated with adrenal failure, which was the first or only endocrinopathy in 47% of males vs. 7% of females. In contrast, we found no linkage to the HLA class II. By immunofluorescence, 19% of the patients had antibodies to parathyroid epithelia. By immunoblotting, these recognized several parathyroid proteins. No antibodies were observed against the CaSR or PTH. By RT-PCR, AIRE mRNA was not found in the parathyroid.


Assuntos
Hipoparatireoidismo/epidemiologia , Hipoparatireoidismo/imunologia , Poliendocrinopatias Autoimunes/epidemiologia , Poliendocrinopatias Autoimunes/imunologia , Adolescente , Adulto , Autoanticorpos/sangue , Criança , Pré-Escolar , Feminino , Frequência do Gene , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Hipoparatireoidismo/genética , Incidência , Masculino , Glândulas Paratireoides/imunologia , Hormônio Paratireóideo/imunologia , Poliendocrinopatias Autoimunes/genética , RNA Mensageiro/análise , Receptores de Detecção de Cálcio , Receptores de Superfície Celular/imunologia , Distribuição por Sexo , Fatores de Transcrição/genética , Proteína AIRE
16.
Eur J Hum Genet ; 11(2): 112-20, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12634858

RESUMO

Epidemiological and genetic linkage studies have indicated a strong genetic basis for development of inflammatory bowel disease (IBD) which was recently supported by discovery of the Crohn's disease (CD) susceptibility gene termed NOD2/CARD15. We carried out a genome-wide linkage study in Finnish IBD families, providing a particular advantage to map susceptibility genes for ulcerative colitis (UC) within a genetic isolate. Initially, 92 IBD families with 138 affected sib-pairs (ASPs), were genotyped for 429 markers spaced at approximately 10 cM intervals. Next, the loci on chromosomes 2p13-11, 11p12-q13, and 12p13-12 were high-density mapped in the extended family cohort of 130 families with 173 ASPs. In this study, the most significant lod scores were observed for the UC families on chromosome 2p11 (D2S2333), in the vicinity of the REG gene cluster which is strikingly overexpressed in the IBD mucosa. The maximum two-point lod score was 3.34 (dominant model), and the corresponding NPL score 2.61. For UC, the second highest two-point NPL score of 2.00 was observed at proximal 12p13, where also some evidence for linkage disequilibrium emerged (P=0.07 and P=0.007 for the basic and extended IBD cohorts, respectively). The highest two-point NPL score for the CD families was 2.34 at D12S78 (12q23) with significant evidence for linkage disequilibrium (P=0.004), and for the mixed (MX) families 2.07 at D4S406 near the linkage peak reported previously. This study confirmed several of the IBD loci that have previously been reported and gives evidence for new IBD loci on chromosomes 2p11, 11p12-q13, 12p13-12, 12q23, and 19q13.


Assuntos
Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/genética , Feminino , Finlândia , Ligação Genética , Genoma Humano , Humanos , Escore Lod , Masculino , Repetições de Microssatélites
17.
Transplantation ; 75(11): 1853-8, 2003 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-12811245

RESUMO

BACKGROUND: Cytomegalovirus (CMV) infection is known to cause ulceration and mucosal hemorrhage in the gastrointestinal tract. Gastroduodenal and biliary complications were prospectively evaluated in 100 consecutive liver transplant patients in whom CMV was monitored during the first posttransplant year. METHOD: Gastroduodenal biopsy specimens were taken from 36 patients by endoscopies and in 28 patients by endoscopic retrograde cholangiopancreatography, and bile duct specimens were taken from three patients who underwent surgical reconstruction because of biliary complication. CMV was demonstrated from blood by the pp65 antigenemia test and from frozen sections of tissue specimens by immunohistochemistry and in situ hybridization. RESULTS: Symptomatic CMV infection, treated with ganciclovir, developed in 49 recipients: 13 (100%) of CMV seropositive donor (D+) seronegative recipient (R-) cases, 29 (45%) D+/R+ cases, and 7 (32%) D-/R+ cases. Duodenal ulcer developed in three and hemorrhagic gastritis in three recipients. CMV antigens were found from the gastroduodenal mucosa in 37 (69%) of the 54 studied recipients. The biliary complication rate was 24%. Preceding or concomitant CMV antigenemia was demonstrated in 75% of patients with a biliary complication (68% in CMV D+/R+ or D-/R+ and 100% in D+/R- recipients). The biliary complication rate was higher among recipients with CMV antigenemia, compared with recipients without (P<0.05). CMV antigenemia, CMV infection, or both in the duodenal mucosa was found in 96% of patients with a biliary complication. In two patients who underwent surgical reconstruction, CMV antigens and DNA were demonstrated in the bile ducts. CONCLUSIONS: Liver transplant patients are at risk of developing biliary complications after CMV infection, especially those with primary CMV infection.


Assuntos
Doenças Biliares/mortalidade , Doenças Biliares/virologia , Infecções por Citomegalovirus/mortalidade , Falência Hepática/cirurgia , Transplante de Fígado , Adolescente , Adulto , Idoso , Doenças Biliares/patologia , Colangiopancreatografia Retrógrada Endoscópica , Infecções por Citomegalovirus/patologia , Úlcera Duodenal/mortalidade , Úlcera Duodenal/patologia , Úlcera Duodenal/virologia , Feminino , Gastrite/mortalidade , Gastrite/patologia , Gastrite/virologia , Sobrevivência de Enxerto , Humanos , Falência Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/virologia
20.
APMIS ; 118(11): 888-94, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20955462

RESUMO

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.


Assuntos
DNA Viral/sangue , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/genética , Transplante de Fígado/efeitos adversos , Adulto , Antígenos CD/sangue , Linfócitos B/imunologia , Linfócitos B/virologia , Moléculas de Adesão Celular/metabolismo , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/imunologia , Humanos , Integrina alfa4beta1/metabolismo , Antígenos CD15/metabolismo , Transplante de Fígado/imunologia , Antígeno-1 Associado à Função Linfocitária/metabolismo , Masculino , Antígeno Sialil Lewis X , Transplante Homólogo
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