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El aprendizaje mediado por la tecnología ha requerido el desarrollo de nuevas habilidades para enseñar y construir el conocimiento. Asociado a esto, la introducción de los dispositivos móviles como herramienta de enseñanza ha aportado flexibilidad y libertad sin precedentes, revolucionado las prácticas educativas del siglo XXI. En este trabajo se realizó una investigación sobre el aprendizaje móvil o M-learning con el objetivo de determinar los elementos esenciales a considerar para la inserción del M-learning en el proceso de enseñanza-aprendizaje de la Ingeniería de Software en la carrera de Informática de la Facultad de Informática y Ciencias Exactas en la Universidad de Ciego de Ávila, teniendo en cuenta como elemento esencial el diseño de los contenidos. Para el desarrollo de la investigación se utilizaron métodos y técnicas que permitieron constatar las relaciones esenciales del objeto de investigación no observables directamente, así como para revelar y explicar las características fenomenológicas del objeto.

La informática ha marcado un cambio significativo en la sociedad contemporánea. Las posibilidades en el acceso, almacenamiento, y control de los datos que cotidianamente circulan y se generan, han originado una toma de decisiones sobre el valor de la información como recurso y sus necesidades de conservarlos. Actualmente se hace casi imposible el manejo de forma eficiente de la misma sin el apoyo de herramientas auxiliares. Las insuficiencias detectadas en la gestión de información referente a la actividad mercantil en el Grupo Empresarial Flora y Fauna de la provincia Ciego de Ávila dan origen al objetivo del presente trabajo, diseñar una base de datos que permita la gestión de la información de la actividad mercantil. Para su implementación se utilizan las herramientas DBDesigner para el manejo de las tablas y relaciones que figuran en el proyecto y como gestor de Base de Datos PostgreSQL, que se encuentra entre los más usados a nivel mundial. Se empleó como técnica de recopilación de información la encuesta a profesionales que laboran en el proceso de la actividad mercantil en la referida entidad. Se diseña una base de datos relacional que permite el almacenamiento de manera rápida de la información gestionada, lo que posibilita tomar decisiones oportunas.

Las ciencias médicas a través de los años se han visto en la constante necesidad de evolucionar y buscar alternativas para lograr sus objetivos a través de la tecnología. Con el auge de la telefonía celular y el desarrollo paulatino de las aplicaciones para móviles es cada vez más común ver como las App se han apoderado de gran parte de la vida diaria. Es por ello que en la actual crisis sanitaria mundial estas tecnologías juegan un papel fundamental. En el marco de la situación global de la pandemia. El presente trabajo recomienda características generales que debe poseer una aplicación y expone varios de los beneficios que le han aportado estas a la sociedad y al sector médico durante el enfrentamiento a la COVID-19. En el estudio realizado resaltan las aplicaciones de uso social, finanzas y entretenimiento. En este marco se destacan las aplicaciones médicas en especial la App cubana Pesquisidor virtual el cual permite recabar información sobre el estado de salud de la población, como complemento del proceso de pesquisa activa. Queda en evidencia además que el confinamiento y la nueva normalidad han sido más llevaderas gracias al uso de las aplicaciones móviles las cuales todo parece indicar que su crecimiento seguirá en aumento

El enfrentamiento a la COVID-19 es una guerra mundial que se libera paso a paso, día a día, mientras el nacimiento de una vacuna es toda una incertidumbre, el control de la información en las áreas de salud es un proceso importante en la toma de decisiones y el fortalecimiento de las acciones de vigilancia. En los consultorios médicos en Cuba se realiza el enfrentamiento a la COVID-19, se registran del área las personas confirmadas, sospechosas, en vigilancia, además de controlar los enfermos de padecimientos crónicos, todo ello requiere de mecanismos ágiles para obtener información de forma eficiente. El presente trabajo tiene el objetivo de desarrollar un sistema informático para la gestión de información relacionada con el enfrentamiento a la COVID-19. Se empleó como método teórico el análisis documental, y como método empírico la encuesta a profesionales de la salud que realizan consultas clínicas en los hogares. Se utiliza como bases de datos MySql, y como ambientes de desarrollo de alto nivel, el framework Web2py. El sistema informático permite el registro de los datos que se manejan en el enfrentamiento a la COVID-19. Además de generar los informes que se necesitan para fortalecer las acciones de vigilancia. Se diseña un sistema informático con interfaz web, que mediante sus páginas se tiene acceso a una base de datos relacional que permite generar informes de manera rápida y sin errores de cálculo, ni duplicidad de información, lo que posibilita tomar decisiones oportunas relacionadas con el enfrentamiento a la COVID-19.

