RESUMEN
Acute colitis is a common feature of infection with Shiga-toxin producing Escherichia coli (STEC) and can mimic acute severe ulcerative colitis. Early recognition is important as there is a risk of developing Shiga toxin-induced haemolytic uremic syndrome (STEC-HUS), defined by the triad of microangiopathic haemolytic anemia, thrombocytopenia and organ damage. In severe cases STEC-HUS can cause severe neurological complications and can be fatal. We present a patient with a medical history of refractory ulcerative colitis, where making the diagnosis of STEC-HUS was challenging since the initial clinical presentation was difficult to differentiate from a flare of ulcerative colitis. This case illustrates that STEC induced colitis can mimic acute severe ulcerative colitis. This finding is of utmost clinical importance because of the potential life-threatening complications of STEC-HUS. Therefore it should be excluded promptly in patients with acute severe ulcerative colitis by using multiplex-PCR assay on a faecal sample.
Asunto(s)
Colitis Ulcerosa , Colitis , Infecciones por Escherichia coli , Síndrome Hemolítico-Urémico , Escherichia coli Shiga-Toxigénica , Humanos , Infecciones por Escherichia coli/complicaciones , Infecciones por Escherichia coli/diagnóstico , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/diagnóstico , Síndrome Hemolítico-Urémico/diagnóstico , Síndrome Hemolítico-Urémico/complicaciones , Colitis/diagnósticoRESUMEN
To assess the effects of interferon gamma (IFN-gamma) on very primitive hematopoietic progenitor cells, CD34(2+)CD38- human bone marrow cells were isolated and cultured in a two-stage culture system, consisting of a primary liquid culture phase followed by a secondary semisolid colony assay. CD34(2+)CD38- cells needed at least the presence of interleukin 3 (IL-3) and kit ligand (KL) together with either IL-1, IL-6, or granulocyte-colony-stimulating factor (G-CSF) in the primary liquid phase in order to proliferate and differentiate into secondary colony-forming cells (CFC). Addition of IFN-gamma to the primary liquid cultures inhibited cell proliferation and generation of secondary CFC in a dose-dependent way. This was a direct effect since it was also seen in primary single cell cultures of CD34(2+)CD38- cells. The proliferation of more mature CD34+CD38+ cells, however, was not inhibited by IFN-gamma, demonstrating for the first time that IFN-gamma is a specific and direct hematopoietic stem cell inhibitor. IFN-gamma, moreover, preserves the viability of CD34(2+)CD38- cells in the absence of other cytokines. IFN-gamma could, therefore, play a role in the protection of the stem cell compartment from exhaustion in situations of hematopoietic stress and may be useful as stem cell protecting agent against chemotherapy for cancer.
Asunto(s)
Antígenos CD/análisis , Antígenos de Diferenciación/análisis , Células Madre Hematopoyéticas/efectos de los fármacos , Interferón gamma/farmacología , ADP-Ribosil Ciclasa , ADP-Ribosil Ciclasa 1 , Antígenos CD34 , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/fisiología , Humanos , Glicoproteínas de MembranaRESUMEN
BACKGROUND: Necrotizing skin and soft-tissue infections (NSTI) are rare but potentially life-threatening and disabling infections that often require intensive care unit admission. OBJECTIVES: To review all aspects of care for a critically ill individual with NSTI. SOURCES: Literature search using Medline and Cochrane library, multidisciplinary panel of experts. CONTENT: The initial presentation of a patient with NSTI can be misleading, as features of severe systemic toxicity can obscure sometimes less impressive skin findings. The infection can spread rapidly, and delayed surgery worsens prognosis, hence there is a limited role for additional imaging in the critically ill patient. Also, the utility of clinical scores is contested. Prompt surgery with aggressive debridement of necrotic tissue is required for source control and allows for microbiological sampling. Also, prompt administration of broad-spectrum antimicrobial therapy is warranted, with the addition of clindamycin for its effect on toxin production, both in empirical therapy, and in targeted therapy for monomicrobial group A streptococcal and clostridial NSTI. The role of immunoglobulins and hyperbaric oxygen therapy remains controversial. IMPLICATIONS: Close collaboration between intensive care, surgery, microbiology and infectious diseases, and centralization of care is fundamental in the approach to the severely ill patient with NSTI. As many aspects of management of these rare infections are supported by low-quality data only, multicentre trials are urgently needed.
