RESUMO
We examined tolerance mechanisms in patients receiving HLA-mismatched combined kidney-bone marrow transplantation (CKBMT) that led to transient chimerism under a previously published nonmyeloablative conditioning regimen (Immune Tolerance Network study 036). Polychromatic flow cytometry and high-throughput sequencing of T cell receptor-ß hypervariable regions of DNA from peripheral blood regulatory T cells (Tregs) and CD4 non-Tregs revealed marked early enrichment of Tregs (CD3+ CD4+ CD25high CD127low Foxp3+ ) in blood that resulted from peripheral proliferation (Ki67+ ), possibly new thymic emigration (CD31+ ), and, in one tolerant subject, conversion from non-Tregs. Among recovering conventional T cells, central memory CD4+ and CD8+ cells predominated. A large proportion of the T cell clones detected in posttransplantation biopsy specimens by T cell receptor sequencing were detected in the peripheral blood and were not donor-reactive. Our results suggest that enrichment of Tregs by new thymic emigration and lymphopenia-driven peripheral proliferation in the early posttransplantation period may contribute to tolerance after CKBMT. Further, most conventional T cell clones detected in immunologically quiescent posttransplantation biopsy specimens appear to be circulating cells in the microvasculature rather than infiltrating T cells.
Assuntos
Transplante de Medula Óssea , Sobrevivência de Enxerto/imunologia , Tolerância Imunológica/imunologia , Transplante de Rim , Linfócitos T Reguladores/imunologia , Tolerância ao Transplante/imunologia , Feminino , Humanos , Masculino , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Quimeras de Transplante/imunologiaRESUMO
Tolerance of allografts achieved in mice via stable mixed hematopoietic chimerism relies essentially on continuous elimination of developing alloreactive T cells in the thymus (central deletion). Conversely, while only transient mixed chimerism is observed in nonhuman primates and patients, it is sufficient to ensure tolerance of kidney allografts. In this setting, it is likely that tolerance depends on peripheral regulatory mechanisms rather than thymic deletion. This implies that, in primates, upsetting the balance between inflammatory and regulatory alloimmunity could abolish tolerance and trigger the rejection of previously accepted renal allografts. In this study, six monkeys that were treated with a mixed chimerism protocol and had accepted a kidney allograft for periods of 1-10 years after withdrawal of immunosuppression received subcutaneous injections of IL-2 cytokine (0.6-3 × 10(6) IU/m(2) ). This resulted in rapid rejection of previously tolerated renal transplants and was associated with an expansion and reactivation of alloreactive pro-inflammatory memory T cells in the host's lymphoid organs and in the graft. This phenomenon was prevented by anti-CD8 antibody treatment. Finally, this process was reversible in that cessation of IL-2 administration aborted the rejection process and restored normal kidney graft function.
Assuntos
Rejeição de Enxerto/etiologia , Interleucina-2/administração & dosagem , Falência Renal Crônica/cirurgia , Transplante de Rim , Complicações Pós-Operatórias , Quimeras de Transplante/imunologia , Tolerância ao Transplante/imunologia , Animais , Transplante de Medula Óssea , Quimerismo , Taxa de Filtração Glomerular , Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto , Injeções Subcutâneas , Testes de Função Renal , Macaca fascicularis , Camundongos , Fatores de Risco , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
Blood chimerism has been reported sporadically among visceral transplant recipients, mostly in association with graft-vs-host disease (GVHD). We hypothesized that a higher degree of mixed chimerism would be observed in multivisceral (MVTx) than in isolated intestinal (iITx) and isolated liver transplant (iLTx) recipients, regardless of GVHD. We performed a longitudinal prospective study investigating multilineage blood chimerism with flow cytometry in 5 iITx and 4 MVTx recipients up to one year posttransplant. Although only one iITx patient experienced GVHD, T cell mixed chimerism was detected in 8 out of 9 iITx/MVTx recipients. Chimerism was significantly lower in the four subjects who displayed early moderate to severe rejection. Pre-formed high-titer donor-specific antibodies, bound in vivo to the circulating donor cells, were associated with an accelerated decline in chimerism. Blood chimerism was also studied in 10 iLTx controls. Among nonsensitized patients, MVTx recipients exhibited greater T and B cell chimerism than either iITx or iLTx recipients. Myeloid lineage chimerism was present exclusively among iLTx and MVTx (6/13) recipients, suggesting that its presence required the hepatic allograft. Our study demonstrates, for the first time, frequent T cell chimerism without GVHD following visceral transplantation and a possible relationship with reduced rejection rate in MVTx recipients.
