Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 15 de 15
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
NPJ Precis Oncol ; 8(1): 120, 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38796637

RESUMO

A small number of cancer patients respond exceptionally well to therapies and survive significantly longer than patients with similar diagnoses. Profiling the germline genetic backgrounds of exceptional responder (ER) patients, with extreme survival times, can yield insights into the germline polymorphisms that influence response to therapy. As ERs showed a high incidence in autoimmune diseases, we hypothesized the differences in autoimmune disease risk could reflect the immune background of ERs and contribute to better cancer treatment responses. We analyzed the germline variants of 51 ERs using polygenic risk score (PRS) analysis. Compared to typical cancer patients, the ERs had significantly elevated PRSs for several autoimmune-related diseases: type 1 diabetes, hypothyroidism, and psoriasis. This indicates that an increased genetic predisposition towards these autoimmune diseases is more prevalent among the ERs. In contrast, ERs had significantly lower PRSs for developing inflammatory bowel disease. The left-skew of type 1 diabetes score was significant for exceptional responders. Variants on genes involved in the T1D PRS model associated with cancer drug response are more likely to co-occur with other variants among ERs. In conclusion, ERs exhibited different risks for autoimmune diseases compared to typical cancer patients, which suggests that changes in a patient's immune set point or immune surveillance specificity could be a potential mechanistic link to their exceptional response. These findings expand upon previous research on immune checkpoint inhibitor-treated patients to include those who received chemotherapy or radiotherapy.

3.
Pharmacogenomics ; 18(13): 1199-1213, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28745549

RESUMO

AIM: To determine parents' use of their children's CYP2D6 research result. We hypothesized that perceived utility, likelihood of sharing and actual sharing of results would differ between parents with children previously exposed (cases) or unexposed (controls) to opioids. METHODS: We returned results by phone (baseline). We surveyed parents about perceived utility and likelihood of sharing their child's research result at baseline, and actual sharing at 3 and 12 months. RESULTS: Cases were more likely than controls to agree that they (p = 0.022) and the doctors (p = 0.041) could use the results to care for their child, to report higher likelihood of sharing (p = 0.042) and to actually share results with the child's doctor (p = 0.026). CONCLUSION: Prior opioid exposure influenced perceived clinical utility and sharing behaviors.


Assuntos
Analgésicos Opioides/efeitos adversos , Citocromo P-450 CYP2D6/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pais , Percepção/fisiologia , Inquéritos e Questionários
4.
Health Commun ; 32(9): 1104-1111, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-27573590

RESUMO

Concerns about the ethical and social implications of genetics persist as more applications of genetic and genomic technology have become available. Pediatric testing for genetic influences on response to opioids like codeine is one area of application. We interviewed parents of children enrolled in a mixed-methods study following the communication of actual or hypothetical results for CYP2D6, which impacts opioid response. Forty-one parents of children naive to opioids and 42 parents of children previously exposed to opioids participated in qualitative interviews. Findings did not differ by the child's opioid exposure or by actual versus hypothetical results. Parents' responses centered on the experience of the parent(s) and the potential impact of that information on the parent, rather than the result's impact on the child. Parents also emphasized that the results did not impact their perceptions of the child, reaffirming that the child was still "normal" regardless of test result. When asked about the impact of receiving secondary results, parents' responses emphasized how the results would impact their ability to advocate for the child or impact their state of mind. While the answers reflect parents' role as surrogate decision maker for their child, they also reinforced concerns that health care decisions might be influenced by secondary parental concerns as much as by the best interests of the child. Emphasis on the child's "normality" challenges concerns about the impact of genetic essentialism, but further research is required to see whether the type of testing done or the way results were communicated shaped this response.