Asunto(s)
Fascitis Necrotizante/microbiología , Unidades de Cuidados Intensivos/estadística & datos numéricos , Piel/microbiología , Infecciones de los Tejidos Blandos/microbiología , Antibacterianos/uso terapéutico , Bacterias/efectos de los fármacos , Enfermedad Crítica , Desbridamiento , Manejo de la Enfermedad , Fascitis Necrotizante/tratamiento farmacológico , Fascitis Necrotizante/cirugía , Humanos , Piel/patología , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Infecciones de los Tejidos Blandos/cirugíaRESUMEN
Essentials Conformational changes in ADAMTS-13 are part of its mode-of-action. The murine anti-ADAMTS-13 antibody 1C4 discriminates between folded and open ADAMTS-13. ADAMTS-13 conformation is open in acute acquired thrombotic thrombocytopenic purpura (TTP). Our study forms an important basis to fully elucidate the pathophysiology of TTP. SUMMARY: Background Acquired thrombotic thrombocytopenic purpura (aTTP) is an autoimmune disorder characterized by absent ADAMTS-13 activity and the presence of anti-ADAMTS-13 autoantibodies. Recently, it was shown that ADAMTS-13 adopts a folded or an open conformation. Objectives As conformational changes in self-antigens play a role in the pathophysiology of different autoimmune diseases, we hypothesized that the conformation of ADAMTS-13 changes during acute aTTP. Methods Antibodies recognizing cryptic epitopes in the spacer domain were generated. Next, the conformation of ADAMTS-13 in 40 healthy donors (HDs), 99 aTTP patients (63 in the acute phase versus 36 in remission), 12 hemolytic-uremic syndrome (HUS) patients and 63 sepsis patients was determined with ELISA. Results The antibody 1C4 recognizes a cryptic epitope in ADAMTS-13. Therefore, we were able to discriminate between a folded and an open ADAMTS-13 conformation. We showed that ADAMTS-13 in HDs does not bind to 1C4, indicating that ADAMTS-13 circulates in a folded conformation. Similar results were obtained for HUS and sepsis patients. In contrast, ADAMTS-13 of acute aTTP patients bound to 1C4 in 92% of the cases, whereas, in most cases, this binding was abolished during remission, showing that the conformation of ADAMTS-13 is open during an acute aTTP episode. Conclusions Our study shows that, besides absent ADAMTS-13 activity and the presence of anti-ADAMTS-13 autoantibodies, an open ADAMTS-13 conformation is also a hallmark of acute aTTP. Demonstrating this altered ADAMTS-13 conformation in acute aTTP will help to further unravel the pathophysiology of aTTP and lead to improved therapy and diagnosis.
Asunto(s)
Proteína ADAMTS13/química , Púrpura Trombocitopénica Trombótica/enzimología , Proteína ADAMTS13/sangre , Proteína ADAMTS13/inmunología , Autoanticuerpos/inmunología , Autoanticuerpos/metabolismo , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Mapeo Epitopo , Epítopos , Humanos , Unión Proteica , Conformación Proteica , Pliegue de Proteína , Púrpura Trombocitopénica Trombótica/sangre , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/inmunología , Relación Estructura-ActividadRESUMEN
Essentials Staphylococcus aureus (S. aureus) binds to endothelium via von Willebrand factor (VWF). Secreted VWF-binding protein (vWbp) mediates S. aureus adhesion to VWF under shear stress. vWbp interacts with VWF and the Sortase A-dependent surface protein Clumping factor A (ClfA). VWF-vWbp-ClfA anchor S. aureus to vascular endothelium under shear stress. SUMMARY: Objective When establishing endovascular infections, Staphylococcus aureus (S. aureus) overcomes shear forces of flowing blood by binding to von Willebrand factor (VWF). Staphylococcal VWF-binding protein (vWbp) interacts with VWF, but it is unknown how this secreted protein binds to the bacterial cell wall. We hypothesized that vWbp interacts with a staphylococcal surface protein, mediating the adhesion of S. aureus to VWF and vascular endothelium under shear stress. Methods We studied the binding of S. aureus to vWbp, VWF and endothelial cells in a micro-parallel flow chamber using various mutants deficient in Sortase A (SrtA) and SrtA-dependent surface proteins, and Lactococcus lactis expressing single staphylococcal surface proteins. In vivo adhesion of bacteria was evaluated in the murine mesenteric circulation using real-time intravital vascular microscopy. Results vWbp bridges the bacterial cell wall and VWF, allowing shear-resistant binding of S. aureus to inflamed or damaged endothelium. Absence of SrtA and Clumping factor A (ClfA) reduced adhesion of S. aureus to vWbp, VWF and activated endothelial cells. ADAMTS-13 and an anti-VWF A1 domain antibody, when combined, reduced S. aureus adhesion to activated endothelial cells by 90%. Selective overexpression of ClfA in the membrane of Lactococcus lactis enabled these bacteria to bind to VWF and activated endothelial cells but only in the presence of vWbp. Absence of ClfA abolished bacterial adhesion to the activated murine vessel wall. Conclusions vWbp interacts with VWF and with the SrtA-dependent staphylococcal surface protein ClfA. The complex formed by VWF, secreted vWbp and bacterial ClfA anchors S. aureus to vascular endothelium under shear stress.