La era en la que se vive muestra un estrecho vínculo existente entre la tecnología y la medicina. La informática como sus ramas derivadas ha permitido a los profesionales de este sector disponer de ciertas herramientas de innovación como lo es la Realidad Aumentada para desempeñar sus competencias de una manera rápida y efectiva. Esta tecnología representa una forma reciente de visualización que combina, de manera funcional, la virtualidad con la realidad misma, generando posibilidades nuevas para la interpretación de información antes no disponible, que abren nuevas maneras para aprender y reconocer los datos, procesarlos en información y convertirlos fácilmente en conocimiento. Las diferentes formas para llevar a cabo experiencias en realidad aumentada, se encuentran listas desde diferentes plataformas informáticas y de telecomunicaciones, que facilitan adelantar proyectos en este sentido, de manera rápida y económica. La Medicina, y particularmente en la detección y control de virus, puede asistirse de este tipo de medios para proporcionar un diagnóstico veraz de cada paciente contagiado, para así poder lograr prevenir la propagación del mismo. Este artículo tiene como objetivo analizar el uso de la realidad aumentada en el enfrentamiento a la COVID-19, con el fin de conocer las ventajas y beneficios que representa en el mismo, para su incorporación en las investigaciones médicas.

Los asentamientos humanos constituyen el marco donde transcurre buena parte de la vida de la población, se materializan todos los problemas sociales y tienen una mayor incidencia los problemas económicos. La investigación realizada tiene como objetivo general analizar el comportamiento de la dinámica del sistema de asentamientos humanos (SAH) y la población de la provincia de Ciego de Ávila en el período comprendido entre 1981 y 2012. Para ello se analizó la estructura del sistema de asentamientos humanos teniendo en cuenta las categorías y rangos de población; así como el cálculo de distintos indicadores, tales como densidad de población, tasas de crecimiento de la población, coeficiente de Gini e índice de masculinidad. Los resultados revelan una marcada tendencia a la concentración de la población en asentamientos urbanos mayores de 10 000 habitantes y asentamientos rurales mayores de 200 habitantes, localizados cerca de las principales vías de comunicación a nivel provincial. Human settlements constitute the framework where a good part of the population’s life takes place, all social problems materialize and economic problems have a greater incidence. The general objective of the research carried out is to analyze the behavior of the dynamics of the Human Settlements System and population in the province of Ciego de Ávila during the period 1981-2012. For this purpose, the structure of the Human Settlements System was analyzed, taking into account the population categories and ranges, as well as the calculation of different indicators such as population density, population growth rates, Gini coefficient, and masculinity index. The results reveal a marked trend towards population concentration in urban settlements with more than 10,000 inhabitants and rural settlements with more than 200 inhabitants, located near the main communication routes at provincial level.

In this study, the effect of a tackifier on the viscoelastic and adhesion properties of acrylic pressure-sensitive adhesives (PSAs) was investigated. The intermediate products in the process of PSA synthesis, including an acrylate-based copolymer solution, a cross-linked copolymer, and the final product with a tackifier, were prepared and characterized using dynamic mechanical analysis (DMA). A significant increase in storage and loss moduli at high angular velocities was observed for the final product with the tackifier. The adhesion forces of the copolymer solution and the cross-linked copolymer measured by atomic force microscopy (AFM) were found to be almost independent of the release velocity, whereas that of the final product with the tackifier significantly increased at higher release velocities because of viscoelastic effects. Their fibrillations during the release process were also visualized using a charge-coupled device (CCD) camera installed on the cantilever holder. Although the contact area of the copolymer solution and the cross-linked copolymer with the probe surface decreased until detachment, the final product with the tackifier remained constant, with necking just below the probe surface. The increased storage and loss moduli were considered to resist the shrinkage of the contact area because the contact outline was subject to high shearing deformation, which led to localized high strain rates. Overall, the crucial role of the tackifier in maintaining the contact area for sufficient elongation during fibrillation was established.

This present study sought to analyze acute lymphoblastic leukemia (ALL) patients with hemophagocytic lymphohistiocytosis (HLH) registered in Kyushu-Yamaguchi Children's Cancer Study Group studies conducted between 1996 and 2007. Four of 357 patients, including two of 318 patients with B cell precursor acute lymphoblastic leukemia (BCP-ALL) and two of 39 of those with T cell acute lymphoblastic leukemia (T-ALL), were identified. HLH was observed more frequently in the T-ALL patients than in the BCP-ALL patients (P = 0.061). The mean age of 13.0 years at the diagnosis of leukemia in the HLH + ALL group was significantly higher than the 6.05 years observed in the remaining ALL groups (P = 0.001). A female predisposition was noted, as all four patients were female (P = 0.043). In two of four patients, the leukemic cells exhibited deletions on the long arm of chromosome 6 (P = 0.003). Three patients suffered from HLH during maintenance therapy. Parvovirus B19 infection and cytomegalovirus reactivation were identified as causes of HLH in one and two patients, respectively. All four patients are currently in complete remission, although one developed relapse of leukemia after receiving maintenance therapy. Based on the genetic analyses, non-synonymous single nucleotide polymorphisms (SNPs) in UNC13D, syntaxin 11, and STXBP2 were identified in all patients. Clinicians should therefore be aware of the risk of HLH during maintenance therapy, especially in older T-ALL patients with SNPs in familial HLH causative genes.

