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1.
J Bone Miner Res ; 36(7): 1211-1219, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33949002

RESUMO

Erythropoietin (EPO) is the primary regulator of bone marrow erythropoiesis. Mouse models have provided evidence that EPO also promotes bone remodeling and that EPO-stimulated erythropoiesis is accompanied by bone loss independent of increased red blood cell production. EPO has been used clinically for three decades to treat anemia in end-stage renal disease, and notably, although the incidence of hip fractures decreased in the United States generally after 1990, it rose among hemodialysis patients coincident with the introduction and subsequent dose escalation of EPO treatment. Given this clinical paradox and findings from studies in mice that elevated EPO affects bone health, we examined EPO treatment as a risk factor for fractures in hemodialysis patients. Relationships between EPO treatment and hip fractures were analyzed using United States Renal Data System (USRDS) datasets from 1997 to 2013 and Consolidated Renal Operations in a Web-enabled Network (CROWNWeb) datasets for 2013. Fracture risks for patients treated with <50 units of EPO/kg/week were compared to those receiving higher doses by multivariable Cox regression. Hip fracture rates for 747,832 patients in USRDS datasets (1997-2013) increased from 12.0 per 1000 patient years in 1997 to 18.9 in 2004, then decreased to 13.1 by 2013. Concomitantly, average EPO doses increased from 11,900 units/week in 1997 to 18,300 in 2004, then decreased to 8,800 by 2013. During this time, adjusted hazard ratios for hip fractures with EPO doses of 50-149, 150-299, and ≥ 300 units/kg/week compared to <50 units/kg/week were 1.08 (95% confidence interval [CI], 1.01-1.15), 1.22 (95% CI, 1.14-1.31), and 1.41 (95% CI, 1.31-1.52), respectively. Multivariable analyses of 128,941 patients in CROWNWeb datasets (2013) replicated these findings. This study implicates EPO treatment as an independent risk factor for hip fractures in hemodialysis patients and supports the conclusion that EPO treatment may have contributed to changing trends in fracture incidence for these patients during recent decades. Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Anemia , Eritropoetina , Fraturas do Quadril , Falência Renal Crônica , Anemia/complicações , Anemia/tratamento farmacológico , Anemia/epidemiologia , Animais , Fraturas do Quadril/epidemiologia , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Camundongos , Diálise Renal , Estados Unidos/epidemiologia
3.
Antiviral Res ; 168: 61-67, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31125632

RESUMO

BACKGROUND: Fibrosis regression has been associated with nucleoside analogue (NA) treatment in chronic hepatitis B (CHB) patients. Although non-invasive fibrosis markers have been evaluated in CHB, their utility for monitoring on-treatment histologic regression has not been evaluated. AIMS: To characterize improvements in disease severity and the utility of non-invasive biomarkers in CHB NA treated patients. METHODS: Histology, labs, AST-to-platelet ratio index, and Fibrosis-4 (Fib-4) from treatment-naïve CHB patients were evaluated at baseline and longitudinally. Relative change from baseline to various time points during treatment were evaluated. Correlative analysis of APRI and Fib-4 with histology was performed longitudinally. RESULTS: 80 CHB patients (84% male, median age 45 (IQR 32, 54)) with histology up to 17 years (median 6(IQR 3.9, 8.0)) years were studied. Median baseline Ishak fibrosis was 3 (IQR 2, 4), histologic activity index (HAI) inflammation was 9 (IQR 7, 11), and AUROC of fibrosis markers for detecting cirrhosis (Ishak ≥ 5) was >0.64. HAI improved at a rate of 54% during year 1 and 37% in year 2, both greater than in the remaining follow-up periods. Within the first year, fibrosis improved by 35%, greater than all other time periods. Non-invasive biomarkers began to correlate with histology beyond 4 years (APRI: 4-6 years: r = 0.33, p = 0.03; ≥6 years: r = 0.41, p = 0.009; Fib-4: ≥6 years: r = 0.35, p = 0.03). CONCLUSION: Early dynamic changes in histology occur in CHB patients on NA followed by linear improvements. Non-invasive fibrosis biomarkers do not capture these dynamic changes and may demonstrate clinical utility beyond 4 years of treatment.