Asunto(s)
Adhesión Bacteriana , Coagulasa/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/microbiología , Mesenterio/irrigación sanguínea , Glicoproteínas de Membrana Plaquetaria/metabolismo , Staphylococcus aureus/metabolismo , Factor de von Willebrand/metabolismo , Aminoaciltransferasas/genética , Aminoaciltransferasas/metabolismo , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Velocidad del Flujo Sanguíneo , Células Cultivadas , Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/metabolismo , Interacciones Huésped-Patógeno , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Ratones Endogámicos C57BL , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Flujo Sanguíneo Regional , Circulación Esplácnica , Staphylococcus aureus/genética , Estrés Mecánico , Factores de TiempoRESUMEN
Pentostatin was used to treat 26 patients with advanced B-cell chronic lymphocytic leukemia resistant to conventional treatment. Twenty patients had progressive disease on previous regimens and six had had partial remission and then relapsed 3-34 months after previous chemotherapy. Eleven patients had previously been treated with three different regimens. 10 had been treated with two regimens, and five had been treated with one regimen. Pentostatin was administered at a dosage of 4 mg/m2 weekly for 3 weeks, then 4 mg/m2 every other week for 6 weeks and once a month for 6 months. Seven of 26 assessable patients (27%) achieved partial remission and five (19%) achieved clinical improvement. The median duration of partial remission until relapse or death was 210 days. Myelosuppression was minor and transient in responsive patients, indicating some degree of selective effect on lymphocytes. Except for one patient who died of cerebral hemorrhage during the first 6 weeks of treatment, no drug-related deaths were registered. Major toxic effects included nausea in 17 patients (mainly grade 1), infections in 15, and liver enzyme elevations in five. Thus, pentostatin is active, even in patients with advanced B-cell chronic lymphocytic leukemia that is refractory to multiple chemotherapy regimens. Response can be achieved with mild myelosuppression.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Pentostatina/uso terapéutico , Adulto , Anciano , Evaluación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pentostatina/efectos adversosRESUMEN
PURPOSE: To assess the value of granulocyte-macrophage colony-stimulating factor (GM-CSF) for induction treatment of acute myeloid leukemia (AML), both for priming of leukemic cells and for acceleration of hematopoietic recovery. PATIENTS AND METHODS: GM-CSF was administered 5 micrograms/kg/d by continuous intravenous (i.v.) infusion during induction therapy with daunorubicin (DNR) (days 1 to 3) and cytarabine (ARA-C) (days 1 to 7). A total of 102 patients were randomized onto four arms, as follows: (1) GM-CSF 24 hours before and during chemotherapy (arm +/-); (2) GM-CSF after chemotherapy until day 28 or recovery of polymorphonuclear leukocytes (PMNs) (arm -/+);(3) GM-CSF before, during, and after chemotherapy (arm +/+); or (4) no GM-CSF (arm -/-). Stopping rules were applied in case of an initial WBC count greater than 30 x 10(9)/L or a secondary increase of circulating blast cells. Analyses were performed according to the intention-to-treat principle. RESULTS: The complete remission (CR) rates were 77% (arm -/-), 72% (arm +/-), 48% (arm -/+), and 46% (arm +/+). Patients randomized to receive GM-CSF after induction (arms -/+ and +/+) had a significantly lower CR rate (P = .008) and a trend toward accelerated recovery of neutrophils, but no fewer infections or induction deaths. The lower CR rate appeared to be related to an increased resistance rate, with persistent leukemia. The main side effects of GM-CSF were fluid retention and hypotension. CONCLUSION: GM-CSF administered during induction treatment of AML with a DNR/Ara-C combination did not provide any clinical benefit. Furthermore, there was a significant decrease in the CR rate with more persistent leukemia when GM-CSF was administered during the hypoplastic phase after the chemotherapy courses.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Daunorrubicina/administración & dosificación , Daunorrubicina/efectos adversos , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Humanos , Infusiones Intravenosas , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Tasa de SupervivenciaRESUMEN
