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1.
Acta Radiol ; 59(8): 953-958, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29202584

RESUMO

Background Acute portomesenteric venous thrombosis (PMVT) is a potentially life-threatening condition and urgent treatment is required. Purpose To retrospectively evaluate the efficacy and safety of treating acute PMVT by the creation of a transjugular intrahepatic portosystemic shunt (TIPS) followed by thrombectomy. Material and Methods Six patients (all men, age range = 39-51 years) presenting with acute PMVT were treated with transjugular thrombectomy (TT) through a TIPS created in the same session. The intervention included iterated venography through the TIPS one to three times within the first week after diagnosis and repeated thrombectomy if needed (n = 5). Results Recanalization was successful with persistent blood flow through the main superior mesenteric vein, portal vein, and TIPS in all six patients. Five patients were treated primarily with thrombectomy through a TIPS with clinical improvement. The final patient was initially treated with surgical thrombectomy and bowel resection. TIPS and TT was performed two days after surgery due to re-thrombosis but the patient deteriorated and died of multi-organ failure. Procedure-related complications were transient hematuria (n = 3) and transient encephalopathy (n = 2). In-hospital time was <14 days in four of the five patients with primary TIPS and TT. No sign of re-thrombosis was noted during follow-up (mean = 18 months, range = 8-28 months). Conclusion Thrombectomy through a TIPS is feasible and can be effective in recanalization and symptom-relief in acute PMVT.


Assuntos
Veias Mesentéricas/cirurgia , Veia Porta/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/métodos , Trombectomia/métodos , Trombose Venosa/cirurgia , Doença Aguda , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
2.
Scand J Gastroenterol ; 51(9): 1075-80, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27142339

RESUMO

OBJECTIVE: It is assumed that cytomegaloviral (CMV) infection in inflammatory bowel disease (IBD) is caused by reactivation due to the immunosuppressive therapy, but the role of CMV as a pathophysiological factor and prognostic marker in IBD is unclear. The aim of this study was to investigate CMV infection in IBD, with real-time polymerase chain reaction (PCR) and immunohistochemistry, with emphasis on newly diagnosed disease. MATERIALS AND METHODS: In this prospective, controlled study, 67 patients with IBD and 34 control patients with irritable bowel syndrome (IBS) or rectal bleeding were included. Serology for CMV was analysed along with CMV DNA in plasma, mucosal biopsies, and faeces. Mucosal biopsies were further analysed with histopathology and CMV immunohistochemistry. RESULTS: Detection of CMV IgM was more common in patients with IBD, compared to controls, 21% versus 3%. CMV DNA was found in 16% of patients with newly diagnosed, untreated IBD and in 38% of steroid-treated patients. Four of the five patients that needed urgent surgery were CMV-DNA positive in at least one of three sample types. None of the controls had detectable CMV DNA. CONCLUSIONS: Active CMV infection was found in high proportions of newly diagnosed untreated patients with IBD, in patients on immunosuppression and in patients in the need of surgery. Low CMV-DNA levels in non-immunosuppressed patients were not a risk factor for the development of more severe IBD, while the detection of CMV DNA in patients on immunosuppressive therapy may foresee disease progression.


Assuntos
Infecções por Citomegalovirus/diagnóstico , DNA Viral/análise , Terapia de Imunossupressão/efeitos adversos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Citomegalovirus , Fezes/virologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Índice de Gravidade de Doença , Suécia , Adulto Jovem
3.
Acta Radiol ; 57(5): 572-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26253926

RESUMO

BACKGROUND: Treatment of patients with portal vein thrombosis (PVT) differs due to different etiology and wide range of symptoms but certain patients seems to benefit from endovascular intervention. PURPOSE: To assess the safety and efficiency of endovascular treatment of acute and chronic PVT in patients with cirrhotic and non-cirrhotic liver. MATERIAL AND METHODS: Twenty-one patients with PVT treated with an endovascular procedure in 2002-2013 were studied retrospectively. Data on etiology, onset and extension of thrombus, presenting symptoms, methods of intervention, portal pressure gradients, complications, recurrence of symptoms, re-interventions, clinical status at latest follow-up, and survival were collected. RESULTS: Four non-cirrhotic patients with acute extensive PVT and bowel ischemia were treated with local thrombolysis, in three combined with placement of a transjugular intrahepatic portosystemic shunt (TIPS) placement. Three recovered and have survived more than 6 years. In six non-cirrhotic patients with chronic PVT and acute or threatening variceal bleeding recanalization and TIPS were successful in three and failed in three. Eleven cirrhotic patients with PVT and variceal bleeding or refractory ascites were successfully treated with recanalization and TIPS. Re-intervention was performed in five of these patients and five patients died, three within 12 months of intervention. Four cirrhotic patients had episodes of shunt-related encephalopathy and three had variceal re-bleeding. CONCLUSION: TIPS was found to be effective in reducing portal hypertension in patients with PVT. In patients with extensive PVT and bowel ischemia treatment with TIPS combined with thrombolysis should be considered.


