RESUMO
The biological pathways which link lead (Pb) and long-term outcomes are unclear, though rodent models and a few human studies suggest Pb may alter the body's stress response systems, which over time, can elicit dysregulated stress responses with cumulative impacts. This study examined associations between prenatal and early childhood Pb exposure and adolescent allostatic load, an index of an individual's body burden of stress in multiple biological systems, and further examined sex-based associations. Among 391 (51% male) participants in the ELEMENT birth cohort, we related trimester-specific maternal blood Pb, 1-month postpartum maternal tibia and patella Pb, and child blood Pb at 12-24 months to an allostatic load index in adolescence comprised of biomarkers of cardiovascular, metabolic, neuroendocrine, and immune function. The results were overall mixed, with prenatal exposure, particularly maternal bone Pb, being positively associated with allostatic load, and early childhood Pb showing mixed results for males and females. In adjusted Poisson regression models, 1 mcg/g increase in tibia Pb was associated with a 1% change in expected allostatic load (IRR = 1.01; 95%CI 0.99, 1.02). We found a significant Pb × sex interaction (IRR = 1.05; 95%CI 1.01, 1.10); where males saw an increasing percent change in allostatic load as 12 month Pb levels increased compared to females who saw a decreasing allostatic load. Further examination of allostatic load will facilitate the determination of potential mechanistic pathways between developmental toxicant exposures and later-in-life cardiometabolic outcomes.
Assuntos
Alostase , Chumbo , Adolescente , Pré-Escolar , Feminino , Humanos , Masculino , Gravidez , Alostase/fisiologia , Biomarcadores , Estudos de Coortes , Família , Vitaminas , LactenteRESUMO
Few studies have related early life lead exposure to adolescent biological aging, a period characterized by marked increases in maturational tempo. We examined associations between prenatal and childhood lead exposure and adolescent biological age (mean 14.5 years) utilizing multiple epigenetic clocks including: intrinsic (IEAA), extrinsic (EEAA), Horvath, Hannum, PhenoAge, GrimAge, Skin-Blood, Wu, PedBE, as well as DNA methylation derived telomere length (DNAmTL). Epigenetic clocks and DNAmTL were calculated via adolescent blood DNA methylation measured by Infinium MethylationEPIC BeadChips. We constructed general linear models (GLMs) with individual lead measures predicting biological age. We additionally examined sex-stratified models and lead by sex interactions, adjusting for adolescent age and lead levels, maternal smoking and education, and proportion of cell types. We also estimated effects of lead exposure on biological age using generalized estimating equations (GEE). First trimester blood lead was positively associated with a 0.14 increase in EEAA age in the GLMs though not the GEE models (95%CI 0.03, 0.25). First and 2nd trimester blood lead levels were associated with a 0.02 year increase in PedBE age in GLM and GEE models (1st trimester, 95%CI 0.004, 0.03; 2nd trimester, 95%CI 0.01, 0.03). Third trimester and 24 month blood lead levels were associated with a -0.06 and -0.05 decrease in Skin-Blood age, respectively, in GLM models. Additionally, 3rd trimester blood lead levels were associated with a 0.08 year decrease in Hannum age in GLM and GEE models (95%CI -0.15, -0.01). There were multiple significant results in sex-stratified models and significant lead by sex interactions, where males experienced accelerated biological age, compared to females who saw a decelerated biological age, with respect to IEAA, EEAA, Horvath, Hannum, and PedBE clocks. Further research is needed to understand sex-specific relationships between lead exposure and measures of biological aging in adolescence and the trajectory of biological aging into young adulthood.
Assuntos
Envelhecimento , Chumbo , Masculino , Gravidez , Feminino , Humanos , Adolescente , Criança , Adulto Jovem , Adulto , Chumbo/toxicidade , Chumbo/metabolismo , Envelhecimento/genética , Envelhecimento/metabolismo , Metilação de DNA , Fumar , Biomarcadores/metabolismo , Epigênese GenéticaRESUMO
The adoptive transfer of antigen-specific T cells to establish immunity is an effective therapy for viral infections and tumors in animal models. The application of this approach to human disease would require the isolation and in vitro expansion of human antigen-specific T cells and evidence that such T cells persist and function in vivo after transfer. Cytomegalovirus-specific CD8+ cytotoxic T cell (CTL) clones could be isolated from bone marrow donors, propagated in vitro, and adoptively transferred to immunodeficient bone marrow transplant recipients. No toxicity developed and the clones provided persistent reconstitution of CD8+ cytomegalovirus-specific CTL responses.