Assuntos
Comunicação , Citocromo P-450 CYP2D6/genética , Pais/psicologia , Pediatria , Testes Farmacogenômicos/estatística & dados numéricos , Pesquisa Biomédica , Criança , Feminino , Humanos , Masculino , Relações Profissional-Família
5.
PLoS One ; 11(7): e0159621, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27472449

RESUMO

OBJECTIVE: Cohort selection is challenging for large-scale electronic health record (EHR) analyses, as International Classification of Diseases 9th edition (ICD-9) diagnostic codes are notoriously unreliable disease predictors. Our objective was to develop, evaluate, and validate an automated algorithm for determining an Autism Spectrum Disorder (ASD) patient cohort from EHR. We demonstrate its utility via the largest investigation to date of the co-occurrence patterns of medical comorbidities in ASD. METHODS: We extracted ICD-9 codes and concepts derived from the clinical notes. A gold standard patient set was labeled by clinicians at Boston Children's Hospital (BCH) (N = 150) and Cincinnati Children's Hospital and Medical Center (CCHMC) (N = 152). Two algorithms were created: (1) rule-based implementing the ASD criteria from Diagnostic and Statistical Manual of Mental Diseases 4th edition, (2) predictive classifier. The positive predictive values (PPV) achieved by these algorithms were compared to an ICD-9 code baseline. We clustered the patients based on grouped ICD-9 codes and evaluated subgroups. RESULTS: The rule-based algorithm produced the best PPV: (a) BCH: 0.885 vs. 0.273 (baseline); (b) CCHMC: 0.840 vs. 0.645 (baseline); (c) combined: 0.864 vs. 0.460 (baseline). A validation at Children's Hospital of Philadelphia yielded 0.848 (PPV). Clustering analyses of comorbidities on the three-site large cohort (N = 20,658 ASD patients) identified psychiatric, developmental, and seizure disorder clusters. CONCLUSIONS: In a large cross-institutional cohort, co-occurrence patterns of comorbidities in ASDs provide further hypothetical evidence for distinct courses in ASD. The proposed automated algorithms for cohort selection open avenues for other large-scale EHR studies and individualized treatment of ASD.


Assuntos
Algoritmos , Transtorno do Espectro Autista/diagnóstico , Registros Eletrônicos de Saúde , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino
6.
Clin Pediatr (Phila) ; 55(12): 1152-9, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26676994

RESUMO

Identification of obesity at well-child care (WCC) examinations is a step toward intervention. Studies have shown suboptimal documentation in primary care clinics that can improve with the use of electronic health records (EHRs). This study investigated the impact of a standardized EHR template on documentation of obesity at WCC visits and its impact on physician behavior. A cohort of 585 children with severe early onset obesity (body mass index >99th percentile, age <6 years) was identified with an electronic algorithm. Complete records of visit notes were reviewed to extract history taking, counseling, and recording of obesity at a WCC visit. Use of a standardized EHR template for WCC visits is associated with improvement in rates of documentation of obesity (47% vs 34%, P < .01), without interruption of workflow. Documentation of obesity in the chart improved nutritional (66% vs 44%, P < .001) and physical activity counseling (23% vs 9%, P < .001).


Assuntos
Documentação/métodos , Registros Eletrônicos de Saúde/estatística & dados numéricos , Obesidade Infantil/diagnóstico , Obesidade Infantil/terapia , Atenção Primária à Saúde/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Aconselhamento/estatística & dados numéricos , Documentação/estatística & dados numéricos , Feminino , Humanos , Masculino , Padrões de Prática Médica/estatística & dados numéricos , Adulto Jovem
7.
PLoS One ; 10(9): e0138677, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26413716