Assuntos
Hepatite B Crônica/sangue , Hepatite B Crônica/tratamento farmacológico , Cirrose Hepática/sangue , Cirrose Hepática/tratamento farmacológico , Nucleosídeos/uso terapêutico , Adulto , Biomarcadores/sangue , Biópsia , Feminino , Hepatite B Crônica/patologia , Humanos , Inflamação , Fígado/patologia , Cirrose Hepática/patologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores de Tempo
4.
Hepatology ; 68(6): 2078-2088, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29704252

RESUMO

Hepatitis C virus (HCV) infection induces interferon (IFN)-stimulated genes (ISGs) and downstream innate immune responses. This study investigated whether baseline and on-treatment differences in these responses predict response versus virological breakthrough during therapy with direct-acting antivirals (DAAs). Thirteen HCV genotype 1b-infected patients who had previously failed a course of pegylated IFN/ribavirin were retreated with asunaprevir/daclatasvir for 24 weeks. After pretreatment biopsy, patients were randomized to undergo a second biopsy at week 2 or 4 on therapy. Microarray and NanoString analyses were performed on paired liver biopsies and analyzed using linear mixed models. As biomarkers for peripheral IFN responses, peripheral blood natural killer cells were assessed for phosphorylated signal transducer and activator of transcription 1 (pSTAT1) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and degranulation. Nine of 13 (69%) patients achieved sustained virological response at 12 weeks off therapy (SVR12), and 4 experienced virological breakthroughs between weeks 4 and 12. Patients who achieved SVR12 displayed higher ISG expression levels in baseline liver biopsies and a higher frequency of pSTAT1 and TRAIL-expressing, degranulating natural killer cells in baseline blood samples than those who experienced virological breakthrough. Comparing gene expression levels from baseline and on-therapy biopsies, 408 genes (±1.2-fold, P < 0.01) were differentially expressed. Genes down-regulated on treatment were predominantly ISGs. Down-regulation of ISGs was rapid and correlated with HCV RNA suppression. Conclusion: An enhanced IFN signature is observed at baseline in liver and blood of patients who achieve SVR12 compared to those who experience a virological breakthrough; the findings suggest that innate immunity may contribute to clearance of HCV during DAA therapy by preventing the emergence of resistance-associated substitutions that lead to viral breakthrough during DAA therapy.


Assuntos
Antivirais/uso terapêutico , Expressão Gênica , Hepatite C/tratamento farmacológico , Imidazóis/uso terapêutico , Imunidade Inata , Isoquinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Estudos de Coortes , Quimioterapia Combinada , Feminino , Hepatite C/imunologia , Hepatite C/metabolismo , Humanos , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Resultado do Tratamento
5.
JCI Insight ; 3(8)2018 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-29669938

RESUMO

BACKGROUND: Sodium glucose cotransporter-2 (SGLT2) inhibitors are the most recently approved class of drugs for type 2 diabetes and provide both glycemic efficacy and cardiovascular risk reduction. A number of safety issues have been identified, including treatment-emergent bone fractures. To understand the overall clinical profile, these safety issues must be balanced against an attractive efficacy profile. Our study was designed to investigate pathophysiological mechanisms mediating treatment-emergent adverse effects on bone health. METHODS: We conducted a single-blind randomized crossover study in hospitalized healthy adults (n = 25) receiving either canagliflozin (300 mg/d) or placebo for 5 days. The primary end-point was the drug-induced change in AUC for plasma intact fibroblast growth factor 23 (FGF23) immunoactivity between 24 and 72 hours. RESULTS: Canagliflozin administration increased placebo-subtracted mean levels of serum phosphorus (+16%), plasma FGF23 (+20%), and plasma parathyroid hormone (PTH) (+25%), while decreasing the level of 1,25-dihydroxyvitamin D (-10%). There was substantial interindividual variation in the magnitude of each of these pharmacodynamic responses. The increase in plasma FGF23 was correlated with the increase in serum phosphorus, and the decrease in plasma 1,25-dihydroxyvitamin D was correlated with the increase in plasma FGF23. CONCLUSIONS: Canagliflozin induced a prompt increase in serum phosphorus, which triggers downstream changes in FGF23, 1,25-dihydroxyvitamin D, and PTH, with potential to exert adverse effects on bone health. These pharmacodynamic data provide a foundation for future research to elucidate pathophysiological mechanisms of adverse effects on bone health, with the objective of devising therapeutic strategies to mitigate the drug-associated fracture risk. TRIAL REGISTRATION: ClinicalTrial.gov (NCT02404870). FUNDING: Supported by the Intramural Program of NIDDK.


