RESUMO
BACKGROUND/AIMS: We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft-versus-host disease (GVHD) on OSR. METHODS: Data on 386 patients from nine Australian centres with relapsed AML post-alloHSCT were collected retrospectively. OSR was calculated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using the log-rank test and proportional hazards modelling, respectively and a prognostic index for OSR was derived from multivariate modelling. RESULTS: On multivariate analysis, relapse within 6 months (hazard ratio (HR) 2.4, P < 0.001) and grade 3-4 acute GVHD preceding relapse (HR 2.0, P = 0.004), were associated with inferior OSR. Patients with 1-2 factors had inferior OSR compared to those with zero factors (all patients: HR 2.3, P < 0.001, patients given salvage: HR 1.8, P < 0.001). The first salvage therapy used post-relapse was donor cell therapy (DCT) (second alloHSCT or donor lymphocyte infusion) in 75, re-induction chemotherapy (CT) in 103, radiotherapy in 8 and interferon-α in 6. Although re-induction CT death rate was low (2%), survival after CT was inferior to DCT (HR 1.9, P < 0.001). No survival benefit was seen for patients who developed GVHD following salvage therapy (P = 0.405). CONCLUSION: Patients with AML who relapse beyond 6 months from alloHSCT without prior grade 3-4 acute GVHD have a better outcome from salvage therapy. Salvage treatments employing DCT as the initial treatment of AML relapse confer a survival advantage over CT.
Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Transplante de Células-Tronco Hematopoéticas/tendências , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Idoso , Bases de Dados Factuais/tendências , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Transplante Homólogo/mortalidade , Transplante Homólogo/tendências , Resultado do TratamentoRESUMO
OBJECTIVES: To compare maternal characteristics, prenatal care, and newborn outcomes in a cohort of opioid-dependent pregnant women treated with methadone versus buprenorphine. METHODS: In a retrospective cohort study, 609 pregnant, opioid-dependent women were treated with methadone (n = 248) or buprenorphine (n = 361) between 2000 and 2012 at a single institution. RESULTS: Mothers treated with buprenorphine were more likely to start medication before or earlier in pregnancy, had longer gestation, and gave birth to larger infants. Newborns of buprenorphine- versus methadone-maintained mothers required treatment for neonatal abstinence significantly less often and for a shorter duration. CONCLUSIONS: These data suggest pregnancy outcomes with buprenorphine to treat opioid dependence during pregnancy in clinical practice are as good and often better than outcomes with methadone. These results are consistent with efficacy data from randomized clinical trials and further support the use of buprenorphine for the treatment of opioid dependence during pregnancy.
Assuntos
Buprenorfina/uso terapêutico , Metadona/uso terapêutico , Tratamento de Substituição de Opiáceos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Resultado da Gravidez , Adulto , Analgésicos Opioides/uso terapêutico , Feminino , Humanos , Gravidez , Estudos Retrospectivos , Adulto JovemRESUMO
The insulin receptor substrate (IRS) proteins act as important mediators of insulin action. Their regulation serves to augment the specificity of the insulin signalling cascade. They can be regulated--both positively and negatively--at the level of phosphorylation, and signalling through these proteins can be further modulated through the actions of SOCS (suppressor of cytokine signalling) proteins. Understanding the mechanisms of IRS regulation will provide further insight into the pathophysiology of insulin resistance and type 2 diabetes.
Assuntos
Insulina/metabolismo , Proteínas/metabolismo , Receptor de Insulina/metabolismo , Transdução de Sinais , Animais , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Resistência à Insulina , Modelos Biológicos , Fosforilação , Proteínas Repressoras/metabolismoRESUMO
BACKGROUND: The recommended standard of care calls for treating opioid-dependent pregnant women with methadone and observing neonates exposed in utero for five to seven postnatal days to see if treatment for neonatal abstinence syndrome (NAS) is needed. Data from a large multi-site randomized clinical trial comparing buprenorphine vs. methadone for the treatment of opioid dependence during pregnancy suggest buprenorphine-exposed neonates had less severe NAS, but may require pharmacologic treatment for NAS later than methadone-exposed neonates. The present study examined whether time to pharmacologic treatment initiation differed in a relatively large non-blinded clinical sample of buprenorphine- vs. methadone-exposed neonates treated for NAS. METHODS: Medical records for 75 neonates exposed to buprenorphine (n=47) or methadone (n=28) in utero who required treatment for NAS were examined. Time elapsed between birth and initiation of pharmacologic treatment was calculated for each neonate and time to treatment initiation compared between groups. RESULTS: Median time to treatment initiation (hours:minutes, IQR) was significantly later in buprenorphine- vs. methadone-exposed neonates (71:02, 44:21-96:27 vs. 34:12, 21:00-55:41, respectively, p<.001). Estimates of mean time to treatment initiation from parametric analyses that adjusted for maternal and neonatal characteristics were very similar (73:10 (95% CI: 61:00-87:18) vs. 42:36 (95% CI: 33:06-53:30), respectively, p=.0005). This difference was not dependent on maternal age or neonatal sex, gestational age, or birth weight. CONCLUSIONS: These findings confirm results from randomized clinical trials, adding generality to the observation that buprenorphine-exposed neonates require treatment significantly later than methadone-exposed neonates.
