Middle East respiratory syndrome coronavirus vaccine based on a propagation-defective RNA replicon elicited sterilizing immunity in mice.

Self-amplifying RNA replicons are promising platforms for vaccine generation. Their defects in one or more essential functions for viral replication, particle assembly, or dissemination make them highly safe as vaccines. We previously showed that the deletion of the envelope (E) gene from the Middle East respiratory syndrome coronavirus (MERS-CoV) produces a replication-competent propagation-defective RNA replicon (MERS-CoV-ΔE). Evaluation of this replicon in mice expressing human dipeptidyl peptidase 4, the virus receptor, showed that the single deletion of the E gene generated an attenuated mutant. The combined deletion of the E gene with accessory open reading frames (ORFs) 3, 4a, 4b, and 5 resulted in a highly attenuated propagation-defective RNA replicon (MERS-CoV-Δ[3,4a,4b,5,E]). This RNA replicon induced sterilizing immunity in mice after challenge with a lethal dose of a virulent MERS-CoV, as no histopathological damage or infectious virus was detected in the lungs of challenged mice. The four mutants lacking the E gene were genetically stable, did not recombine with the E gene provided in trans during their passage in cell culture, and showed a propagation-defective phenotype in vivo. In addition, immunization with MERS-CoV-Δ[3,4a,4b,5,E] induced significant levels of neutralizing antibodies, indicating that MERS-CoV RNA replicons are highly safe and promising vaccine candidates.

Childhood and adolescent lymphoma in Spain: incidence and survival trends over 20 years

Background: Lymphoma is the third most common malignancy in children (0-14 years) and the first in adolescents (15-19 years). This population-based study-the largest ever done in Spain-analyses incidence and survival of lymphomas among Spanish children and adolescents. Patients and methods 1664 lymphoma cases (1983-2007) for incidence and 1030 for survival (1991-2005) followed until 31/12/2010, were provided by 11 cancer registries. Age-adjusted incidence rates (ASRw) to the world standard population were obtained; incidence trends were modelled using the Joinpoint programme, observed survival (OS) was estimated with Kaplan-Meier and trends tested with a log-rank test. Results are presented according to the International Classification of Childhood Cancer-3. Results: In Spain, the ASRw0-14 for lymphomas was 17.5 per 1.000.000 child-years and 50.0 the specific rate for adolescents. Overall incidence increased significantly during 1983-1997 with no increases thereafter. Patients over 9 years old showed significant rising trends for all subtypes, except for Burkitt lymphoma (BL) in adolescents. During 2001-2005 (age 0-19 years), 5-year OS was 94 (90-98), 73 (64-83) and 86 (78-94) for Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and BL, respectively. No improvement in survival was found. The incidence in Spain was higher than overall European rates, but within the range of that in Southern Europe. Comparing OS in Spain 1991-1995 and 2001-2005 with results for Europe of the Automated Childhood Cancer Information System (ACCIS) (1988-1997) and the European cancer registry-based study on survival and care of cancer patients (EUROCARE) (2000-2007), it was similar for HL and lower for NHL and BL. Conclusions: Systematic monitoring and analysis of lymphoma paediatric data would provide clinical and epidemiological information to improve the health care of these patients and the outcomes for these malignancies in Spain

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Childhood and adolescent lymphoma in Spain: incidence and survival trends over 20 years.

BACKGROUND: Lymphoma is the third most common malignancy in children (0-14 years) and the first in adolescents (15-19 years). This population-based study-the largest ever done in Spain-analyses incidence and survival of lymphomas among Spanish children and adolescents. PATIENTS AND METHODS: 1664 lymphoma cases (1983-2007) for incidence and 1030 for survival (1991-2005) followed until 31/12/2010, were provided by 11 cancer registries. Age-adjusted incidence rates (ASRw) to the world standard population were obtained; incidence trends were modelled using the Joinpoint programme, observed survival (OS) was estimated with Kaplan-Meier and trends tested with a log-rank test. Results are presented according to the International Classification of Childhood Cancer-3. RESULTS: In Spain, the ASRw0-14 for lymphomas was 17.5 per 1.000.000 child-years and 50.0 the specific rate for adolescents. Overall incidence increased significantly during 1983-1997 with no increases thereafter. Patients over 9 years old showed significant rising trends for all subtypes, except for Burkitt lymphoma (BL) in adolescents. During 2001-2005 (age 0-19 years), 5-year OS was 94 (90-98), 73 (64-83) and 86 (78-94) for Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and BL, respectively. No improvement in survival was found. The incidence in Spain was higher than overall European rates, but within the range of that in Southern Europe. Comparing OS in Spain 1991-1995 and 2001-2005 with results for Europe of the Automated Childhood Cancer Information System (ACCIS) (1988-1997) and the European cancer registry-based study on survival and care of cancer patients (EUROCARE) (2000-2007), it was similar for HL and lower for NHL and BL. CONCLUSIONS: Systematic monitoring and analysis of lymphoma paediatric data would provide clinical and epidemiological information to improve the health care of these patients and the outcomes for these malignancies in Spain.

