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An adult female patient was diagnosed with arginase 1 deficiency (ARG1-D) at 4â¯years of age, and had been managed with protein restriction combined with sodium benzoate therapy. Though the treatment was successful in ameliorating hyperammonemia, hyperargininemia persisted. After being under control with a strict restriction of dietary protein, severe fall of serum albumin levels appeared and her condition became strikingly worsened. However, after sodium phenylbutyrate (NaPB) therapy was initiated, the clinical condition and metabolic stability was greatly improved. Current management of ARG1-D is aimed at lowering plasma arginine levels. The nitrogen scavengers, such as NaPB can excrete the waste nitrogen not through the urea cycle but via the alternative pathway. The removal of nitrogen via alternative pathway lowers the flux of arginine in the urea cycle. Thereby, the clinical complications due to insufficient amount of protein intake can be prevented. Thus, NaPB therapy can be expected as a useful therapeutic option, particularly in patients with ARG1-D.
Assuntos
Arginase/genética , Hiperargininemia/tratamento farmacológico , Fenilbutiratos/uso terapêutico , Adulto , Arginase/metabolismo , Arginina/metabolismo , Feminino , Humanos , Hiperamonemia/sangue , Hiperargininemia/sangue , Hiperargininemia/genética , Fenilbutiratos/metabolismoRESUMO
Objective Interferon-free regimens of direct-acting antiviral agents have improved the treatment response for chronic hepatitis C virus (HCV) infection, and improvement in the serum albumin level during interferon-free therapy has been reported. The aim of this study was to identify the factors that influence the improvement in the serum albumin level in patients receiving interferon-free antiviral therapy. Methods This retrospective, multicenter study consisted of 471 Japanese patients with chronic hepatitis and compensated liver cirrhosis infected with HCV who completed 12-week interferon-free sofosbuvir (SOF)-based therapy [SOF plus ledipasvir for genotype 1 (n=276) and SOF with ribavirin for genotype 2 (n=195)]. We evaluated the changes in the serum albumin level from baseline to the end of treatment (ΔAlb). Results When compared with the normal-albumin group (baseline serum albumin >35 g/L, n=406), the low-albumin group (baseline serum albumin ≤35 g/L, n=65) showed a significant increase in the mean ΔAlb (5.5 g/L vs. 1.0 g/L, p<0.001). In the low-albumin group, a multivariate logistic regression analysis extracted diabetes mellitus as a negative predictive factor of median ΔAlb >5.0 g/L (odds ratio: 0.19, 95% confidence interval: 0.048-0.79, p=0.020). In the low-albumin group, the mean ΔAlb was significantly lower in the diabetic patients (n=14) than in the non-diabetic patients (n=51) (3.9 g/L and 5.7 g/L, p=0.049). Conclusion Interferon-free SOF-based therapy significantly improved the serum albumin in the low-albumin group patients with chronic HCV infection. However, the improvement in the serum albumin level was significantly lower in the diabetic patients than in the non-diabetic patients.
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Antivirais/uso terapêutico , Complicações do Diabetes/sangue , Hepatite C Crônica/sangue , Albumina Sérica/análise , Sofosbuvir/uso terapêutico , Adulto , Idoso , Benzimidazóis/uso terapêutico , Complicações do Diabetes/complicações , Quimioterapia Combinada , Feminino , Fluorenos/uso terapêutico , Genótipo , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Interferons/uso terapêutico , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ribavirina/uso terapêutico , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/uso terapêuticoRESUMO
Primary biliary cirrhosis(PBC)is a chronic cholestatic liver disease and the association of osteoporosis is high. In this paper, the practical guidelines for PBC of Japan as well as those of America(AASLD)and Europe(EASL)are mentioned. Description of each guideline is essentially the same;taking sufficient calcium(1,000~1,200 mg/day)with vitamin D and weight-bearing exercise, and thereafter medication such as alendronate is recommended.
