RESUMO
Sensitization is common in pediatric heart transplant candidates and waitlist mortality is high. Transplantation across a positive crossmatch may reduce wait time, but is considered high risk. We prospectively recruited consecutive candidates at eight North American centers. At transplantation, subjects were categorized as nonsensitized or sensitized (presence of ≥1 HLA antibody with MFI ≥1000 using single antigen beads). Sensitized subjects were further classified as complement-dependent cytotoxicity crossmatch (CDC-crossmatch) positive or negative and as donor-specific antibodies (DSA) positive or negative. Immunosuppression was standardized. CDC-crossmatch-positive subjects also received perioperative antibody removal, maintenance corticosteroids, and intravenous immunoglobulin. The primary endpoint was the 1 year incidence rate of a composite of death, retransplantation, or rejection with hemodynamic compromise. 317 subjects were screened, 290 enrolled and 240 transplanted (51 with pretransplant DSA, 11 with positive CDC-crossmatch). The incidence rates of the primary endpoint did not differ statistically between groups; nonsensitized 6.7% (CI: 2.7%, 13.3%), sensitized crossmatch positive 18.2% (CI: 2.3%, 51.8%), sensitized crossmatch negative 10.7% (CI: 5.7%, 18.0%), P = .2354. The primary endpoint also did not differ by DSA status. Freedom from antibody-mediated and cellular rejection was lower in the crossmatch positive group and/or in the presence of DSA. Follow-up will determine if acceptable outcomes can be achieved long-term.
Assuntos
Tipagem e Reações Cruzadas Sanguíneas/mortalidade , Rejeição de Enxerto/mortalidade , Antígenos HLA/imunologia , Transplante de Coração/efeitos adversos , Isoanticorpos/imunologia , Complicações Pós-Operatórias , Doadores de Tecidos , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Teste de Histocompatibilidade , Humanos , Terapia de Imunossupressão , Lactente , Isoanticorpos/sangue , Masculino , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
Data on the clinical importance of newly detected donor-specific anti-HLA antibodies (ndDSAs) after pediatric heart transplantation are lacking despite mounting evidence of the detrimental effect of de novo DSAs in solid organ transplantation. We prospectively tested 237 pediatric heart transplant recipients for ndDSAs in the first year posttransplantation to determine their incidence, pattern, and clinical impact. One-third of patients developed ndDSAs; when present, these were mostly detected within the first 6 weeks after transplantation, suggesting that memory responses may predominate over true de novo DSA production in this population. In the absence of preexisting DSAs, patients with ndDSAs had significantly more acute cellular rejection but not antibody-mediated rejection, and there was no impact on graft and patient survival in the first year posttransplantation. Risk factors for ndDSAs included common sensitizing events. Given the early detection of the antibody response, memory responses may be more important in the first year after pediatric heart transplantation and patients with a history of a sensitizing event may be at risk even with a negative pretransplantation antibody screen. The impact on late graft and patient outcomes of first-year ndDSAs is being assessed in an extended cohort of patients.
Assuntos
Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Transplante de Coração/efeitos adversos , Isoanticorpos/efeitos adversos , Complicações Pós-Operatórias , Doadores de Tecidos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Teste de Histocompatibilidade , Humanos , Incidência , Lactente , Isoanticorpos/sangue , Isoanticorpos/imunologia , Masculino , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
The intent of this National Institutes of Health-sponsored study was to compare a belatacept-based immunosuppressive regimen with a maintenance regimen of tacrolimus and mycophenolate. Nineteen primary, Epstein-Barr virus-immune renal transplant recipients with a negative cross-match were randomized to one of three groups. All patient groups received perioperative steroids and maintenance mycophenolate mofetil. Patients in groups 1 and 2 were induced with alemtuzumab and maintained on tacrolimus or belatacept, respectively. Patients in group 3 were induced with basiliximab, received 3 mo of tacrolimus, and maintained on belatacept. There was one death with a functioning allograft due to endocarditis (group 1). There were three graft losses due to vascular thrombosis (all group 2) and one graft loss due to glomerular disease (group 1). Biopsy-proven acute cellular rejection was more frequent in the belatacept-treated groups, with 10 treated episodes in seven participants compared with one episode in group 1; however, estimated GFR was similar between groups at week 52. There were no episodes of posttransplant lymphoproliferative disorder or opportunistic infections in any group. Protocol enrollment was halted prematurely because of a high rate of serious adverse events. Such negative outcomes pose challenges to clinical investigators, who ultimately must weigh the risks and benefits in randomized trials.