Actualización del tratamiento con L-asparraginasa en Pediatría / Update on L-asparaginase treatment in paediatrics

La L-asparraginasa (L-ASP) es una de las piedras angulares del tratamiento de la leucemia linfoblástica aguda y del linfoma no Hodgkin. Es una enzima de origen bacteriano con capacidad de transformar la L-Asparragina en ácido aspártico; la depleción extracelular de este aminoácido inhibe la síntesis proteica en los linfoblastos induciendo su apoptosis. Numerosos estudios han demostrado que los tratamientos con L-ASP mejoran la supervivencia de estos pacientes, pero existen diferencias en las características de las 3 formulaciones disponibles en la actualidad. Este artículo revisa la dosificación, actividad y efectos secundarios de las 2 L-ASP derivadas de Escherichia coli (la nativa y la pegilada) y de la única derivada de Erwinia chrysanthemi (Erwinia ASP). A pesar de su indiscutible indicación en los últimos 50 años, siguen existiendo numerosos puntos de controversia, y su uso todavía sigue marcado por los efectos secundarios derivados de la inhibición de la síntesis proteica. La vida media corta de las formas nativas y la vía de administración intramuscular, la más utilizada hasta el momento, afecta la calidad de vida de estos pacientes por la frecuencia con la que han de acudir al centro hospitalario y las múltiples punciones que conlleva. Por ello, los estudios más recientes pretenden valorar otras alternativas como la formulación de vida media más larga (L-ASP pegilada) y la vía intravenosa, con resultados alentadores. Aun así, son necesarios más estudios para establecer cuál es la formulación y la vía de administración indicada en primera línea, la dosificación óptima y el manejo de los efectos adversos (AU)

L-asparaginase (L-ASP) is one of the cornerstones of the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphoma. It is an enzyme of bacterial origin capable of transforming L-asparagine to aspartic acid. The extracellular depletion of L-asparagine inhibits protein synthesis in lymphoblasts, inducing their apoptosis. Numerous studies have demonstrated that treatment with L-ASP improves survival of patients, but there are clear differences in the characteristics of the three currently available formulations. This article reviews the dosage, activity and side effects of the two L-ASP derived from Escherichia coli (native and pegylated), and the one derived from Erwinia chrysanthemi (Erwinia ASP). Despite its indisputable indication over the past50 years, there are still many points of contention, and its use is still marked by the side effects of the inhibition of protein synthesis. The short half-life of native forms, and the most frequently used parenteral administration by intramuscular injections, affects the quality of life of the patients. Therefore, recent studies claim to evaluate alternatives, such as the formulation of longer half-life pegylated L-ASP, and the use of intravenous formulations. There are encouraging results to date with both preparations. Still, further studies are needed to establish which should be the formulation and frontline indicated route of administration, optimal dosing, and management of adverse effects (AU)

[Update on L-asparaginase treatment in paediatrics]. / Actualización del tratamiento con L-asparraginasa en Pediatría.