Assuntos
Canagliflozina/efeitos adversos , Fatores de Crescimento de Fibroblastos/sangue , Fraturas Ósseas/induzido quimicamente , Adulto , Canagliflozina/administração & dosagem , Canagliflozina/farmacologia , Estudos Cross-Over , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Fatores de Crescimento de Fibroblastos/efeitos dos fármacos , Fraturas Ósseas/fisiopatologia , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fósforo/sangue , Placebos/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Vitamina D/análogos & derivados , Vitamina D/sangue
6.
Clin Gastroenterol Hepatol ; 14(6): 896-902, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26820399

RESUMO

BACKGROUND & AIMS: Hepatitis E (HEV) can cause acute-on-chronic liver failure in persons with pre-existing liver disease. We investigated whether HEV infection contributes to hepatic decompensation in patients with previously stable, advanced chronic hepatitis C. METHODS: We performed a case-control study using stored serum samples from subjects enrolled in the randomized phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial (n = 1050; mean age, 51 y; 70% male; 40% with cirrhosis at baseline). Cases were subjects who developed hepatic decompensation within a 24-week period. Controls (3 per case) were subjects without hepatic decompensation matched for fibrosis stage and followed up for a similar period. A serum sample obtained within 6 months after the decompensation event in cases and the same follow-up period in controls were tested for anti-HEV IgG. Subjects with a positive result had a baseline sample similarly tested for anti-HEV IgG. We measured levels of anti-HEV IgM and HEV RNA in blood samples from incident cases. RESULTS: Of the 1050 subjects analyzed, 314 (30%) experienced a clinical event. Of the 314 subjects who experienced decompensation as defined, 89 (28%) were tested for anti-HEV, along with 267 controls (without decompensation). Similar proportions of cases and controls tested positive for anti-HEV (22.5% and 20.6%, respectively; P = .70). Ten incident HEV infections were identified-4 in cases (4.5%) and 6 in controls (2.2%) (P = .28). HEV RNA was not detected in blood samples from the 10 incident infections. Only 2 of the 4 incident infections among cases were related temporally to the decompensation event. CONCLUSIONS: HEV does not appear to be a significant cause of hepatic decompensation among persons with previously stable, advanced chronic hepatitis C in the United States.


Assuntos
Insuficiência Hepática Crônica Agudizada/epidemiologia , Hepatite C Crônica/complicações , Hepatite E/complicações , Adulto , Estudos de Casos e Controles , Feminino , Anticorpos Anti-Hepatite/sangue , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Estados Unidos
8.
J Clin Sleep Med ; 12(2): 203-13, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26414978

RESUMO

STUDY OBJECTIVES: To identify cross-sectional and seasonal patterns of sleep and physical activity (PA) in community-dwelling, older Icelandic adults using accelerometers. METHODS: A seven-day free-living protocol of 244 (110 female) adults aged 79.7 ± 4.9 years was conducted as part of a larger population-based longitudinal observational-cohort study in the greater Reykjavik area of Iceland. A subpopulation (n = 72) repeated the 7-day measurement during seasonal periods with greater (13.4 ± 1.4 h) and lesser (7.7 ± 1.8 h) daylight. RESULTS: Cross-sectional analyses using multiple linear regression models revealed that day length was a significant independent predictor of sleep duration, mid-sleep, and rise time (all p < 0.05). However, the actual within-individual differences in sleep patterns of the repeaters were rather subtle between periods of longer and shorter day-lengths. Compared to women, men had a shorter sleep duration (462 ± 80 vs. 487 ± 68 minutes, p = 0.008), earlier rise time, and a greater number of awakenings per night (46.5 ± 18.3 vs. 40.2 ± 15.7, p = 0.007), but sleep efficiency and onset latency were similar between the two sexes. Daily PA was also similar between men and women and between periods of longer and shorter day-lengths. BMI, age, gender, and overall PA all contributed to the variations in sleep parameters using multiple regression analysis. CONCLUSIONS: The sleep and PA characteristics of this unique population revealed some gender differences, but there was limited variation in response to significant daylight changes which may be due to long-term adaptation.