Assuntos
Abatacepte/uso terapêutico , Corticosteroides/uso terapêutico , Inibidores de Calcineurina/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim , Adolescente , Adulto , Idoso , Feminino , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Identification of biomarkers that assess posttransplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti-HLA- and auto-antibodies, angiogenic proteins, peripheral blood allo-reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti-HLA antibody (p < 0.04). Recipient CMV-negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor-C (OR 20; 95%CI:1.9-218) combined with decreases in endothelin-1 (OR 0.14; 95%CI:0.02-0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation.
Assuntos
Biomarcadores/metabolismo , Doença da Artéria Coronariana/diagnóstico , Rejeição de Enxerto/diagnóstico , Cardiopatias/cirurgia , Transplante de Coração/efeitos adversos , Adulto , Western Blotting , Estudos de Casos e Controles , Ensaios Clínicos como Assunto , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Endotelina-1/metabolismo , Feminino , Perfilação da Expressão Gênica , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator A de Crescimento do Endotélio VascularRESUMO
Previous studies suggest that quantifying donor-reactive memory T cells prior to kidney transplantation by interferon gamma enzyme-linked immunosorbent spot assay (IFNγELISPOT) can assist in assessing risk of posttransplant allograft injury. Herein, we report an analysis of IFNγELISPOT results from the multicenter, Clinical Trials in Organ Transplantation-01 observational study of primary kidney transplant recipients treated with heterogeneous immunosuppression. Within the subset of 176 subjects with available IFNγELISPOT results, pretransplant IFNγELISPOT positivity surprisingly did not correlate with either the incidence of acute rejection (AR) or estimated glomerular filtration rate (eGFR) at 6- or 12-month. These unanticipated results prompted us to examine potential effect modifiers, including the use of T cell-depleting, rabbit anti-thymocyte globulin (ATG). Within the no-ATG subset, IFNγELISPOT(neg) subjects had higher 6- and 12-month eGFRs than IFNγELISPOT(pos) subjects, independent of biopsy-proven AR, peak PRA, human leukocyte antigen mismatches, African-American race, donor source, and recipient age or gender. In contrast, IFNγELISPOT status did not correlate with posttransplant eGFR in subjects given ATG. Our data confirm an association between pretransplant IFNγELISPOT positivity and lower posttransplant eGFR, but only in patients who do not receive ATG induction. Controlled studies are needed to test the hypothesis that ATG induction is preferentially beneficial to transplant candidates with high frequencies of donor-reactive memory T cells.
Assuntos
Biomarcadores/análise , Ensaio de Imunoadsorção Enzimática/métodos , Rejeição de Enxerto/diagnóstico , Interferon gama/análise , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias , Adulto , Animais , Soro Antilinfocitário/imunologia , Criança , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Coelhos , Fatores de Risco , Doadores de TecidosRESUMO
OBJECTIVE: To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS: Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION: Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Granulomatose com Poliangiite/tratamento farmacológico , Imunossupressores/uso terapêutico , Poliangiite Microscópica/tratamento farmacológico , Indução de Remissão/métodos , Adulto , Anticorpos Monoclonais Murinos/administração & dosagem , Azatioprina/administração & dosagem , Azatioprina/uso terapêutico , Estudos Cross-Over , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Rituximab , Resultado do TratamentoRESUMO
Emerging evidence indicates memory donor-reactive T cells are detrimental to transplant outcome and that quantifying the frequency of IFNγ-producing, donor-reactive PBMCs by ELISPOT has potential utility as an immune monitoring tool. Nonetheless, differences in assay performance among laboratories limit the ability to compare results. In an effort to standardize assays, we prepared a panel of common cellular reagent standards, developed and cross validated a standard operating procedure (SOP) for alloreactive IFNγ ELISPOT assays in several research laboratories supported by the NIH-funded Clinical Trials in Organ Transplantation (CTOT) Consortium. We demonstrate that strict adherence to the SOP and centralized data analysis results in high reproducibility with a coefficient of variance (CV) of ≈ 30%. This standardization of IFNγ ELISPOT assay will facilitate interpretation of data from multicenter transplantation research studies and provide the foundation for developing clinical laboratory testing strategies to guide therapeutic decision-making in transplant patients.
