RESUMO
BACKGROUND: Seladelpar is a potent and selective peroxisome proliferator-activated receptor-δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects. AIMS: To evaluate the long-term safety and efficacy of seladelpar in patients with PBC. METHODS: In an open-label, international, long-term extension study, patients with PBC completing seladelpar lead-in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non-alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years. RESULTS: There were no serious treatment-related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2. CONCLUSIONS: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. CLINICALTRIALS: gov: NCT03301506; Clinicaltrialsregister.eu: 2017-003910-16.
Assuntos
Colestase , Cirrose Hepática Biliar , Humanos , Ácido Ursodesoxicólico/efeitos adversos , Cirrose Hepática Biliar/tratamento farmacológico , Colestase/tratamento farmacológico , Colestase/induzido quimicamente , Biomarcadores , Fosfatase Alcalina , BilirrubinaRESUMO
Nonalcoholic steatohepatitis (NASH), the clinically aggressive variant of nonalcoholic fatty liver disease, is characterized by hepatocellular injury and inflammation.1 Patients with NASH are at higher risk of progression to cirrhosis and it is therefore targeted for drug development efforts.2 Lifestyle modifications and weight loss are the only recommended modalities and no drug is yet approved for the treatment of patients with NASH. Saroglitazar is a dual PPAR α/γ agonist, which has shown promise for treatment of nonalcoholic fatty liver disease.3 Because of its combined PPAR-α/γ agonism, it has a clinically favorable impact of glucose and lipid metabolism. Saroglitazar has shown to improve liver-related histology in patients with NASH and was recently approved for treatment of NASH in India.4 The current study builds on the published literature in this proof of concept study to determine if there is a signal for histologic improvement of NASH with saroglitazar in a Western population.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Fenilpropionatos , Humanos , Fígado , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR alfa , PirróisRESUMO
BACKGROUND AND AIMS: Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease. APPROACH AND RESULTS: In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients. CONCLUSIONS: In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH.
Assuntos
Azetidinas/administração & dosagem , Doença Hepática Terminal/prevenção & controle , Isobutiratos/administração & dosagem , Ácidos Isonicotínicos/administração & dosagem , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Oxazóis/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Azetidinas/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Biomarcadores/sangue , Biópsia , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Doença Hepática Terminal/patologia , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Isobutiratos/efeitos adversos , Ácidos Isonicotínicos/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Oxazóis/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Pirimidinas/efeitos adversos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Caspases play a central role in apoptosis, inflammation, and fibrosis. They produce hemodynamically active, proinflammatory microparticles that cause intrahepatic inflammation, vasoconstriction, and extrahepatic splanchnic vasodilation. Emricasan is a pan-caspase inhibitor that lowers portal hypertension (PH) and improves survival in murine models of cirrhosis. This exploratory study assessed whether emricasan lowers PH in patients with compensated cirrhosis. This multicenter, open-label study enrolled 23 subjects with compensated cirrhosis and PH (hepatic vein pressure gradient [HVPG] >5 mm Hg). Emricasan 25 mg twice daily was given for 28 days. HVPG measurements were standardized and performed before and after emricasan. A single expert read all HVPG tracings. Median age was 59 (range 49-80); 70% were male. Cirrhosis etiologies were nonalcoholic steatohepatitis and hepatitis C virus. Subjects were Child class A (87%) with a median Model for End-Stage Liver Disease score of 8 (range 6-15). Twelve had severe PH (HVPG ≥12 mm Hg). Overall, there was no significant change in HVPG after emricasan (mean [standard deviation, SD] -1.1 [4.57] mm Hg). HVPG decreased significantly (mean [SD] -3.7[4.05] mm Hg; P = 0.003) in those with severe PH: 4/12 had a ≥20% decrease, 8/12 had a ≥10% decrease, and 2/12 HVPG decreased below 12 mm Hg. There were no significant changes in blood pressure or heart rate. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) decreased significantly in the entire group and in those with severe PH. Serum cleaved cytokeratin 18 and caspase-3/7 decreased significantly. Emricasan was well tolerated. One subject discontinued for nonserious adverse events. Conclusion: Emricasan administered for 28 days decreased HVPG in patients with compensated cirrhosis and severe PH; an effect upon portal venous inflow is likely, and concomitant decreases in AST/ALT suggest an intrahepatic anti-inflammatory effect.