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Doenças Ósseas/tratamento farmacológico , Cirrose Hepática Biliar/complicações , Guias de Prática Clínica como Assunto , Densidade Óssea , Doenças Ósseas/etiologia , Cálcio/uso terapêutico , Humanos , Vitamina D/uso terapêutico , Suporte de CargaRESUMO
AIM: The aim of the present study is to evaluate the factors influencing biochemical response to treatment and the value of biochemical response for predicting long-term outcomes in Japanese patients with primary biliary cirrhosis (PBC). METHODS: Biochemical response to ursodeoxycholic acid (UDCA) or UDCA plus bezafibrate was defined as good (≤upper limit of normal [ULN]), fair (≤1.5 × ULN) or poor (>1.5 × ULN) at 2 years after initiation of UDCA treatment. Associations between various factors (including age, sex, autoantibody status and histological variables at baseline), biochemical response to treatment and long-term outcomes were evaluated in 164 Japanese PBC patients. RESULTS: Anti-gp210 positivity and a higher bile duct loss score were significant risk factors for worse alkaline phosphatase (ALP) response (odds ratios [OR], 2.78 and 1.85, respectively). Age, anti-gp210 positivity and anticentromere positivity were significant risk factors for worse alanine aminotransferase (ALT) response (OR, 1.05, 4.0 and 2.77, respectively). Anti-gp210 positivity and a higher hepatitis score were significant risk factors for worse immunoglobulin (Ig)M response (OR, 2.10 and 2.06, respectively). Worse ALP and IgM response were significant risk factors for progression to late-stage disease without jaundice (OR, 2.27 and 2.32, respectively). Worse ALT response was a significant risk factor for progression to late-stage disease with persistent jaundice (OR, 11.11). CONCLUSION: Biochemical response to treatment at 2 years, which is influenced by autoantibody status and histological variables at baseline, can predict long-term outcomes in Japanese patients with PBC.
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Recent genome-wide association studies suggest that genetic factors contribute to primary biliary cirrhosis (PBC) susceptibility. Although several reports have demonstrated that the interleukin (IL) 12 signaling pathway is involved in PBC pathogenesis, its precise genetic factors have not been fully clarified. Here, we performed an association analysis between IL12A, IL12RB, and signal transducer and activator of transcription 4 (STAT4) genetic variations and susceptibility to PBC. Single nucleotide polymorphisms (SNPs) were genotyped in 395 PBC patients and 458 healthy subjects of Japanese ethnicity and evaluated for associations with PBC susceptibility, anti-nuclear antibody (ANA) status, and anti-mitochondrial antibody (AMA) status. We detected significant associations with PBC susceptibility for several STAT4 SNPs (rs10168266; P = 9.4 × 10(-3), rs11889341; P = 1.2 × 10(-3), rs7574865; P = 4.0 × 10(-4), rs8179673; P = 2.0 × 10(-4), and rs10181656; P = 4.2 × 10(-5)). Three risk alleles (rs7574865; P = 0.040, rs8179673; P = 0.032, and rs10181656; P = 0.031) were associated with ANA status, but not with AMA positivity. Our findings confirm that STAT4 is involved in PBC susceptibility and may play a role in ANA status in the Japanese population.
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Anticorpos Antinucleares/sangue , Cirrose Hepática Biliar/genética , Fator de Transcrição STAT4/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Subunidade p35 da Interleucina-12/genética , Japão , Desequilíbrio de Ligação , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-12/genéticaRESUMO
BACKGROUND: To identify the genetic factors involved in the pathogenesis of primary biliary cirrhosis (PBC), we focused on the organic cation transporter 1 (OCT1/SLC22A1), which is closely associated with phosphatidylcholine synthesis in hepatocytes. METHODS: We selected four (rs683369, rs2282143, rs622342 and rs1443844) OCT-1 single nucleotide polymorphisms (SNPs), and genotyped these SNPs using the TaqMan probe method in 275 Japanese PBC patients and 194 gender-matched, healthy volunteers as controls. RESULTS: The Chi-square test revealed that the rs683369 variant allele (G) was associated with insusceptibility to PBC development [P = 0.009, odds ratio (OR) 0.60, 95 % confidence interval (CI) 0.40-0.88] in an allele model, and that the rs683369 variant allele (G) was associated with jaundice-type progression in a minor allele dominant genotype model (P = 0.032, OR 3.10, 95 % CI 1.05-9.14). The OCT-1 rs2282143 variant (T) and rs622342 variant (C) were also associated with jaundice-type progression in a minor allele recessive genotype model (P = 0.0002, OR 10.58, 95 % CI 2.36-47.54, and P = 0.006, OR 7.84, 95 % CI 1.39-44.36, respectively). Furthermore, the association of OCT-1 rs683369 and rs622342 with susceptibility to jaundice-type progression was confirmed by a replication study with a distinct set of PBC patients who underwent liver transplantation. CONCLUSIONS: The present study is the first report on the association of OCT-1 genetic polymorphisms with the overall development and jaundice-type progression of PBC.