Assuntos
Buprenorfina/efeitos adversos , Metadona/efeitos adversos , Síndrome de Abstinência Neonatal/tratamento farmacológico , Tratamento de Substituição de Opiáceos/métodos , Peso ao Nascer , Estudos de Casos e Controles , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de TempoRESUMO
BACKGROUND: Pupil diameter is a frequently assessed objective index of the pharmacodynamic effects of opioids in adults, but to our knowledge has never been examined in infants. Such a measure could improve assessment and treatment of neonates exposed to opioids in utero. The present study examined changes in pupil diameter after opioid administration in opioid-exposed infants who required pharmacological treatment for neonatal abstinence syndrome (NAS) to test the feasibility of using pupil diameter as a measure of opioid effects in these infants. METHODS: Ten infants (2-7 days old) receiving methadone (0.4-0.5 mg every 12 h) for the treatment of NAS participated. A picture of one of each infant's eyes was taken under controlled illumination conditions with a standard digital camera just prior to dosing and 0-1, 2-4, 5-7, and 8-10h after dosing. The diameters of the pupil and iris were measured and relative pupil diameter (pupil diameter expressed as a percentage of iris diameter) was analyzed. RESULTS: Mean (±SE) relative pupil diameter decreased significantly after dosing from 41±2% to 29±2%. After dosing, a significant increasing linear trend was observed over time, with values of 29±2%, 33±3%, 38±3%, and 41±3% at 0-1, 2-4, 5-7, and 8-10h after dosing. CONCLUSIONS: Infant pupils respond to opioid administration in the same sensitive, orderly manner as is commonly observed in adults. Pupil diameter appears to be an objective, sensitive measure of neonatal response to opioids that may be a useful complement to, or perhaps at times a replacement for, observer-rated scale scores.
Assuntos
Metadona/farmacologia , Metadona/uso terapêutico , Entorpecentes/farmacologia , Entorpecentes/uso terapêutico , Síndrome de Abstinência Neonatal/tratamento farmacológico , Reflexo Pupilar/efeitos dos fármacos , Análise de Variância , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Recém-Nascido , Masculino , Síndrome de Abstinência Neonatal/fisiopatologiaRESUMO
OBJECTIVE: Family-centered care has become integral to the provision of quality neonatal intensive care. However, practices that reflect the core principles of family-centered care have not been described fully in the literature or implemented and evaluated consistently within newborn intensive care. The objective of this study was to create a family-centered care map that enhances the ability of the health care team to work with families to coordinate and deliver care in a holistic manner to meet the developmental, physical, and psychosocial needs of NICU patients and their families. METHODS: Potentially better practices were developed for sequential clinical phases by using standardized methods. These included focus groups with families, brainstorming sessions with staff, literature review, and input from established family advisory groups and family-centered care experts. Potentially better practices then were integrated into the family-centered care map that was configured in a Web-based format. Overall utility will be evaluated by determining the effect of the family-centered care map on length of stay, parental satisfaction, and family-centered care beliefs and practices among NICU staff. RESULTS: Sixty-three potentially better practices were identified for 7 clinical phases and 3 variations that were believed to characterize the clinical course of a typical NICU patient. A prototype of the Web-based family-centered care map that illustrates the clinical phases with links to the related potentially better practices, operational processes, and case studies was created. Baseline data from a care provider survey, from a family satisfaction survey, and on length of stay have been collected. CONCLUSIONS: Quality improvement methods and collaboration among 3 centers led to the development of an innovative Web-based resource to assist individual care providers and family advisors to provide comprehensive family-centered care to infants and families. Implementation of the family-centered care map has potential to affect positively the quality of newborn intensive care and lead to improved long-term outcomes.
Assuntos
Unidades de Terapia Intensiva Neonatal/organização & administração , Terapia Intensiva Neonatal/métodos , Relações Profissional-Família , Garantia da Qualidade dos Cuidados de Saúde , Comportamento do Consumidor , Continuidade da Assistência ao Paciente/organização & administração , Continuidade da Assistência ao Paciente/normas , Grupos Focais , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal/normas , Terapia Intensiva Neonatal/normas , Alta do Paciente , Estados UnidosRESUMO
OBJECTIVE: The objective of this study was to enhance the ability to coordinate and deliver care in a holistic manner, through a family-centered care map, so that the developmental, physical, and psychosocial needs of the infant and family are met. METHODS: A Web-based map was based on 7 distinct clinical phases with 3 variations of an infant's course through a NICU. Sixty-three potentially better practices were identified and 7 potentially better practices were implemented through case studies. RESULTS: Measures of family satisfaction revealed improvements in delivery of family-centered care. Increases in discharge growth parameters for extremely low birth weight infants were demonstrated. Length of stay for very low birth weight infants decreased from 73 to 60 days in Vermont. CONCLUSIONS: The collaborative process enhances identification of potentially better practices and results in both qualitative and quantitative improvements in family-centered care.