Assuntos
Rejeição de Enxerto/imunologia , Doença Enxerto-Hospedeiro/imunologia , Intestinos/transplante , Transplante de Fígado , Linfócitos T/imunologia , Quimeras de Transplante/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Seguimentos , Rejeição de Enxerto/sangue , Doença Enxerto-Hospedeiro/sangue , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Quimeras de Transplante/sangue , Adulto JovemRESUMO
Antibody-mediated rejection (ABMR) represents a significant clinical challenge for solid organ transplantation. Mechanistic understanding of ABMR is incomplete and diagnostic accuracy for ABMR is limited, and as a result, targeted treatment remains elusive and new treatment modalities are difficult to validate. Three hundred twenty-six participants from 15 countries met for the first Cutting Edge of Transplantation (CEOT) symposium organized by the American Society of Transplantation (AST) in Chandler, Arizona, February 14-16, 2013. During the 3-day interactive symposium, presentations, moderated poster sessions and round table discussions addressed cutting edge knowledge of B and plasma cell biology, mechanisms of antibody-mediated tissue injury, advances and limitations in ABMR diagnostics, as well as current and potential new treatment options for ABMR. The outcome of the meeting identified the following unmet needs for: (a) improved understanding of the regulation of B cell maturation and antibody response to enable targeted therapies; (b) more precise diagnostics of ABMR, including molecular pathology, risk stratification by sensitive antibody testing and monitoring of treatment effects; and (c) innovative multicenter trial designs that enhance observational power, in particular, in assessing synergistic multimodality therapies with reduced toxicities.
Assuntos
Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Rejeição de Enxerto/imunologia , Isoanticorpos/imunologia , Transplante de Órgãos , Relatório de Pesquisa , Rejeição de Enxerto/prevenção & controle , HumanosRESUMO
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
We report here the long-term results of HLA-mismatched kidney transplantation without maintenance immunosuppression (IS) in 10 subjects following combined kidney and bone marrow transplantation. All subjects were treated with nonmyeloablative conditioning and an 8- to 14-month course of calcineurin inhibitor with or without rituximab. All 10 subjects developed transient chimerism, and in seven of these, IS was successfully discontinued for 4 or more years. Currently, four subjects remain IS free for periods of 4.5-11.4 years, while three required reinstitution of IS after 5-8 years due to recurrence of original disease or chronic antibody-mediated rejection. Of the 10 renal allografts, three failed due to thrombotic microangiopathy or rejection. When compared with 21 immunologically similar living donor kidney recipients treated with conventional IS, the long-term IS-free survivors developed significantly fewer posttransplant complications. Although most recipients treated with none or two doses of rituximab developed donor-specific antibody (DSA), no DSA was detected in recipients treated with four doses of rituximab. Although further revisions of the current conditioning regimen are planned in order to improve consistency of the results, this study shows that long-term stable kidney allograft survival without maintenance IS can be achieved following transient mixed chimerism induction.
Assuntos
Transplante de Medula Óssea , Sobrevivência de Enxerto/imunologia , Terapia de Imunossupressão , Nefropatias/cirurgia , Transplante de Rim , Complicações Pós-Operatórias , Tolerância ao Transplante/imunologia , Adulto , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Isoanticorpos/sangue , Nefropatias/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Quimeras de Transplante , Condicionamento Pré-Transplante , Transplante Homólogo , Adulto JovemRESUMO
Antibody mediated rejection (AMR) is associated with a variety of graft-reactive antibodies following kidney transplant. To characterize these antibodies, we immortalized 107 B cell clones from a patient with AMR. In a previous study, we showed that six clones were reacting to multiple self-antigens as well as to HLA and MICA for two of them, thus displaying a pattern of polyreactivity. We show here that all six polyreactive clones also reacted to apoptotic but not viable cells. More generally we observed a nearly perfect overlap between polyreactivity and reactivity to apoptotic cells. Functionally, polyreactive antibodies can activate complement, resulting in the deposition of C3d and C4d at the surface of target cells. Testing the serum of 88 kidney transplant recipients revealed a significantly higher IgG reactivity to apoptotic cells in AMR patients than in patients with stable graft function. Moreover, total IgG purified from AMR patients had increased complement activating properties compared to IgG from non-AMR patients. Overall, our studies show the development of polyreactive antibodies cross-reactive to apoptotic cells during AMR. Further studies are now warranted to determine their contribution to the detection of C4d in graft biopsies as well as their role in the pathophysiology of AMR.