L-asparaginase (L-ASP) is one of the cornerstones of the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphoma. It is an enzyme of bacterial origin capable of transforming L-asparagine to aspartic acid. The extracellular depletion of L-asparagine inhibits protein synthesis in lymphoblasts, inducing their apoptosis. Numerous studies have demonstrated that treatment with L-ASP improves survival of patients, but there are clear differences in the characteristics of the three currently available formulations. This article reviews the dosage, activity and side effects of the two L-ASP derived from Escherichia coli (native and pegylated), and the one derived from Erwinia chrysanthemi (Erwinia ASP). Despite its indisputable indication over the past50 years, there are still many points of contention, and its use is still marked by the side effects of the inhibition of protein synthesis. The short half-life of native forms, and the most frequently used parenteral administration by intramuscular injections, affects the quality of life of the patients. Therefore, recent studies claim to evaluate alternatives, such as the formulation of longer half-life pegylated L-ASP, and the use of intravenous formulations. There are encouraging results to date with both preparations. Still, further studies are needed to establish which should be the formulation and frontline indicated route of administration, optimal dosing, and management of adverse effects.

Alteraciones hematológicas en las personas con síndrome de Down / Blood disorders in persons with Down’s syndrome

Las personas con síndrome de Down presentan una mayor frecuencia de enfermedades clonales hematológicas que la población general. La mayor parte de las veces se presentan con características particulares y en ocasiones son causa de muerte. Destaca la entidad conocida como síndrome mieloproliferativo transitorio, asociado a mutaciones en el gen GATA, generalmente de carácter autolimitado, pero que en, aproximadamente, un 20% de pacientes evoluciona a leucemia aguda. La incidencia global de leucemia es muy superior a la de la población infantil general. De entre ellas, la leucemia aguda megacarioblástica presenta características especiales en este grupo poblacional y suele tener buen pronóstico, con un tratamiento menos intenso que en otros niños sin trisomía. Las leucemias de estirpe linfoblástica, sin embargo, pueden tener un pronóstico peor que el de los niños sin alteración cromosómica constitucional. un aspecto menos descrito es el que concierne a la patología benigna, así como a las peculiaridades de las 3 líneas hematopoyéticas encontradas frecuentemente en el SD (AU)

Persons with Down’s syndrome have clonal blood disease more frequently than the general population. Most of the times, these occur with specific characteristics and sometimes may also be a cause of death. The condition known as transient myeloproliferative syndrome stands out. This condition is associated to mutations in the GATA gene and generally of self-limited character. However, this syndrome evolves to acute leukemia in approximately 20% of these patients. The global incidence of leukemia is much higher than in the general pediatric population. Among these, acute megakaryoblastic leukemia has special characteristics in this population group and generally has a good prognosis, with a treatment that is less intense than in other children without trisomy. Lymphoblastic leukemia, however, may have a worse prognosis than that of children without constitutional chromosomal disorder. A less described aspect is that regarding the benign conditions and the characteristics of the 3 hematopoietic lines frequently found in DS (AU)

Programa de Salud para niños y adolescentes con síndrome de Down / Health Program for children and adolescents with Down’s syndrome

Los problemas específicos de salud que presentan los niños con síndrome de Down deben ser objeto de atención por los pediatras. Para integrar estos cuidados con los propios de la edad, diversas organizaciones pediátricas han elaborado programas de salud para personas con síndrome de Down. En ellos se puntualiza sobre las necesidades específicas de los pacientes con trisomía 21, añadiéndolas a las propias de las diversas edades. Los programas de salud suponen una ayuda importante para la atención pediátrica a este grupo poblacional (AU)

Special attention should be given by the pediatricians to the specific health problems that children with Down’s Syndrome have. In order to integrate these cares into those cares characteristic for their age, different pediatric organizations have elaborated health programs for persons with Down’s Syndrome. In these, the specific needs of the patients with trisomy 21 are highlighted, adding these to those characteristic for the different ages. The health programs suppose an important aid for the pediatric care to this population group (AU)

Protocolo de estudio y tratamiento de la trombocitopenia inmune primaria (PTI-2010) / Protocol for the study and treatment of Immune Thrombocytopenic Purpura (ITP). ITP-2010

La trombocitopenia inmune primaria, anteriormente conocida como púrpura trombocitopénica inmune, es una enfermedad cuyo manejo diagnóstico y terapéutico ha sido siempre controvertido. La Sociedad Española de Hematología y Oncología Pediátricas, a través del grupo de trabajo de la PTI, ha actualizado el documento con las recomendaciones protocolizadas para el diagnóstico y tratamiento de esta enfermedad, basándose en las guías clínicas disponibles actualmente, revisiones bibliográficas, ensayos clínicos y el consenso de sus miembros. El objetivo principal es disminuir la variabilidad clínica en los procedimientos diagnósticos y terapéuticos con el fin de obtener los mejores resultados clínicos, con menor incidencia en la calidad de vida y los mínimos efectos adversos (AU)