Assuntos
Exercício Físico/fisiologia , Fotoperíodo , Sono/fisiologia , Actigrafia , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Islândia , Masculino , Estações do Ano , Fatores Sexuais , Fatores de Tempo
9.
Clin J Am Soc Nephrol ; 10(10): 1822-30, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-26358266

RESUMO

BACKGROUND AND OBJECTIVES: Recombinant human erythropoietin (epoetin) is used routinely to increase blood hemoglobin levels in patients with ESRD and anemia. Although lower doses of epoetin are required to achieve equivalent hemoglobin responses when administered subcutaneously rather than intravenously, standard practice has been to administer epoetin to patients on hemodialysis intravenously. Randomized trials of alternative epoetin treatment regimens in patients with kidney failure have shown that risks of cardiovascular complications and death are related to the dose levels of epoetin used. Therefore, given the dose-sparing advantages of subcutaneous epoetin administration, the possibility that treatment of patients on hemodialysis with subcutaneous epoetin might be associated with more favorable outcomes compared with intravenous treatment was investigated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A retrospective cohort study of 62,710 adult patients on hemodialysis treated with either intravenous or subcutaneous epoetin-α and enrolled in the Centers for Medicare and Medicaid Services ESRD Clinical Performance Measures Project from 1997 to 2005 was carried out. Risks of death and/or hospitalization for cardiovascular complications (adverse composite event outcomes) during 2 years of follow-up were determined in relationship to epoetin dose and route of administration (intravenous versus subcutaneous) by multivariate Cox proportional hazard modeling adjusted for demographics and clinical parameters. RESULTS: Epoetin doses used to achieve equivalent hemoglobin responses in study patients were, on average, 25% higher when epoetin was administered intravenously rather than subcutaneously (as expected). Moreover, adverse composite event outcomes were found to be significantly more likely to occur during follow-up for patients on hemodialysis managed with intravenous rather than subcutaneous epoetin (adjusted hazard ratio for adverse events within 1 year [intravenous versus subcutaneous] was 1.11 [95% confidence interval, 1.04 to 1.18]). CONCLUSIONS: This study finds that treatment of patients on hemodialysis with subcutaneous epoetin is associated with more favorable clinical outcomes than those associated with intravenous epoetin treatment.


Assuntos
Anemia/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Epoetina alfa/administração & dosagem , Hematínicos/administração & dosagem , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Administração Intravenosa , Idoso , Anemia/sangue , Doenças Cardiovasculares/etiologia , Epoetina alfa/efeitos adversos , Feminino , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/etiologia , Hematínicos/efeitos adversos , Hemoglobinas/metabolismo , Hospitalização/estatística & dados numéricos , Humanos , Injeções Subcutâneas , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Diálise Renal , Estudos Retrospectivos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Estados Unidos/epidemiologia
10.
Am J Hematol ; 89(9): 904-6, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24891147

RESUMO

Prior analyses of the Cooperative Study of Sickle Cell Disease (CSSCD) newborn cohort identified elevated white blood cell (WBC) count, low baseline hemoglobin and dactylitis between the ages of 1 and 2 years as markers of severe disease. Reticulocytosis was also associated with severe disease. Here, we further analyzed data collected on enrolled CSSCD infants for the predictive value of those markers for stroke and death later in life. Three hundred fifty-four CSSCD subjects were identified who had absolute reticulocyte counts (ARC) measured during infancy (2 to 6 months of age). Infants with higher ARC had significantly increased risk of stroke or death during childhood; lower hemoglobin levels also increased the risk but to a lesser degree than ARC. WBC levels and dactylitis were not predictive of death or stroke. These data suggest that reticulocytosis among asymptomatic infants with sickle cell anemia is associated with an increased risk of death or stroke during childhood.


Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/mortalidade , Reticulócitos , Reticulocitose , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/mortalidade , Anemia Falciforme/complicações , Pré-Escolar , Feminino , Hemoglobinas/análise , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Masculino , Valor Preditivo dos Testes , Contagem de Reticulócitos , Reticulócitos/citologia , Risco , Acidente Vascular Cerebral/etiologia
11.
Trials ; 15: 159, 2014 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-24886378

RESUMO

BACKGROUND: The timely publication of findings in peer-reviewed journals is a primary goal of clinical research. In clinical trials, the processes leading to publication can be complex from choice and prioritization of analytic topics through to journal submission and revisions. As little literature exists on the publication process for multicenter trials, we describe the development, implementation, and effectiveness of such a process in a multicenter trial. METHODS: The Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial included a data coordinating center (DCC) and clinical centers that recruited and followed more than 1,000 patients. Publication guidelines were approved by the steering committee, and the publications committee monitored the publication process from selection of topics to publication. RESULTS: A total of 73 manuscripts were published in 23 peer-reviewed journals. When manuscripts were closely tracked, the median time for analyses and drafting of manuscripts was 8 months. The median time for data analyses was 5 months and the median time for manuscript drafting was 3 months. The median time for publications committee review, submission, and journal acceptance was 7 months, and the median time from analytic start to journal acceptance was 18 months. CONCLUSIONS: Effective publication guidelines must be comprehensive, implemented early in a trial, and require active management by study investigators. Successful collaboration, such as in the HALT-C trial, can serve as a model for others involved in multidisciplinary and multicenter research programs. TRIAL REGISTRATION: The HALT-C Trial was registered with clinicaltrials.gov (NCT00006164).


Assuntos
Comitês de Monitoramento de Dados de Ensaios Clínicos/normas , Interpretação Estatística de Dados , Fidelidade a Diretrizes/normas , Guias como Assunto/normas , Manuscritos Médicos como Assunto , Publicações Periódicas como Assunto/normas , Projetos de Pesquisa/normas , Antivirais/uso terapêutico , Quimioterapia Combinada , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Humanos , Disseminação de Informação , Interferon-alfa/uso terapêutico , Revisão da Pesquisa por Pares/normas , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Projetos de Pesquisa/estatística & dados numéricos , Ribavirina/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
13.
PLoS One ; 8(8): e70794, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23951011

RESUMO

OBJECTIVE: Among older children with sickle cell anemia, leukocyte counts, hemoglobin, and reticulocytosis have previously been suggested as disease severity markers. Here we explored whether these blood parameters may be useful to predict early childhood disease severity when tested in early infancy, defined as postnatal ages 60-180 days. STUDY DESIGN: Data from fifty-nine subjects who were followed at Children's National Medical Center's Sickle Cell Program for at least three years was retrospectively analyzed. Comparisons were made between white blood cell counts, hemoglobin and reticulocyte levels measured at ages 60-180 days and the clinical course of sickle cell anemia during infancy and childhood. RESULTS: A majority of subjects had demonstrable anemia with increased reticulocytosis. Only increased absolute reticulocyte levels during early infancy were associated with a significant increase in hospitalization during the first three years of life. Higher absolute reticulocyte counts were also associated with a markedly shorter time to first hospitalizations and a four-fold higher cumulative frequency of clinical manifestations over the first three years of life. No significant increase in white blood cell counts was identified among the infant subjects. CONCLUSIONS: These data suggest that during early infancy, increased reticulocytosis among asymptomatic SCA subjects is associated with increased severity of disease in childhood.


Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/complicações , Hospitalização/estatística & dados numéricos , Reticulocitose , Anemia Falciforme/patologia , Pré-Escolar , Hemoglobinas/metabolismo , Humanos , Lactente , Contagem de Leucócitos , Modelos Logísticos , Modelos de Riscos Proporcionais , Reticulócitos/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença
14.
Hepatology ; 58(5): 1548-57, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23703931