RESUMO

INTRODUCTION: Liver enzyme levels and total serum bilirubin are under genetic control and in recent years genome-wide population-based association studies have identified different susceptibility loci for these traits. We conducted a genome-wide association study in European ancestry participants from the Electronic Medical Records and Genomics (eMERGE) Network dataset of patient medical records with available genotyping data in order to identify genetic contributors to variability in serum bilirubin levels and other liver function tests and to compare the effects between adult and pediatric populations. METHODS: The process of whole genome imputation of eMERGE samples with standard quality control measures have been described previously. After removing missing data and outliers based on principal components (PC) analyses, 3294 samples from European ancestry were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and total serum bilirubin and other liver function tests was tested using linear regression, adjusting for age, gender, site, platform and ancestry principal components (PC). RESULTS: Consistent with previous results, a strong association signal has been detected for UGT1A gene cluster (best SNP rs887829, beta = 0.15, p = 1.30x10-118) for total serum bilirubin level. Indeed, in this region more than 176 SNPs (or indels) had p<10-8 spanning 150Kb on the long arm of chromosome 2q37.1. In addition, we found a similar level of magnitude in a pediatric group (p = 8.26x10-47, beta = 0.17). Further imputation using sequencing data as a reference panel revealed association of other markers including known TA7 repeat indels (rs8175347) (p = 9.78x10-117) and rs111741722 (p = 5.41x10-119) which were in proxy (r2 = 0.99) with rs887829. Among rare variants, two Asian subjects homozygous for coding SNP rs4148323 (G71R) were identified. Additional known effects for total serum bilirubin were also confirmed including organic anion transporters SLCO1B1-SLCO1B3, TDRP and ZMYND8 at FDR<0.05 with no gene-gene interaction effects. Phenome-wide association studies (PheWAS) suggest a protective effect of TA7 repeat against cerebrovascular disease in an adult cohort (OR = 0.75, p = 0.0008). Among other liver function tests, we also confirmed the previous effect of the ABO blood group locus for variation in serum alkaline phosphatase (rs579459, p = 9.44x10-15). CONCLUSIONS: Taken together, our data present interesting findings with strong confirmation of previous effects by simply using the eMERGE electronic health record phenotyping. In addition, our findings indicate that similar to the adult population, the UGT1A1 is the main locus responsible for normal variation of serum bilirubin in pediatric populations.


Assuntos
Registros Eletrônicos de Saúde , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Genômica , Testes de Função Hepática , Adulto , Fosfatase Alcalina/sangue , Bilirrubina/sangue , Estudos de Casos e Controles , Criança , Estudos de Coortes , Demografia , Feminino , Glucuronosiltransferase/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , População Branca/genética
8.
Front Genet ; 5: 401, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25477900

RESUMO

OBJECTIVE: We report the first pediatric specific Phenome-Wide Association Study (PheWAS) using electronic medical records (EMRs). Given the early success of PheWAS in adult populations, we investigated the feasibility of this approach in pediatric cohorts in which associations between a previously known genetic variant and a wide range of clinical or physiological traits were evaluated. Although computationally intensive, this approach has potential to reveal disease mechanistic relationships between a variant and a network of phenotypes. METHOD: Data on 5049 samples of European ancestry were obtained from the EMRs of two large academic centers in five different genotyped cohorts. Recently, these samples have undergone whole genome imputation. After standard quality controls, removing missing data and outliers based on principal components analyses (PCA), 4268 samples were used for the PheWAS study. We scanned for associations between 2476 single-nucleotide polymorphisms (SNP) with available genotyping data from previously published GWAS studies and 539 EMR-derived phenotypes. The false discovery rate was calculated and, for any new PheWAS findings, a permutation approach (with up to 1,000,000 trials) was implemented. RESULTS: This PheWAS found a variety of common variants (MAF > 10%) with prior GWAS associations in our pediatric cohorts including Juvenile Rheumatoid Arthritis (JRA), Asthma, Autism and Pervasive Developmental Disorder (PDD) and Type 1 Diabetes with a false discovery rate < 0.05 and power of study above 80%. In addition, several new PheWAS findings were identified including a cluster of association near the NDFIP1 gene for mental retardation (best SNP rs10057309, p = 4.33 × 10(-7), OR = 1.70, 95%CI = 1.38 - 2.09); association near PLCL1 gene for developmental delays and speech disorder [best SNP rs1595825, p = 1.13 × 10(-8), OR = 0.65(0.57 - 0.76)]; a cluster of associations in the IL5-IL13 region with Eosinophilic Esophagitis (EoE) [best at rs12653750, p = 3.03 × 10(-9), OR = 1.73 95%CI = (1.44 - 2.07)], previously implicated in asthma, allergy, and eosinophilia; and association of variants in GCKR and JAZF1 with allergic rhinitis in our pediatric cohorts [best SNP rs780093, p = 2.18 × 10(-5), OR = 1.39, 95%CI = (1.19 - 1.61)], previously demonstrated in metabolic disease and diabetes in adults. CONCLUSION: The PheWAS approach with re-mapping ICD-9 structured codes for our European-origin pediatric cohorts, as with the previous adult studies, finds many previously reported associations as well as presents the discovery of associations with potentially important clinical implications.