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Predisposição Genética para Doença/genética , Icterícia/genética , Cirrose Hepática Biliar/genética , Transportador 1 de Cátions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Estudos de Casos e Controles , Progressão da Doença , Feminino , Genótipo , Humanos , Japão , Icterícia/etiologia , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
A 17-year-old male was admitted to our hospital and diagnosed with acute hepatitis B. Six weeks later, a 15-year-old male was admitted with acute hepatitis B as well. They were Sumo wrestling players in the same club. A detailed survey in the club revealed that a 28-year-old male coach was a hepatitis B surface antigen carrier with high-level viremia. The consistency of hepatitis B virus (HBV) DNA in the infected players was revealed by analyzing the complete HBV genome sequences. Sumo players are more likely to get injured, including cuts and bleeding, compared with players of other sports because of the characteristic wrestling style. Several past reports have suggested that highly viremic HBV carriers have high HBV DNA titers in both their blood and other body fluids such as sweat. In our cases, percutaneous HBV transmission through the bleeding wounds was the most probable infection route. We conclude that a universal HBV immunization program should be introduced urgently in Japan, similar to those implemented in other countries worldwide.
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BACKGROUND & AIMS: Through a genome-wide association study of a Japanese population, we recently identified TNFSF15, a gene encoding TNF-like ligand 1A (TL1A), as a susceptibility gene for primary biliary cirrhosis (PBC). We investigated the clinical significance of TL1A and one of its receptors, decoy receptor 3 (DcR3), in PBC. METHODS: We analysed the systemic and local expression of TL1A and DcR3 in 110 PBC patients and 46 healthy controls using enzyme-linked immunosorbent assay, quantitative polymerase chain reaction and immunohistochemical staining. RESULTS: Serum TL1A levels were significantly increased in PBC patients at both early and late stages as compared with healthy controls, and its levels were significantly decreased in early-stage PBC patients after ursodeoxycholic acid (UDCA) treatment. TL1A was immunohistochemically localized to biliary epithelial cells, Kupffer cells, blood vessels and infiltrating mononuclear cells in the PBC liver. In addition, TL1A messenger RNA expression was increased in the PBC liver as compared with the non-diseased liver. Serum DcR3 levels were also significantly increased in PBC patients, and were significantly decreased after UDCA treatment in early-stage PBC patients. CONCLUSIONS: These results indicate that TL1A and DcR3 may play an important role in the pathogenesis of PBC.
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Cirrose Hepática Biliar/sangue , Membro 6b de Receptores do Fator de Necrose Tumoral/sangue , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Adulto , Idoso , Anticorpos Antinucleares/sangue , Estudos de Casos e Controles , Colagogos e Coleréticos/uso terapêutico , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/patologia , Masculino , Pessoa de Meia-Idade , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
BACKGROUND/AIMS: Recent studies demonstrated an association of STAT4 polymorphisms with autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, indicating multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 polymorphisms on the susceptibility and phenotype of type-1 autoimmune hepatitis in a Japanese National Hospital Organization (NHO) AIH multicenter cohort study. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 460 individuals of Japanese origin including 230 patients with type-1 autoimmune hepatitis and 230 healthy controls was analyzed for two single nucleotide polymorphisms in the STAT4 gene (rs7574865, rs7582694). The STAT4 rs7574865T allele conferred risk for type-1 autoimmune hepatitis (ORâ=â1.61, 95% CIâ=â1.23-2.11; Pâ=â0.001), and patients without accompanying autoimmune diseases exhibited an association with the rs7574865T allele (ORâ=â1.50, 95%CIâ=â1.13-1.99; Pâ=â0.005). Detailed genotype-phenotype analysis of type-1 autoimmune hepatitis patients with (nâ=â44) or without liver cirrhosis (nâ=â186) demonstrated that rs7574865 was not associated with the development of liver cirrhosis and phenotype (biochemical data and the presence of auto-antibodies). CONCLUSIONS/SIGNIFICANCE: This is the first study to show a positive association between a STAT4 polymorphism and type-1 autoimmune hepatitis, suggesting that autoimmune hepatitis shares a gene commonly associated with risk for other autoimmune diseases.