Assuntos
Ensaios Clínicos como Assunto , Sobrevivência de Enxerto/imunologia , Monitorização Imunológica/normas , Transplante de Órgãos/normas , Linfócitos T/imunologia , Doadores de Tecidos , Ensaio de Imunoadsorção Enzimática , ELISPOT , Humanos , Monitorização Imunológica/métodos , Projetos Piloto , Reprodutibilidade dos Testes , Estados UnidosRESUMO
Noninvasive biomarkers are needed to assess immune risk and ultimately guide therapeutic decision-making following kidney transplantation. A requisite step toward these goals is validation of markers that diagnose and/or predict relevant transplant endpoints. The Clinical Trials in Organ Transplantation-01 protocol is a multicenter observational study of biomarkers in 280 adult and pediatric first kidney transplant recipients. We compared and validated urinary mRNAs and proteins as biomarkers to diagnose biopsy-proven acute rejection (AR) and stratify patients into groups based on risk for developing AR or progressive renal dysfunction. Among markers tested for diagnosing AR, urinary CXCL9 mRNA (odds ratio [OR] 2.77, positive predictive value [PPV] 61.5%, negative predictive value [NPV] 83%) and CXCL9 protein (OR 3.40, PPV 67.6%, NPV 92%) were the most robust. Low urinary CXCL9 protein in 6-month posttransplant urines obtained from stable allograft recipients classified individuals least likely to develop future AR or a decrement in estimated glomerular filtration rate between 6 and 24 months (92.5-99.3% NPV). Our results support using urinary CXCL9 for clinical decision-making following kidney transplantation. In the context of acute dysfunction, low values can rule out infectious/immunological causes of injury. Absent urinary CXCL9 at 6 months posttransplant defines a subgroup at low risk for incipient immune injury.
Assuntos
Injúria Renal Aguda/urina , Biomarcadores/urina , Quimiocina CXCL9/urina , Rejeição de Enxerto/urina , Transplante de Rim , Injúria Renal Aguda/cirurgia , Adulto , Biomarcadores/sangue , Quimiocina CXCL9/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Humanos , Testes de Função Renal , Masculino , Prognóstico , Estudos Prospectivos , Fatores de RiscoRESUMO
Gene expression profiling of transplant recipient blood and urine can potentially be used to monitor graft function, but the multitude of protocols in use make sharing data and comparing results from different laboratories difficult. The goal of this study was to evaluate the performance of current methods of RNA isolation, reverse transcription and quantitative polymerase chain reaction (qPCR) and to test whether multiple centers using a standardized protocol can obtain the same results. Samples, reagents and detailed instructions were distributed to six participating sites that performed RNA isolation, reverse transcription and qPCR for 18S, PRF, GZB, IL8, CXCL9 and CXCL10 as instructed. All data were analyzed at a single site. All sites demonstrated proficiency in RNA isolation and qPCR analysis. Gene expression measurements for all targets and samples had correlations >0.938. The coefficient of variation of fold-changes between pairs of samples was less than 40%. All sites were able to accurately quantify a control sample of known concentration within a factor of 1.5. Collectively, we have formulated and validated detailed methods for measuring gene expression in blood and urine that can yield consistent results in multiple laboratories.
Assuntos
Perfilação da Expressão Gênica/normas , Regulação da Expressão Gênica , Transplante de Rim , RNA Mensageiro/análise , DNA Polimerase Dirigida por RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Perfilação da Expressão Gênica/métodos , Humanos , Limite de Detecção , RNA Mensageiro/genética , DNA Polimerase Dirigida por RNA/genética , Sensibilidade e Especificidade , Transplante HomólogoRESUMO
In an effort to reduce rejection, extend allograft survival and minimize complications, we hypothesized that robust immunosuppression during the first 6 months after transplantation would allow for the safe withdrawal of steroids. A total of 274 pediatric subjects were enrolled and received an anti-CD25 antibody, sirolimus, calcineurin inhibitor and steroids. At 6 months after transplantation, subjects were randomized to steroid withdrawal (n=73) versus continued low-dose steroids (n=59). This study was stopped prior to target enrollment because of the incidence of post-transplant lymphoproliferative disorder. At the time of study termination, 132 subjects had been randomized and were available for analysis. At 18 months after transplantation, there was no difference in the standardized height z score; however, the standardized height velocity was greater in the steroid withdrawal group compared to the control group (p=0.033). There were no differences in acute rejection episodes between treatment groups. The 3-year allograft survival rate was 84.5% in the control group and 98.6% in the steroid withdrawal group (p=0.002). The immunosuppressive protocol utilized in this study allowed for the withdrawal of steroids without an increased risk of rejection or allograft loss. However, the complications associated with the use of this immunosuppressive protocol were too high to recommend its routine use in pediatric patients.