Assuntos
Hipertensão Portal/tratamento farmacológico , Ácidos Pentanoicos/uso terapêutico , Pressão na Veia Porta/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Caspase 3/sangue , Feminino , Humanos , Hipertensão Portal/sangue , Hipertensão Portal/etiologia , Queratina-18/sangue , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Ácidos Pentanoicos/farmacologiaAssuntos
Neoplasias dos Ductos Biliares/diagnóstico , Colangiocarcinoma/diagnóstico , Histiocitose Sinusal/diagnóstico , Adulto , Anemia Falciforme/complicações , Biópsia , Colangiopancreatografia por Ressonância Magnética , Diagnóstico Diferencial , Histiocitose Sinusal/complicações , Humanos , Icterícia Obstrutiva/etiologia , Fígado/patologia , MasculinoRESUMO
Hepatitis E, although commonly recognized in the Eastern Hemisphere, is less well recognized in the West. Particularly owing to this disease's grave impact on outcomes after liver transplantation, greater consideration of hepatitis E is necessary in the context of abnormal liver tests. Here, we review the most recent data on detecting and managing hepatitis E, both pre- and post-liver transplantation, discuss major detection assay limitations, consider future directions, and propose an algorithm for the diagnosis and management of pre-and post-transplantation hepatitis E.
Assuntos
Gerenciamento Clínico , Vírus da Hepatite E/genética , Hepatite E , Hospedeiro Imunocomprometido , Transplante de Fígado , Complicações Pós-Operatórias , RNA Viral/análise , Técnicas de Diagnóstico do Sistema Digestório , Saúde Global , Hepatite E/diagnóstico , Hepatite E/epidemiologia , Hepatite E/terapia , Humanos , Incidência , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Suboptimal colon preparation is a significant barrier to quality colonoscopy. The impact of pharmacologic agents associated with gastrointestinal dysmotility on quality of colon preparation has not been well characterized. AIMS: Evaluate impact of opiate pain medication and psychoactive medications on colon preparation quality in outpatients undergoing colonoscopy. METHODS: Outpatients undergoing colonoscopy at a single medical centre during a 6-month period were retrospectively identified. Demographics, clinical characteristics and pharmacy records were extracted from electronic medical records. Colon preparation adequacy was evaluated using a validated composite colon preparation score. RESULTS: 2600 patients (57.3 ± 12.9 years, 57% female) met the inclusion and exclusion criteria. 223 (8.6%) patients were regularly using opioids, 92 antipsychotics, 83 tricyclic antidepressants and 421 non-tricyclic antidepressants. Opioid use was associated with inadequate colon preparation both with low dose (OR = 1.4, 95%CI 1.0-2.1, p = 0.05) and high dose opioid users (OR = 1.7, 95%CI 1.1-2.9, p = 0.039) in a dose dependent manner. Other significant predictors of inadequate colon preparation included use of tricyclics (OR = 1.9, 95%CI 1.1-3.0, p = 0.012), non-tricyclic antidepressants (OR = 1.5, 95%CI 1.1-2.0, p = 0.013), and antipsychotic medications (OR = 2.2, 95%CI 1.4-3.4, p = 0.001). CONCLUSIONS: Opiate pain medication use independently predicts inadequate quality colon preparation in a dose dependent fashion; furthermore psychoactive medications have even more prominent effects and further potentiates the negative impact of opiates with concurrent use.