RESUMO

UNLABELLED: Interleukin (IL)28B polymorphisms are associated with spontaneous clearance of hepatitis C virus (HCV) infection and response to therapy. Whether IL28B genotype affects fibrosis progression or clinical outcome is unclear. Our aim was to study the relationship between IL28B genotype and both histological and clinical outcomes in patients with chronic hepatitis C (CHC). Hepatic fibrosis was scored using the Ishak (0-6) scale; progression was defined as a 2-point increase in Ishak score between biopsies. Multiple logistic and Cox regressions were used to identify variables associated with fibrosis progression. In all, 1,483 patients were included in a baseline cross-sectional analysis, from which 276 were eligible for a paired biopsy analysis (median time between biopsies 4 years), and 400 for a clinical outcome analysis. At baseline biopsy, patients with IL28B CC genotype had significantly higher portal inflammation (2.4 versus 2.2) and alanine aminotransferase (ALT) levels (133 versus 105 U/L; P < 0.05 for all). In the paired biopsy analysis, there was no difference in the frequency of fibrosis progression between patients with IL28B CC and non-CC genotypes (17% versus 23%). In logistic regression, only higher baseline alkaline phosphatase, lower platelets, and greater hepatic steatosis were associated with fibrosis progression. Patients with IL28B CC were twice as likely to develop adverse clinical outcomes compared to non-CC (32% versus 16%; P = 0.007). CONCLUSION: IL28B CC genotype was associated with greater hepatic necroinflammation, higher ALT, and worse clinical outcomes in CHC patients. This suggests that IL28B CC is associated with a state of enhanced immunity that, on the one hand, can promote viral clearance, but alternately can increase necroinflammation and hepatic decompensation without enhancing fibrosis progression.


Assuntos
Hepatite C Crônica/genética , Interleucinas/genética , Cirrose Hepática/etiologia , Polimorfismo de Nucleotídeo Único , Adulto , Alanina Transaminase/sangue , Estudos Transversais , Progressão da Doença , Feminino , Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/patologia , Humanos , Interferons , Cirrose Hepática/genética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade
15.
Hepatology ; 57(5): 1725-33, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23258530

RESUMO

UNLABELLED: Increased γ-glutamyl transferase (GGT) activity is associated with liver injury and with mortality in the general population. Less is known about its association with chronic hepatitis C (HCV) outcomes. We examined GGT as a predictor of both virological response to treatment and long-term clinical outcomes in the Hepatitis C Anti-viral Treatment Against Cirrhosis Trial (HALT-C). HALT-C enrolled patients with advanced liver disease (Ishak fibrosis score ≥3) in two phases: a lead-in to establish lack of sustained viral response with full dose pegylated interferon (IFN) and ribavirin followed by a 3.5-year randomized trial with low-dose IFN. Low-dose IFN did not prevent liver disease progression, and patients were then followed for up to an additional 5 years off therapy. Analyses were performed for 1,319 patients who had GGT measured prior to initiation of treatment. Increases in risk with each increase in quintile of GGT (10-57, 58-89, 90-139, 140-230, 231-2,000 IU/L) were determined by logistic regression for treatment response or Cox regression for clinical outcomes. Baseline GGT was associated with male sex, nonwhite ethnicity, diabetes and insulin resistance, interleukin (IL)28B rs12979860 CT and TT genotypes, and numerous markers of liver disease injury and severity. In the lead-in phase, increasing GGT was strongly associated with diminished week 20 response, end of treatment response, and sustained virological response in both univariate and multivariate analyses controlling for factors known to be associated with treatment response (P < 0.0001). GGT was also associated with all clinical outcomes in univariate and multivariate analysis (P < 0.05) except for hepatocellular carcinoma (P = 0.46 in multivariate analysis). CONCLUSION: GGT is an independent predictor of both virological response and clinical outcomes among patients with advanced liver disease due to HCV.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/sangue , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , gama-Glutamiltransferase/sangue , Adulto , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Hepatite C Crônica/diagnóstico , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento
16.
Am J Gastroenterol ; 107(9): 1388-98, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22688849

RESUMO

OBJECTIVES: During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 previous interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation. METHODS: Relationships between change in hepatic inflammation (Ishak hepatic activity index, (HAI)) and serum alanine aminotransferase level, fibrosis progression and clinical outcomes after randomization, and hepatitis C virus (HCV) RNA decline before and after randomization were evaluated. Histological change was defined as a ≥ 2-point difference in HAI or Ishak fibrosis score between biopsies. RESULTS: Among 657 patients who received full-dose peginterferon/ribavirin "lead-in" therapy before randomization, year-1.5 HAI improvement was associated with lead-in HCV RNA suppression in both the randomized treated (P<0.0001) and control (P=0.0001) groups, even in the presence of recurrent viremia. This relationship persisted at year 3.5 in both the treated (P=0.001) and control (P=0.01) groups. Among 834 patients followed for a median of 6 years, fewer clinical outcomes occurred in patients with improved HAI at year 1.5 compared with those without such improvement in both the treated (P=0.03) and control (P=0.05) groups. Among patients with Ishak 3-4 fibrosis at baseline, those with improved HAI at year 1.5 had less fibrosis progression at year 1.5 in both the treated (P=0.0003) and control (P=0.02) groups. CONCLUSIONS: Reduced hepatic inflammation (measured 1.5 and 3.5 years after randomization) was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized treatment.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Cirrose Hepática/patologia , Fígado/patologia , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Idoso , Biópsia , Progressão da Doença , Quimioterapia Combinada , Feminino , Seguimentos , Hepatite C Crônica/patologia , Humanos , Estimativa de Kaplan-Meier , Fígado/virologia , Cirrose Hepática/virologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento
17.
Blood ; 119(24): 5671-3, 2012 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-22547579

