RESUMO
OBJECTIVE: Medication nonadherence is common in patients with systemic lupus erythematosus (SLE) and negatively affects outcomes. To better recognize and address nonadherence in this population, there is a need for an easily implementable tool with interpretable scores. Domains of Subjective Extent of Nonadherence (DOSE-Nonadherence) is a measure that captures both extent of and reasons for nonadherence. We refined and evaluated DOSE-Nonadherence for patients with SLE. METHODS: We refined the reasons for the nonadherence domain of DOSE-Nonadherence through rheumatologist feedback and patient cognitive interviewing. We then administered the refined instrument to patients prescribed oral SLE medications and compared the results to the Beliefs About Medicines Questionnaire (BMQ), the Medication Adherence Self-Report Inventory (MASRI), medication possession ratios (MPRs), and hydroxychloroquine (HCQ) blood levels using Pearson correlations. RESULTS: Five rheumatologists provided feedback; 16 patients (median age 43 yrs, 100% female, 50% Black) participated in cognitive interviews and 128 (median age 49 yrs, 95% female, 49% Black, 88% on antimalarials, and 59% on immunosuppressants) completed the refined instrument. Items assessing extent of nonadherence produced reliable scores (α 0.89) and identified 47% as nonadherent. They showed convergent validity with MASRI (r = -0.57), HCQ blood levels (r = -0.55), to a lesser extent MPRs (r = -0.34 to -0.40), and discriminant validity with BMQ domains (r = -0.27 to 0.32). Nonadherent patients reported on average 3.5 adherence barriers, the most common being busyness/forgetting (62%), physical fatigue (38%), and pill fatigue (33%). CONCLUSION: Our results support the reliability and validity of DOSE-Nonadherence for SLE medications. This refined instrument, DOSE-Nonadherence-SLE, can be used to identify, rigorously study, and guide adherence intervention development in SLE.
Assuntos
Lúpus Eritematoso Sistêmico , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Masculino , Reprodutibilidade dos Testes , Lúpus Eritematoso Sistêmico/epidemiologia , Adesão à Medicação/psicologia , Hidroxicloroquina/uso terapêutico , FadigaAssuntos
Endocardite Bacteriana , Endocardite , Linfo-Histiocitose Hemofagocítica , Endocardite/diagnóstico , Endocardite/diagnóstico por imagem , Endocardite Bacteriana/diagnóstico , Endocardite Bacteriana/diagnóstico por imagem , Humanos , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnósticoRESUMO
Coronary heart disease (CHD) is the leading cause of mortality in both developed and developing countries worldwide. Genome-wide association studies (GWAS) have now identified 46 independent susceptibility loci for CHD, however, the biological and disease-relevant mechanisms for these associations remain elusive. The large-scale meta-analysis of GWAS recently identified in Caucasians a CHD-associated locus at chromosome 6q23.2, a region containing the transcription factor TCF21 gene. TCF21 (Capsulin/Pod1/Epicardin) is a member of the basic-helix-loop-helix (bHLH) transcription factor family, and regulates cell fate decisions and differentiation in the developing coronary vasculature. Herein, we characterize a cis-regulatory mechanism by which the lead polymorphism rs12190287 disrupts an atypical activator protein 1 (AP-1) element, as demonstrated by allele-specific transcriptional regulation, transcription factor binding, and chromatin organization, leading to altered TCF21 expression. Further, this element is shown to mediate signaling through platelet-derived growth factor receptor beta (PDGFR-ß) and Wilms tumor 1 (WT1) pathways. A second disease allele identified in East Asians also appears to disrupt an AP-1-like element. Thus, both disease-related growth factor and embryonic signaling pathways may regulate CHD risk through two independent alleles at TCF21.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Doença das Coronárias/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Fator de Transcrição AP-1/genética , Alelos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Doença das Coronárias/patologia , Vasos Coronários/citologia , Vasos Coronários/crescimento & desenvolvimento , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica no Desenvolvimento , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Miócitos de Músculo Liso/citologia , Polimorfismo de Nucleotídeo Único , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Fator de Transcrição AP-1/metabolismo , Tumor de Wilms/genética , Tumor de Wilms/metabolismoRESUMO
OBJECTIVE: Genomewide association studies have implicated allelic variation at 9p21.3 in multiple forms of vascular disease, including atherosclerotic coronary heart disease and abdominal aortic aneurysm. As for other genes at 9p21.3, human expression quantitative trait locus studies have associated expression of the tumor suppressor gene CDKN2B with the risk haplotype, but its potential role in vascular pathobiology remains unclear. METHODS AND RESULTS: Here we used vascular injury models and found that Cdkn2b knockout mice displayed the expected increase in proliferation after injury, but developed reduced neointimal lesions and larger aortic aneurysms. In situ and in vitro studies suggested that these effects were attributable to increased smooth muscle cell apoptosis. Adoptive bone marrow transplant studies confirmed that the observed effects of Cdkn2b were mediated through intrinsic vascular cells and were not dependent on bone marrow-derived inflammatory cells. Mechanistic studies suggested that the observed increase in apoptosis was attributable to a reduction in MDM2 and an increase in p53 signaling, possibly due in part to compensation by other genes at the 9p21.3 locus. Dual inhibition of both Cdkn2b and p53 led to a reversal of the vascular phenotype in each model. CONCLUSIONS: These results suggest that reduced CDKN2B expression and increased smooth muscle cell apoptosis may be one mechanism underlying the 9p21.3 association with aneurysmal disease.
Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Apoptose , Doenças das Artérias Carótidas/metabolismo , Inibidor de Quinase Dependente de Ciclina p15/deficiência , Músculo Liso Vascular/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adolescente , Adulto , Idoso , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/prevenção & controle , Apoptose/efeitos dos fármacos , Benzotiazóis/farmacologia , Transplante de Medula Óssea , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/patologia , Doenças das Artérias Carótidas/prevenção & controle , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Neointima , Elastase Pancreática , Fenótipo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Tolueno/análogos & derivados , Tolueno/farmacologia , Transfecção , Proteína Supressora de Tumor p53/antagonistas & inibidoresRESUMO
Cephalostatin 1, OSW-1, ritterazine B and schweinfurthin A are natural products that potently, and in some cases selectively, inhibit the growth of cultured human cancer cell lines. The cellular targets of these small molecules have yet to be identified. We have discovered that these molecules target oxysterol binding protein (OSBP) and its closest paralog, OSBP-related protein 4L (ORP4L)--proteins not known to be involved in cancer cell survival. OSBP and the ORPs constitute an evolutionarily conserved protein superfamily, members of which have been implicated in signal transduction, lipid transport and lipid metabolism. The functions of OSBP and the ORPs, however, remain largely enigmatic. Based on our findings, we have named the aforementioned natural products ORPphilins. Here we used ORPphilins to reveal new cellular activities of OSBP. The ORPphilins are powerful probes of OSBP and ORP4L that will be useful in uncovering their cellular functions and their roles in human diseases.