Assuntos
Procedimentos Endovasculares , Varizes Esofágicas e Gástricas/complicações , Cirrose Hepática/complicações , Veia Porta , Trombose Venosa/etiologia , Trombose Venosa/terapia , Adulto , Idoso , Transfusão de Sangue , Varizes Esofágicas e Gástricas/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Derivação Portossistêmica Transjugular Intra-Hepática , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/terapia , Estudos Retrospectivos , Stents , Taxa de Sobrevida , Terapia Trombolítica , Resultado do Tratamento
4.
Scand J Gastroenterol ; 50(2): 217-23, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25483724

RESUMO

OBJECTIVES: Cirrhosis is a well-known risk factor for hepatocellular cancer, but the true risk in autoimmune hepatitis (AIH) is scarcely studied. Other cancers may arise after prolonged use of immune-modulating drugs. The aim of this study was to investigate the cancer risk in a large cohort of AIH patients. MATERIAL AND METHODS: Six hundred and thirty-four Swedish patients in a well-defined cohort were matched to the Cause of Death Registry and the Cancer Registry. Standard incidence ratios were calculated by relating the incidences in the cohort to an age-matched material from the Swedish background population. RESULTS: A higher overall incidence of malignancies than the background population was found, counting from the date of diagnosis (standard incidence ratio (SIR) 2.08, 95% CI 1.68-2.55). The highest risk was found for hepatocellular carcinoma (HCC). We found 10 cases (4.0%) in 248 patients with cirrhosis, which gives an incidence rate of 0.3%. Standard incidence ratio for developing hepatobiliary cancer was 54.55 (95% CI 19.92-99.99). HCC only occurred in cirrhotic patients. There was also an increased risk for non-melanoma skin cancer (SIR 9.87, 95% CI 6.26-14.81). CONCLUSION: A slightly enhanced risk for malignancies in general compared to the background population was found. The risk of hepatobiliary cancer was increased, but the annual risk over the observational period was well under the postulated 1.5% when surveillance in cirrhotic patients is considered to be cost-effective.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Hepatite Autoimune/epidemiologia , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Cutâneas/epidemiologia , Adulto , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Risco , Suécia/epidemiologia
5.
J Hepatol ; 61(6): 1352-7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25111173

RESUMO

BACKGROUND & AIMS: Despite a high risk of cholangiocellular adenocarcinoma (CCA) it is unclear how surveillance of patients with primary sclerosing cholangitis (PSC) should be performed. METHODS: We evaluated a follow-up algorithm of brush cytology and positron emission tomography/computed tomography with [(18)F] fluorodeoxyglucose ([(18)F]FDG-PET/CT), measured as maximum standardized uptake values, normalized to the liver background (SUVmax/liver) at 180 min, in PSC patients with dominant bile duct strictures. RESULTS: Brush cytology with high grade dysplasia (HGD) was detected in 12/70 patients (17%), yielding a diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 56%, 89%, 75%, and 88%, respectively. Preemptive liver transplantations due to repeated HGD before manifest CCA were performed in six patients. Receiver operating characteristic (ROC) analysis of [(18)F]FDG uptake showed that a SUVmax/liver quotient of 3.3 was able to discriminate between CCA and non-malignant disease with a sensitivity, specificity, PPV and NPV for CCA of 89%, 92%, 62%, 98%, respectively. A SUVmax/liver >3.3 detected CCA in 8/9 patients whereas a quotient <2.4 excluded CCA. Combining brush cytology and quantitative [(18)F]FDG-PET/CT yielded a sensitivity for HGD and/or CCA of 100% and a specificity of 88%. CONCLUSION: Early detection of HGD before manifest CCA is feasible with repeated brush cytology and may allow for preemptive liver transplantation. [(18)F]FDG-PET/CT has a high sensitivity for manifest CCA and a negative scan indicates a non-malignant state of the disease. Brush cytology and [(18)F]FDG-PET/CT are complementary in monitoring and managing PSC patients with dominant strictures.