Assuntos
Analgésicos Opioides/efeitos adversos , Antidepressivos Tricíclicos/efeitos adversos , Antipsicóticos/efeitos adversos , Catárticos/uso terapêutico , Colonoscopia , Motilidade Gastrointestinal/efeitos dos fármacos , Polietilenoglicóis/uso terapêutico , Adulto , Idoso , Assistência Ambulatorial , Antidepressivos/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVE: Several studies have shown that patients with end-stage liver disease (ESLD) have lower bone mineral density (BMD) and a higher prevalence of osteoporosis compared to an age-matched population. Hyperinsulinemia and insulin resistance are typically associated with increased BMD. We hypothesized that patients with nonalcoholic steatohepatitis (NASH) and underlying insulin resistance may have higher BMD than patients with cirrhosis from other causes. METHODS: We performed a retrospective chart review of patients with ESLD who underwent liver transplant evaluation at Ochsner Clinic Foundation and had a BMD study as part of initial work up and compared BMD values of patients diagnosed with NASH to patients with cirrhosis due to other causes. Patients were categorized into 3 groups based on the etiology of their liver disease as NASH, alcoholic cirrhosis, or viral hepatitis C or B (HCV/HBV). RESULTS: A total of 63 patients met the study inclusion criteria, including 15 with NASH, 17 with alcoholic cirrhosis, and 31 with HCV/HBV. The overall prevalence rates of osteopenia and osteoporosis were 44% and 12%, respectively. BMD values were higher in the NASH group than the HCV/HBV group at lumbar spine, total hip, and femoral neck (P = .01, .03, and .02, respectively). There were no statistical differences in BMD values between NASH and alcoholic cirrhosis groups at any site. CONCLUSIONS: We found a high prevalence of low BMD among patients with ESLD awaiting liver transplantation. NASH patients had higher BMDs than HCV/HBV patients. The effects of NASH and insulin resistance on bone are complex and should be examined further.
Assuntos
Densidade Óssea/fisiologia , Fígado Gorduroso/fisiopatologia , Hepatopatias/fisiopatologia , Transplante de Fígado , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Spontaneous clearance of hepatitis C virus (HCV) after orthotopic liver transplantation (OLT) is a rare occurrence. Here, we present detailed immunological analysis of an interferon naive OLT recipient receiving uninterrupted immunosuppression who cleared HCV spontaneously 2 years after transplantation. METHODS: Enzyme-linked immunospot assay analysis of peripheral T-cell interferon gamma (IFN-γ), interleukin (IL)-10, and IL-17 response to HCV core and nonstructural antigen 4 and enzyme-linked immunosorbent assay (ELISA) to collagen (Col) subtypes I, II, IV, and V were performed in the index patient at the time of viral clearance and compared with an OLT cohort with persistent viremia matched for time from OLT, immunosuppression, and histology. Enzyme-linked immunospot assay and ELISA analysis were repeated on the patient 4 years after OLT. Transcription-mediated amplification assays were used to confirm viral clearance. RESULTS: Compared with a cohort of post-OLT and nontransplanted viremic HCV patients, the index patient with HCV clearance demonstrated higher IL-17, IL-10, and lower IFN-γ response to nonstructural antigen 4 and core antigen and a higher titer of antibodies (Abs) to Col subtypes I, II, and V during clearance. On follow-up 2 years later, HCV-specific IFN-γ was increased in the index patient, with a decline in IL-17 and IL-10 response and Col I, II, and V Ab titer. CONCLUSIONS: Virus-induced activation of Th-17 cells may contribute to HCV clearance post-OLT. Maintenance of viral suppression may be facilitated by restoration of Th1 (IFN-γ) responses. Modulation of Th17 immunity deserves further attention as a therapeutic strategy in the treatment of HCV recurrence post-OLT.