RESUMO

Peripheral blood stem cell (PBSC) infusions are associated with complications such as elevated blood pressure and decreased creatinine clearance. Patients with sickle cell disease experience similar manifestations, and some have postulated release of plasma-free hemoglobin with subsequent nitric oxide consumption as causative. We sought to evaluate whether the infusion of PBSC grafts containing lysed red blood cells (RBCs) leads to the toxicity observed in transplant subjects. We report a prospective cohort study of 60 subjects divided into 4 groups based on whether their infusions contained dimethyl sulfoxide (DMSO) and lysed RBCs, no DMSO and fresh RBCs, DMSO and no RBCs, or saline. Our primary end point, change in maximum blood pressure compared with baseline, was not significantly different among groups. Tricuspid regurgitant velocity and creatinine levels also did not differ significantly among groups. Our data do not support free hemoglobin as a significant contributor to toxicity associated with PBSC infusions. This study was registered at clinicaltrials.gov (NCT00631787).


Assuntos
Anemia Falciforme/fisiopatologia , Anemia Falciforme/terapia , Eritrócitos/fisiologia , Hemólise/fisiologia , Transplante de Células-Tronco de Sangue Periférico , Pressão Sanguínea/fisiologia , Haptoglobinas/metabolismo , Frequência Cardíaca/fisiologia , Humanos , Infusões Intravenosas , L-Lactato Desidrogenase/metabolismo
18.
Am J Gastroenterol ; 107(1): 64-74, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21931376

RESUMO

OBJECTIVES: Prospective studies of serum hepatocellular carcinoma (HCC) biomarkers in patients with advanced hepatitis C are lacking. The aim of this study was to determine the frequencies and performance of elevated α-fetoprotein (AFP), AFP-L3, and des-γ-carboxy prothrombin (DCP) levels as HCC biomarkers in advanced hepatitis C. METHODS: Patients in the HALT-C Trial were tested every 3 months for 42 months. Screening ultrasound was performed every 12 months. Levels of biomarkers were compared in patients in whom HCC did or did not develop. RESULTS: In all, 855 patients were evaluated; HCC developed in 46. Among patients without HCC, 73.2% had AFP consistently <20, 24.5% had at least one AFP between 20 and 199, and 2.3% had at least one AFP value ≥200 ng/ml; 73.7% had DCP consistently <90, 11.6% had at least one DCP between 90 and 149, and 14.7% had at least one DCP value ≥150 mAU/ml. AFP-L3 ≥10% was present at least once in 9.0% and in 17.1% of those with AFP ≥20 ng/ml. Among all patients with elevated biomarkers, a diagnosis of HCC was made in 0-31.6% (depending on the biomarker and cutoff) during the subsequent 24 months. AFP ≥200 ng/ml had the highest specificity (99%), but sensitivity was ≤20%. DCP ≥40 mAU/ml had the highest sensitivity (76%), but specificity was ≤58%. Independent predictors of elevated AFP were gender (female), race (Black), more advanced disease, and HCC. Elevated DCP was associated with more advanced disease and HCC. CONCLUSIONS: Mild-moderate elevations in total AFP and DCP but not in AFP-L3 occur frequently in patients with chronic hepatitis C and advanced fibrosis, are related to factors other than HCC, and are poor predictors of HCC.