Assuntos
Colangite Esclerosante/diagnóstico por imagem , Colangite Esclerosante/patologia , Técnicas Citológicas/métodos , Progressão da Doença , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons/métodos , Adenocarcinoma/diagnóstico , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/diagnóstico por imagem , Colangiocarcinoma/patologia , Constrição Patológica/diagnóstico por imagem , Constrição Patológica/patologia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade
6.
Scand J Gastroenterol ; 46(7-8): 849-54, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21557718

RESUMO

BACKGROUND AND AIMS: Fecal calprotectin (FC) is used as a marker for intestinal inflammation in inflammatory bowel disease (IBD) but there is no reliable marker for collagenous colitis (CC). We have previously demonstrated that the mucosal inflammation in CC is characterized by eosinophil activation, which is restored during budesonide treatment, but there is no enhanced neutrophil activity. The aim of this study was to evaluate the use of fecal eosinophil cationic protein (F-ECP) and eosinophil protein X (F-EPX) compared with the neutrophil-derived myeloperoxidase (F-MPO) and FC in patients treated for active CC. METHODS: Patients with active CC (n = 12) were studied before and after 3, 7, 28 and 56 days of budesonide treatment. Clinical symptoms and stool frequency were recorded, fecal samples were collected, and F-ECP, F-EPX, F-MPO and FC were measured at each occasion. RESULTS: All but one patient achieved remission. On inclusion 92%, 67%, 67% and 75% of the patients had elevated F-ECP, F-EPX, F-MPO and FC levels, respectively. All markers decreased during the treatment, particularly F-ECP and F-EPX, which decreased after only 3 days. At the end of the study 100%, 92%, 83% and 75% of the patients had normal F-ECP, F-EPX, F-MPO and FC values, respectively. CONCLUSION: F-ECP demonstrated the best discriminating capacity in detecting active CC. A normalized F-ECP and F-EPX may further be studied as a marker for successful treatment. During budesonide treatment there is a rapid fall in F-ECP and F-EPX, accompanied by clinical improvement, indicating an essential role for the eosinophil participating in the pathophysiology of CC.


Assuntos
Colite Colagenosa/metabolismo , Colite Colagenosa/patologia , Proteína Catiônica de Eosinófilo/análise , Fezes/química , Adolescente , Adulto , Idoso , Análise de Variância , Anti-Inflamatórios/uso terapêutico , Biomarcadores/análise , Budesonida/uso terapêutico , Colite Colagenosa/tratamento farmacológico , Defecação/fisiologia , Proteína Catiônica de Eosinófilo/metabolismo , Neurotoxina Derivada de Eosinófilo/análise , Neurotoxina Derivada de Eosinófilo/metabolismo , Feminino , Humanos , Complexo Antígeno L1 Leucocitário/análise , Complexo Antígeno L1 Leucocitário/metabolismo , Masculino , Pessoa de Meia-Idade , Peroxidase/análise , Peroxidase/metabolismo , Projetos Piloto , Adulto Jovem
7.
Scand J Gastroenterol ; 45(4): 457-67, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20082594

RESUMO

OBJECTIVES: Autoimmune hepatitis (AIH) is a liver disease which, if untreated, may lead to liver cirrhosis and hepatic failure. Limited data exist regarding factors predicting the long-term outcome. The aims of this study were to investigate symptoms at presentation, prognostic features, management and treatment in relation to long-term outcome of AIH. MATERIAL AND METHODS: A cohort of 473 Swedish patients with AIH was characterized regarding initial symptoms and signs, factors predicting death and future need for liver transplantation. Survival and causes of death were retrieved from Swedish national registers. RESULTS: At diagnosis, fatigue was a predominant symptom (69%), 47% of the patients were jaundiced and 30% had liver cirrhosis. Another 10% developed cirrhosis during follow-up. Markedly elevated alanine aminotransferase levels at presentation were correlated with a better outcome. A high international normalized ratio (INR) at diagnosis was the only risk factor predicting a need for later liver transplantation. Histological cirrhosis, decompensation and non-response to initial treatment were all factors that correlated with a worse outcome. Overall life expectancy was generally favourable. However, most deaths were liver-related, e.g. liver failure, shock and gastrointestinal bleeding. CONCLUSIONS: Cirrhosis at diagnosis, a non-response to initial immune-suppressive treatment or elevated INR values were associated with worse outcome and a need for later liver transplantation. In contrast, an acute hepatitis-like onset with intact synthetic capacity indicated a good response to treatment and favourable long-term prognosis. Lifetime maintenance therapy is most often required.


