RESUMO
Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Recém-Nascido , Humanos , Doadores de Tecidos , Linfócitos T , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Diagnóstico Precoce , Efeitos Psicossociais da Doença , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Estudos Retrospectivos , Doadores não Relacionados , Condicionamento Pré-TransplanteRESUMO
BACKGROUND: Reliable data on the course and treatment of pediatric COVID-19 ("corona virus disease 2019") in immunosuppressed patients with rheumatic diseases are missing. AIM: Delineation of individual strategies of the members of the Society for Pediatric Rheumatology (GKJR) in cases of COVID-19. METHODS: In May 2020 all GKJR members were invited to take part in an online survey. Opinion data regarding an approach using disease-modifying anti-rheumatic drugs (DMARD) in cases of COVID-19 as well as the readiness to use new therapeutic agents in patients in different stages of the disease were collected. RESULTS: A total of 71 respondents (27.3% of all contacted pediatric rheumatologists) took part in the survey. Of these 28.2% had treated patients with COVID-19. Over 95% of the respondents did not support a preventive adaptation of the anti-rheumatic treatment during the SARS-CoV2 pandemic. In the case of outpatients under immunosuppression with proven COVID-19 more than 50% of the respondents would refrain from administering intravenous high-dose steroids, cyclophosphamide, anti-CD20 antibodies as well as BAFF, CTLA4 and TNF-alpha blockades. Conversely, >70% of the respondents would continue the treatment with nonsteroidal anti-inflammatory drugs, hydroxychloroquine (HCQ), oral steroids, mycophenolate, IL1 blockade and immunoglobulins (Ig). In the case of inpatients 74.6% of respondents would consider targeted COVID-19 treatment. In stable patients with oxygen treatment (stage I) HCQ (18.3%), azithromycin (16.9%) and Ig (9.9%) were most frequently used. In cases of early signs (stage II) or a manifest cytokine storm (stage III) anakinra (40.8% for stage II and 46.5% for stage III), tocilizumab (26.8% and 40.8%, respectively), steroids (25.4% and 33.8%, respectively) and remdesivir (29.6% and 38.0%, respectively) were most frequently used. The need for a personalized approach based on the current clinical situation was emphasized by many respondents. CONCLUSION: The currently low prevalence of COVID-19 in Germany limits the general clinical experience. Therefore, the presented results have to be interpreted with caution and mostly as hypothetical treatment considerations. It is to be expected that there will always be a limited amount of evidence on pediatric COVID-19; therefore, a continuous and critical exchange of expert opinions on the treatment strategies is important.
Assuntos
Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Reumatologistas , Antirreumáticos/uso terapêutico , Betacoronavirus , COVID-19 , Criança , Infecções por Coronavirus/tratamento farmacológico , Alemanha , Humanos , Pandemias , SARS-CoV-2 , Inquéritos e Questionários , Tratamento Farmacológico da COVID-19RESUMO
Immunologic tolerance to solid organ and islet cell grafts has been achieved in various rodent models by using antibodies directed at CD45RB and Tim-1. We have shown that this form of tolerance depends on regulatory B cells (Bregs). To elucidate further the mechanism by which Bregs induce tolerance, we investigated the requirement of natural killer (NK) and NKT cells in this model. To do so, hyperglycemic B6, µMT, Beige, or CD1d-/- mice received BALB/c islet grafts and treatment with the tolerance-inducing regimen consisting of anti-CD45RB and anti-TIM1. B6 mice depleted of both NK and NKT cells by anti-NK1.1 antibody and mice deficient in NK activity (Beige) did not develop tolerance after dual-antibody treatment. In contrast, transplant tolerance induction was successful in CD1d-/- recipients (deficient in NKT cells), indicating that NK, but not NKT, cells are essential in B cell-dependent tolerance. In addition, reconstitution of Beige host with NK cells restored the ability to induce transplant tolerance with dual-antibody treatment. Transfer of tolerance by B cells from tolerant mice was also dependent on host Nk1.1+ cells. In conclusion, these results show that regulatory function of B cells is dependent on NK cells in this model of transplantation tolerance.