9.
Front Genet ; 4: 268, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24348519

RESUMO

UNLABELLED: Common variations at the loci harboring the fat mass and obesity gene (FTO), MC4R, and TMEM18 are consistently reported as being associated with obesity and body mass index (BMI) especially in adult population. In order to confirm this effect in pediatric population five European ancestry cohorts from pediatric eMERGE-II network (CCHMC-BCH) were evaluated. METHOD: Data on 5049 samples of European ancestry were obtained from the Electronic Medical Records (EMRs) of two large academic centers in five different genotyped cohorts. For all available samples, gender, age, height, and weight were collected and BMI was calculated. To account for age and sex differences in BMI, BMI z-scores were generated using 2000 Centers of Disease Control and Prevention (CDC) growth charts. A Genome-wide association study (GWAS) was performed with BMI z-score. After removing missing data and outliers based on principal components (PC) analyses, 2860 samples were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and BMI was tested using linear regression adjusting for age, gender, and PC by cohort. The effects of SNPs were modeled assuming additive, recessive, and dominant effects of the minor allele. Meta-analysis was conducted using a weighted z-score approach. RESULTS: The mean age of subjects was 9.8 years (range 2-19). The proportion of male subjects was 56%. In these cohorts, 14% of samples had a BMI ≥95 and 28 ≥ 85%. Meta analyses produced a signal at 16q12 genomic region with the best result of p = 1.43 × 10(-) (7) [p (rec) = 7.34 × 10(-) (8)) for the SNP rs8050136 at the first intron of FTO gene (z = 5.26) and with no heterogeneity between cohorts (p = 0.77). Under a recessive model, another published SNP at this locus, rs1421085, generates the best result [z = 5.782, p (rec) = 8.21 × 10(-) (9)]. Imputation in this region using dense 1000-Genome and Hapmap CEU samples revealed 71 SNPs with p < 10(-) (6), all at the first intron of FTO locus. When hetero-geneity was permitted between cohorts, signals were also obtained in other previously identified loci, including MC4R (rs12964056, p = 6.87 × 10(-) (7), z = -4.98), cholecystokinin CCK (rs8192472, p = 1.33 × 10(-) (6), z = -4.85), Interleukin 15 (rs2099884, p = 1.27 × 10(-) (5), z = 4.34), low density lipoprotein receptor-related protein 1B [LRP1B (rs7583748, p = 0.00013, z = -3.81)] and near transmembrane protein 18 (TMEM18) (rs7561317, p = 0.001, z = -3.17). We also detected a novel locus at chromosome 3 at COL6A5 [best SNP = rs1542829, minor allele frequency (MAF) of 5% p = 4.35 × 10(-) (9), z = 5.89]. CONCLUSION: An EMR linked cohort study demonstrates that the BMI-Z measurements can be successfully extracted and linked to genomic data with meaningful confirmatory results. We verified the high prevalence of childhood rate of overweight and obesity in our cohort (28%). In addition, our data indicate that genetic variants in the first intron of FTO, a known adult genetic risk factor for BMI, are also robustly associated with BMI in pediatric population.