Assuntos
Infecções por Citomegalovirus/prevenção & controle , Linfócitos T Citotóxicos/imunologia , Vacinação/métodos , Antígenos de Diferenciação de Linfócitos T/imunologia , Transplante de Medula Óssea/imunologia , Complexo CD3 , Linfócitos T CD4-Positivos/imunologia , Antígenos CD8/imunologia , Células Cultivadas , Humanos , Receptores de Antígenos de Linfócitos T/imunologiaRESUMO
We prospectively monitored 61 allogeneic BMT patients for evidence of CMV infection and disease starting 7 days prior to transplant until day 110 after transplant. Patients receiving pre- and post-transplantation ganciclovir prophylaxis were followed for the incidence of infection by the CMV antigenemia assay and shell vial cultures. The median age of all patients was 32 years (range 5-54 years). Fourteen (25%) of 57 evaluable patients became CMV antigenemia or culture positive. The incidence of culture or antigenemia positivity in CMV seropositive or seronegative patients with a seropositive donor was 29% (14 of 49 patients). The antigenemia assay became positive a median of 29 days (range 12-89 days) after BMT as compared to 46 days (range 26-98 days) by shell vial assay (P < 0.001). There were no cases of CMV disease in the first 110 days after transplant. This study demonstrates that despite the use of prophylactic ganciclovir, BMT patients developed CMV infection but did not progress to disease in this study, the CMV antigenemia assay may be used to monitor for CMV infection during prophylaxis, and the current regimens for CMV prophylaxis with ganciclovir may require further evaluation to determine an optimal regimen to prevent CMV infection.
Assuntos
Antivirais/administração & dosagem , Transplante de Medula Óssea/efeitos adversos , Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus/isolamento & purificação , Ganciclovir/administração & dosagem , Adolescente , Adulto , Antígenos Virais/análise , Criança , Pré-Escolar , Citomegalovirus/imunologia , Infecções por Citomegalovirus/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transplante HomólogoRESUMO
Respiratory syncytial virus (RSV) infections in adult BMT recipients are frequently complicated by fatal pneumonias. Therapy of RSV pneumonia with aerosolized ribavirin alone has been reported to be associated with a 70% mortality rate. Because immune globulin therapy has been reported to be beneficial, we conducted a prospective trial of combination therapy with aerosolized ribavirin and intravenous immunoglobulin (IVIG). Aerosolized ribavirin was administered at 20 mg/ml for 18 h a day and IVIG was administered at 500 mg/kg every other day for the length of ribavirin therapy. Four lots of IVIG were chosen with RSV microneutralization Ab titers of 1:2048 to 1:8102. Between 8 January and 3 March 1993, during a community outbreak, 19 (45%) of 42 hospitalized adult BMT recipients with an acute respiratory illness were documented to have RSV disease. Two-thirds of these infections were hospital-acquired. All 19 patients presented with signs and symptoms of an upper respiratory tract illness. Sixteen patients developed pneumonia. The mortality was 22% in nine patients with pneumonia in whom therapy was initiated prior to the onset of profound respiratory failure. In contrast, the mortality was 100% in three patients with pneumonia in whom therapy was initiated within 24 h of respiratory failure requiring mechanical ventilation and in four untreated patients. We conclude that RSV may cause devastating outbreaks of severe pneumonia among hospitalized adult BMT recipients. Early diagnosis and combination therapy with ribavirin and IVIG was associated with a favorable outcome.