Assuntos
Hepatite Autoimune/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Progressão da Doença , Feminino , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/epidemiologia , Humanos , Testes de Função Hepática , Transplante de Fígado/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Sistema de Registros , Fatores de Risco , Taxa de Sobrevida , Suécia , Resultado do Tratamento
8.
Acta Radiol Open ; 9(10): 2058460120964074, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33110628

RESUMO

BACKGROUND: Portomesenteric vein thrombosis may be life-threatening due to bowel ischemia caused by venous stasis, or variceal bleeding caused by portal hypertension. PURPOSE: To evaluate the effectiveness and safety of recanalization combined with transjugular intrahepatic portosystemic shunt in acute and chronic portomesenteric vein thrombosis in patients with and without liver cirrhosis. MATERIAL AND METHODS: 21 consecutive patients (5 women, 16 men; mean 48 years) with portomesenteric vein thrombosis (8 acute, 13 chronic) treated at the Interventional Radiology department between March 2014 and September 2018 were retrospectively reviewed. The main portal vein was completely obliterated and the portomesenteric vein thrombosis extended into the superior mesenteric vein in all patients. The portomesenteric vein thromboses were recanalized transhepatically, a transjugular intrahepatic portosystemic shunt was inserted, thrombectomy was performed in acute portomesenteric vein thrombosis, and angioplasty with or without additional stenting was performed in chronic portomesenteric vein thrombosis. RESULTS: Recanalization was successful in 8/8 patients (100%) with acute portomesenteric vein thrombosis, and in 11/13 patients (85%) with chronic portomesenteric vein thrombosis. In 12 patients, blood flow was restored in one session. Several sessions were more frequently needed in patients with acute portomesenteric vein thrombosis compared to those with chronic portomesenteric vein thrombosis (p = 0.003). Re-occlusion occurred and was recanalized in 10/19 patients and was more frequent in patients with chronic (n = 8/11) than on those with acute (n = 2/8) portomesenteric vein thrombosis (p = 0.04). Adverse events occurred in five patients. There was no 30-day mortality. CONCLUSION: Recanalization and insertion of a transjugular intrahepatic portosystemic shunt is safe and effective in patients with acute and chronic portomesenteric vein thrombosis with or without cirrhosis. Recanalization was more likely to stay patent in acute compared with chronic portomesenteric vein thrombosis.

9.
Liver Int ; 29(2): 253-9, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18694401

RESUMO

BACKGROUND: The exact incidence and prevalence of Budd-Chiari syndrome (BCS) is unknown in the general population. Published reports differ in terms of the clinical characteristics, effects of therapy and survival. AIMS: To investigate the epidemiology, clinical presentation and survival in patients with BCS. METHODS: Retrospective multicentre study in Sweden reviewing the medical records of all patients with BCS 1986-2003, identified from the computerised diagnosis database of 11 hospitals, including all university hospitals and liver transplantation centres. RESULTS: Forty-three patients with BCS were identified, of whom nine (21%) had concomitant portal vein thrombosis. The mean age-standardised incidence and prevalence rates in 1990-2001 were calculated to be 0.8 per million per year and 1.4 per million inhabitants respectively. Myeloproliferative disorders (38%), thrombophilic factors (31%) and oral contraceptives (30%) were common aetiological factors. Two or more risk factors were present in 44%. In 23%, no risk factor was evident. The median follow-up time was 2.7 years. Seventy-two percent were on anticoagulant therapy during follow-up. Transjugular intrahepatic portosystemic shunting, surgical shunting procedures and liver transplantation were performed in 4, 6 and 18 patients respectively. Nineteen patients died. The overall transplantation-free survival at 1, 5 and 10 years was 47, 28 and 17% respectively. CONCLUSIONS: Budd-Chiari syndrome is a rare disorder; the mean age-standardised incidence and prevalence rates in Sweden in 1990-2001 were calculated to be 0.8 per million per year and 1.4 per million inhabitants respectively. The presence of a myeloproliferative disorder was a common aetiological factor in our cohort and about half of the patients had a multifactorial aetiology. The transplantation-free survival was poor.