10.
Drug Metab Dispos ; 41(1): 188-96, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23091188

RESUMO

Inhibition of the bile salt export pump (BSEP) can cause intracellular accumulation of bile acids and is a risk factor for drug-induced liver injury in humans. Antiretroviral protease inhibitors lopinavir (LPV) and ritonavir (RTV) are reported BSEP inhibitors. However, the consequences of LPV and RTV, alone and combined (LPV/r), on hepatocyte viability, bile acid transport, and endogenous bile acid disposition in rat hepatocytes have not been examined. The effect of LPV, RTV, and LPV/r on cellular viability and the disposition of [(3)H]taurocholic acid (TCA) and [(14)C]chenodeoxycholic acid (CDCA) was determined in sandwich-cultured rat hepatocytes (SCRH) and suspended rat hepatocytes. Lactate dehydrogenase and ATP assays revealed a concentration-dependent effect of LPV and RTV on cellular viability. LPV (5 µM), alone and combined with 5 µM RTV, significantly decreased [(3)H]TCA accumulation in cells + bile of SCRHs compared with control. LPV/r significantly increased [(3)H]TCA cellular accumulation (7.7 ± 0.1 pmol/mg of protein) compared with vehicle and 5 µM LPV alone (5.1 ± 0.7 and 5.0 ± 0.5 pmol/mg of protein). The [(3)H]TCA biliary clearance was reduced significantly by LPV and RTV and further reduced by LPV/r. LPV and RTV did not affect the initial uptake rates of [(3)H]TCA or [(14)C]CDCA in suspended rat hepatocytes. LPV (50 µM), RTV (5 µM), and LPV/r (5 and 50 µM/5 µM) significantly decreased the accumulation of total measured endogenous bile acids (TCA, glycocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, and α/ß-tauromuricholic acid) in SCRH. Quantification of endogenous bile acids in SCRH may reveal important adaptive responses associated with exposure to known BSEP inhibitors.


Assuntos
Ácidos e Sais Biliares/metabolismo , Inibidores da Protease de HIV/farmacologia , Hepatócitos/metabolismo , Lopinavir/farmacologia , Ritonavir/farmacologia , Animais , Radioisótopos de Carbono/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inibidores da Protease de HIV/administração & dosagem , Lopinavir/administração & dosagem , Ratos , Ritonavir/administração & dosagem
11.
Toxicol Appl Pharmacol ; 261(1): 1-9, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22342602

RESUMO

Sandwich-cultured hepatocytes (SCH) are used commonly to investigate hepatic transport protein-mediated uptake and biliary excretion of substrates. However, little is known about the disposition of endogenous bile acids (BAs) in SCH. In this study, four endogenous conjugated BAs common to rats and humans [taurocholic acid (TCA), glycocholic acid (GCA), taurochenodeoxycholic acid (TCDCA), and glycochenodeoxycholic acid (GCDCA)], as well as two BA species specific to rodents (α- and ß-tauromuricholic acid; α/ß TMCA), were profiled in primary rat and human SCH. Using B-CLEAR® technology, BAs were measured in cells+bile canaliculi, cells, and medium of SCH by LC-MS/MS. Results indicated that, just as in vivo, taurine-conjugated BA species were predominant in rat SCH, while glycine-conjugated BAs were predominant in human SCH. Total intracellular BAs remained relatively constant over days in culture in rat SCH. Total BAs in control (CTL) cells+bile, cells, and medium were approximately 3.4, 2.9, and 8.3-fold greater in human than in rat. The estimated intracellular concentrations of the measured total BAs were 64.3±5.9 µM in CTL rat and 183±56 µM in CTL human SCH, while medium concentrations of the total BAs measured were 1.16±0.21 µM in CTL rat SCH and 9.61±6.36 µM in CTL human SCH. Treatment of cells for 24h with 10 µM troglitazone (TRO), an inhibitor of the bile salt export pump (BSEP) and the Na⁺-taurocholate cotransporting polypeptide (NTCP), had no significant effect on endogenous BAs measured at the end of the 24-h culture period, potentially due to compensatory mechanisms that maintain BA homeostasis. These data demonstrate that BAs in SCH are similar to in vivo, and that SCH may be a useful in vitro model to study alterations in BA disposition if species differences are taken into account.