Assuntos
Antivirais/uso terapêutico , Transplante de Medula Óssea/efeitos adversos , Infecção Hospitalar/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sinciciais Respiratórios/isolamento & purificação , Ribavirina/uso terapêutico , Administração por Inalação , Adulto , Infecção Hospitalar/mortalidade , Quimioterapia Combinada , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Vírus Respiratório Sincicial/etiologia , Infecções por Vírus Respiratório Sincicial/mortalidade , Ribavirina/administração & dosagem , Análise de SobrevidaRESUMO
CMV infection represents a major cause of morbidity and mortality in immunosuppressed bone marrow transplant (BMT) recipients. Life-threatening CMV infection was found to occur only in patients who did not develop a CMV-specific CD8+ Tc response. Therefore, methods to clone and expand CMV-specific Tc were developed to facilitate analysis of the specificity of the CD8+ Tc response to CMV responsible for protective immunity in seropositive donors, and to permit adoptive transfer of in vitro expanded CMV-specific Tc derived from bone marrow donors into immunocompetent HLA-matched BMT recipients to augment resistance to CMV. The immunodominant class I-restricted Tc response present in healthy seropositive individuals was found to be specific for a conserved CMV antigen introduced into the cytoplasm and presented shortly following viral penetration and uncoating, and did not require endogenous viral gene expression and protein synthesis. Thus, the protective immune response to CMV mediates lysis of virally-infected cells prior to virion assembly. Processing of viral proteins and access to presentation in the context of class I MHC molecules immediately following infection of target cells was selective for internal virion proteins, such as the tegument protein pp65. By contrast, presentation by infected cells of GB, the major CMV envelope protein, or IE, the major regulatory protein, was delayed due to a requirement for endogenous synthesis in infected cells, and CD8+ Tc specific for these proteins were detected in low frequency as compared to the immundominant response.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Infecções por Citomegalovirus/terapia , Citomegalovirus/imunologia , Imunoterapia Adotiva , Linfócitos T/imunologia , Antígenos Virais/análise , Antígenos CD8/análise , Células Clonais , HumanosRESUMO
We vaccinated six captive badgers housed with five controls, and monitored blood antibody titers and white cell counts of both groups for 63 days postvaccination between 29 August and 3 December 1992. Five vaccinated badgers responded with antibody titers ranging from 1:64 to 1:1024 by 63 days postvaccination, whereas the sixth badger did not respond. Treatment badgers also had significant (P < 0.05) decreases in lymphocytes on days 16, 29, and 63. No badgers developed clinical signs of distemper. Control badgers did not produce antibodies against CD virus; thus, the vaccine virus probably was not transmitted between treatment and control animals. The vaccine appears safe for use in healthy badgers, but additional safety and efficacy study is needed.
Assuntos
Anticorpos Antivirais/sangue , Carnívoros , Vírus da Cinomose Canina/imunologia , Cinomose/prevenção & controle , Vacinas Virais , Animais , Feminino , Masculino , Testes de Neutralização/veterinária , Vacinação/veterinária , Vacinas Virais/imunologiaRESUMO
Phosphonoacetic acid and phosphonoformate were examined as inhibitors of Herpesvirus sylvilagus replication in cultured cells. Both drugs produced significant inhibition at a minimum concentration of 25 micrograms per milliliter.
Assuntos
Herpesviridae/efeitos dos fármacos , Compostos Organofosforados/farmacologia , Ácido Fosfonoacéticos/farmacologia , Relação Dose-Resposta a Droga , Foscarnet , Herpesviridae/crescimento & desenvolvimento , Ácido Fosfonoacéticos/análogos & derivados , Replicação Viral/efeitos dos fármacosRESUMO
The purposes of this review are to examine the epidemiology of disease due to cytomegalovirus (CMV) in recipients of autologous and allogeneic marrow transplants and to compare different antiviral regimens used for the prevention of such disease in recipients of allogeneic marrow transplants, with an emphasis on ganciclovir. In seven studies, ganciclovir reduced the incidence of CMV infection and disease after allogeneic marrow transplantation. In one study mortality after transplantation was reduced because of a decreased rate of CMV-related death among ganciclovir-treated patients. Ganciclovir was effective when given to all CMV-seropositive patients (prophylaxis) or to patients who were considered at high risk for CMV disease on the basis of a positive surveillance culture (early treatment). The effectiveness of ganciclovir for the prevention of CMV infection and disease is limited by drug-induced neutropenia. Experience with other antiviral agents, such as foscarnet, has been limited. Initial studies of the adoptive transfer of CMV-specific CD8+ cytotoxic T cells have been conducted. In short, ganciclovir is currently effective for the prevention of CMV disease in allogeneic marrow transplant recipients, but its usefulness is limited by neutropenia. Future studies must be aimed at confining the toxicity of ganciclovir to patients at the highest risk for CMV disease.