Assuntos
Linfócitos B Reguladores/imunologia , Transplante das Ilhotas Pancreáticas/imunologia , Células Matadoras Naturais/imunologia , Células T Matadoras Naturais/imunologia , Tolerância ao Transplante/imunologia , Animais , Anticorpos Monoclonais/imunologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
The full potential of islet transplantation will only be realized through the development of tolerogenic regimens that obviate the need for maintenance immunosuppression. Here, we report an immunotherapy regimen that combines 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (ECDI)-treated donor lymphoid cell infusion (ECDI-DLI) with thymoglobulin, anti-interleukin-6 receptor antibody and rapamycin to achieve prolonged allogeneic islet graft survival in a nonhuman primate (NHP) model. Prolonged graft survival is associated with Treg expansion, donor-specific T cell hyporesponsiveness and a transient absence of donor-specific alloantibody production during the period of graft survival. This regimen shows promise for clinical translation.
Assuntos
Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/imunologia , Imunossupressores/uso terapêutico , Transplante das Ilhotas Pancreáticas/imunologia , Isoantígenos/imunologia , Transfusão de Linfócitos/métodos , Linfócitos T Reguladores/imunologia , Animais , Quimioterapia Combinada , Rejeição de Enxerto/imunologia , Projetos Piloto , PrimatasRESUMO
Defective glucagon secretion during hypoglycemia after islet transplantation has been reported in animals and humans with type 1 diabetes. To ascertain whether this is true of islets from nondiabetic humans, subjects with autoislet transplantation in the intrahepatic site only (TP/IAT-H) or in intrahepatic plus nonhepatic (TP/IAT-H+NH) sites were studied. Glucagon responses were examined during stepped hypoglycemic clamps. Glucagon and symptom responses during hypoglycemia were virtually absent in subjects who received islets in the hepatic site only (glucagon increment over baseline = 1 ± 6, pg/mL, mean ± SE, n = 9, p = ns; symptom score = 1 ± 1, p = ns). When islets were transplanted in both intrahepatic + nonhepatic sites, glucagon and symptom responses were not significantly different than Control Subjects (TP/IAT-H + NH: glucagon increment = 54 ± 14, n = 5; symptom score = 7 ± 3; control glucagon increment = 67 ± 15, n = 5; symptom score = 8 ± 1). In contrast, glucagon responses to intravenous arginine were present in TP/IAT-H recipients (TP/IAT: glucagon response = 37 ± 8, n = 7). Transplantation of a portion of the islets into a nonhepatic site should be seriously considered in TP/IAT to avoid posttransplant abnormalities in glucagon and symptom responses to hypoglycemia.
Assuntos
Diabetes Mellitus Tipo 1/terapia , Glucagon/metabolismo , Hipoglicemia/metabolismo , Transplante das Ilhotas Pancreáticas/fisiologia , Ilhotas Pancreáticas/patologia , Adulto , Arginina/metabolismo , Arginina/uso terapêutico , Autoenxertos/fisiologia , Glicemia/metabolismo , Peptídeo C/sangue , Feminino , Humanos , Hipoglicemia/sangue , Hipoglicemia/terapia , Insulina/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Pancreatectomia , Pancreatopatias/cirurgia , Pancreatopatias/terapia , Ductos Pancreáticos/patologia , Pancreatite/terapia , Resultado do TratamentoRESUMO
Preexisting serum antibodies have long been associated with graft loss in transplant recipients. While most studies have focused on HLA-specific antibodies, the contribution of non-HLA-reactive antibodies has been largely overlooked. We have recently characterized mAbs secreted by B cell clones derived from kidney allograft recipients with rejection that bind to apoptotic cells. Here, we assessed the presence of such antibodies in pretransplant serum from 300 kidney transplant recipients and examined their contribution to the graft outcomes. Kaplan-Meier survival analysis revealed that patients with high pretransplant IgG reactivity to apoptotic cells had a significantly increased rate of late graft loss. The effect was only apparent after approximately 1 year posttransplant. Moreover, the association between pretransplant IgG reactivity to apoptotic cells and graft loss was still significant after excluding patients with high reactivity to HLA. This reactivity was almost exclusively mediated by IgG1 and IgG3 with complement fixing and activating properties. Overall, our findings support the view that IgG reactive to apoptotic cells contribute to presensitization. Taking these antibodies into consideration alongside anti-HLA antibodies during candidate evaluation would likely improve the transplant risk assessment.