Assuntos
Ácidos e Sais Biliares/metabolismo , Hepatócitos/metabolismo , Modelos Biológicos , Adulto , Idoso , Animais , Transporte Biológico , Técnicas de Cultura de Células , Células Cultivadas , Cromanos/farmacologia , Cromatografia Líquida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos Dependentes de Sódio/farmacologia , Ratos , Ratos Wistar , Especificidade da Espécie , Simportadores/farmacologia , Espectrometria de Massas em Tandem , Tiazolidinedionas/farmacologia , Troglitazona , Adulto Jovem
12.
J Biomol Screen ; 16(4): 427-35, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21393626

RESUMO

Predictions of the absorption, distribution, metabolism, excretion, and toxicity of compounds in pharmaceutical development are essential aspects of the drug discovery process. B-CLEAR is an in vitro system that uses sandwich-cultured hepatocytes to evaluate and predict in vivo hepatobiliary disposition (hepatic uptake, biliary excretion, and biliary clearance), transporter-based hepatic drug-drug interactions, and potential drug-induced hepatotoxicity. Automation of predictive technologies is an advantageous and preferred format in drug discovery. In this study, manual and automated studies are investigated and equivalence is demonstrated. In addition, automated applications using model probe substrates and inhibitors to assess the cholestatic potential of drugs and evaluate hepatic drug transport are examined. The successful automation of this technology provides a more reproducible and less labor-intensive approach, reducing potential operator error in complex studies and facilitating technology transfer.


Assuntos
Bioensaio/métodos , Avaliação de Medicamentos/métodos , Hepatócitos/citologia , Proteínas de Membrana Transportadoras/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Ácidos e Sais Biliares/metabolismo , Transporte Biológico/efeitos dos fármacos , Técnicas de Cultura de Células , Células Cultivadas , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Ratos
13.
Toxicol Sci ; 120(2): 371-80, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21262925

RESUMO

Inhibition of bile acid (BA) transport may contribute to the hepatotoxicity of troglitazone (TRO), a peroxisome proliferator-activated receptor gamma agonist. Typically, studies use taurocholic acid (TCA) as a model substrate to investigate effects of xenobiotics on BA disposition. However, TRO may differentially affect the transport of individual BAs, potentially causing hepatocyte accumulation of more cytotoxic BAs. The effects of TRO on the disposition of [(14)C]-labeled chenodeoxycholic acid ([(14)C]CDCA), an unconjugated cytotoxic BA, were determined in suspended hepatocytes and sandwich-cultured hepatocytes (SCH) from rats. (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid (MK571), a multidrug resistance-associated protein (MRP) inhibitor, was included to evaluate involvement of MRPs in CDCA disposition. Accumulation in cells + bile of total [(14)C]CDCA species in SCH was sixfold greater than [(3)H]TCA and unaffected by 1 and 10µM TRO; 100µM TRO and 50µM MK571 ablated biliary excretion and significantly increased intracellular accumulation of total [(14)C]CDCA species. Results were similar in Mrp2-deficient TR(-) rat hepatocytes. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed that taurine- and glycine-conjugated CDCA, in addition to unconjugated CDCA, accumulated in hepatocytes during the 10-min incubation. In suspended rat hepatocytes, initial [(14)C]CDCA uptake was primarily Na(+)-independent, whereas initial [(3)H]TCA uptake was primarily Na(+)-dependent; TRO and MK571 decreased [(14)C]CDCA uptake to a lesser extent than [(3)H]TCA. Unexpectedly, MK571 inhibited Na(+)-taurocholate cotransporting polypeptide and bile salt export pump. Differential effects on uptake and efflux of individual BAs may contribute to TRO hepatotoxicity. Although TCA is the prototypic BA used to investigate the effects of xenobiotics on BA transport, it may not be reflective of other BAs.