Primary immune thrombocytopenia (ITP), formerly known as immune thrombocytopenic purpura, is a disease in which clinical and therapeutic management has always been controversial. The ITP working group of the Spanish Society of Paediatric Haematology and Oncology has updated its guidelines for diagnosis and treatment of ITP in children based on current guidelines, literature review, clinical trials and member consensus. The primary objective was to lessen clinical variability in diagnostic and therapeutic procedures in order to obtain best clinical results with minimal adverse events and good quality of life (AU)

[Protocol for the study and treatment of immune thrombocytopenic purpura (ITP). ITP-2010]. / Protocolo de estudio y tratamiento de la trombocitopenia inmune primaria (PTI-2010).

Primary immune thrombocytopenia (ITP), formerly known as immune thrombocytopenic purpura, is a disease in which clinical and therapeutic management has always been controversial. The ITP working group of the Spanish Society of Paediatric Haematology and Oncology has updated its guidelines for diagnosis and treatment of ITP in children based on current guidelines, literature review, clinical trials and member consensus. The primary objective was to lessen clinical variability in diagnostic and therapeutic procedures in order to obtain best clinical results with minimal adverse events and good quality of life.

Leucemia aguda linfoblástica infantil y síndrome de Down: análisis de los protocolos shop/lal-99 y 05 / Acute lymphoblastic leukemia in children and Down syndrome: Analysis of SHOP/ ALL-’99 and ’05 Protocols

Introducción y objetivo: El síndrome de Down (SD) tiene una predisposición conocida a distintos tipos de leucemia infantil. En el caso de la leucemia aguda linfoblástica (LAL), la mayoría de autores refieren peores resultados con respecto a los pacientes no Down. Pacientes y método: En el presente trabajo analizamos los resultados obtenidos en los pacientes con SD y LAL <18 años tratados según los protocolos del grupo SHOP (Sociedades Españolas de Hematología y Oncología Pediátricas) durante la última década. Resultados: Los datos obtenidos a partir de casi 1.000 pacientes que proceden de 32 centros, confirman diversos aspectos: se trata de leucemias agudas con características clínicas y biológicas de bajo riesgo, por lo que suelen estratificarse en grupos de riesgo bajo y reciben quimioterapias de intensidad moderada. Sin embargo, el número de complicaciones infecciosas y tóxicas es superior al de las de pacientes sin SD, por lo que tanto la supervivencia global (SG) como la supervivencia libre de eventos (SLE) se ven marcadamente afectadas. Conclusiones: Debemos optimizar el conocimiento de la biología de estas leucemias para interpretar cuáles son los factores sobre los que podemos incidir para mejorar su pronóstico (AU)

Introduction and objective: Down syndrome bears a known predisposition to childhood leukemia. In regards to acute lymphoblastic leukemia (ALL), most international groups show poorer results when compared to non-Down patients. Patients and methods: With this study we analyze the results obtained with Down syndrome patients and ALL younger than 18 years who were treated with SHOP (Spanish Pediatric Hematology and Oncology Societies) protocols for the past decade. Results: Current data obtained from 1000 patients out of 32 centers confirm several aspects: those are related to acute leukemia showing clinical and biological low risk treats, thereof they may be categorized in low risk groups hence receive scheduled chemotherapy of moderate intensity. However, the number of infectious and toxic complications is greater than those for non-Down patients, therefore both overall survival (OS) and event free survival (EFS) are markedly affected. Conclusions: The future aim is to optimize the knowledge on biological aspects of these leukemia, in order to determine those features to be acted upon to improve their outcome (AU)

Allogeneic hemopoietic stem cell transplantation for childhood acute lymphoblastic leukemia in second complete remission-similar outcomes after matched related and unrelated donor transplant: a study of the Spanish Working Party for Blood and Marrow Transplantation in Children (Getmon).