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Predisposição Genética para Doença , Hepatite Autoimune/genética , Polimorfismo Genético , Fator de Transcrição STAT4/genética , Adulto , Idoso , Alelos , Povo Asiático/genética , Estudos de Coortes , Feminino , Variação Genética , Genótipo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
OBJECTIVE: Pentraxin 3 (PTX3) is an acute-phase reactant that is involved in amplification of the inflammatory response and innate immunity. In the present study, we evaluated the relationship between PTX3 and serum amyloid A (SAA), another acute-phase reactant, in rheumatoid synoviocytes. METHODS: PTX3 mRNA expression was examined by reverse transcription polymerase chain reaction, and PTX3 protein was measured by enzyme-linked immunosorbent assay. RESULTS: SAA induced PTX3 mRNA and PTX3 protein expression in rheumatoid synoviocytes. SAA-induced PTX3 expression was attenuated when rheumatoid synoviocytes were nucleofected with N-formyl peptide receptor ligand-1 (FPRL-1)-specific siRNA, suggesting the involvement of FPRL-1. Furthermore, SAA-induced PTX3 expression was inhibited by NF-κB or mitogen-activated protein kinase-specific inhibitors. Neither soluble TNF receptor (etanercept) nor recombinant IL-1 receptor antagonist affected PTX3 production by SAA-stimulated synoviocytes, suggesting that SAA directly induces PTX3. CONCLUSION: Our data suggest that SAA plays a role in the proinflammatory and immune responses in rheumatoid synovium by inducing PTX3. We provide the first evidence that the acute-phase reactant SAA, which is produced systemically by hepatocytes, perpetuates the rheumatoid inflammatory processes by inducing another proinflammatory molecule, PTX3, locally in rheumatoid synovial tissues.
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Artrite Reumatoide/metabolismo , Proteína C-Reativa/metabolismo , Osteoartrite/metabolismo , Proteína Amiloide A Sérica/farmacologia , Componente Amiloide P Sérico/metabolismo , Membrana Sinovial/efeitos dos fármacos , Artrite Reumatoide/patologia , Proteína C-Reativa/antagonistas & inibidores , Proteína C-Reativa/genética , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Osteoartrite/patologia , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/farmacologia , Receptores de Formil Peptídeo/genética , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/genética , Receptores de Lipoxinas/metabolismo , Proteínas Recombinantes , Componente Amiloide P Sérico/antagonistas & inibidores , Componente Amiloide P Sérico/genética , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , TransfecçãoRESUMO
BACKGROUND/AIMS: Although the incidence of hepatocellular carcinoma (HCC) has been shown to be reduced after pegylated glycol-interferon plus ribavirin (Peg-IFN/RBV) therapy in patients with chronic hepatitis C, the risk factors for the development of HCC are not fully understood. The aim of this study was to clarify the incidence and the risk factors for the development of HCC after Peg-IFN/RBV therapy in patients with chronic hepatitis C. METHODOLOGY: A total of 474 patients with chronic hepatitis C who received Peg-IFN/RBV therapy between December 2004 and August 2010 were enrolled and followed in a multicenter trial. The patients were assessed for HCC by either ultrasound or computed tomography every 6 months. The incidence and risk factors for the development of HCC were identified. RESULTS: Of the 474 patients, 23 developed HCC during a median follow-up of 4 years and 8 months (range 1-6 years and 3 months) after completion of Peg-IFN/RBV therapy. According to a univariate analysis, higher age, low platelet counts, a low level of serum albumin, a high level of alpha-fetoprotein (AFP) and a sustained viral response (SVR) to Peg-IFN/RBV therapy were independent factors associated with the occurrence of HCC. The multivariate analysis using the Cox proportional hazard model revealed the risk factors for HCC were the platelet count, AFP level and the outcome of Peg-IFN/RBV therapy. CONCLUSIONS: To reduce the incidence of HCC in chronic hepatitis C, attainment of a sustained response rate is an essential issue. For patients with low platelet counts and/or a high AFP level, strict surveillance should be continued even after eradication of HCV because the risk of HCC was found to be higher for these patients.