Assuntos
Apoptose/imunologia , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoglobulina G/sangue , Falência Renal Crônica/mortalidade , Transplante de Rim/efeitos adversos , Aloenxertos , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/mortalidade , Humanos , Células Jurkat , Falência Renal Crônica/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Taxa de SobrevidaRESUMO
BACKGROUND: The CD3 co-receptor complex is essential for signal transduction after specific binding of the T-cell receptor (TCR). CD3E encodes the CD3ε chain, one of the protein components (γ-, δ-, ε- and ζ-chain) of the CD3 co-receptor. As previously reported in one family CD3ε deficiency causes SCID. PATIENT: We report on a patient with SCID due to CD3ε deficiency treated by HLA-haploidentical stem cell transplantation (SCT) (donor: mother) 15 years ago which resulted in development of normal T- and B-cell immunity. Despite conditioning donor cell engraftment was confined to T cells, while all other blood cell lineages remained of patient origin (split chimerism). In spite of normal functions, T-cell numbers never reached normal levels and naïve CD45+RA+ T-cells remained low. At 6 years after SCT the patient developed signs of humoral immunodeficiency, requiring regular substitution of IgG. RESULTS: In a retrospective genetic work up 11 years after SCT, a homozygous splice site mutation in CD3E was identified resulting in the loss of CD3ε protein. The loss of B-cell function as observed in the patient was reflected by a lack of switched memory B cells. To rule out a primary role of CD3ε in B-cell function we studied expression of CD3E in B-cells which was found not to be expressed. DISCUSSION: The clinical presentation of a secondary loss of specific humoral immunity in this constellation of split chimerism after allogeneic haploidentical SCT is unusual and unexpected in a patient with a primary T-cell defect. A most likely explanation is the gradual loss of T-helper-cell function.
Assuntos
Complexo CD3/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade , Imunoglobulina G/administração & dosagem , Imunodeficiência Combinada Severa/terapia , Linfócitos B/imunologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Triagem de Portadores Genéticos , Genótipo , Haploidia , Homozigoto , Humanos , Imunidade Humoral/genética , Imunidade Humoral/imunologia , Lactente , Recém-Nascido , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
It has been suggested that the number of exception model for end-stage liver disease (MELD) points for hepatocellular carcinoma (HCC) overestimates mortality risk. Average MELD at transplant, a measure of organ availability, correlates with mortality on an intent-to-treat basis and varies by donation service area (DSA). We analyzed Scientific Registry of Transplant Recipients data from 2005 to 2010, comparing transplant and death parameters for patients transplanted with HCC exception points to patients without HCC diagnosis (non-HCC), to determine whether the two groups were impacted differentially by DSA organ availability. HCC candidates are transplanted at higher rates than non-HCC candidates and are less likely to die on the waitlist. Overall risk of death trends downward by 1% per MELD point (p = 0.65) for HCC, but increases by 7% for non-HCC patients (p < 0.0001). The difference in the change of mortality with MELD is statistically significant between HCC and non-HCC candidates p < 0.0001. Posttransplant risk of death trends downward by 2% per MELD point (p = 0.28) for HCC patients, but increases by 3% per MELD point in non-HCC patients (p = 0.027), with the difference being statistically significant with p < 0.005. In summary, increasing wait time impacts HCC candidates less than non-HCC candidates and under increased competition for donor organs, HCC candidates' advantage increases.
Assuntos
Carcinoma Hepatocelular/cirurgia , Doença Hepática Terminal/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Seleção de Pacientes , Doadores de Tecidos/provisão & distribuição , Obtenção de Tecidos e Órgãos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/mortalidade , Feminino , Geografia , Acessibilidade aos Serviços de Saúde , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Listas de Espera/mortalidadeRESUMO
Recent studies of human oocytes have demonstrated an enrichment for distal exchanges among meiosis I (MI) nondisjunction events and for proximal exchanges among meiosis II (MII) events. Our characterization of 103 cases of spontaneous X chromosome nondisjunction in Drosophila oocytes strongly parallels these observations. The recombinational histories of MI (97/103) and MII (6/103) nondisjunctional ova were strikingly different. MI nondisjunction occurred primarily in oocytes with non-exchange X chromosomes; of the new nondisjoining exchange bivalents, most carried distal crossovers. Thus, spontaneous MI nondisjunction reflects the failure of the achiasmate segregation systems. MII nondisjunction occurred only in oocytes with proximal exchanges. We propose several models to explain how very proximal exchanges might impair proper segregation.