Assuntos
Biomarcadores/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/complicações , Hepatite C/complicações , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/complicações , Precursores de Proteínas/sangue , alfa-Fetoproteínas/análise , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Isoformas de Proteínas/sangue , Protrombina
19.
Hepatology ; 55(4): 1019-29, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22030902

RESUMO

UNLABELLED: Risk for future clinical outcomes is proportional to the severity of liver disease in patients with chronic hepatitis C virus (HCV). We measured disease severity by quantitative liver function tests (QLFTs) to determine cutoffs for QLFTs that identified patients who were at low and high risk for a clinical outcome. Two hundred and twenty-seven participants in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial underwent baseline QLFTs and were followed for a median of 5.5 years for clinical outcomes. QLFTs were repeated in 196 patients at month 24 and in 165 patients at month 48. Caffeine elimination rate (k(elim)), antipyrine (AP) clearance (Cl), MEGX concentration, methionine breath test (MBT), galactose elimination capacity (GEC), dual cholate (CA) clearances and shunt, perfused hepatic mass (PHM), and liver and spleen volumes (by single-photon emission computed tomography) were measured. Baseline QLFTs were significantly worse (P = 0.0017 to P < 0.0001) and spleen volumes were larger (P < 0.0001) in the 54 patients who subsequently experienced clinical outcomes. QLFT cutoffs that characterized patients as "low" and "high risk" for clinical outcome yielded hazard ratios ranging from 2.21 (95% confidence interval [CI]: 1.29-3.78) for GEC to 6.52 (95% CI: 3.63-11.71) for CA clearance after oral administration (Cl(oral)). QLFTs independently predicted outcome in models with Ishak fibrosis score, platelet count, and standard laboratory tests. In serial studies, patients with high-risk results for CA Cl(oral) or PHM had a nearly 15-fold increase in risk for clinical outcome. Less than 5% of patients with "low risk" QLFTs experienced a clinical outcome. CONCLUSION: QLFTs independently predict risk for future clinical outcomes. By improving risk assessment, QLFTs could enhance the noninvasive monitoring, counseling, and management of patients with chronic HCV.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/epidemiologia , Cirrose Hepática/fisiopatologia , Fígado/fisiopatologia , Índice de Gravidade de Doença , Quimioterapia Combinada , Hepatite C Crônica/fisiopatologia , Humanos , Interferon-alfa/uso terapêutico , Testes de Função Hepática , Estudos Longitudinais , Polietilenoglicóis/uso terapêutico , Valor Preditivo dos Testes , Estudos Prospectivos , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Ribavirina/uso terapêutico , Medição de Risco , Resultado do Tratamento
20.
Clin Chem ; 58(2): 391-401, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22166253

RESUMO

BACKGROUND: Standardized calibration does not change a creatinine measurement procedure's susceptibility to potentially interfering substances. METHODS: We obtained individual residual serum or plasma samples (n = 365) from patients with 19 different disease categories associated with potentially interfering substances and from healthy controls. Additional sera at 0.9 mg/dL (80 µmol/L) and 3.8 mg/dL (336 µmol/L) creatinine were supplemented with acetoacetate, acetone, ascorbate, and pyruvate. We measured samples by 4 enzymatic and 3 Jaffe commercially available procedures and by a liquid chromatography/isotope dilution/mass spectrometry measurement procedure against which biases were determined. RESULTS: The number of instances when 3 or more results in a disease category had biases greater than the limits of acceptability was 28 of 57 (49%) for Jaffe and 14 of 76 (18%) for enzymatic procedures. For the aggregate group of 59 diabetes samples with increased ß-hydroxybutyrate, glucose, or glycosylated hemoglobin (Hb A(1c)), the enzymatic procedures had 10 biased results of 236 (4.2%) compared with 89 of 177 (50.3%) for the Jaffe procedures, and these interferences were highly procedure dependent. For supplemented sera, interferences were observed in 11 of 24 (46%) of groups for Jaffe and 8 of 32 (25%) of groups for enzymatic procedures and were different at low or high creatinine concentrations. CONCLUSIONS: There were differences in both magnitude and direction of bias among measurement procedures, whether enzymatic or Jaffe. The influence of interfering substances was less frequent with the enzymatic procedures, but no procedure was unaffected. The details of implementation of a method principle influenced its susceptibility to potential interfering substances.


Assuntos
Creatinina/sangue , Biomarcadores/sangue , Calibragem , Doenças Cardiovasculares/sangue , Estudos de Casos e Controles , Diabetes Mellitus/sangue , Humanos , Nefropatias/sangue , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade
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