We report the results of a prospective study in patients more than 65 years of age in whom two different therapeutic strategies were compared: immediate intensive-induction chemotherapy (arm A) versus "wait and see" and supportive care and mild cytoreductive chemotherapy only for relief of progressive acute myeloid leukemia (AML)-related symptoms (arm B). The major objective of the study was to compare survival outcome of both regimens. Thirty-one patients on arm A received one or two courses of daunorubicin, vincristine, and cytarabine for remission induction followed by one additional cycle for consolidation in case of complete remission (CR). Among 29 patients on arm B, cytoreductive chemotherapy (hydroxyurea, cytarabine) had to be initiated for palliation of leukemia-associated complications in 21 patients at a median of 9 days after diagnosis. Overall survival duration for patients treated on arm A was significantly (P = .015) longer than the survival in arm B (median survival, 21 weeks v 11 weeks; projected survival at 2.5 years, 13% v 0%). Eighteen (58%) of arm A patients and none (0%) of arm B patients entered CR. Of the first group, projected disease-free survival at 2 years is 17%. The median percentages of days spent in the hospital by arm A and B patients were 55% and 50%, respectively. This study shows that a strategy based on modern supportive care and a wait and see approach yields extremely poor results. It is not superior in regard to the frequency of hospital admission and is inferior regarding survival outcome.
Asunto(s)
Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide/tratamiento farmacológico , Anciano de 80 o más Años , Ensayos Clínicos como Asunto , Hospitalización , Humanos , Leucemia Mieloide/complicaciones , Leucemia Mieloide/mortalidad , Cuidados Paliativos , Estudios Prospectivos , Calidad de Vida , Distribución Aleatoria , Inducción de RemisiónRESUMEN
Immunofluorescence microscopy of the adherent layer of human long-term bone marrow cultures (HLTBMCs) consistently revealed motility-associated features in a part of the plasma cells. Not only were small surface blebs observed, but also long extensions whose morphology was reminiscent of neuronal axons. The observations were made in all HLTBMCs established with normal as well as myelomatous bone marrow (BM). Plasma cells with long extensions were also noticed on May-Grünwald-Giemsa smears of original uncultured BM from normal individuals and patients with myelomatous disorders. This suggests that the motility-associated morphological features occur in vivo as well as in vitro. The observations were most striking in the one case of plasma cell leukemia, both in culture as well as in the BM smear.
Asunto(s)
Células de la Médula Ósea , Células Plasmáticas/citología , Movimiento Celular , Células Cultivadas , Técnica del Anticuerpo Fluorescente , Humanos , Leucemia de Células Plasmáticas/patología , Coloración y EtiquetadoRESUMEN
An immunological analysis of the nonmacrophage hemopoietic cells in the adherent layer of human long-term bone marrow cultures was performed in situ. It revealed not only the expected granulocytic and monocytic cells, but an important lymphoid population as well. The latter consisted of cells bearing the markers of mature T lymphocytes, B lymphocytes, and plasma cells. These cells were also present in the hemopoietic foci of the adherent layer, the so-called cobblestone areas. Although more CD8+ than CD4+ lymphocytes were generally present in the initial bone marrow inoculum, both the adherent layer and the nonadherent fraction disclosed a preponderance of CD4+ cells after a short period of culture. The majority of the lymphoid cells were present in the adherent layer, rather than in the nonadherent fraction of the cultures. The long-term presence of lymphoid elements in the adherent layer suggests their affinity for the bone marrow stroma and the possible enhancement of their persistence in vitro by contact with these cells.