Assuntos
Corticosteroides/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Doença Aguda , Adolescente , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Lactente , Transplante de Rim/efeitos adversos , Transplante de Rim/fisiologia , Transtornos Linfoproliferativos/etiologia , Masculino , Medição de Risco , Fatores de Tempo , Adulto JovemRESUMO
Pediatric renal transplant recipients were enrolled in a multicenter, randomized, double-blind trial of steroid withdrawal. Subjects received basiliximab, calcineurin inhibitor, sirolimus and steroids. Of 274 subjects enrolled, 19 (6.9%) subjects developed posttransplant lymphoproliferative disorder (PTLD). The relative hazard (RH) for PTLD was 5.3-fold higher in children aged < or =5 versus those >12 years (p = 0.0017). EBV seronegative subjects had a 4.7-fold higher RH compared to EBV positive subjects (p = 0.02). Among EBV donor+/recipient- (D+/R-) subjects, the RH increased by 6.1-fold (p = 0.0001). In a multivariate model, risk factors included recipient age < or =5 years (RH 3.2, 95% CI: 1.1-9.6, p = 0.034) and EBV D+/R- status (RH 7.7, 95% CI: 1.6-35.9, p = 0.010). Of 19 patients with PTLD, 17 are alive with functioning grafts and 2 lost their grafts, 1 of whom subsequently died of recurrent PTLD. This 'robust' immunosuppression protocol was associated with low rejection rates but an unacceptably high incidence of PTLD. The combination of basiliximab, calcineurin inhibitor, sirolimus and steroids resulted in over-immunosuppression in a high-risk pediatric population and we do not recommend its use. Future studies must include routine viral monitoring to permit early identification of viral activity and a protocol driven reduction of immunosuppression aimed at avoiding complications.
Assuntos
Corticosteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Transplante de Rim/imunologia , Transtornos Linfoproliferativos/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Proteínas Recombinantes de Fusão/uso terapêutico , Sirolimo/uso terapêutico , Adolescente , Corticosteroides/efeitos adversos , Adulto , Anticorpos Monoclonais/efeitos adversos , Basiliximab , Criança , Pré-Escolar , Ciclosporina/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Imunossupressores/efeitos adversos , Lactente , Masculino , Análise Multivariada , Proteínas Recombinantes de Fusão/efeitos adversos , Sirolimo/efeitos adversos , Tacrolimo/uso terapêuticoRESUMO
OBJECTIVE: Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated with prednisone according to a prespecified protocol. METHODS: RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission. Patients who experienced nonsevere relapses between months 1 and 18 were treated with a prednisone increase without a concomitant change in their nonglucocorticoid immunosuppressants, followed by a taper. RESULTS: Forty-four patients with a first nonsevere relapse were analyzed. In comparison to the 71 patients who maintained relapse-free remission over 18 months, these patients were more likely to have proteinase 3-ANCAs, diagnoses of granulomatosis with polyangiitis (Wegener's), and a history of relapsing disease at baseline. A prednisone increase led to remission in 35 patients (80%). However, only 13 patients (30%) were able to maintain second remissions through the followup period (mean 12.5 months); 31 patients (70%) had a second disease relapse, 14 of them with severe disease. The mean time to second relapse was 9.4 months (4.7 months in the group treated with RTX versus 13.7 months in the group treated with CYC/AZA; P < 0.01). Patients who experienced nonsevere relapses received more glucocorticoids than those who maintained remission (6.7 grams versus 3.8 grams; P < 0.01). CONCLUSION: Treatment of nonsevere relapses in AAV with an increase in glucocorticoids is effective in restoring temporary remission in the majority of patients, but recurrent relapses within a relatively short interval remain common. Alternative treatment approaches are needed for this important subset of patients.