Assuntos
Carcinoma Hepatocelular , Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Neoplasias Hepáticas , Transplante de Fígado , Células Th17/imunologia , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Hepatite C Crônica/complicações , Hepatite C Crônica/fisiopatologia , Humanos , Terapia de Imunossupressão , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-17/imunologia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Recidiva , Remissão Espontânea , Transplante HomólogoRESUMO
Hepatitis C virus (HCV) infection and its recurrence after orthotopic liver transplantation (OLT) are associated with the remodeling of extracellular matrix (ECM) components [particularly collagen (Col)], which leads to fibrosis. Our aim was to determine whether the development of antibodies (Abs) to self-antigen Col in HCV-infected patients correlates with the fibrosis stage and the peripheral cytokine response. Patients with chronic HCV infection, patients with HCV recurrence after OLT who had undergone a biopsy procedure, and healthy control subjects were enrolled. The HCV subjects (n = 70) were stratified as follows: (1) a non-OLT group without fibrosis (Scheuer stages 0-2), (2) a non-OLT group with fibrosis (Scheuer stages 3-4), (3) a post-OLT group without fibrosis (Scheuer stages 0-2), and (4) a post-OLT group with fibrosis (Scheuer stages 3-4). Serum samples were analyzed for Abs against Col1, Col2, Col4, Col5, and vimentin with enzyme-linked immunosorbent assays. Serum levels of cytokines were measured with multiplex bead immunoassays. The levels of Abs to Col1 were higher in the fibrosis groups versus the no-fibrosis groups and the controls for both non-OLT patients (P < 0.001) and post-OLT patients (P = 0.01). There were increased levels of Abs to Col2, Col4, Col5, and vimentin in the non-OLT fibrosis group (Col2, P = 0.0001; Col4, P = 0.122; Col5, P < 0.0001; vimentin, P = 0.36) and in the post-OLT fibrosis group (Col2, P = 0.006; Col4, P = 0.19; Col5, P < 0.0001; vimentin, P = 0.24) in comparison with the no-fibrosis groups. The non-OLT and post-OLT fibrosis groups demonstrated significantly higher T helper 2 (T(h) 2) and T helper 17 (T(h) 17) cytokine levels and lower T helper 1 cytokine levels in comparison with the no-fibrosis groups. Our results demonstrate that in HCV-infected patients, the levels of Abs to ECM Col1, Col2, and Col5 positively correlate with liver fibrosis, which is associated with a predominantly T(h) 2 and T(h) 17 cytokine profile.
Assuntos
Colágeno/metabolismo , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Hepatite C/metabolismo , Cirrose Hepática/complicações , Adulto , Idoso , Doença Crônica , Estudos de Coortes , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Hepatite C/complicações , Hepatite C/imunologia , Humanos , Sistema Imunitário , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , RNA Viral/metabolismoRESUMO
OBJECTIVES: Endoscopist fatigue potentially impacts colonoscopy. Fatigue is difficult to quantitate, but polyp detection rates between non-fatigued and fatigued time periods could represent a surrogate marker. We assessed whether timing variables impacted polyp detection rates at a busy tertiary care endoscopy suite. METHODS: Consecutive patients undergoing colonoscopy were retrospectively identified. Indications, clinical demographics, pre-procedural, and procedural variables were extracted from chart review; colonoscopy findings were determined from the procedure reports. Three separate timing variables were assessed as surrogate markers for endoscopist fatigue: morning vs. afternoon procedures, start times throughout the day, and queue position, a unique variable that takes into account the number of procedures performed before the colonoscopy of interest. Univariate and multivariate analyses were performed to determine whether timing variables and other clinical, pre-procedural, and procedural variables predicted polyp detection. RESULTS: During the 4-month study period, 1,083 outpatient colonoscopy procedures (57.5±0.5 years, 59.5% female) were identified, performed by 28 endoscopists (mean 38.7 procedures/endoscopist), with a mean polyp detection rate of 0.851/colonoscopy. At least, one adenoma was detected in 297 procedures (27.4%). A 12.4% reduction in mean detected polyps was detected between morning and afternoon procedures (0.90±0.06 vs. 0.76±0.06, P=0.15). Using start time on a continuous scale, however, each elapsed hour in the day was associated with a 4.6% reduction in polyp detection (P=0.005). When queue position was assessed, a 5.4% reduction in polyp detection was noted with each increase in queue position (P=0.016). These results remained significant when controlled for each individual endoscopist. CONCLUSIONS: Polyp detection rates decline as time passes during an endoscopist's schedule, potentially from endoscopist fatigue. Queue position may be a novel surrogate measure for operator fatigue.