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Infecções por Citomegalovirus/prevenção & controle , Ensaios Clínicos como Assunto , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/etiologia , Foscarnet/uso terapêutico , Ganciclovir/uso terapêutico , HumanosRESUMO
To determine whether HHV-6 infection induces expression and production of IL-10 and IL-12 in monocytes/macrophages, and to explore the influence of IFN-gamma on cytokine production in HHV-6-infected cells, expression and production of IL-10 and IL-12 were evaluated through reverse transcription-polymerase chain reaction (RT-PCR) and sandwich ELISA. HHV-6 infection induced the expression and the production of IL-10 and IL-12 in monocytes and THP-1 cells. Kinetic study showed that the expression of IL-12 mRNA decreased with accumulation of IL-10 mRNA. Expression and production of IL-12 were markedly increased when anti-human IL-10 MoAbs were added to the cultures, implying that endogenous IL-10 induced by HHV-6 inhibited IL-12 production. Addition of increasing concentrations of IFN-gamma to the cultures of HHV-6-infected cells enhanced the expression of IL-12 gene, while the accumulation of IL-10 mRNA was down-regulated. Determination of protein levels of IL-10 and IL-12 by ELISA also showed that IFN-gamma increased IL-12 and decreased IL-10 production. These results suggest that IFN-gamma regulates the production of IL-10 and IL-12 at transcriptional level mainly through inhibiting endogenous IL-10 production in HHV-6-infected monocyte/macrophage lineage.
Assuntos
Infecções por Herpesviridae/imunologia , Herpesvirus Humano 6 , Interferon gama/imunologia , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Monócitos/imunologia , Anticorpos Bloqueadores , Anticorpos Monoclonais/imunologia , Células Cultivadas , Regulação para Baixo , Expressão Gênica , Humanos , Interleucina-10/genética , Interleucina-12/genética , Leucócitos Mononucleares/imunologia , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Linfócitos T/imunologiaRESUMO
Both myxoma and fibroma viruses were found to be sensitive in vitro to the effects of phosphonoacetic acid. Detectable myxoma virus replication was inhibited at a drug concentration of 100 micrograms/ml. Fibroma virus replication was inhibited at a concentration of 500 micrograms/ml. Because of this difference in sensitivity, myxoma virus was used to infect rabbits to test that efficacy of phosphonoacetic acid in the treatment of a systemic viral disease. Rabbits were given 400 mg kg-1 day-1 of phosphonoacetic acid subcutaneously in two injections. Phosphonoacetic acid-treated animals showed a reduction in the severity of disease. Neither serum viral antigen nor infectious virus could be detected. In phosphate buffered saline-treated animals both serum viral antigen and infectious virus were found. All animals treated with phosphate buffered saline died of myxomatosis.
Assuntos
Antivirais , Myxoma virus/efeitos dos fármacos , Mixomatose Infecciosa/tratamento farmacológico , Compostos Organofosforados/farmacologia , Ácido Fosfonoacéticos/farmacologia , Animais , Anticorpos Antivirais/análise , Myxoma virus/imunologia , Ácido Fosfonoacéticos/uso terapêutico , Coelhos , Ensaio de Placa Viral , Replicação Viral/efeitos dos fármacosRESUMO
In this report, interleukin 10(IL-10) and other cytokines were evaluated through reverse transcription-polymerase chain reaction (RT-PCR) and sandwich ELISA to explore possible immune pathogenesis of human herpesvirus 6 (HHV-6) infection. The results showed that IL-10 was expressed in HHV-6 infected monocytes. Kinetic studies found that transcription of IL-1 beta, IL-6 and TNF-alpha mRNA decreased with accumulation of IL-10 mRNA. When endogenous IL-10 induced by HHV-6 was blocked using anti-human IL-10 monoclonal antibody, the production and the expression of TNF-alpha, IL-1 beta and IL-6 markedly increased as compared with infection by HHV-6 alone, indicating that endogenous IL-10 inhibited cytokine production at the transcription level in HHV-6 infected monocytes. IL-10 has been shown to suppress Th1 response and down-regulate monocyte/macrophage function. The data from our studies suggest that disturbance of immune function and latent infection resulting from HHV-6 infection might partially contribute to endogenous IL-10 production.