Assuntos
Glucocorticoides/uso terapêutico , Granulomatose com Poliangiite/tratamento farmacológico , Poliangiite Microscópica/tratamento farmacológico , Prednisona/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Monoclonais Murinos/uso terapêutico , Autoanticorpos/imunologia , Azatioprina/uso terapêutico , Ciclofosfamida/uso terapêutico , Método Duplo-Cego , Feminino , Granulomatose com Poliangiite/imunologia , Humanos , Imunossupressores/uso terapêutico , Quimioterapia de Manutenção , Masculino , Poliangiite Microscópica/imunologia , Mieloblastina/imunologia , Peroxidase/imunologia , Recidiva , Indução de Remissão , Rituximab , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Dietary zinc (Zn) intake and selected biochemical indices of Zn status were studied longitudinally at monthly intervals in 46 pregnant middle-income women, 10 of whom received a daily supplement of 15 mg Zn. Mean dietary Zn intake for the nonsupplemented subjects (group A) was 11.3 +/- 4.1 mg/day (56% of the Recommended Dietary Allowances), and for the Zn-supplemented subjects (group B) was 21.7 mg/day (109% of the Recommended Dietary Allowance), including an average intake of 11.1 mg/day as supplemental Zn. The mean plasma Zn concentration of group A at 2 months gestation, 71.4 +/- 9.8 micrograms/dl, was 17% lower than that of nonpregnant control women, and continued to decline significantly (p less than 0.01) between 2 and 10 months gestation. Plasma Zn of group B did not differ significantly from group A at any stage of gestation. Mean serum alkaline phosphatase activity of group B was higher than that of group A at 7 of 8 months studied (p less than 0.05). The level of prenatal iron supplementation in group A was negatively correlated with alkaline phosphatase activity and plasma Zn in the 2nd and 3rd trimesters, respectively. It is concluded that an early and progressive decline in plasma Zn which is not influenced by Zn intake occurs during gestation. Tentative standards for lower limits of normal at monthly intervals have been suggested. The higher alkaline phosphatase activity of group B compared with group A suggested that the dietary Zn intake of the latter was suboptimal. Prenatal supplemental iron may adversely affect maternal Zn status.
Assuntos
Fenômenos Fisiológicos da Nutrição , Gravidez , Zinco/metabolismo , Adolescente , Adulto , Fosfatase Alcalina/sangue , Proteínas Sanguíneas/análise , Cobre/sangue , Dieta , Feminino , Cabelo/análise , Humanos , Ferro/uso terapêutico , Estudos Longitudinais , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Saliva/análise , Espectrofotometria Atômica , Zinco/uso terapêuticoRESUMO
Some patients with breast cancer currently undergo bone marrow biopsy to make clinical decisions regarding therapy; however, lobular carcinoma can be difficult to detect in routine histologic sections. The authors reviewed retrospectively all available bone marrow biopsies from patients with lobular carcinoma diagnosed between January, 1, 1989, and September, 25, 1997, at the City of Hope National Medical Center to identify useful morphologic features and to determine the utility of pan-keratin immunohistochemical (IHC) staining. A total of 65 biopsies from 54 patients were reviewed. Thirteen of the 65 biopsies were classified initially as containing metastatic tumor based on histologic features alone. With the addition of keratin IHC, seven additional cases of metastatic disease were detected. Forty of the 54 patients received stem cell replacement or autologous bone marrow transplantation. Disease-free survival after high-dose chemotherapy with stem cell replacement or autologous bone marrow transplantation was stratified into three groups based on hematoxylin and eosin (H&E) staining and IHC results. Two-year disease-free survival was 33% for the H&E-/IHC+ group versus 90% for the H&E-/IHC- group (p = 0.005) among patients clinically free of disease at the time of stem cell replacement or autologous bone marrow transplantation. Two-year disease-free survival was 0% in the H&E+/IHC+ group (p = 0.04, compared with the H&E-/ IHC+ group). The authors conclude that routine morphologic examination without the aid of keratin IHC is unreliable in detecting clinically relevant metastatic lobular carcinoma in bone marrow biopsies. These findings suggest that pan-keratin immunostaining may be indicated on bone marrow biopsy specimens from lobular carcinoma patients if the biopsy appears histologically negative for metastatic tumor on H&E sections.