Assuntos
Meiose/genética , Não Disjunção Genética , Oócitos , Recombinação Genética , Cromossomo X , Animais , Centrômero , Cruzamentos Genéticos , Drosophila , Feminino , Marcadores Genéticos , Heterocromatina , Humanos , Masculino , MitoseRESUMO
Selective mutism is rare with a prevalence below 1% in the general population, but a higher prevalence in populations at risk (children with speech retardation, migration). Evidence for treatment strategies is hardly available. This case report provides information on the treatment of selective mutism in an 8-year-old girl with preexisting thalassaemia major. As medications she received penicillin prophylaxis (500000 IE/d) and deferasirox (Exjade; 20-25mg/kg/d), an iron chelator. The preexisting somatic disease and treatment complicated the treatment, as there are no data about pharmacological combination therapy. Psychotherapy in day treatment, supported by the use of the SSRI fluoxetine (10 mg), led to a decrease in the selective mutism score from 33 to 12 points, GAF improved by 21 points. Mean levels of fluoxetine plus norfluoxetine were 287.8 ng/ml without significant level fluctuations.
Assuntos
Transplante de Medula Óssea/psicologia , Criança Hospitalizada/psicologia , Mutismo/psicologia , Talassemia beta/psicologia , Transplante de Medula Óssea/efeitos adversos , Criança , Terapia Cognitivo-Comportamental , Terapia Combinada , Feminino , Fluoxetina/uso terapêutico , Humanos , Mutismo/tratamento farmacológico , Mutismo/terapia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Resultado do Tratamento , Talassemia beta/tratamento farmacológico , Talassemia beta/terapiaRESUMO
Donation after cardiac death (DCD) has proven effective at increasing the availability of organs for transplantation.We performed a retrospective examination of Massachusetts General Hospital (MGH) records of all 201 donors from 1/1/98 to the 11/2008, including 54 DCD, 115 DBD and 32 DCD candidates that did not progress to donation (DCD-dnp). Comparing three time periods, era 1 (01/98-12/02), era 2 (01/03-12/05) and era 3 (01/06-11/08), DCD's comprised 14.8,48.4% and 60% of donors, respectively (p = 0.002). A significant increase in the incidence of cardiovascular/cerebrovascular as cause of death was evident in era 3 versus eras 1 and 2; 74% versus 57.1% (p<0.001),as was a corresponding decrease in the incidence of traumatic death. Interestingly, we noted an increase in utilization of aggressive neurological management over time, especially in the DCD group.We detected significant changes in the make-up of the donor pool over the past decade. That the changes in diagnosis over time did not differ between DCD and DBD groups suggests this difference is not responsible for the increase in DCD rates. Instead, we suggest that changes in clinical practice, especially in management of patients with severe brain injury may account for the increased proportion of DCD.
Assuntos
Morte Encefálica , Morte , Obtenção de Tecidos e Órgãos/tendências , Adulto , Lesões Encefálicas/terapia , Humanos , Transplante de Órgãos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
We report on 12 patients with chronic granulomatous disease transplanted with hematopoietic stem cells from matched unrelated (n = 9) or matched sibling donors (n = 3). The most common infectious complication was pulmonary aspergillosis, which nine patients had previously developed. Only 5 of 12 individuals had normal lung function prior to transplantation. At a mean follow-up of 53 months 9 of the 12 patients are alive including 7 of 9 following matched unrelated donor (MUD) transplantation. One patient died from ARDS, another from systemic BK virus infection, the third from complications of chronic graft-versus-host disease. Seven of nine surviving patients have normal lung function now. HSCT from a MUD is an option worth considering when no matched family donor is available. Restricted lung function prior to HSCT does not appear to be a limiting factor for such treatment.