Assuntos
Apoptose/fisiologia , Autoanticorpos/sangue , Ativação do Complemento/imunologia , Complemento C4b/imunologia , Rejeição de Enxerto/imunologia , Transplante de Rim , Fragmentos de Peptídeos/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Imunofluorescência , Humanos , Imunidade Humoral , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Pessoa de Meia-Idade , Transplante Homólogo , Adulto JovemRESUMO
Antibody rejection is often accompanied by nondonor HLA specific antibodies (NDSA) and self-reactive antibodies that develop alongside donor-specific antibodies (DSA). To determine the source of these antibodies, we immortalized 107 B-cell clones from a kidney transplant recipient with humoral rejection. Two of these clones reacted to HLA class I or MICA. Both clones were also reactive to self-antigens and a lysate of a kidney cell line, hence revealing a pattern of polyreactivity. Monoclonality was verified by the identification of a single rearranged immunoglobulin heavy chain variable region (VH) sequence for each clone. By tracking their unique CDR3 sequence, we found that one such polyreactive clone was highly expanded in the patient blood, representing ~0.2% of circulating B cells. The VH sequence of this clone showed evidence of somatic mutations that were consistent with its memory phenotype and its expansion. Lastly, the reactivity of the expanded polyreactive B-cell clone was found in the patient serum at time of rejection. In conclusion, we provide here proof of principle at the clonal level that human antibodies can cross-react to HLA and self. Our findings strongly suggest that polyreactive antibodies contribute to DSA, NDSA as well as autoantibodies, in transplant recipients.
Assuntos
Linfócitos B/imunologia , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Transplante de Rim/imunologia , Reações Cruzadas , Imunofluorescência , HumanosRESUMO
The basalts of the 2021 Fagradalsfjall eruption were the first erupted on the Reykjanes Peninsula in 781 years and offer a unique opportunity to determine the composition of the mantle underlying Iceland, in particular its oxygen isotope composition (δ18O values). The basalts show compositional variations in Zr/Y, Nb/Zr and Nb/Y values that span roughly half of the previously described range for Icelandic basaltic magmas and signal involvement of Icelandic plume (OIB) and Enriched Mid-Ocean Ridge Basalt (EMORB) in magma genesis. Here we show that Fagradalsfjall δ18O values are invariable (mean δ18O = 5.4 ± 0.3 2 SD, N = 47) and indistinguishable from "normal" upper mantle, in contrast to significantly lower δ18O values reported for erupted materials elsewhere in Iceland (e.g., the 2014-2015 eruption at Holuhraun, Central Iceland). Thus, despite differing trace element characteristics, the melts that supplied the Fagradalsfjall eruption show no evidence for 18O-depleted mantle or interaction with low-δ18O crust and may therefore represent a useful mantle reference value in this part of the Icelandic plume system.
RESUMO
Chronic humoral rejection (CHR) is an important cause of late graft failures following kidney transplantation. Overall, the pathophysiology of CHR is poorly understood. Matrix metalloproteinase-2 (MMP-2), a type IV collagenase, has been implicated in chronic kidney disease and allograft rejection in previous studies. We examined the presence of MMP-2 in allograft biopsies and in the urine of kidney transplant recipients with CHR. MMP-2 staining was detected by immunohistochemistry in podocytes for all CHR patients but less frequently in patients with other renal complications. Urinary MMP-2 levels were also significantly higher in CHR patients (median 4942 pg/mL, N = 27) compared to non-CHR patients (median 598 pg/mL, N = 65; p < 0.001). Elevated urinary MMP-2 correlated with higher levels of proteinuria in both CHR and non-CHR patients. Longitudinal analysis indicated that increase in urine MMP-2 coincided with initial diagnosis of CHR as documented by the biopsies. Using an enzymatic assay, we demonstrated that MMP-2 was present in its active form in the urine of patients with CHR. Overall, our findings associate MMP-2 with glomerular injury as well as interstitial fibrosis and tubular atrophy observed in patients with CHR.