The authors report the results of 58 children with ALL in 2CR after related (n = 31) or unrelated (n = 27) AHSCT. Characteristics at diagnosis and initial and after relapse antileukemic treatment were similar in the related donor (RD) and the unrelated donor (UD) groups. Conditioning consisted of TBI/CY +/- VP-16 for patients > or = 3 years old (n = 43) and Bu/CY for the rest. Median recipient age was 8 years (range 1-17) in the RD and 9 years (range 3-14) in the UD group. Median follow-up was 54 months (range 24-80) and 52 months (range 22-85) in the RD and the UD groups repectively. The 5-year EFS probability was 43 +/- 9% for the RD group and 36 +/- 9% in the UD group (p = .25). The transplant-related mortality was 16% in the RD and 37% in the UD group (p = .016). In the RD group 36.7% of patients relapsed versus 18.6% in the UD group (p = .05). GvHD associated with organ failure or infection caused most of the transplant-related deaths in both groups. Survivor quality of life for both groups was good (Lansky score < or = 90).

Long-term results of two consecutive trials in childhood acute lymphoblastic leukaemia performed by the Spanish Cooperative Group for Childhood Acute Lymphoblastic Leukemia Group (SHOP) from 1989 to 1998

INTRODUCTION: The first multi-centric protocol for childhood acute lymphoblastic leukaemia (ALL) treatment in Spain started in 1989 and was conducted by the Spanish Pediatric Hematology and Oncology Societies. MATERIALS AND METHODS: A total of 673 patients were included in two consecutive trials, SHOP-89 (1989-1993) and SHOP- 94 (1994-1998). Approximately 67% of the children diagnosed with ALL in Spain during this period were enrolled in these trials. The 250 eligible patients enrolled in the SHOP- 89 study were stratified to either a standard or a high-risk group. Therapy schedule was based on the central nervous system (CNS) therapy designed by St Jude CRH and the Children's Cancer Group, and the post-induction intensification developed by the BFM group. In the SHOP-94 study, a further high-risk group was included in the stratification of the 423 enrolled patients. The therapeutic protocol was characterised by intensification of systemic chemotherapy and the administration of cranial radiotherapy only to patients at high risk of relapse or with CNS involvement at diagnosis. RESULTS: Event-free survival (EFS) increased from 0.57+/- 0.03 at 15 years in SHOP-89, to 0.68+/-0.03 at 11 years in SHOP-94 (p=0.01). Relapse rate decreased from SHOP-89 to SHOP-94: 0.38 vs. 0.25 (p=0.01). CNS relapse rate was 9.1% in SHOP-89 and 4.6% in SHOP-94 (p=0.001). EFS in patients with T-immunophenotype was 0.40+/-0.08 in SHOP-89 and 0.44+/-0.06 in SHOP-94 (p=ns). CONCLUSIONS: Our therapeutic results evidence a significant improvement in EFS and systemic and CNS relapse rates among the two consecutive trials after modification of patient stratification and intensification of systemic chemotherapy (AU)

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Long-term outcome of allogeneic or autologous haemopoietic cell transplantation for acute lymphoblastic leukaemia in second remission in children. GETMON experience 1983-1998.

We present a retrospective study of long-term outcome and predictive factors of survival and relapse in 219 paediatric patients with acute lymphoblastic leukaemia (ALL) in second remission. They received allogeneic (allo) or autologous (auto) haemopoietic cell transplantation (HCT) depending on the availability of a matched sibling donor. The probability of event-free survival (EFS) for the total patient group was 0.35+0.03 at 14 years. No significant differences were observed for EFS between allo- and auto-HCT: 0.39+0.05 vs 0.32+0.04 (P=0.43). A better EFS was seen in patients with a late relapse (LR) (P=0.06 and 0.02, for allogeneic and autologous respectively). Significantly better EFS was observed in allo-HCT patients under 10 years of age and in auto-HCT patients with leukocytes at diagnosis below 25 x 109/l and late relapse. Predictive factors of failure in both groups were early relapse (ER), medullary relapse and age over 10 years. The probability of relapse (RP) for the total group of patients was 0.57+0.03, and it was significantly higher in auto-HCT patients: 0.65+0.04 vs 0.42+0.06 (P=0.002). Factors predictive for relapse were medullary and early relapse, auto-HCT and WBC >25 x 109/l at diagnosis.