Assuntos
Doença Granulomatosa Crônica/cirurgia , Transplante de Células-Tronco Hematopoéticas/métodos , Adolescente , Bussulfano/administração & dosagem , Bussulfano/uso terapêutico , Criança , Pré-Escolar , Quimerismo , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Seguimentos , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Histocompatibilidade/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Melfalan/administração & dosagem , Melfalan/uso terapêutico , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/mortalidade , Aspergilose Pulmonar/etiologia , Aspergilose Pulmonar/mortalidade , Estudos Retrospectivos , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: Immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome) is a rare autosomal recessive disease characterised by facial dysmorphism, immunoglobulin deficiency and branching of chromosomes 1, 9 and 16 after PHA stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients which is explained by mutations in the DNA methyltransferase gene DNMT3B in some, but not all, ICF patients. OBJECTIVE: To obtain a comprehensive description of the clinical features of this syndrome as well as genotype-phenotype correlations in ICF patients. METHODS: Data on ICF patients were obtained by literature search and additional information by means of questionnaires to corresponding authors. RESULTS AND CONCLUSIONS: 45 patients all with proven centromeric instability were included in this study. Facial dysmorphism was found to be a common characteristic (n = 41/42), especially epicanthic folds, hypertelorism, flat nasal bridge and low set ears. Hypo- or agammaglobulinaemia was demonstrated in nearly all patients (n = 39/44). Opportunistic infections were seen in several patients, pointing to a T cell dysfunction. Haematological malignancy was documented in two patients. Life expectancy of ICF patients is poor, especially those with severe infections in infancy or chronic gastrointestinal problems and failure to thrive. Early diagnosis of ICF is important since early introduction of immunoglobulin supplementation can improve the course of the disease. Allogeneic stem cell transplantation should be considered as a therapeutic option in patients with severe infections or failure to thrive. Only 19 of 34 patients showed mutations in DNMT3B, suggesting genetic heterogeneity. No genotype-phenotype correlation was found between patients with and without DNMT3B mutations.
Assuntos
Instabilidade Cromossômica , Anormalidades Craniofaciais/genética , Síndromes de Imunodeficiência/genética , Adolescente , Adulto , Centrômero/genética , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , DNA (Citosina-5-)-Metiltransferases/genética , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação , Fenótipo , Síndrome , DNA Metiltransferase 3BRESUMO
Severe burn induces destabilization of the immune system and the likelihood of multiple organ dysfunction syndrome. Current studies focus on RNA-expression analyses of immune system cells, however, the present methods of analysis are complex, potentially altered by artefacts and therefore not feasible for routine analyses. The new PAXgene Blood RNA System provides "snapshot" analysis of RNA by immediate cell lysis and prevention of RNA-degradation. Using this system the aim of this study was to analyse intracellular cytokine RNA-expression under clinical conditions. Whole blood samples (PAXgene tubes) of nine severely burned patients were drawn at admission and 6, 12, 24, 48 and 72h after trauma during routine treatment. Four healthy individuals served as control. Analysis of RNA-expression of TNF-alpha as pro-inflammatory and IL-10 as anti-inflammatory mediator was performed by RT-PCR. The RNA-expression of TNF-alpha was increased at 72h after burn. The increase occurred mainly in surviving patients. In contrast, RNA-expression of IL-10 was elevated already at 24h and the difference between surviving and deceased patients occurred earlier. We demonstrate for the first time a "snapshot" analysis of cytokine RNA-expression in severely burned patients under routine conditions. The results correspond well to current hypothesis of posttraumatic MODS development.