Assuntos
Neoplasias da Medula Óssea/metabolismo , Neoplasias da Medula Óssea/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/secundário , Queratinas/análise , Adulto , Idoso , Biópsia , Neoplasias da Medula Óssea/patologia , Carcinoma Lobular/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Análise de Regressão , Estudos RetrospectivosRESUMO
OBJECTIVE: Results from previous investigations that examined the psychological side effects of theophylline have been inconsistent, and none have reported about inhaled corticosteroids. The objective of this study was to assess the relative psychological side effects of theophylline and beclomethasone in asthmatic children. METHODS: This was a multicenter, randomized, double-blind, parallel-groups study in which 102 asthmatic patients were assigned to one of two treatments: beclomethasone three times daily or theophylline twice daily. At baseline, 1 month, and 1 year, parents completed standardized behavioral questionnaires while the children received psychometric testing of attention and concentration, memory and learning, and problem-solving. RESULTS: Although power was sufficient to detect meaningful mean score changes, no consistent differential treatment effects were observed. Two significant treatment-by-period interactions were discordant, with one suggesting slightly better attention in the theophylline group, whereas the other indicated a small advantage in attention scores in the beclomethasone group. Numerous significant period effects revealed that behavior and cognitive test performance improved over the 1-year period, regardless of treatment, and confirmed a well established practice effect resulting from repeated administrations of such tests. CONCLUSIONS: Neither theophylline nor beclomethasone should be avoided out of concern for significant psychological side effects. The possibility remains that a subset of asthmatic children may be susceptible to such medication-induced changes; investigators have suggested that preschool children may be at particular risk, although no controlled studies with this age group have been conducted. Parental perceptions of medication side effects can be influenced by temporary effects present at initiation of treatment or by erroneous attribution of the psychological effects of the chronic illness. Reports of psychological changes in response to asthma medications must be addressed respectfully but objectively, with due consideration of available evidence and an awareness of other potential explanations.
Assuntos
Antiasmáticos/efeitos adversos , Asma/psicologia , Beclometasona/efeitos adversos , Glucocorticoides/efeitos adversos , Psicologia do Adolescente , Psicologia da Criança , Teofilina/efeitos adversos , Administração por Inalação , Adolescente , Comportamento do Adolescente/efeitos dos fármacos , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Beclometasona/uso terapêutico , Criança , Transtornos do Comportamento Infantil/induzido quimicamente , Método Duplo-Cego , Feminino , Glucocorticoides/uso terapêutico , Humanos , Masculino , Psicometria , Teofilina/uso terapêuticoRESUMO
Absence or deficit of FMR1 protein (FMRP) resulting from methylation of full mutation genes is the fundamental defect in fragile X syndrome. We used FMRP immunocytochemistry and detailed phenotypic assessment to investigate the relationship between degree of FMRP expression and the broad clinical spectrum of impairment in 80 individuals affected with fragile X syndrome. FMRP expression correlated with IQ in mosaic males (P=0.043), males with a partially methylated full mutation (P=0.0005), and females with a full mutation (P=0.046). In the females, FMRP expression also correlated with the number of fragile X physical features (P=0.0003). Even modest deficits in FMRP result in some manifestations of fragile X syndrome. In this initial study of 53 males, FMRP expression testing had a very high positive predictive value (100%, confidence interval of 29-100%) for a nonretarded IQ among males with expression of FMRP in > or = 50% of lymphocytes (3 males), suggesting that FMRP expression may have potential as a prognostic indicator in males with fragile X syndrome.