Assuntos
Síndrome de Budd-Chiari/epidemiologia , Síndrome de Budd-Chiari/etiologia , Síndrome de Budd-Chiari/patologia , Adolescente , Adulto , Idoso , Análise Química do Sangue , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Estatísticas não Paramétricas , Análise de Sobrevida , Suécia/epidemiologia
11.
Scand J Infect Dis ; 41(6-7): 389-402, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20001276

RESUMO

In a recent expert meeting, Swedish recommendations for the treatment of HCV infection were upgraded. The panel recommends vaccination against both hepatitis A and B in patients with HCV. Therapy for symptomatic acute HCV infection should be initiated if spontaneous resolution has not occurred within 12 weeks, whereas asymptomatic acute HCV should be treated upon detection. Patients with genotype 2/3 infection should generally be treated for 24 weeks. In patients with a very rapid viral response (vRVR), i.e. HCV RNA below 1000 IU/ml on d 7, treatment can be shortened to 12-16 weeks, provided that no dose reduction has been made. For genotype 1 patients with rapid viral response (RVR), 24 weeks treatment is recommended. For patients with a complete early viral response (cEVR), 48 weeks treatment is recommended, whereas 72 weeks treatment should be considered for patients with partial early viral response (pEVR). For patients with difficult-to-treat disease and with pronounced anaemia, erythropoietin can be used to maintain the ribavirin dose. In HCV-HIV coinfected patients, combination therapy for HCV should, if possible, be initiated before anti-retroviral therapy (ART) is indicated. For liver transplant patients pre-emptive therapy is not recommended; hence, treatment should be deferred until histological recurrence.


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Doença Aguda , Adulto , Antivirais/efeitos adversos , Criança , Hepacivirus , Hepatite C Crônica/tratamento farmacológico , Humanos , Ribavirina/efeitos adversos , Ribavirina/uso terapêutico , Suécia
12.
J Leukoc Biol ; 84(6): 1392-9, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18801925

RESUMO

The aim of this investigation was to study the involvement of eosinophil and neutrophil granulocytes in different stages of Crohn's disease (CD) and ulcerative colitis (UC). Biopsy samples were taken from the right flexure of the colon and from the rectum in patients with active (n=12) and inactive colonic CD (n=7), patients with active (n=33) and inactive UC (n=24), and from control subjects (n=11). Cell suspensions from biopsies and blood were analyzed by flow cytometry with regards to activation markers and viability. Immunohistochemistry was used to evaluate cell number and degranulation. Blood eosinophils were cultured with Th1 and Th2 cytokines, and the expression of activity markers was assessed by flow cytometry. Eosinophil number, viability, and activity were increased during active CD and UC compared with controls. The activity, assessed as CD44 expression, tended to diminish during inactive CD but was increased further in quiescent UC. Neutrophil number and activity were increased only during inflammation in both diseases. Culture of blood eosinophils with IL-5 and IL-13 caused increased CD44 expression, whereas IL-5 and IFN-gamma induced elevated CD69 expression. We observed different patterns of eosinophil activation in CD and UC, with the highest CD44 expression during quiescent UC. Our in vitro experiments with recombinant cytokines suggest that the diverse mechanisms of eosinophil activation in CD and UC are a result of different cytokine milieus (Th1 vs. Th2). In contrast, neutrophil activation reflects the disease activity in CD and UC, irrespective of Th cell skewing.


Assuntos
Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Eosinófilos/fisiologia , Adolescente , Adulto , Idoso , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Apoptose/imunologia , Células Cultivadas , Colite Ulcerativa/patologia , Doença de Crohn/patologia , Feminino , Citometria de Fluxo , Humanos , Receptores de Hialuronatos/imunologia , Técnicas Imunoenzimáticas , Interleucina-13/imunologia , Interleucina-5/imunologia , Lectinas Tipo C , Masculino , Pessoa de Meia-Idade , Neutrófilos/fisiologia , Adulto Jovem
13.
Cancer Res ; 67(19): 9006-12, 2007 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-17909001