Asunto(s)
Células de la Médula Ósea , Adhesión Celular , Células Madre Hematopoyéticas/citología , Linfocitos/citología , Células Plasmáticas/citología , Anticuerpos Monoclonales/análisis , Antígenos de Diferenciación/análisis , Diferenciación Celular , Células Cultivadas , Técnica del Anticuerpo Fluorescente , Humanos , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Linfocitos/clasificación , Linfocitos/inmunología , Células Plasmáticas/inmunología , Factores de TiempoRESUMEN
Human long-term bone marrow cultures (HLTBMCs) were established with bone marrow (BM) collected from five patients with myelomatous disorders (four with multiple myeloma, one with plasma cell leukemia). In all cases, up to at least 6 weeks of culture, there was a persistence of the monoclonal plasma cell population in the adherent layer of the culture. In some cultures proliferating plasma cells could be demonstrated by the Ki-67 monoclonal antibody. In all instances a paraprotein could be shown in the conditioned medium. This study demonstrates that malignant plasma cells, in analogy to their normal counterparts, have an affinity for the BM stroma and suggests that their long-term survival might be enhanced by their interaction with it.
Asunto(s)
Médula Ósea/patología , Mieloma Múltiple/patología , Células Plasmáticas/patología , Plasmacitoma/patología , Adhesión Celular , Células Clonales , Ensayo de Unidades Formadoras de Colonias , Medios de Cultivo , Humanos , Paraproteínas/biosíntesis , Factores de Tiempo , Células Tumorales Cultivadas/patologíaRESUMEN
We studied the effects of interleukin 4 (IL4) on myelopoiesis supported by either granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF) or IL3 on purified CD34+ bone marrow progenitor cells. IL4 stimulates the colony-forming unit granulocyte (CFU-G) induced by G-CSF and inhibits all colony types supported by either IL3 and GM-CSF, although inhibition of CFU-M (macrophage) was significantly stronger than that of CFU-G and CFU-GM. When the cells were first incubated in liquid culture for 4 days in IL4, followed by agar culture in G-CSF, there was a significant increase in the number of CFU-G compared to cells which had been incubated in medium alone for 4 days before plating out in agar containing G-CSF. The inhibitory effects of IL4 on GM-CSF or IL3 supported colony formation, however, disappear with sequential incubation in IL4 in liquid culture followed by culture in agar with either GM-CSF or IL3.
Asunto(s)
Antígenos CD , Médula Ósea/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Interleucina-4/farmacología , Antígenos CD34 , Células de la Médula Ósea , Células Cultivadas , Relación Dosis-Respuesta a Droga , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Proteínas Recombinantes/farmacología , Factores de TiempoRESUMEN
With the use of a monoclonal anti-glycophorin A antibody and flow cytometric cell sorting, an erythroleukemic bone marrow sample was separated in highly purified erythroblast and myeloblast fractions. Similar karyotypic anomalies were found in both cell populations as in the unseparated bone marrow. This study confirms that acute nonlymphocytic leukemia can originate at the level of a multipotential hemopoietic stem cell.