Assuntos
Coleta de Amostras Sanguíneas/métodos , Queimaduras/sangue , Interleucina-10/metabolismo , Insuficiência de Múltiplos Órgãos/sangue , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Idoso , Análise de Variância , Queimaduras/complicações , Queimaduras/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/prevenção & controle , Projetos Piloto , Fatores de TempoRESUMO
Aneuploidy induction in male germ cells of mice and men after chronic exposure to diazepam (DZ; CAS 439-14-5; Valium was assessed by multicolor fluorescence in situ hybridization (FISH). DZ, a widely administered sedative and muscle relaxant, was proposed to act as an aneugen by disturbing spindle function in various assay systems. Male mice were treated by oral intubation with 3mg/kg DZ once or daily for 14 consecutive days. At 22 days after the last treatment, epididymal sperm were collected from the caudae epididymes. Evaluation of aneuploid and diploid sperm (10,000 sperm per animal) was performed by multicolor FISH employing DNA probes specific for chromosomes X, Y, and 8 simultaneously. We found a significant increase in the frequency of disomy 8 in subchronically DZ-treated mice when compared to the concurrent solvent control group (2.4-fold; P<0.01), while no increase was detected for sex-chromosome hyperhaploidies. No effect was seen when mice were treated with a single dose (3mg/kg DZ). In a parallel human approach, two men were evaluated who chronically ingested >0.3mg/kg/d DZ for more than 6 months. Multicolor FISH was applied to human sperm probing for chromosomes X, Y, and 13. Frequencies for sperm with disomy 13, disomy X, and total sex-chromosomal disomies were found to be elevated among the two subjects after chronic DZ-exposure compared to control subjects. In conclusion, the results indicate that diazepam acts as an aneugen during meiosis in male spermatogenesis, both in mice and humans. The quantitative comparison indicates that humans may be at least 10 times more sensitive than mice for aneuploidy induction by DZ during male meiosis.
Assuntos
Aneuploidia , Diazepam/efeitos adversos , Hibridização in Situ Fluorescente/métodos , Espermatozoides/efeitos dos fármacos , Adulto , Animais , Cromossomos Humanos Par 13 , Sondas de DNA , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Espermatozoides/fisiologia , Cromossomo X , Cromossomo YRESUMO
BACKGROUND: Now that generic atorvastatin has become available, a process of switching from rosuvastatin to atorvastatin may occur and could persist until the patent on branded rosuvastatin expires. It is important to understand the impact that such therapy may have on patients' cardiovascular (CV) health. OBJECTIVES: This simulated study estimates the impact of switching patients treated with rosuvastatin to atorvastatin on rates of CV events over a 5-year period. METHODS: A study of 50,038 virtual dyslipidemic patients aged 45 to 70 years was conducted using the Archimedes model. Virtual patients were created based on the profiles of patients in the National Health and Nutrition Examination Survey (NHANES). Statin treatment models were constructed based on data from published studies, including STELLAR, JUPITER, CARDS, ASCOT, and TNT. Patients were started on a dose of rosuvastatin based on their ATP III low-density lipoprotein cholesterol (LDL-C) goal and the distributions of statin use observed in US pharmacy claims data. Patients were monitored for 5 years, during which time they received regular visits with the opportunity to increase their dosage if they were above their LDL-C goal. In the experimental arm, patients were switched from rosuvastatin to atorvastatin at the first clinic visit 6 weeks after initiating rosuvastatin (using an atorvastatin dose twice the rosuvastatin milligram-dose). No switching occurred in the control arm, and patients were titrated as necessary per ATP III cholesterol management guidelines. The rate of first occurrence of a major adverse cardiovascular event (MACE; myocardial infarction, stroke, and/or cardiovascular-related death) over the 5-year period was estimated for each study arm. RESULTS: After 5 years, in the atorvastatin-switched arm compared with continuing rosuvastatin, 4.8% fewer patients reached goal (87% vs 91%, respectively). The 5-year relative risk for MACE with switching was 1.109 (95% CI, 1.092-1.127), and the number needed to harm (NNH) to incur 1 additional MACE over 5 years was 262, favoring treatment with rosuvastatin. In diabetic individuals who were switched to atorvastatin, the 5-year relative risk for MACE was 1.121 (95% CI, 1.091-1.151), and the NNH over 5 years was 195, indicating greater risk in diabetic individuals. The results were insensitive to adherence rates and LDL-C goal values. CONCLUSIONS: This study found that switching from rosuvastatin to atorvastatin led to fewer patients attaining LDL-C goal and a greater risk for MACE.