Assuntos
Adenoma/diagnóstico , Agendamento de Consultas , Neoplasias do Colo/diagnóstico , Pólipos do Colo/diagnóstico , Colonoscopia , Fadiga , Desempenho Psicomotor , Adulto , Idoso , Análise de Variância , Colonoscopia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Fatores de Tempo , Carga de TrabalhoRESUMO
BACKGROUND & AIMS: HBV infection may reactivate in the setting of immunosuppression, although the frequency and consequences of HBV reactivation are not well known. We report 6 patients who experienced loss of serologic markers of hepatitis B immunity and reappearance of HBsAg in the serum as a result of a variety of acquired immune deficiencies. METHODS: Between 2000 and 2005, six patients with reactivation of hepatitis B were seen in consultation by the Liver Diseases Branch at the Clinical Center, National Institutes of Health. The course and outcome of these 6 patients were reviewed. RESULTS: All 6 patients developed reappearance of HBsAg and evidence of active liver disease after stem cell transplantation (n = 4), immunosuppressive therapy (n = 1), or change in human immunodeficiency virus antiretroviral regimen (n = 1), despite having antibody to HBsAg (anti-HBs) or antibody to hepatitis B core antigen (anti-HBc) without HBsAg before. All 6 patients developed chronic hepatitis B, 2 patients transmitted hepatitis B to their spouses, and 1 patient developed cirrhosis. The diagnosis of hepatitis B reactivation was frequently missed or delayed and often required interruption of the therapy for the underlying condition. None of the patients received antiviral prophylaxis against HBV reactivation. CONCLUSIONS: Serologic evidence of recovery from hepatitis B infection does not preclude its reactivation after immunosuppression. Screening for serologic evidence of hepatitis B and prophylaxis of those with positive results by using nucleoside analogue antiviral therapy should be provided to individuals in whom immunosuppressive therapy is planned.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Antígenos de Superfície da Hepatite B/sangue , Hepatite B/induzido quimicamente , Imunossupressores/efeitos adversos , Ativação Viral/efeitos dos fármacos , Adulto , Fármacos Anti-HIV/uso terapêutico , Feminino , Infecções por HIV/complicações , Anticorpos Anti-Hepatite B/sangue , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco/efeitos adversosRESUMO
BACKGROUND & AIMS: An inadequately cleansed colon can lead to missed lesions, repeat procedures, increased cost, and complications from colonoscopy. Because obesity, with its known link to colorectal neoplasia, might be associated with inadequate bowel cleansing, we investigated the impact of increased body mass index (BMI) on quality of bowel preparation at colonoscopy. METHODS: All colonoscopy procedures performed at a tertiary referral center during a 4-month period were evaluated. Bowel preparation was assigned a unique composite outcome score that took into account a subjective bowel preparation score, earlier recommendation for follow-up colonoscopy as a result of inadequate bowel preparation, and the endoscopist's confidence in adequate evaluation of the colon. Univariate and multivariate logistic regression analyses were performed to identify the role of BMI in predicting an inadequate bowel preparation. RESULTS: During the study period, 1588 patients (59.1% female; mean age, 57.4 +/- 0.34 years) fulfilled inclusion criteria. An abnormal BMI (> or =25) was associated with an inadequate composite outcome score (P = .002). In multivariate logistic regression analyses, both BMI > or =25 (P = .04) and > or =30 (P = .006) were retained as independent predictors of inadequate bowel preparation. Each unit increase in BMI increased the likelihood of an inadequate composite outcome score by 2.1%. Additional independent predictors of inadequate preparation exponentially increased the likelihood of an inadequate composite outcome score; 7 additional risk factors identified 97.5% of overweight patients with an inadequate composite outcome score. CONCLUSIONS: Obesity is an independent predictor of inadequate bowel preparation at colonoscopy. The presence of additional risk factors further increases the likelihood of a poorly cleansed colon.