Assuntos
Rejeição de Enxerto/patologia , Transplante de Rim/efeitos adversos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/urina , Podócitos/enzimologia , Feminino , Fibrose , Rejeição de Enxerto/imunologia , Humanos , Nefropatias/patologia , Glomérulos Renais/patologia , Transplante de Rim/imunologia , Masculino , Pessoa de Meia-Idade , Proteinúria/complicaçõesRESUMO
Five patients with end-stage kidney disease received combined kidney and bone marrow transplants from HLA haploidentical donors following nonmyeloablative conditioning to induce renal allograft tolerance. Immunosuppressive therapy was successfully discontinued in four patients with subsequent follow-up of 3 to more than 6 years. This allograft acceptance was accompanied by specific T-cell unresponsiveness to donor antigens. However, two of these four patients showed evidence of de novo antibodies reactive to donor antigens between 1 and 2 years posttransplant. These humoral responses were characterized by the presence of donor HLA-specific antibodies in the serum with or without the deposition of the complement molecule C4d in the graft. Immunofluorescence staining, ELISA assays and antibody profiling using protein microarrays demonstrated the co-development of auto- and alloantibodies in these two patients. These responses were preceded by elevated serum BAFF levels and coincided with B-cell reconstitution as revealed by a high frequency of transitional B cells in the periphery. To date, these B cell responses have not been associated with evidence of humoral rejection and their clinical significance is still unclear. Overall, our findings showed the development of B-cell allo- and autoimmunity in patients with T-cell tolerance to the donor graft.
Assuntos
Linfócitos B/imunologia , Transplante de Medula Óssea/métodos , Tolerância Imunológica , Transplante de Rim/métodos , Linfócitos T/imunologia , Linhagem Celular , Complemento C4b/química , Ensaio de Imunoadsorção Enzimática/métodos , Rejeição de Enxerto/imunologia , Antígenos HLA/química , Humanos , Sistema Imunitário , Microscopia de Fluorescência/métodos , Fragmentos de Peptídeos/química , Análise Serial de Proteínas , Fatores de TempoRESUMO
In this paper we used a multiparametric approach to analyze extensively the events occurring during apoptotic cell death of thymocytes, and furthermore, we asked whether alterations in mitochondrial structure and function are occurring in early stages of apoptosis. A multiparametric quantitative analysis was performed on normal or apoptotic thymocytes emerging from a few-hour culture performed in culture medium or in the presence of dexamethasone. Simultaneous detection of light scattering properties, integrity of plasma membrane (trypan blue exclusion), chromatin condensation (AO/EB staining of entire cells or PI staining of nuclei), and DNA fragmentation (in situ nick-translation in apoptotic cells) allowed a precise analysis of the preapoptotic and apoptotic stages. Moreover a thorough study of mitochondrial transmembrane potential (delta psi m) assessed following in a time course study the uptake by apoptotic cells of the cationic lipophilic dye DiOC6(3) or the J-aggregate-forming cation JC-1, indicates that a drop in delta psi m occurs very early in thymocyte apoptosis, before DNA fragmentation. This is associated with alteration in mitochondrial structure assessed by cytofluorimetric study of NAO uptake in apoptotic cells. Finally these dramatic alterations in mitochondrial structure and function occurring in early stages of apoptosis were confirmed by confocal and electron microscopy analysis.
Assuntos
Apoptose/efeitos dos fármacos , Dexametasona/farmacologia , Mitocôndrias/efeitos dos fármacos , Timo/efeitos dos fármacos , Animais , Dano ao DNA , Citometria de Fluxo , Membranas Intracelulares/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica , Mitocôndrias/ultraestrutura , ATPases Translocadoras de Prótons/metabolismo , Timo/citologia , Fatores de TempoRESUMO
BACKGROUND AND PURPOSE: Infants with congenital diaphragmatic hernia are reported to have evidence of brain MR imaging abnormalities. Our study aimed to identify perinatal clinical factors in infants with congenital diaphragmatic hernia that are associated with evidence of brain injury on MR imaging performed before hospital discharge. MATERIALS AND METHODS: MRIs performed before hospital discharge in infants with congenital diaphragmatic hernia were scored for brain injury by 2 pediatric neuroradiologists. Perinatal variables and clinical variables from the neonatal intensive care unit stay were analyzed for potential associations with brain MR imaging findings. RESULTS: Fifty-three infants with congenital diaphragmatic hernia (31 boys) were included. At least 1 abnormality was seen on MR imaging in 32 infants (60%). The most common MR imaging findings were enlarged extra-axial spaces (36%), intraventricular hemorrhage (23%), ventriculomegaly (19%), white matter injury (17%), and cerebellar hemorrhage (17%). The MR imaging brain injury score was associated with extracorporeal membrane oxygenation (P = .0001), lack of oral feeding at discharge (P = .012), use of inotropes (P = .027), and gastrostomy tube placement before hospital discharge (P = .024). The MR imaging brain injury score was also associated with a large diaphragmatic defect size (P = .011). CONCLUSIONS: Most infants with congenital diaphragmatic hernia have at least 1 abnormality identified on MR imaging of the brain performed before discharge. The main predictors of brain injury in this population are a requirement for extracorporeal membrane oxygenation, large diaphragmatic defect size, and lack of oral feeding at discharge.