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Antivirais/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Neoplasias Hepáticas/epidemiologia , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/virologia , Distribuição de Qui-Quadrado , Quimioterapia Combinada , Hepatite C Crônica/sangue , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/epidemiologia , Humanos , Incidência , Interferon alfa-2 , Japão/epidemiologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/virologia , Análise Multivariada , Contagem de Plaquetas , Modelos de Riscos Proporcionais , Estudos Prospectivos , Proteínas Recombinantes/uso terapêutico , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima , Carga Viral , alfa-Fetoproteínas/metabolismoRESUMO
BACKGROUND: Hepatitis B e antigen (HBeAg) seroconversion is an important hallmark in the natural course of chronic hepatitis B. This study was designed to predict early HBeAg seroconversion within 1 year, by not only biochemical and virological markers, but also pathological parameters in patients with chronic hepatitis B. MATERIAL/METHODS: In a retrospective cohort study, 234 patients with HBeAg were reviewed for demographic, biochemical, virological and pathological data at the time of liver biopsy. Then, the patients who accomplished HBeAg seroconversion within 1 year thereafter were compared with those who did not, for sorting out factors predictive of early HBeAg seroconversion. RESULTS: Early HBeAg seroconversion occurred in 58 (24.8%) patients. In univariate analysis, factors predictive of early HBeAg seroconversion were: alanine aminotransferase (ALT) (p=0.002), IP-10 (p=0.029), HBsAg (p=0.003), HBeAg (p<0.001), HBV DNA (p=0.001), HBcrAg (p=0.001), core-promoter mutations (p=0.040), fibrosis (p=0.033) and lobular inflammation (p=0.002). In multivariate analysis, only serum HBeAg levels <100 Paul Ehrlich Institute (PEI) U/ml and grades of lobular inflammation ≥2 were independent factors for early HBeAg seroconversion (odds ratio 8.430 [95% confidence interval 4.173-17.032], p<0.001; and 4.330 [2.009-9.331], p<0.001; respectively). CONCLUSIONS: HBeAg levels < 100 PEIU/ml combined with grades of lobular inflammation ≥2 are useful for predicting early HBeAg seroconversion. In patients without liver biopsies, high ALT levels (≥200 IU/L) can substitute for lobular inflammation (grades ≥2).
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Antígenos E da Hepatite B/sangue , Inflamação/imunologia , Inflamação/patologia , Fígado/patologia , Fígado/virologia , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Biópsia , Criança , Demografia , Feminino , Hepatite B Crônica/sangue , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Fígado/imunologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Curva ROC , Fatores de Risco , Resultado do Tratamento , Carga ViralRESUMO
Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease that is prevalent in Mediterranean populations. While it is considered a rare disease in the rest of world, a significant number of FMF patients have been reported in East Asia, including Japan. Our aim was to determine the prevalence of FMF in Japan and elucidate the clinical and genetic features of Japanese patients. A primary nationwide survey of FMF was conducted between January and December 2009. Hospitals specializing in pediatrics and hospitals with pediatric, internal medicine, and rheumatology/allergy departments were asked to report all patients with FMF during the survey year. The estimated total number of Japanese FMF patients was 292 (95% confidence interval, 187-398 people). We evaluated the clinical and genetic profiles of Japanese patients from the data obtained in a secondary survey of 134 FMF patients. High-grade fever was observed in 95.5%, chest pain (pleuritis symptoms) in 36.9%, abdominal pain (peritonitis symptoms) in 62.7%, and arthritis in 31.3%. Of the patients profiled, 25.4% of patients experienced their first attack before 10 years of age, 37.3% in their teens, and 37.3% after age 20 years. Colchicine was effective in 91.8% of patients at a relatively low dose (mean dose, 0.89 ± 0.45 mg/d). AA amyloidosis was confirmed in 5 patients (3.7%). Of the 126 patients studied, 109 (86.5%) were positive for 1 or more genetic mutations and 17 (13.5%) had no mutation detected. Common Mediterranean fever gene (MEFV) mutations were E148Q/M694I (19.8%) and M694I/normal (12.7%). The differences in the prevalence of peritonitis, pleuritis, and a family history of FMF were statistically significant between FMF patients with MEFV exon 10 mutations compared with those without exon 10 mutations.In conclusion, a significant number of patients with FMF exist in Japan. Although Japanese patients with FMF are clinically or genetically different from Mediterranean patients, the delay in diagnosis is an issue that should be resolved.