RESUMO

The ubiquitin-proteasome system is a major regulatory pathway of protein degradation and plays an important role in cellular division. Fbxw7 (or hCdc4), a member of the F-box family of proteins, which are substrate recognition components of the multisubunit ubiquitin ligase SCF (Skp1-Cdc53/Cullin-F-box-protein), has been shown to mediate the ubiquitin-dependent proteolysis of several oncoproteins including cyclin E1, c-Myc, c-Jun, and Notch. The oncogenic potential of Fbxw7 substrates, frequent allelic loss in human cancers, and demonstration that mutation of FBXW7 cooperates with p53 in mouse tumorigenesis have suggested that Fbxw7 could function as a tumor suppressor in human cancer. Here, we carry out an extensive genetic screen of primary tumors to evaluate the role of FBXW7 as a tumor suppressor in human tumorigenesis. Our results indicate that FBXW7 is inactivated by mutation in diverse human cancer types with an overall mutation frequency of approximately 6%. The highest mutation frequencies were found in tumors of the bile duct (cholangiocarcinomas, 35%), blood (T-cell acute lymphocytic leukemia, 31%), endometrium (9%), colon (9%), and stomach (6%). Approximately 43% of all mutations occur at two mutational "hotspots," which alter Arg residues (Arg465 and Arg479) that are critical for substrate recognition. Furthermore, we show that Fbxw7Arg465 hotspot mutant can abrogate wild-type Fbxw7 function through a dominant negative mechanism. Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas F-Box/genética , Genes Supressores de Tumor , Neoplasias/genética , Ubiquitina-Proteína Ligases/genética , 5-Metilcitosina/metabolismo , Aminação , Proteínas de Ciclo Celular/metabolismo , Metilação de DNA , Repetições de Dinucleotídeos , Proteínas F-Box/metabolismo , Proteína 7 com Repetições F-Box-WD , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Modelos Moleculares , Mutação , Neoplasias/metabolismo , Isoformas de Proteínas , Especificidade por Substrato , Ubiquitina-Proteína Ligases/metabolismo
14.
Dig Liver Dis ; 51(2): 253-257, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389427

RESUMO

BACKGROUND: Data on rescue treatment of autoimmune hepatitis in patients that fail standard treatment are sparse. AIMS: To report our long-term experience with mycophenolate mofetil. METHODS: Retrospective study in 22 patients with autoimmune hepatitis who failed azathioprine and prednisolone due to adverse events (n = 14, 64%), lack of remission (n = 5, 23%) or a combination (n = 3, 13%). RESULTS: Mycophenolate mofetil was started at a dose of 20 mg/kg/day and increased to a maximum of 3 g/day. Follow-up was 0-6 months in 7 patients; more than 12 months in 15 (68%) and more than 24 months in 10. Normal aminotransferase levels were obtained (n = 3) or maintained (n = 7) in 10 patients (45%) after three to 30 weeks. 12 patients (55%) were withdrawn during the first 6 months, due to adverse events. Three patients were switched to cyclosporine and one underwent liver transplantation. Successful treatment with mycophenolate mofetil continued in 10 patients (45%) for a median of 71 months (range 20-124). Of these, one stopped prednisolone, five have a prednisolone dose <5 mg daily and four patients 5-10 mg. CONCLUSION: Approximately one of two patients with autoimmune hepatitis that fail standard treatment benefit from long-term maintenance with mycophenolate mofetil, especially those with previous intolerance to thiopurines, where mycophenolate mofetil is effective in two thirds.


Assuntos
Azatioprina , Substituição de Medicamentos/métodos , Hepatite Autoimune , Ácido Micofenólico , Prednisolona , Adolescente , Adulto , Idoso , Alanina Transaminase/sangue , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Monitoramento de Medicamentos/métodos , Resistência a Medicamentos , Feminino , Hepatite Autoimune/sangue , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/epidemiologia , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Testes de Função Hepática/métodos , Quimioterapia de Manutenção/métodos , Quimioterapia de Manutenção/estatística & dados numéricos , Masculino , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Estudos Retrospectivos , Suécia/epidemiologia , Resultado do Tratamento
15.
Scand J Gastroenterol ; 43(4): 465-72, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18365912

RESUMO

OBJECTIVE: To evaluate compliance, serologic response and the cost-benefit of a low-dose intradermal hepatitis B vaccination programme, followed by intramuscular boosters in non-responders. MATERIAL AND METHODS: The study comprised a retrospective survey of 1521 health-care workers and 968 students. Response was defined as hepatitis B antibody titres > or =10 IU/L. Non-response included vaccinees with undetectable antibodies and a hypo-response if antibodies were detectable. RESULTS: Overall, 2145/2489 (86%) subjects completed the intradermal series, whereof 1840/2489 (74%) complied with the serological check-up. Response was achieved in 1517/1840 (82.5%), whereas 107/1840 (5.8%) had a hypo-response and 216/1840 (11.7%) had an undetectable response. In a logistic regression model, younger age (odds ratio 0.73 (95% CI: 0.65-0.82, p<0.001)) and female gender (odds ratio 2.16 (95% CI: 1.67-2.80; p<0.001)) were predictive of response. In hypo-responders and those with undetectable responses, 43/46 (94%) and 71/136 (52%), respectively, had a response after the first intramuscular booster. Hence, in compliant vaccinees an overall seroprotection rate of 94% was reached after a single intramuscular booster. A cost-benefit analysis indicated a cost reduction exceeding 50% compared to a standard intramuscular vaccine regimen. CONCLUSIONS: In the clinical setting, a low-dose intradermal hepatitis B vaccination programme, followed by intramuscular boosters to non-responders, is effective and cost saving.