Assuntos
Lesões Encefálicas/diagnóstico por imagem , Hérnias Diafragmáticas Congênitas/diagnóstico por imagem , Hemorragia Encefálica Traumática/diagnóstico por imagem , Diafragma/anormalidades , Oxigenação por Membrana Extracorpórea/efeitos adversos , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Hemorragias Intracranianas/diagnóstico por imagem , Intubação Gastrointestinal/efeitos adversos , Imageamento por Ressonância Magnética , Masculino , Gravidez , Substância Branca/diagnóstico por imagemRESUMO
Seven consecutive patients with Klinefelter's syndrome were studied and found to have elevated levels of testosterone-binding globulin. The mechanism could not be accounted for by increased levels of circulating estradiol.
Assuntos
Síndrome de Klinefelter/sangue , Globulina de Ligação a Hormônio Sexual/metabolismo , Adolescente , Adulto , Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Testosterona/sangueRESUMO
A patient with isolated LH deficiency ("fertile eunuch" syndrome) was given synthetic gonadotropin releasing hormone (GnRH) by a single intravenous injection and serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone and dihydrotestosterone were measured. A significant rise in both gonadotropins was found after GnRH and the increase was similar to that reported for normal men. No significant change was noted in the serum androgen levels. The patient was re-tested with another single intravenous injection after a 6-h infusion of GnRH two days later. The rise in serum Fsh and LH levels during the infusion was greater than with the initial bolus. A further increase in LH but not FSH concentration was noted when a 150 mug bolus was given at the end of the infusion. Acute (4 day) treatment with human chorionic gonadotropin (hCG) resulted in an increase in the serum testosterone and dihydrotestosterone levels to those observed in normal adult males. The "fertile eunuch" syndrome thus appears to be a hypothalamic disorder. It is consistent with the concept of more than one hypothalamic factor controlling gonadotropin secretion. Other possibilities would be deficient or defective production of a releasing factor affecting one or both gonadotropins. The lack of a definite response of serum androgens to GnRH would appear to be secondary to a decreased number of differentiated Leyding cells.
Assuntos
Eunuquismo/sangue , Hormônio Foliculoestimulante/sangue , Hormônio Luteinizante/sangue , Hormônios Liberadores de Hormônios Hipofisários/farmacologia , Adulto , Di-Hidrotestosterona/sangue , Humanos , Cinética , Masculino , Estimulação Química , Síndrome , Testosterona/sangueRESUMO
BACKGROUND: In patients with chronic myelocytic leukemia (CML), the breakpoint cluster region and fusion between the BCR and the c-ABL genes (BCR-ABL) oncogen product is a potential tumor-specific antigen. Previous studies have shown that T cells specific for the junctional region peptides of the BCR-ABL oncoprotein can be detected in healthy individuals as well as in patients with CML in chronic phase. We assessed whether BCR-ABL- specific T cells could be found in a patient achieving a complete cytogenetic remission after CD4+ donor lymphocyte infusion. METHODS: Using dendritic cells pulsed with BCR-ABL breakpoint peptides as antigen-presenting cells, we stimulated patient peripheral blood lymphocytes to isolate peptide-specific T cell clones present at the time of the cytogenetic response. T cell clones were isolated and the cellular specificity of these cells was examined. RESULTS: A CD3+ CD4+ T cell clone (1F7) that recognizes overlapping p210 junctional peptides presented by HLA-DR molecules was identified and expanded in vitro. Clone 1F7 failed to recognize autologous tumor cells as well as dendritic cells derived from patient CML cells. Clone 1F7 did not inhibit the growth and differentiation of CML precursor cells in a standard colony formation assay. Finally, using a clone-specific probe, 1F7 cells could not be detected in patient peripheral blood at the time of the donor lymphocyte infusion response. CONCLUSIONS: These results suggest that clone 1F7 was selected in vitro using highly potent peptide pulsed dendritic cells but was not representative of the anti-leukemia immune response in vivo. Based on these findings, CD4+ T cells with BCR-ABL specificity do not appear to be mediators of the anti-leukemia response in vivo after donor lymphocyte infusion.