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Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Feminino , Genótipo , Inquéritos Epidemiológicos , Humanos , Japão/epidemiologia , Masculino , Mutação , Prevalência , Inquéritos e QuestionáriosRESUMO
AIM: To establish an animal model with human hepatocyte-repopulated liver for the study of liver cancer metastasis. METHODS: Cell transplantation into mouse livers was conducted using alpha-fetoprotein (AFP)-producing human gastric cancer cells (h-GCCs) and h-hepatocytes as donor cells in a transgenic mouse line expressing urokinase-type plasminogen activator (uPA) driven by the albumin enhancer/promoter crossed with a severe combined immunodeficient (SCID) mouse line (uPA/SCID mice). Host mice were divided into two groups (A and B). Group A mice were transplanted with h-GCCs alone, and group B mice were transplanted with h-GCCs and h-hepatocytes together. The replacement index (RI), which is the ratio of transplanted h-GCCs and h-hepatocytes that occupy the examined area of a histological section, was estimated by measuring h-AFP and h-albumin concentrations in sera, respectively, as well as by immunohistochemical analyses of h-AFP and human cytokeratin 18 in histological sections. RESULTS: The h-GCCs successfully engrafted, repopulated, and colonized the livers of mice in group A (RI = 22.0% ± 2.6%). These mice had moderately differentiated adenocarcinomatous lesions with disrupted glandular structures, which is a characteristics feature of gastric cancers. The serum h-AFP level reached 211.0 ± 142.2 g/mL (range, 7.1-324.2 g/mL). In group B mice, the h-GCCs and h-hepatocytes independently engrafted, repopulated the host liver, and developed colonies (RI = 12.0% ± 6.8% and 66.0% ± 12.3%, respectively). h-GCC colonies also showed typical adenocarcinomatous glandular structures around the h-hepatocyte-colonies. These mice survived for the full 56 day-study and did not exhibit any metastasis of h-GCCs in the extrahepatic regions during the observational period. The mice with an h-hepatocyte-repopulated liver possessed metastasized h-GCCs and therefore could be a useful humanized liver animal model for studying liver cancer metastasis in vivo. CONCLUSION: A novel animal model of human liver cancer metastasis was established using the uPA/SCID mouse line. This model could be useful for in vivo testing of anti-cancer drugs and for studying the mechanisms of human liver cancer metastasis.
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Neoplasias Hepáticas Experimentais/secundário , Animais , Modelos Animais de Doenças , Hepatócitos/transplante , Humanos , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos SCID , Camundongos Transgênicos , Transplante de Neoplasias , Neoplasias Gástricas , Transplante Heterólogo , Células Tumorais Cultivadas , Ativador de Plasminogênio Tipo Uroquinase/genéticaAssuntos
Predisposição Genética para Doença , Antígenos HLA-DP/genética , Hepatite B/epidemiologia , Hepatite B/genética , Polimorfismo Genético , Adolescente , Adulto , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Portador Sadio/epidemiologia , Feminino , Genótipo , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/genética , Humanos , Japão/epidemiologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
AIM: Add-on adefovir dipivoxil (ADV) therapy has been a standard rescue treatment for patients with lamivudine (LAM)-resistant chronic hepatitis B, but the overall benefits of long-term add-on ADV therapy are still limited. The aim of this study was to evaluate the long-term efficiency of add-on ADV treatment and to explore predictive factors associated with it. METHODS: A total of 158 patients with LAM-resistant chronic hepatitis B were included in this retrospective, multicenter, nationwide study in Japan. After confirming LAM resistance, ADV was added to LAM treatment. Three types of events were considered as outcomes: virological response, hepatitis B e antigen (HBeAg) clearance and alanine aminotransferase (ALT) normalization. Virological response was defined as serum hepatitis B virus (HBV) DNA levels of less than 3 log copies/mL. Baseline factors contributing to these outcomes were examined by univariate and multivariate analyses. RESULTS: The median total duration of ADV treatment was 41 months (range, 6-84). The rate of virological response was 90.8% at 4 years of treatment; HBeAg clearance and ALT normalization were achieved by 34.0% and 82.7%, respectively, at the end of follow up. Each outcome had different predictive factors: baseline HBV DNA and albumin level were predictive factors for virological response, history of interferon therapy and ALT level for HBeAg clearance, and sex and baseline albumin level for ALT normalization. CONCLUSION: Long-term add-on ADV treatment was highly effective in LAM-resistant chronic hepatitis B patients in terms of virological and biochemical responses. Lower HBV replication and lower albumin level at baseline led to better outcomes.