Assuntos
Síndrome do Cromossomo X Frágil/genética , Expressão Gênica/genética , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA , Adolescente , Adulto , Criança , Pré-Escolar , DNA/análise , Feminino , Proteína do X Frágil da Deficiência Intelectual , Humanos , Imuno-Histoquímica , Lactente , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Mosaicismo/genética , Fenótipo , Valor Preditivo dos Testes , PrognósticoRESUMO
Seventeen commercially available jet nebulizers from 15 commercial sources were studied (Acorn-I, Acorn-II, AquaTower, AVA-NEB, Cirrhus, Dart, DeVilbiss 646, Downdraft, Fan Jet, MB-5, Misty Neb, PARI LC JET, PARI-JET, Salter 8900, Sidestream, Updraft-II, Whisper Jet). All nebulizers were filled with 2 ml of saline solution plus 0.5 ml of albuterol and powered with the same source (DeVilbiss PulmoAide). We compared total output (TO), time for total output (TTO), and percent output in respirable range (PORR). The TO was obtained by weighing before nebulization and at the point of eight-fold decline in output. The TTO was calculated from initiation of nebulization to the point of eightfold decline in output. The PORR was measured by a laser particle analyzer in continuous nebulization to the same point of abrupt drop in output. The TO varied from 0.98 To 1.86 ml (p < 0.0001) with the Acorn-I, Acorn-II, Updraft-II, and Sidestream, significantly greater than the others (p < 0.05). The TTO varied from 2.28 to 20.95 min (p < 0.0001). The AquaTower, PARI LC JET and PARI-JET, DeVilbiss, and Dart were significantly shorter than the others (p < 0.05). The PORR varied from 21.89 to 71.95 percent (p < 0.0001). The Sidestream was significantly greater than all others (p < 0.05). The PARI LC JET and PARI-JET were, in turn, significantly greater than the remaining models (p < 0.05). To combine these characteristics, we calculated respirable particle delivery rate (RPDR) by dividing TO by TTO and multiplying by PORR. The RPDR varied from 0.03 ml/min to 0.26 ml/min (p < 0.0001). The PARI LC JET (0.24 ml/min) and the PARI-JET (0.26 mg/min) had a RPDR that was significantly greater than the other models except the AquaTower, which, however, had a markedly variable performance. The Sidestream (0.19 mg/ml) did not differ significantly from the above group, nor from the DeVilbiss and Downdraft. All other models had significantly lower outputs (p < 0.05). We conclude that the output characteristics of commercial nebulizers vary greatly and will impact on the time required for treatment as well as the total amount of drug delivered to the lungs.
Assuntos
Nebulizadores e Vaporizadores , AerossóisRESUMO
OBJECTIVE: To test the hypotheses that the burden of childhood asthma compromises psychological adaptation and that the degree of compromise increases with disease severity. DESIGN: The Childhood Asthma Management Program (CAMP) is a multicenter randomized clinical trial initiated and funded by the National Heart, Lung, and Blood Institute. SETTING: Study sites were located in Albuquerque, NM, Baltimore, Md, Boston, Mass, Denver, Colo, St Louis, Mo, San Diego, Calif, Seattle, Wash, and Toronto, Ontario. PARTICIPANTS: A total of 1,041 children aged 5 to 12 years were randomized to the trial after confirming their mild to moderate asthma. MAIN OUTCOME MEASURES: Psychological questionnaires administered at baseline to parents and participants assessed anxiety, depression, behavioral competence, social support, and family functioning. RESULTS: Psychological difficulty was not increased in this group of asthmatic children and their families. Psychological adaptation in the children was associated with the psychological adaptation of the family but not with disease-related variables. Scores from the Impact on Family Scale, a measure of family quality of life related to the child's illness, were associated more strongly with the overall psychological characteristics of the family and child and very little with disease characteristics or severity. CONCLUSIONS: Mild to moderate asthma has imposed modest effects on the daily life but not the psychological health of this group of children. Variation in the psychological characteristics of these children was, as is the case for most children, traceable to the overall psychological adaptation of their families.
Assuntos
Adaptação Psicológica , Asma/psicologia , Família/psicologia , Papel do Doente , Asma/reabilitação , Criança , Pré-Escolar , Efeitos Psicossociais da Doença , Feminino , Humanos , Masculino , Relações Pais-Filho , Determinação da PersonalidadeRESUMO
STUDY OBJECTIVE: To determine the bioavailability and renal elimination of isoniazid, acetylisoniazid, monoacetylhydrazine, diacetylhydrazine, aconiazide, and 2-formylphenoxyacetic acid. STUDY DESIGN: Randomized, double-blind, two-period, crossover phase I study. SETTING: Pharmacokinetics unit at a referral hospital that specializes in the treatment of mycobacterial infections. SUBJECTS: Twelve healthy volunteers selected from the hospital staff. INTERVENTIONS: Subjects received aconiazide tablets 650 mg (containing isoniazid 300 mg) and isoniazid tablets 300 mg. Blood and urine samples were collected over 24 hours after the dose. MEASUREMENTS AND MAIN RESULTS: Intact aconiazide and 2-formylphenoxyacetic acid were not detected in the serum. Compared with isoniazid tablets, aconiazide's relative bioavailability (based on the area under the serum concentration-time curve) was 50.7%; its relative maximum serum concentration was 13.4%. CONCLUSIONS: Isoniazid is less bioavailable after aconiazide tablets than after isoniazid tablets. The optimum dose of aconiazide remains to be determined.