Assuntos
Pessoal de Saúde , Vacinas contra Hepatite B/administração & dosagem , Transmissão de Doença Infecciosa do Paciente para o Profissional/prevenção & controle , Estudantes de Medicina , Vacinação , Adulto , Análise Custo-Benefício , Coleta de Dados , Feminino , Anticorpos Anti-Hepatite B/sangue , Vacinas contra Hepatite B/economia , Humanos , Programas de Imunização , Imunização Secundária , Transmissão de Doença Infecciosa do Paciente para o Profissional/economia , Injeções Intradérmicas , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Vacinação/economia , Vacinas Sintéticas
16.
Scand J Gastroenterol ; 43(10): 1232-40, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18609163

RESUMO

OBJECTIVE: Autoimmune hepatitis (AIH) is a chronic liver disease, which if untreated can lead to cirrhosis and hepatic failure. The aim of the study was to investigate the incidence, prevalence, diagnostic tradition and clinical initial presentation of AIH. MATERIAL AND METHODS: Analyses were performed in 473 patients identified as having probable or definite AIH. RESULTS: The incidence of AIH was 0.85/100,000 (95% CI 0.69-1.01) inhabitants, which is somewhat lower than reported previously. The point prevalence amounted to 10.7/100,000 (95% CI 8.8-13.1), and 76% of the cases were females. The age-related incidence curve was bimodal but men were found to have only one incidence peak in the late teens, whereas women had a peak after menopause. AIH was presented as a spectrum of clinical settings from detected "en passant" to acute liver failure. Almost 30% of patients already had liver cirrhosis at diagnosis. Autoantibodies indicative of AIH type 1 were found in 79% of cases. Other concomitant autoimmune diseases were frequently found (49%). CONCLUSIONS: The incidence and prevalence figures confirm that AIH is a fairly uncommon disease in the Swedish population. Symptoms at presentation were unspecific, but almost half of the patients were jaundiced, with around 30% having liver cirrhosis. The majority of Swedish AIH patients had AIH type 1.


Assuntos
Hepatite Autoimune/diagnóstico , Hepatite Autoimune/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Masculino , Prevalência , Estudos Retrospectivos , Suécia/epidemiologia
17.
World J Gastroenterol ; 14(36): 5584-9; discussion 5588, 2008 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-18810778

RESUMO

AIM: To evaluate fecal calprotectin (FC) as a surrogate marker of treatment outcome of relapse of inflammatory bowel disease (IBD) and, to compare FC with fecal myeloperoxidase (MPO) and fecal eosinophil protein X (EPX). METHODS: Thirty eight patients with IBD, comprising of 27 with ulcerative colitis (UC) and 11 with Crohn's disease (CD) were investigated before treatment (inclusion), and after 4 and 8 wk of treatment. Treatment outcomes were evaluated by clinical features of disease activity and endoscopy in UC patients, and disease activity in CD patients. In addition, fecal samples were analyzed for FC by enzyme-linked immunosorbent assay (ELISA), and for MPO and EPX with radioimmunoassay (RIA). RESULTS: At inclusion 37 of 38 (97%) patients had elevated FC levels (> 94.7 microg/g). At the end of the study, 31 of 38 (82%) patients fulfilled predefined criteria of a complete response [UC 21/27 (78%); CD 10/11 (91%)]. Overall, a normalised FC level at the end of the study predicted a complete response in 100% patients, whereas elevated FC level predicted incomplete response in 30%. Normalised MPO or EPX levels predicted a complete response in 100% and 90% of the patients, respectively. However, elevated MPO or EPX levels predicted incomplete response in 23% and 22%, respectively. CONCLUSION: A normalised FC level has the potential to be used as a surrogate marker for successful treatment outcome in IBD patients. However, patients with persistent elevation of FC levels need further evaluation. FC and MPO provide superior discrimination than EPX in IBD treatment outcome.