Assuntos
Transplante de Medula Óssea/imunologia , Linfócitos T CD4-Positivos/imunologia , Proteínas de Fusão bcr-abl/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Transfusão de Linfócitos , Adulto , Sequência de Aminoácidos , Células Apresentadoras de Antígenos/imunologia , Células Clonais , Células Dendríticas/imunologia , Feminino , Antígenos HLA/imunologia , Humanos , Dados de Sequência Molecular , Fragmentos de Peptídeos/imunologiaRESUMO
We report a case of the TAR syndrome with severe abnormalities of the lower limbs. The syndrome of thrombocytopenia and radial deformities occasionally presents diagnostic difficulties when severe limb anomalies are present. Based on this case and 2 additional cases from the literature, reduction anomalies of the lower limbs should be considered part of the TAR syndrome.
Assuntos
Fíbula/anormalidades , Rádio (Anatomia)/anormalidades , Trombocitopenia/genética , Tíbia/anormalidades , Feminino , Humanos , Recém-Nascido , Fenótipo , SíndromeRESUMO
We have found the mean levels of combined serum testosterone and dihydrotestosterone (T+DHT) and the free index (FI) to be significantly higher and the mean dihydrotestosterone precipitation index (DHT-PI) to be significantly lower in hirsute women than in normal women. Although the mean T+DHT values of the different groups of hirsute patients were comparable, the FI value of the oligomenorrheic and/or obese patient was higher than that of the nonobese, normally menstruating group. In addition, the mean DHT-PI level of obese patients was significantly lower than that of nonobese patients. The lowest androgen binding was found in obese patients with oligomenorrhea. In our experience, hirsutism is associated with T+DHT values of 150 ng/dl or lower. Measurement of androgen binding and androgen levels in unchromatographed serum extracts provides valuable information in the treatment of hirsute women.
Assuntos
Androgênios/sangue , Hirsutismo/sangue , Obesidade/sangue , Adolescente , Adulto , Di-Hidrotestosterona/sangue , Feminino , Humanos , Pessoa de Meia-Idade , Oligomenorreia/sangue , Testes de Precipitina , Testosterona/sangueRESUMO
The hormonal profile of the aging male reveals an associated decrease in free testosterone and 5 alpha-dihydrotestosterone (DHT) levels and increased luteinizing hormone levels. Later events consist of a decrease in total testosterone, stable DHT, and increased follicle-stimulating hormone and estradiol levels. Although most available information supports the concept of impaired Leydig cell reserve, our study suggests some degree of hypothalamic-pituitary dysfunction. The signal for increased androgen binding with age is not clear. There is a great deal of individual variation in the time of onset of these events.
Assuntos
Envelhecimento , Di-Hidrotestosterona/sangue , Células Intersticiais do Testículo/metabolismo , Hormônio Luteinizante/sangue , Ligação Proteica , Testosterona/sangue , Idoso , Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Guidelines introduced in 1979 for breast-feeding infants with phenylketonuria included a formula containing low amounts of phenylalanine (PHE) as part of the dietary prescription. Although the guidelines were revised in 1988, new PHE-free products were not included. In addition, the guidelines recommend infant weight checks before and after feeding to ensure correct dietary intake of breast milk. In this study, we present data based on treatment of 13 infants for the first 6 months of life using a PHE-free product and human milk (n = 9) or commercial formula (n = 4). The study began with nine breast-fed infants; five were weaned before 6 months of age and were discontinued from the study. Published estimates of volume and energy of daily human milk consumption were used to prescribe and assess intake of breast milk. No differences were noted between the groups in blood levels of PHE at initiation of dietary therapy, age at initiation of dietary therapy, or length of time to achieve metabolic control. Furthermore, blood levels of PHE and growth parameters for each month up to 6 months of age were similar for both groups. These data support the efficacy of PHE-free formula and estimation of breast milk volumes in managing the diet of infants with phenylketonuria.