Assuntos
Doenças Cardiovasculares/induzido quimicamente , Substituição de Medicamentos/efeitos adversos , Dislipidemias/tratamento farmacológico , Fluorbenzenos/uso terapêutico , Ácidos Heptanoicos/efeitos adversos , Pirimidinas/uso terapêutico , Pirróis/efeitos adversos , Sulfonamidas/uso terapêutico , Idoso , Atorvastatina , Doenças Cardiovasculares/epidemiologia , Simulação por Computador , Fluorbenzenos/farmacocinética , Ácidos Heptanoicos/farmacocinética , Ácidos Heptanoicos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Modelos Biológicos , Pirimidinas/farmacocinética , Pirróis/farmacocinética , Pirróis/uso terapêutico , Fatores de Risco , Rosuvastatina Cálcica , Sulfonamidas/farmacocinéticaRESUMO
BACKGROUND: No clinical trials have assessed the effects or cost-effectiveness of health check strategies to detect and manage vascular disease. We used a mathematical model to estimate the cost-effectiveness of several health check strategies in six European countries. METHODS: We used country-specific data from Denmark, France, Germany, Italy, Poland, and the United Kingdom to generate simulated populations of individuals aged 40-75 eligible for health checks in those countries (e.g. individuals without a previous diagnosis of diabetes, myocardial infarction, stroke, or serious chronic kidney disease). For each country, we used the Archimedes model to compare seven health check strategies consisting of assessments for diabetes, hypertension, lipids, and smoking. For patients diagnosed with vascular disease, treatment was simulated in a standard manner. We calculated the effects of each strategy on the incidence of type 2 diabetes, major adverse cardiovascular events (MACE), and microvascular complications in addition to quality of life, costs, and cost per quality-adjusted life-year (QALY). RESULTS: Compared with current care, health checks reduced the incidence of MACE (6-17 events prevented per 1000 people screened) and diabetes related microvasular complications (5-11 events prevented per 1000 people screened), and increased QALYs (31-59 discounted QALYs) over 30 years, in all countries. The cost per QALY of offering a health check to all individuals in the study cohort ranged from 14903 (France) to cost saving (Poland). Pre-screening the population and offering health checks only to higher risk individuals lowered the cost per QALY. Pre-screening on the basis of obesity had a cost per QALY of 10200 (France) or less, and pre-screening with a non-invasive risk score was similar. CONCLUSIONS: A vascular disease health check would likely be cost effective at 30 years in Denmark, France, Germany, Italy, Poland, and the United Kingdom.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/epidemiologia , Modelos Teóricos , Doenças Vasculares/diagnóstico , Adulto , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Análise Custo-Benefício , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/prevenção & controle , Europa (Continente)/epidemiologia , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/prevenção & controle , Incidência , Masculino , Programas de Rastreamento/economia , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Fatores de Tempo , Doenças Vasculares/epidemiologia , Doenças Vasculares/prevenção & controleRESUMO
OBJECTIVE: This study used simulation to compare the effectiveness of rosuvastatin 20 mg vs atorvastatin 40 mg, and rosuvastatin 40 mg vs atorvastatin 80 mg in preventing MACE in a range of patient populations with varying baseline cardiovascular risk. RESEARCH DESIGN AND METHODS: The Archimedes Model was used to simulate head-to-head clinical trials in nine patient populations: Framingham Risk Score (FRS)≥5%, 5-10%, 10-20%, >20%, EURO-SCORE≥5% and >10%, diagnosed diabetes, secondary prevention (history of myocardial infarction or stroke, CVD), and acute coronary syndrome (ACS). Simulated patients, aged 45-70 at trial start, were based on the NHANES 1999-2006. Treatments were modeled using results from the STELLAR, JUPITER, CARDS, ASCOT-LLA, and TNT trials. Treatment models were confirmed using trial validations. RESULTS: Comparing rosuvastatin 20 mg vs atorvastatin 40 mg, the 5-year numbers needed to treat to prevent one MACE event (NNT) were 525, 70, and 55 for the FRS≥5%, CVD, and ACS groups, respectively. Comparing rosuvastatin 40 mg vs atorvastatin 80 mg the corresponding NNT values were 468, 63, and 51. The 20-year relative risks of MACE in the FRS≥5% population were 0.907 (0.901-0.913) for rosuvastatin 20 mg vs atorvastatin 40 mg and 0.892 (0.884-0.901) for rosuvastatin 40 mg vs atorvastatin 80 mg. The relative risks were similar for the remaining populations. CONCLUSIONS: This study found that rosuvastatin 20 mg and 40 mg lowers the risk of MACE more than atorvastatin 40 mg and atorvastatin 80 mg. While simulation models cannot replace real-world clinical trials, this study bridges gaps in the evidence, and identifies high risk cohorts that would likely see additional benefit from treatment with rosuvastatin rather than atorvastatin.
Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Fluorbenzenos/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Fatores Etários , Idoso , Atorvastatina , Doenças Cardiovasculares/prevenção & controle , Pesquisa Comparativa da Efetividade , Simulação por Computador , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controle , Fatores de Risco , Rosuvastatina Cálcica , Fatores Sexuais , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controleRESUMO
Managing diabetes and preventing its associated morbidities require active partnerships between physicians and patients. Studies to date lack the level of detail to quantify the degree to which interventions that are more controlled by physicians influence outcomes versus those that are more controlled by patients. Using the Archimedes model, we simulated a thirty-year clinical trial and compared the effects of three sets of interventions over which physicians have progressively less control: compliance with process-of-care standards, such as conducting foot and retinal exams and screening for signs of early kidney disease; control of biomarkers, such as hemoglobin A1c and blood pressure; and lifestyle modifications, such as patients' switching to healthier diets and losing weight. We found that if all US adults diagnosed with type 2 diabetes met quality targets in all of these areas, they would experience a nearly 16 percent increase in quality-adjusted life-years and a nearly 23 percent reduction in fifteen-year mortality over the thirty-year simulation period. Meeting aggressive biomarker targets yielded the most benefit. Meeting conservative biomarker targets came next, followed closely by meeting process-of-care standards. The incremental benefits of complying fully with diet and smoking cessation yielded the least benefit. Thus, through measures more readily within their control, and through collaboration with their patients, physicians have a substantial opportunity to improve outcomes. These findings can inform policy makers' rational resource allocation decisions and the design of programs to improve diabetes care.
Assuntos
Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 2 , Comportamentos Relacionados com a Saúde , Hipertensão/tratamento farmacológico , Papel do Médico , Idoso , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Atenção Primária à Saúde/métodos , Estados UnidosRESUMO
PURPOSE: Many patients treated for dyslipidemia do not achieve recommended cholesterol goals despite the widespread availability of effective statins. Pharmaceutical claims show a strong tendency for patients to remain on their initially assigned treatment. With computer simulations, the impact of initial statin treatment decisions on medium- and long-term cardiovascular outcomes were examined. PATIENTS AND METHODS: Using the Archimedes Model, three treatment scenarios were simulated. Patients initiated treatment with simvastatin (20, 40, or 80 mg), atorvastatin (10, 20, 40, or 80 mg), or rosuvastatin (10, 20, or 40 mg), and periodically intensified treatment. The simulated population consisted of 50,025 patients, aged 45-70 years, with low-density lipoprotein cholesterol exceeding goal. The proportion of patients initiating each dose was calibrated to United States pharmacy claims. Patients not reaching goal intensified the dose of their current statin or switched to an appropriate dose of rosuvastatin at rates matching pharmacy claims. Biomarkers and major adverse cardiovascular events (MACE) were tracked for 10 years and several high-risk subpopulations were analyzed. Statin models used biomarker effects from the STELLAR (Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin) trial and outcomes data from various trials. RESULTS: Initiating therapy with rosuvastatin reduced MACE more than simvastatin or atorvastatin. The 5- year relative risk of MACE was 0.906 (95% confidence interval: 0.888-0.923; P < 0.001) for initial treatment with atorvastatin rather than simvastatin, 0.831 (0.812-0.850; P < 0.001) for rosuvastatin rather than simvastatin, and 0.918 (0.898-0.938; P < 0.001) for rosuvastatin rather than atorvastatin. Subgroups with higher MACE incidence experienced greater absolute benefit. CONCLUSION: Considering observed rates of treatment intensification, initial treatment choices appear to significantly impact medium- and long-term cardiovascular risk. Patients at high cardiovascular risk are good candidates for aggressive initial therapy.