Enfermedad amigdalar en niños con síndrome de Down / No disponible

Introducción. Nuestro objetivo fue comparar el curso evolutivo y la respuesta al tratamiento quirúrgico en la enfermedad adenoamigdalar en niños con síndrome de Down (SD) y en un grupo de control. Pacientes y métodos. En 28 niños con SD y en 56 controles sanos intervenidos mediante amigdalectomía con/sin adenoidectomía se evaluó la indicación, las características microbiológicas y oxidativas del tejido linfoide, las circunstancias del acto quirúrgico y las eventuales complicaciones y evolución clínica postoperatorias. Resultados. Los niños con SD son principalmente intervenidos por hipertrofia amigdalar (los controles, por amigdalitis de repetición). Entre los niños con SD los títulos de antiestreptolisinas y antioxidantes, así como el número de aislamientos microbiológicos, resultaron significativamente inferiores a los controles. La intervención no condicionó especiales complicaciones en ningún grupo. En niños con SD el alivio en el ronquido y la faringolalia fue inferior, debido a otras anomalías constitucionales en rinofaringe e hipofaringe, pero las pausas de apnea durante el sueño y la expresividad oral mejoraron de forma llamativa. Conclusiones. La hipertrofia amigdalar es un dato que el pediatra debe verificar y remitir al especialista otorrinolaringólogo en situaciones de síndrome de apnea obstructiva, dificultad en la comunicación verbal, trastornos deglutorios e incluso reflujo gastroesofágico (AU)

Introduction. Our aim was to compare the evolutive course and response to surgery in adenotonsillar disease in children with Down´s syndrome (DS) and in a control group. Patients and methods. 28 cases with DS and 56 healthy controls were submitted to tonsillectomy with or without adenoidectomy. An evaluation of surgical indications, bacteriological and oxidative findings of lymphoid tissue and of surgery was carried-out. The eventual postoperative complications and the clinical follow-up was also controlled. Results. Children with DS were mainly operated due to tonsillar hyperthorphy. In controls, surgery was performed usually due to recidivant tonsillitis. Among DS children, antistreptolysin and antioxidant levels, and the number of bacteriological isolations were significantly lower than in controls. Surgery did not provoke serious complications in any group. In children with DS, there was a lesser ameliotation in snoring and pharyngolalia, due to other constitutive anomalies in naso-and hypopharynx, buth sleep apnoea episodes and capacity of oral expression improved to a high degree. Conclusions. Tonsillar hypertrophy is a finding that paediatricians must verify and send to ENT surgeon in circumstances of obstructive sleep apnoea, difficulties in oral communications, swallowing disorders and even gastroesophageal reflux (AU)

Autologous stem cell transplantation for advanced Hodgkin's disease in children. Spanish group for BMT in children (GETMON), Spain.

This study evaluates the outcome of myeloablative chemo-radiotherapy and autologous stem cell transplantation (ASCT) in children with Hodgkin's disease (HD). Twenty children aged 5 to 18 years (median 10.8 years) at diagnosis, with relapsed, refractory or very poor prognosis HD, underwent ASCT in eight hospitals of our country. Status at transplant was: second complete remission (CR2): n = 12; further CR (CR >2): n = 3, partial remission (PR): n = 2, relapse: n = 2 and first CR (CR1): n = 1. Eighteen patients received chemotherapy-based conditioning regimens: cyclophosphamide, carmustine and etoposide (CBV): 11 (55%), carmustine, etoposide, cytarabine and melphalan (BEAM): 5, other: 2; and two patients were conditioned with TBI/Cy. Peripheral blood (PB) was the source of progenitor cells in 12 patients, BM in seven, and BM plus PB, in one. All patients engrafted. One patient died of sepsis and multiorgan failure at day 28 after transplantation. All four patients with measurable disease (PR or relapse) at transplantation attained complete remission. Five patients relapsed 5-34 months after transplant (median: 11 months). Eighteen children remain alive with a median survival time of 40 months. The projected 5-year overall survival and event-free survival (EFS) rates were 0.95 and 0.62. High-dose therapy with stem cell rescue can lead to durable remissions in children with advanced HD. Bone Marrow Transplantation (2000) 25, 31-34.

Serum malondialdehyde in HIV-seropositive children negatively correlates with CD4+ lymphocytes count.