Assuntos
Herpesvirus Humano 6/imunologia , Interleucina-10/biossíntese , Monócitos/metabolismo , Linfócitos T/citologia , Células Cultivadas , Humanos , Interleucina-10/genética , Interleucina-6/biossíntese , Interleucina-6/genética , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Infecções por Roseolovirus/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genéticaRESUMO
Detection of cytomegalovirus (CMV) antigenemia was compared with shell vial centrifugation cultures for rapid detection of CMV infection. In a prospective study, 59 CMV seropositive patients were monitored weekly during the first 100 days after allogeneic marrow transplantation for virus excretion from urine, throat, and blood and for antigenemia by direct staining of peripheral leukocytes using an antibody pool directed against pp 65. Antigenemia was present in 21 of 22 patients with culture-proven CMV infection and in 3 of 37 without culture-proven CMV infection (sensitivity 95%, specificity 91%). The median time of onset of antigenemia and shell vial cultures was day 47 and 55 after transplant, respectively (P = .0006). Among patients who developed CMV disease without preceding cultures, antigenemia was detected in all patients with CMV pneumonia (N = 6) and in two of three patients with gastrointestinal disease by a median of 10 and 7 days, respectively, before the onset of disease (P = .0002). Levels of antigenemia were significantly higher in patients with disease or viremia than in patients with excretion from urine or throat (P less than .05). Whether the antigenemia assay is more sensitive than rapid culture methods to focus antiviral prophylaxis in marrow transplant patients must be determined in controlled studies.
Assuntos
Antígenos Virais/análise , Transplante de Medula Óssea/efeitos adversos , Citomegalovirus/imunologia , Leucócitos/microbiologia , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/diagnóstico , Imunofluorescência , Ganciclovir/uso terapêutico , Humanos , Leucócitos/imunologia , Estudos ProspectivosRESUMO
The effects of ketoconazole alone and in combination with acyclovir and adenine arabinoside upon the replication of herpes simplex virus types 1 and 2 (HSV-1 and -2) were investigated by using a yield reduction assay. Ketoconazole demonstrated antiviral activity against HSV-1 and -2 and synergistic antiviral activity when it was combined with acyclovir. Combinations of ketoconazole with adenine arabinoside resulted in either interference or indifference. The effects of ketoconazole upon the protein synthesis of HSV-2-infected cells were also determined in an effort to define the mechanism of action for the antiviral activity of ketoconazole. There was no reduction of HSV proteins when compared with acyclovir. These findings suggest that further investigations of the use of ketoconazole for the treatment of HSV infections are warranted.
Assuntos
Cetoconazol/farmacologia , Simplexvirus/efeitos dos fármacos , Aciclovir/farmacologia , Animais , Linhagem Celular , Interações Medicamentosas , Humanos , Cetoconazol/antagonistas & inibidores , Simplexvirus/metabolismo , Vidarabina/farmacologia , Proteínas Virais/biossínteseRESUMO
OBJECTIVE: To study the efficacy and toxicity of ganciclovir prophylaxis given at engraftment to cytomegalovirus (CMV)-seropositive, allogeneic bone marrow transplant recipients. DESIGN: A double-blind, placebo-controlled study. SETTING: The Fred Hutchinson Cancer Research Center, a referral marrow transplant center. PATIENTS: This study was conducted from November 1990 to August 1991. Ninety-three CMV-seropositive patients were entered into the study before marrow transplant, with 64 patients randomized to receive the study drug after marrow engraftment. Thirty-one patients received placebo, and 33 received ganciclovir. The dose was 5 mg/kg body weight administered intravenously twice daily for 5 days, followed by once daily until day 100 after transplant. MEASUREMENTS: Outcome variables measured were CMV infection, monitored by weekly cultures, and neutropenia, defined as an absolute neutrophil count of 0.750 x 10(-9)/L for 2 consecutive days. Cytomegalovirus disease and mortality were secondary end points. RESULTS: Fourteen (45%) placebo recipients developed CMV infection in the first 100 days after marrow transplant compared with one (3%) ganciclovir recipient (P < 0.001). Nine (29%) placebo recipients developed CMV disease compared with no cases in the ganciclovir group during the first 100 days (P < 0.001). Neutropenia occurred in 10 ganciclovir recipients (30%) compared with no cases in the placebo group during the period of observation (P = 0.001). In a separate analysis, patients on ganciclovir who became neutropenic were at greater risk (relative risk, 4.3; P = 0.02) for bacterial infection. Mortality between the two study groups did not differ statistically at 100 and 180 days. CONCLUSION: Ganciclovir given prophylactically after engraftment is effective in suppressing CMV infection and disease. Neutropenia is an important side effect of ganciclovir use and is associated with an increased risk for bacterial infection.