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BACKGROUND: Monosodium urate (MSU) has been shown to promote inflammasome activation and interleukin-1ß (IL-1ß) secretion in monocyte/macrophages, but the cellular pathway and nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in synovial tissues, remain elusive. In this study, we investigated the effects of MSU on synovial fibroblasts to elucidate the process of MSU-mediated synovial inflammation. METHODS: Human synovial fibroblasts were stimulated with MSU in the presence or absence of serum amyloid A (SAA). The cellular supernatants were analyzed by immunoblotting using anti-IL-1ß or anti-caspase-1 antibodies. IL-1ß or NLRP3 mRNA expressions were analyzed by real-time PCR or reverse transcription-PCR (RT-PCR) method. RESULTS: Neither SAA nor MSU stimulation resulted in IL-1ß or interleukin-1α (IL-1α) secretions and pro-IL-1ß processing in synovial fibroblasts. However, in SAA-primed synovial fibroblasts, MSU stimulation resulted in the activation of caspase-1 and production of active IL-1ß and IL-1α. The effect of SAA on IL-1ß induction was impaired in cells by silencing NLRP3 using siRNA or treating with caspase-1 inhibitor. In addition, SAA induced the secretion of cathepsin B and NLRP3 mRNA expression in synovial fibroblasts. CONCLUSIONS: Our data demonstrate that exposure of human synovial fibroblasts to SAA promotes MSU-mediated caspase-1 activation and IL-1ß secretion in the absence of microbial stimulation. These findings provide insight into the molecular processes underlying the synovial inflammatory condition of gout.
Assuntos
Antioxidantes/farmacologia , Fibroblastos/metabolismo , Interleucina-1beta/biossíntese , Proteína Amiloide A Sérica/metabolismo , Membrana Sinovial/metabolismo , Ácido Úrico/farmacologia , Fibroblastos/efeitos dos fármacos , Gota/metabolismo , Humanos , Immunoblotting , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Membrana Sinovial/efeitos dos fármacosRESUMO
BACKGROUND/AIMS: Although the outcome of autoimmune hepatitis (AIH) is generally good, the natural course and likelihood of progression to cirrhosis or hepatocellular carcinoma (HCC) remain undefined, and may vary by region and population structure. Our aims were to evaluate risk factors that contribute to poor outcome and particularly development of HCC in a prospective multicentric cohort study of AIH. METHODS: The study group comprised 193 Japanese patients with AIH who were prospectively followed up at annual intervals between 1995 and 2008. The mean follow-up period was 8.0 ± 4.5 years. RESULTS: Twenty-one (10.9%) patients had cirrhosis at presentation and a further 15 (7.8%) developed cirrhosis during the follow-up period. Survival rates were 94.2% at 10 years and 89.3% at 15 years. HCC was diagnosed in seven of the 193 patients. The presence of cirrhosis at presentation was a risk factor for HCC according to a Cox proportional hazard model, and the HCC-free survival rate was significantly lower in those with cirrhosis compared to those without cirrhosis according to Kaplan-Meier analysis. CONCLUSIONS: Although the outcome of AIH is as good if not better among Japanese than for other populations, there was an increased risk of HCC in these patients. Cirrhosis at presentation was predictive of development of HCC in AIH in Japan.