Asunto(s)
Eritroblastos/análisis , Leucemia Eritroblástica Aguda/genética , Anticuerpos Monoclonales , Células de la Médula Ósea , Separación Celular , Citometría de Flujo , Glicoforinas/análisis , Humanos , Cariotipificación , Leucemia Eritroblástica Aguda/patología , Masculino , Persona de Mediana EdadRESUMEN
The quantitative evolution of endothelial cells (ECs) in Dexter-type human long-term bone marrow cultures (HLTBMCs) was investigated. Using monoclonal antibodies directed against von Willebrand factor (vWF) and against membrane antigens (EN-4 and PAL-E), a low percentage--usually less than 1% of stromal cells--of ECs was detected in all confluent cultures established from 11 different bone marrow samples. Generally these cells are not associated directly with the areas of myelopoiesis ("cobblestone areas"). ECs cannot be demonstrated in the adherent layer of most young, non-confluent, and of some old, HLTBMCs. In some instances, morphological features suggestive of dynamic behavior were seen (sprouting, canal formation). In addition, a very low proportion of vWF-positive megakaryocytic cells was found in 4 of 11 cultures, always in direct contact with the stromal fibroblastic cells.
Asunto(s)
Células de la Médula Ósea , Endotelio/fisiología , Megacariocitos/fisiología , Médula Ósea/análisis , Adhesión Celular , Recuento de Células , Supervivencia Celular , Células Cultivadas , Endotelio/análisis , Humanos , Megacariocitos/análisis , Neovascularización Patológica , Seudópodos/fisiología , Factor de von Willebrand/análisisRESUMEN
Human long-term bone marrow cultures (HLTBMCs) were established from thawed post-cryopreservation, as well as from cadaver donor bone marrow (BM) samples. The longevity was similar in the different series of HLTBMCs examined. CFU-GM could be cultured out of cadaver donor BM. This indicates that previously healthy people, under the conditions generally accepted as suitable for organ donation, could become suitable donors for allogeneic BM transplantation.
Asunto(s)
Células de la Médula Ósea , Hematopoyesis , Diferenciación Celular , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Humanos , Factores de Tiempo , Donantes de Tejidos , Conservación de TejidoRESUMEN
We have previously shown that interleukin 4 (IL-4) and interferon gamma (INF-gamma) reciprocally regulate the production of granulocytes and monocytes from mature monopotential hematopoietic progenitor cells, while at the level of the very primitive stem cells IFN-gamma is a selective inhibitor of proliferation and differentiation, and IL-4 has weak stimulatory effects. We investigated the effects of IL-4 and IFN-gamma on the expansion in suspension culture of myeloid colony-forming cells (CFCs) induced by either IL-3 or IL-1+IL-3, using on the one hand more differentiated CD34+HLA-DR strongly positive (HLA-DR++) and on the other hand more primitive Cd34+HLA-DR weakly positive (HLA-DR+/-) human bone marrow cells. It is shown that both IL-4 and IFN-gamma stimulate the IL-3- and IL-3+IL-1-induced expansion of the number of CFCs in the HLA-DR+/- population. In the presence, but not in the absence of IL-1, additive effects of IL-4 and IFN-gamma were seen. We could not demonstrate any IL-3-like effect by IL-4 on early human hematopoietic progenitors. No expansion of CFC number was seen in the HLA-DR++ population. Based on these data and on data which we have published previously, a model for the regulation of myelopoiesis by IL-4 and IFN-gamma is proposed. In this model, IL-4 and IFN-gamma, which are both immune recognition induced inflammatory cytokines, both stimulate the expansion and recruitment of early myeloid progenitors, whereas at the level of their terminal differentiation, the balance between both cytokines determines whether preferentially monocytes/macrophages (IFN-gamma) or granulocytes (IL-4) are being produced. At the level of the most primitive cells, the inhibitory action of IFN-gamma might prevent differentiative exhaustion of the stem cell compartment in situations of hematopoietic stress.