Human immunodeficiency virus (HIV) infection is associated with oxidative stress as it has been demonstrated in adult-seropositive individuals. We show in this study that serum malondialdehyde (MDA) concentration of HIV-infected children was significantly higher than in control children. A negative correlation (r = -0.515) was found in HIV-infected children between their CD4+ lymphocyte count, and MDA concentration but not with serum antioxidant status. The increase of MDA concentration in HIV-seropositive children confirms the involvement of oxidative stress in the pathophysiology of this infection also in childhood. Because of the importance of oxidative stress and antioxidants for HIV viral replication, the adequacy of an adjuvant therapy with antioxidants should be considered; an adequate candidate for it could be N-acetylcysteine.

Serum malondialdehyde in HIV seropositive children.

Human immunodeficiency virus (HIV) infection is associated with oxidative stress as it has been demonstrated in adult seropositive individuals. We show in this study that serum malondialdehyde (MDA) concentration of HIV infected children was significantly higher than in control children. Moreover, a statistically significant decreased serum antioxidant status was detected in HIV infected children when compared with controls. No correlation was found in HIV infected children between their clinical or immunological categories, CD4+ lymphocyte count or CD4+/CD8+ ratio, and MDA concentration or serum antioxidant status. Newborn from HIV seropositive mothers had also a higher MDA concentration in cord blood serum than their corresponding controls from HIV seronegative mothers, whereas no difference could be established in the serum antioxidant status between both groups. No apparent correlation could be established between birth weight, gestational age or APGAR test values, and MDA in any of these groups. The results presented, (i.e., the increase of MDA concentration in HIV seropositive infants and children, and the decrease in serum total antioxidants in HIV seropositive children) confirm the involvement of oxidative stress in the pathophysiology of this infection also in childhood. Because of the importance of oxidative stress and antioxidants for HIV viral replication, the adequacy of an adjuvant therapy with antioxidants should be considered; an adequate candidate for it could be N-acetyl-cysteine.

Factors regulating megakaryocyte progenitor commitment to polyploidization.

Recognizable megakaryocytes are polyploid cells generated by a clonogenic, diploid progenitor, termed CFU-MKC (colony forming unit, megakaryocyte). In order to quantify polyploidization, ploidy histograms of megakaryocytes determined by microphotometric or flow cytometric measurements of megakaryocyte DNA have generally been used. However these techniques provide no information on the rate of commitment of CFU-MKC to polyploidy. Using a technique of clonal analysis determining the distributions of the number of doublings (NbD) undergone by CFU-MKC before committing to polyploidization, the polyploidization probability of CFU-MKC could be derived. This probability was found to be a constant independent from CFU-MKC mitotic history, since NbD distributions are exponential functions characterized by a constant rate of decay per doubling. By studying the effects of growth factors on polyploidization probability, it was also shown that: (1) this parameter is negatively regulated by growth factors contained in poke-weed or WEHI conditioned media, as well as by erythropoietin; (2) commitment to polyploidization does not require prior CFU-MKC division; (3) bipotent erythroid-megakaryocyte progenitors have a lower polyploidization probability than CFU-MKC; (4) determination of polyploidization probability reflects the activity of growth factors with greater accuracy than megakaryocyte colony count.

Factors regulating megakaryocyte progenitor commitment to polyploidization.

Recognizable megakaryocytes are polyploid cells generated by a clonogenic, diploid progenitor, termed CFU-MKC (colony forming unit, megakaryocyte). In order to quantify polyploidization, ploidy histograms of megakaryocytes determined by microphotometric or flow cytometric measurements of megakaryocyte DNA have generally been used. However these techniques provide no information on the rate of commitment of CFU-MKC to polyploidy. Using a technique of clonal analysis determining the distributions of the number of doublings (NbD) undergone by CFU-MKC before committing to polyploidization, the polyploidization probability of CFU-MKC could be derived. This probability was found to be a constant independent from CFU-MKC mitotic history, since NbD distributions are exponential functions characterized by a constant rate of decay per doubling. By studying the effects of growth factors on polyploidization probability, it was also shown that: (1) this parameter is negatively regulated by growth factors contained in poke-weed or WEHI conditioned media, as well as by erythropoietin; (2) commitment to polyploidization does not require prior CFU-MKC division; (3) bipotent erythroid-megakaryocyte progenitors have a lower polyploidization probability than CFU-MKC; (4) determination of polyploidization probability reflects the activity of growth factors with greater accuracy than megakaryocyte colony count.