Assuntos
Transplante de Medula Óssea , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/uso terapêutico , Infecções Oportunistas/prevenção & controle , Adolescente , Adulto , Transplante de Medula Óssea/mortalidade , Criança , Pré-Escolar , Infecções por Citomegalovirus/diagnóstico , Método Duplo-Cego , Feminino , Ganciclovir/efeitos adversos , Infecções por Herpesviridae/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Infecções Oportunistas/microbiologia , Testes SorológicosRESUMO
Protection from cytomegalovirus (CMV) disease in immunocompromised hosts has been shown to correlate with recovery of the host virus-specific CD8+ T-cell response. The administration of ganciclovir to immunosuppressed transplant recipients as antiviral prophylaxis has reduced the early risk of CMV disease, but late disease is observed with increased frequency, suggesting that recovery of the CMV-specific T-cell responses necessary for protective immunity may be delayed in these patients. Therefore, we evaluated reconstitution of CMV-specific T-cell responses in 47 bone marrow transplant (BMT) recipients entered on a randomized placebo-controlled study of ganciclovir. The study drug was initiated at a mean of 24 days after BMT. At day 30 to 40, a minority of patients had recovery of T-cell immunity to CMV and the frequency of reconstitution was equivalent in patients randomized to ganciclovir or placebo. The failure of ganciclovir to effect early reconstitution may reflect the short duration of treatment. Early recovery was associated with the infusion of BM from a CMV seropositive donor (P = .07 for CD8+ cytotoxic T cell (CTL), P = .04 for CD4+ Th). Between day 40 and day 90, recovery of deficient CD8+ and CD4+ CMV-specific T-cell responses occurred in the majority of individuals that received placebo, but in a minority of ganciclovir recipients. Two cases of late-onset CMV disease occurred in ganciclovir recipients. In all patients, the presence of a CTL response to CMV conferred protection from subsequent CMV disease (P = .005), and these protective CTL responses are shown to be specific for structural virion proteins similar to the responses in immunocompetent CMV seropositive individuals. These data confirm the importance of CMV-specific T-cell responses and suggest that a delay in recovery of these responses as a result of ganciclovir prophylaxis may contribute to the occurrence of late CMV disease.
Assuntos
Transplante de Medula Óssea/imunologia , Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus/imunologia , Ganciclovir/uso terapêutico , Linfócitos T/imunologia , Adolescente , Adulto , Feminino , Doença Enxerto-Hospedeiro/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Transplante HomólogoRESUMO
The protective efficacies of bacille Calmette-Guérin (BCG) and Mycobacterium avium-intracellulare (MAI) were examined in guinea pigs that were infected by the respiratory route with one of three strains of Mycobacterium tuberculosis: two strains obtained as recent sputum isolates from an ongoing BCG trial in south India and laboratory strain H37Rv. Groups of animals were given all combinations of two treatments with BCG, MAI, or placebo and than challenged. The numbers of tubercle bacilli recovered from the primary lung lesions, primary lesion-free lung lobes, and spleens were used to estimate the relative protective effects of the various treatments. In general, BCG and MAI protected equally well against the low-virulence strain of M. tuberculosis. For the two more virulent strains the results were less clear; however, a substantial protective effect of MAI compared with BCG was noted. Infection with MAI did not significantly alter the capacity of BCG to protect against tuberculous infection.