Assuntos
Colite Ulcerativa/terapia , Doença de Crohn/terapia , Neurotoxina Derivada de Eosinófilo/análise , Fezes/química , Complexo Antígeno L1 Leucocitário/análise , Peroxidase/análise , Adulto , Idoso , Biomarcadores/análise , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Endoscopia Gastrointestinal , Fezes/enzimologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recidiva , Resultado do Tratamento , Adulto Jovem
18.
Eur J Gastroenterol Hepatol ; 28(6): 656-60, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26958788

RESUMO

INTRODUCTION: Treatment of Budd-Chiari syndrome (BCS) has shifted from mainly medical treatment, with surgical shunt and orthotopic liver transplantation (OLT) as rescue, to medical treatment combined with an early endovascular intervention in the past two decades. PURPOSE: To assess the safety and efficiency of endovascular treatment of symptomatic patients with BCS and to compare mortality with symptomatic BCS patients in the same region treated with only sporadic endovascular techniques. METHODS: This was a retrospective review of clinical data, treatment and survival in 14 patients diagnosed with BCS and treated with endovascular methods from 2003 to 2015. A national epidemiology study of BCS from 1986 to 2003 was used for comparison. RESULTS: Thirteen of the 14 patients eventually had transjugular intrahepatic portosystemic shunt (TIPS), four after previous liver vein angioplasty. TIPS were performed with polytetrafluoroethylene-covered stents and technical success was 100%. Calculated preinterventional prognostic indices indicated a high risk of TIPS dysfunction, OLT and death. However, only one patient died and one had an OLT, and the 1- and 2-year primary TIPS-patency was 85 and 67%, respectively. Episodes of de-novo hepatic encephalopathy occurred in three patients. Overall 1- and 5-year transplantation-free survival was 100 and 93% compared with 47 and 28%, respectively, in 1986 to 2003. CONCLUSION: TIPS seems to be a safe and effective treatment for symptomatic BCS and there is an obvious improvement in transplantation-free survival compared with conservatory medical treatment. It should, therefore, be considered early, as first-line intervention, in patients with insufficient response to medical treatment.


Assuntos
Síndrome de Budd-Chiari/cirurgia , Procedimentos Endovasculares/métodos , Hipertensão Portal/cirurgia , Transplante de Fígado/estatística & dados numéricos , Derivação Portossistêmica Transjugular Intra-Hepática/métodos , Dor Abdominal/etiologia , Adolescente , Adulto , Angioplastia , Ascite/etiologia , Síndrome de Budd-Chiari/complicações , Síndrome de Budd-Chiari/mortalidade , Intervenção Médica Precoce , Feminino , Veias Hepáticas/cirurgia , Síndrome Hepatorrenal/etiologia , Humanos , Hipertensão Portal/etiologia , Masculino , Pessoa de Meia-Idade , Politetrafluoretileno , Estudos Retrospectivos , Stents , Adulto Jovem
19.
Inflammation ; 36(4): 855-61, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23423580

RESUMO

Interactions between the enteric nervous system and the immune system are suggested to play an important role in the pathophysiology of inflammatory bowel disease (IBD). This study aims to determine if chromogranin A (CgA), chromogranin B (CgB), and secretoneurin (SN) are detectable in feces (F) from patients with collagenous colitis (CC) and to compare the levels found in patients with ulcerative colitis (UC) and Crohn's disease (CD) before and during treatment. Patients with CC (n = 12) were studied before and after 3, 7, 28, and 56 days of treatment. Patients with IBD (UC, n = 21; CD, n = 11) were studied before and after 28 and 56 days of treatment. Clinical data were recorded, and fecal samples were collected at each occasion. F-CgA, F-CgB, and F-SN were measured by RIA. Eleven patients with CC, 21 with UC, and 10 with CD achieved remission. On inclusion, CC patients had higher levels of F-CgA, F-CgB, and F-SN than patients with IBD and controls. Patients with IBD expressed markedly lower levels of F-SN than controls. During treatment, F-SN in CC patients decreased to control levels but remained low in IBD patients. No change was found in F-CgA or F-CgB in any of the groups. In conclusion, CgA, CgB, and SN are detectable in feces, and CC patients express higher values than patients with IBD and controls. During treatment, F-SN decreased to control levels in CC. These findings suggest that the enteric nervous system is clearly involved in the pathophysiology of CC.


Assuntos
Cromogranina A/metabolismo , Cromogranina B/metabolismo , Colite Colagenosa/metabolismo , Fezes/química , Neuropeptídeos/metabolismo , Secretogranina II/metabolismo , Adulto , Idoso , Cromogranina A/análise , Cromogranina B/análise , Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Sistema Nervoso Entérico/metabolismo , Fezes/citologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuropeptídeos/análise , Secretogranina II/análise , Adulto Jovem
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