Assuntos
Ácido Quenodesoxicólico/metabolismo , Cromanos/toxicidade , Hepatócitos/efeitos dos fármacos , PPAR gama/agonistas , Ácido Taurocólico/metabolismo , Tiazolidinedionas/toxicidade , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Transporte Biológico , Radioisótopos de Carbono , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Cromatografia Líquida de Alta Pressão , Hepatócitos/metabolismo , Masculino , Propionatos/farmacologia , Quinolinas/farmacologia , Ratos , Ratos Wistar , Espectrometria de Massas em Tandem , Troglitazona
14.
J Genet Couns ; 19(4): 305-14, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20232125

RESUMO

Genetic counselors and other health professionals may encounter adoption during any counseling session. They must be skilled in using appropriate language and understand how to approach and discuss this topic with clients. A thorough knowledge of adoption as an option for clients facing a prenatal or postnatal diagnosis is necessary when presenting individuals with non-biased information needed for informed decision-making. However, three preliminary studies have demonstrated an absence of graduate education and lack of a professional knowledge base regarding this option (Mates 2008; Oksala 2007; Perry 2003). We discuss the impact of medical professionals' preconceptions on client decision-making, increasing early identification of fetal anomalies, deficiency of adoption knowledge and resources, and the resulting need for genetic counselors and other health professionals to develop their skills in discussing adoption with clients.


Assuntos
Adoção , Aconselhamento Genético , Educação de Pacientes como Assunto , Humanos
15.
Drug Metab Dispos ; 38(2): 276-80, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19910518

RESUMO

Drug-induced cholestasis can result from the inhibition of biliary efflux of bile acids in the liver. Drugs may inhibit the hepatic uptake and/or the biliary efflux of bile acids resulting in an increase in serum concentrations. However, it is the intracellular concentration of bile acids that results in hepatotoxicity, and thus serum concentrations may not necessarily be an appropriate indicator of hepatotoxicity. In this study, sandwich-cultured rat hepatocytes were used as an in vitro model to assess the cholestatic potential of drugs using deuterium-labeled sodium taurocholate (d(8)-TCA) as a probe for bile acid transport. Eight drugs were tested as putative inhibitors of d(8)-TCA uptake and efflux. The hepatobiliary disposition of d(8)-TCA in the absence and presence of drugs was measured by using liquid chromatography/tandem mass spectrometry, and the accumulation (hepatocytes and hepatocytes plus bile), biliary excretion index (BEI), and in vitro biliary clearance (Cl(biliary)) were reported. Compounds were classified based on inhibition of uptake, efflux, or a combination of both processes. Cyclosporine A and glyburide showed a decrease in total (hepatocytes plus bile) accumulation, an increase in intracellular (hepatocytes only) accumulation, and a decrease in BEI and Cl(biliary) of d(8)-TCA, suggesting that efflux was primarily affected. Erythromycin estolate, troglitazone, and bosentan resulted in a decrease in accumulation (total and intracellular), BEI, and Cl(biliary) of d(8)-TCA, suggesting that uptake was primarily affected. Determination of a compound's relative effect on bile acid uptake, efflux, and direct determination of alterations in intracellular amounts of bile acids may provide useful mechanistic information on compounds that cause increases in serum bile acids.


Assuntos
Bile/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Colestase Intra-Hepática/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hepatócitos/efeitos dos fármacos , Ácido Taurocólico/metabolismo , Testes de Toxicidade/métodos , Algoritmos , Animais , Bile/metabolismo , Ácidos e Sais Biliares/metabolismo , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Colestase Intra-Hepática/prevenção & controle , Cromatografia Líquida de Alta Pressão , Colágeno , Técnicas de Cultura/métodos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Hepatócitos/metabolismo , Laminina , Masculino , Proteoglicanas , Ratos , Ratos Wistar , Espectrometria de Massas em Tandem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...