Assuntos
Vacina BCG/imunologia , Vacinas Bacterianas/imunologia , Mycobacterium avium/imunologia , Mycobacterium/imunologia , Micobactérias não Tuberculosas/imunologia , Tuberculose Pulmonar/imunologia , Animais , Feminino , Cobaias , Imunidade , Pulmão/microbiologia , Masculino , Mycobacterium tuberculosis/isolamento & purificação , Teste Tuberculínico , Tuberculose Pulmonar/microbiologia , VacinaçãoRESUMO
BACKGROUND: Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after allogeneic bone marrow transplantation. We conducted a controlled trial of ganciclovir for the early treatment of CMV infection in asymptomatic recipients of bone marrow transplants whose surveillance cultures for CMV became positive. METHODS: Bone marrow--allograft recipients who were seropositive for CMV antibodies or who received seropositive marrow were screened for CMV excretion by culture of throat swabs, blood, urine, or bronchoalveolar-lavage fluid. In this double-blind trial, 72 patients who had marrow engraftment and were excreting virus were randomly assigned to receive either placebo or ganciclovir (5 mg per kilogram of body weight twice a day for one week, followed by 5 mg per kilogram per day) for the first 100 days after transplantation. Patients were followed for the development of biopsy-confirmed CMV disease, ganciclovir-related toxicity, and survival. RESULTS: Between assignment to the study drug and day 100 after transplantation, CMV disease developed in only 1 of the 37 patients assigned to receive ganciclovir (3 percent), but in 15 of the 35 patients assigned to receive placebo (43 percent, P less than 0.00001). The ganciclovir recipients had rapid suppression of virus excretion; 85 percent had negative cultures after one week of treatment, as compared with 44 percent of the placebo group (P = 0.001). The principal toxic reaction was neutropenia; 11 ganciclovir recipients had an absolute neutrophil count below 0.75 x 10(9) per liter, as compared with 3 placebo recipients (P = 0.052). Treatment was discontinued in 11 ganciclovir recipients and 1 placebo recipient because of neutropenia (P = 0.003). After treatment was stopped, the neutrophil count recovered in all patients. Overall survival was significantly greater in the ganciclovir group than in the placebo group both 100 days and 180 days after transplantation (P = 0.041 and 0.027, respectively). CONCLUSIONS: Early treatment with ganciclovir in patients with positive surveillance cultures reduces the incidence of CMV disease and improves survival after allogeneic bone marrow transplantation.
Assuntos
Transplante de Medula Óssea , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/uso terapêutico , Adolescente , Adulto , Líquido da Lavagem Broncoalveolar/microbiologia , Criança , Pré-Escolar , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/microbiologia , Infecções por Citomegalovirus/mortalidade , Feminino , Ganciclovir/administração & dosagem , Ganciclovir/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Valor Preditivo dos Testes , Simplexvirus/isolamento & purificação , Fatores de Tempo , Transplante HomólogoRESUMO
Of 1506 marrow transplant patients from 1980 through 1986 reviewed for risk factors for invasive candidal infection defined by positive blood cultures, biopsy, or histologic evidence of tissue invasion, 171 (11.4%) had invasive infection, with a significantly higher incidence in the more recent years of review; 40% (69 patients) had evidence of tissue-invasive disease without fungemia. Of 102 patients with fungemia, 45% had candidemia alone with a mortality of 39%. Mortality in patients with tissue involvement was 90% with or without fungemia. Factors that increased infection were age, acute graft-versus-host disease, and donor mismatch. Factors that decreased infection included conditioning with 12 Gy of fractionated irradiation and cyclophosphamide, transplantation for aplastic anemia, and more rapid engraftment. Among fungemic patients, the number of days of fungemia was a risk factor for tissue invasion while more rapid engraftment was protective.
Assuntos
Transplante de Medula Óssea , Candidíase/etiologia , Adolescente , Adulto , Candidíase/sangue , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Regressão , Estudos Retrospectivos , Fatores de RiscoRESUMO
The objectives of this study were to estimate the frequency of cytomegalovirus (CMV) pneumonia and describe its clinical and radiological presentation in adult nontransplantation patients with cancer. Of the 10,441 autopsies performed at M. D. Anderson Cancer Center (Houston) during the period of January 1964 through December 1990, 9,029 were evaluable. Twenty histopathologically confirmed cases of CMV pneumonia were found, representing a frequency of 2.2 cases per 1,000 autopsies. When the frequency of CMV pneumonia was compared for the periods 1964-1979 (1.5 cases per 1,000 autopsies) and 1980-1990 (4.6 cases per 1,000 autopsies), a statistically significant increase due to an increase in the number of patients with solid malignancies was observed (P < .05). CMV pneumonia is an uncommon diagnosis at autopsy for adult nontransplantation patients with cancer and is usually found in conjunction with a disseminated neoplastic process.