Assuntos
Unidades de Terapia Intensiva Neonatal/organização & administração , Terapia Intensiva Neonatal/métodos , Educação de Pacientes como Assunto , Relações Profissional-Família , Garantia da Qualidade dos Cuidados de Saúde , Comportamento do Consumidor , Continuidade da Assistência ao Paciente/organização & administração , Continuidade da Assistência ao Paciente/normas , Grupos Focais , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Unidades de Terapia Intensiva Neonatal/normas , Terapia Intensiva Neonatal/normas , Tempo de Internação , Avaliação de Processos e Resultados em Cuidados de Saúde , Alta do Paciente , Estados UnidosRESUMO
Impaired glucose tolerance precedes type 2 diabetes and is characterized by hyperinsulinemia, which develops to balance peripheral insulin resistance. To gain insight into the deleterious effects of hyperinsulinemia on skeletal muscle, we studied the consequences of prolonged insulin treatment of L6 myoblasts on insulin-dependent signaling pathways. A 24-h long insulin treatment desensitized the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) and p42/p44 MAPK pathways toward a second stimulation with insulin or insulin-like growth factor-1 and led to decreased insulin-induced glucose uptake. Desensitization was correlated to a reduction in insulin receptor substrate (IRS)-1 and IRS-2 protein levels, which was reversed by the PI3K inhibitor LY294002. Co-treatment of cells with insulin and LY294002, while reducing total IRS-1 phosphorylation, increased its phosphotyrosine content, enhancing IRS-1/PI3K association. PDK1, mTOR, and MAPK inhibitors did not block insulin-induced reduction of IRS-1, suggesting that the PI3K serine-kinase activity causes IRS-1 serine phosphorylation and its commitment to proteasomal degradation. Contrarily, insulin-induced IRS-2 down-regulation occurred via a PI3K/mTOR pathway. Suppression of IRS-1/2 down-regulation by LY294002 rescued the responsiveness of PKB and MAPK toward acute insulin stimulation. Conversely, adenoviral-driven expression of constitutively active PI3K induced an insulin-independent reduction in IRS-1/2 protein levels. IRS-2 appears to be the chief molecule responsible for MAPK and PKB activation by insulin, as knockdown of IRS-2 (but not IRS-1) by RNA interference severely impaired activation of both kinases. In summary, (i) PI3K mediates insulin-induced reduction of IRS-1 by phosphorylating it while a PI3K/mTOR pathway controls insulin-induced reduction of IRS-2, (ii) in L6 cells, IRS-2 is the major adapter molecule linking the insulin receptor to activation of PKB and MAPK, (iii) the mechanism of IRS-1/2 down-regulation is different in L6 cells compared with 3T3-L1 adipocytes. In conclusion, the reduction in IRS proteins via different PI3K-mediated mechanisms contributes to the development of an insulin-resistant state in L6 myoblasts.
Assuntos
Insulina/farmacologia , Mioblastos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/fisiologia , Fosfoproteínas/biossíntese , Proteínas Serina-Treonina Quinases , Animais , Células Cultivadas , Cromonas/farmacologia , Desoxiglucose/metabolismo , Proteínas Substratos do Receptor de Insulina , Peptídeos e Proteínas de Sinalização Intracelular , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Morfolinas/farmacologia , Mioblastos/fisiologia , Fosfoproteínas/análise , Proteínas Quinases/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Proto-Oncogênicas c-akt , Interferência de RNA , Ratos , Serina-Treonina Quinases TORRESUMO
Mutations in the triple PDZ domain-containing protein harmonin have been identified as the cause of Usher deafness syndrome type 1C. Independently, we identified harmonin in a screen for genes expressed in pancreatic beta cells. Using a yeast two-hybrid assay, we show that the first PDZ domain of harmonin interacts with a novel protein, designated harp for harmonin-interacting, ankyrin repeat-containing protein. This interaction was confirmed in an over-expression system and in mammalian cells, and shown to be mediated by the three C-terminal amino acids of harp. Harp is expressed in many of the same epithelia as harmonin and co-localization of native harp and harmonin was demonstrated by confocal microscopy in pancreatic duct epithelium and in a pancreatic beta-cell line. Harp, predicted molecular mass 48 kDa, has a domain structure which includes three ankyrin repeats and a sterile alpha motif. Human harp maps to chromosome 16, and its mouse homologue to chromosome 7. Sequences with similarity to harp include the sans gene, mutations of which are responsible for deafness in the Jackson shaker 2 (js) mutant mouse and in human Usher syndrome type 1G. The functional domain structures of harp and harmonin, their interaction under native conditions and their co-localization suggest they constitute a scaffolding complex to facilitate signal transduction in epithelia.