Asunto(s)
Células de la Médula Ósea , Células Madre Hematopoyéticas/citología , Interferón gamma/farmacología , Interleucina-4/farmacología , Formación de Anticuerpos , Antígenos CD34/metabolismo , Diferenciación Celular , División Celular , Células Cultivadas , Sinergismo Farmacológico , Antígenos HLA-DR/metabolismo , Células Madre Hematopoyéticas/inmunología , Humanos , Inmunidad Celular , Interleucina-1/farmacología , Interleucina-3/farmacología , Modelos BiológicosRESUMEN
An immunofluorescence study of the adherent layer of human long-term bone marrow cultures (HLTBMC) revealed the following surface markers on the different stromal cell populations: stromal fibroblastic cells CD10+, FIB86.3+, CD13+, CD71+; adipocytes CD10+, FIB86.3-, CD13+, CD71-/+; and macrophages CD10-/+, FIB86.3+, CD13+, CD71-/+, CD14+, CD33+, CD25+, HLA-DR+, CD4+, CD19+, CD45+. The markers of the stromal fibroblastic cells in HLTBMC were similar to those of twice-passaged fibroblasts not only from bone marrow and spleen, but also from a hemopoietic non-supportive organ such as the skin. Some of the cultured human umbilical vein endothelial cells used as controls were found to be CD25+, demonstrating for the first time the interleukin-2 receptor p55 chain on normal non-hemopoietic cells. The stromal fibroblastic cells are overrepresented compared to the small non-macrophage hemopoietic cell population in the adherent layer of HLTBMC. In addition, silver staining revealed an increased reticulin content in most of the HLTBMC. An excessive growth of stromal fibroblastic cells and an excessive deposition of their product, the reticulin fibers, are the hallmark of myelofibrosis. The finding of equivalent observations in HLTBMC suggests that the hitherto unexplained, premature quenching of hemopoiesis in HLTBMC might at least partly be due to mechanisms similar to those operating in myelofibrosis in vivo.
Asunto(s)
Células de la Médula Ósea , Mielofibrosis Primaria/etiología , Antígenos CD/análisis , Antígenos de Diferenciación/análisis , Antígenos de Diferenciación de Linfocitos B/análisis , Antígenos de Neoplasias/análisis , Antígenos de Superficie/análisis , Médula Ósea/enzimología , Médula Ósea/inmunología , Células Cultivadas , Fibroblastos/inmunología , Hematopoyesis , Humanos , Neprilisina , Peptidil-Dipeptidasa A/análisis , Receptores de TransferrinaRESUMEN
We conducted a prospective, multicenter pilot study of remission induction therapy in patients with poor prognosis MDS and AML evolving from a preceding phase of MDS. Fifty evaluable patients from 15 institutions were treated with one or two remission-induction courses consisting of i.v. idarubicin 12 mg/m2/day on days 1, 2, and 3 combined with a continuous i.v. infusion of cytarabine of 200 mg/m2/day on days 1 to 7. Of the 27 complete remitters (54%), 23 received a consolidation course which was identical to the remission-induction course except for the idarubicin 12 mg/m2 which was given on day 1 only. Fifteen patients received maintenance therapy consisting of six courses of cytarabine 10 mg/m2, s.c. twice daily, for 14 days. Two complete remitters were allografted and five patients received an ABMT. The median survival of all 50 treated patients was 14 months. The median duration of disease-free survival was 11 months with two patients in CR more than 2 years after entering CR. Twenty-four of the 27 remitters have relapsed. Four patients died during remission-induction therapy, but no patient died as a result of persisting hypoplasia. No fatal complications occurred during the consolidation and maintenance courses. Age and stage of disease had no significant impact on CR rate nor on remission duration. The CR rate was significantly (P = 0.03) higher in patients with only normal metaphases compared to patients with cytogenetic abnormalities. The DFS at 2 years was 33 vs 8%, respectively, for patients without or with cytogenetic abnormalities (P = 0.02). This study shows that patients below the age of 60 years with poor risk features are candidates for treatment with combination chemotherapy. A complete remission rate of more than 50% may be expected. Maintaining remission after remission-induction chemotherapy is a difficult issue. Patients not eligible for allogeneic BMT may be treated with intensive post-remission chemotherapy or autologous BMT.
Asunto(s)
Citarabina/administración & dosificación , Idarrubicina/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Adolescente , Adulto , Factores de Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea , Aberraciones Cromosómicas , Trastornos de los Cromosomas , Europa (Continente) , Humanos , Tiempo de Internación , Persona de Mediana Edad , Neoplasias Primarias Secundarias , Proyectos Piloto , Pronóstico , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
Two cases of pneumococcal sepsis in splenectomized patients were complicated by purpura fulminans. In addition, acute renal failure developed in both patients, and myolysis in one. Immunological findings in the patient with myolysis suggest a possible role of pneumococcal antigen-containing circulating immune complexes in the pathogenesis of these complications.