Assuntos
Neoplasias do Colo/diagnóstico , Colonoscopia , Obesidade , Cuidados Pré-Operatórios , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Sarcoidosis and primary biliary cirrhosis (PBC) are thought to be two distinct disorders of unknown origin. However, both are characterized by hepatic granuloma formation and may also manifest cutaneous granulomatous inflammation. In this report, we describe two cases of cutaneous sarcoidosis occurring in the setting of PBC and review 7 additional cases from the literature of granulomatous skin disease associated with PBC. Although the pathogenesis of both sarcoidosis and PBC remains elusive, the simultaneous occurrence of these uncommon diseases suggests a common pathway may contribute to granuloma formation in both disorders.
Assuntos
Cirrose Hepática Biliar/patologia , Sarcoidose/patologia , Dermatopatias/patologia , Feminino , Humanos , Cirrose Hepática Biliar/complicações , Pessoa de Meia-Idade , Sarcoidose/complicações , Dermatopatias/complicaçõesRESUMO
Recombinant hepatitis C virus (HCV)-like particles (HCV-LPs) containing HCV structural proteins (core, E1, and E2) produced in insect cells resemble the putative HCV virions and are capable of inducing strong and broad humoral and cellular immune responses in mice and baboons. Here, we present evidence on the immunogenicity and induction of protective immunity by HCV-LPs in chimpanzees. Chimpanzees (two in each group), were immunized with HCV-LPs or HCV-LPs plus AS01B adjuvant. After immunizations, all animals developed an HCV-specific immune response including IFN-gamma(+), IL-2(+), CD4(+), and CD8(+) T cell and proliferative lymphocyte responses against core, E1, and E2. Upon challenge with an infectious HCV inoculum, one chimpanzee developed transient viremia with low HCV RNA titers (10(3) to 10(4) copies per ml) in the third and fourth weeks after the challenge. The three other chimpanzees became infected with higher levels of viremia (10(4) to 10(5) copies per ml), but their viral levels became unquantifiable (<10(3) copies per ml) 10 weeks after the challenge. After the HCV challenge, all four chimpanzees demonstrated a significant increase in peripheral and intrahepatic T cell and proliferative responses against the HCV structural proteins. These T cell responses coincided with the fall in HCV RNA levels. Four naïve chimpanzees were infected with the same HCV inoculum, and three developed persistent infection with higher viremia in the range of 10(5) to 10(6) copies per ml. Our study suggests that HCV-LP immunization induces HCV-specific cellular immune responses that can control HCV challenge in the chimpanzee model.
Assuntos
Hepacivirus/imunologia , Hepatite C/prevenção & controle , Imunização , Pan troglodytes/imunologia , Adjuvantes Imunológicos , Animais , Formação de Anticorpos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Fígado/citologia , Fígado/imunologia , Fatores de Tempo , Vacinas/imunologia , Viremia/imunologiaRESUMO
Cytokine polymorphisms are associated with disease outcome and interferon (IFN) treatment response in hepatitis C virus (HCV) infection. We genotyped eight SNPs spanning the entire IFN-gamma gene in two cohorts and assessed the association between those polymorphisms and treatment response or spontaneous viral clearance. The first cohort was composed of 284 chronically HCV-infected patients who had received IFN-alpha-based therapy and the second was 251 i.v. drug users who had either spontaneously cleared HCV or become chronically infected. A SNP variant located in the proximal IFN-gamma promoter region next to the binding motif of heat shock transcription factor (HSF), -764G, was significantly associated with sustained virological response [P = 0.01, odds ratio (OR) = 2.66 [corrected] (confidence interval 1.3-5.6)[corrected]]. The association was independently significant in multiple logistic regression (P = 0.04) along with race, viral titer, and genotype. This variant was also significantly associated with spontaneous recovery [P = 0.04, OR = 3.51 (1.0-12.5)] in the second cohort. Functional analyses show that the G allele confers a two- to three-fold higher promoter activity and stronger binding affinity to HSF1 than the C allele. Our study suggests that the IFN-gamma promoter SNP -764G/C is functionally important in determining viral clearance and treatment response in HCV-infected patients and may be used as a genetic marker to predict sustained virological response in HCV-infected patients.