Background and Purpose: The strategy used to treat pediatric renal tumors in Japan is based on the Japanese Wilms' Tumor Study (JWiTS) protocol, which was based on the National Wilms' Tumor Study (NWTS)-5 regimen. The regimen is characterized by an initial radical operation, followed by adjuvant chemotherapy and radiotherapy. Concerning the histological classification, a new classification based on the International Society of Pediatric Oncology (SIOP) classification was used beginning in 2008. The main points of revision are that the "blastemal predominant type" was classified as an independent category in the Wilms' tumor subtypes. The purpose of this study was to analyze the biological characteristics from the standpoint of the newly established histological classification., Materials and Methods: From 1971 to 2005, 174 cases of Wilms' tumors treated with an initial operation followed by adjuvant therapy were re-evaluated by the new histological classification. Histologically, all these materials showed no secondary changes associated with adjuvant therapy., Results: According to the new classification, Wilms' tumors were classified into four subtypes, including the mixed type (n=112), epithelial type (n=17), mesenchymal type (n=15), and blastemal predominant type (n=26). The 5 year overall survival rates were as follows; mixed type (90.1%), epithelial type (100%), mesenchymal type (93.3%), and blastemal predominant type (65.4%)., Conclusion: The patients with blastemal predominant tumors demonstrated a significantly worse prognosis compared with those of other subtypes. The treatment strategy of blastemal predominant category should be distinguished from the other favorable subtypes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Two consecutive treatment protocols, NHL-89 and NHL-96, for pediatric diffuse large cell lymphoma (DLC) and lymphoblastic lymphoma (LBL) were conducted between March 1989 and December 2004 by Kyushu-Yamaguchi Children's Cancer Study Group. Forty-two patients (DLC: 15, LBL: 27) and 34 patients (DLC: 8, LBL: 26) were enrolled in NHL-89 and NHL-96, respectively. DLC patients received induction therapy of high-dose methotrexate (MTX) followed by repeated administration of intermediate MTX. LBL patients received a 4-drug induction followed by intensification, consolidation with cranial radiotherapy (15 to 24Gy), and maintenance. The maintenance phase consisted of multiple drug treatment; including prednisolone, vincristine, cyclophosphamide, and 6-mercaptopurine. With a median follow-up of 150 months for NHL-89 and 90.5 months for NHL-96, the estimated event-free survival at 5 years are 76.2±6.6% and 67.7±8.0%, respectively. Both studies improved the prognosis of DLC and LBL over our previous study of NHL-858.

Meningitis or encephalitis by varicella-zoster virus (VZV) after hematopoietic stem cell transplantation (HSCT) is rarely reported. We encountered a case of meningoencephalitis with VZV re-activation 18 months after related bone marrow transplantation for recurrent acute lymphoblastic leukemia. The patient had been administered steroid and cyclosporine for chronic graft-versus-host disease. A high DNA copy number of VZV, 4.9×10(7) copies was detected in the cerebrospinal fluid. VZV also caused severe pneumonia and acute renal failure soon after the onset of meningoencephalitis. The patient was successfully treated with acyclovir, although he was left with persistent neurological sequelae. Both prompt diagnosis and early treatment of VZV reactivation are important to avoid a fatal outcome.

Background: A total of 201 pediatric cases of acute lymphoblastic leukemia were treated with the ALL-96 protocol by the Kyushu-Yamaguchi Children's Cancer Study Group., Procedure: Risk stratification was based on white cell counts, immunophenotype, the presence of central nervous system disease at diagnosis, organomegaly, and early treatment response (day 14 bone marrow status). All of the patients were classified into standard-risk (SR) or high-risk (HR) groups and were randomly assigned to receive maintenance therapy with either LSA2L2-type or 6-mercaptopurine (6-MP)/methotrexate (MTX) with vincristine (VCR) and dexamethasone (DEX) pulse in both risk groups., Results: The 7-year event-free survival (EFS) and overall survival (OS) rates in the entire study population were 72.1% (95% CI: 68.0-76.2%) and 84.8% (95% CI: 79.7-89.9%), respectively, and the EFS of the SR patients (85.3% [95% CI: 78.2-92.4%]) was significantly better than HR patients (62.4% [95% CI: 52.2-72.6%]) (P = 0.0007)., Conclusions: There were no differences in the EFS between the different maintenance therapies in each risk group; however, grade IV liver toxicity occurred more often in the patients receiving 6-MP/MTX with VCR and DEX therapy than in patients receiving LSA2L2., ((c) 2010 Wiley-Liss, Inc.)

Background: Most infants with brain tumor may have a poor prognosis. The aim of the present study was to retrospectively analyze the survival and outcome with regard to mental and physical development in 11 subjects with brain tumor; these tumors were diagnosed when the patients were under 1 year of age., Methods: The histological diagnoses of these tumors were astrocytoma, n = 3; pineocytoma, n = 2; teratoma, n = 1; ependymoma, n = 1; atypical teratoid/rhabdoid tumor, n = 1; glioblastoma, n = 1; medulloblastoma, n = 1; and choroid plexus papilloma, n = 1. Surgical resection was performed in eight patients, and adjuvant chemotherapy was administered to all except one patient with choroid plexus papilloma. Radiotherapy was additionally performed for four of the 10 chemotherapy patients., Results: Six patients survived. Among the surviving patients, five were under no treatment for 50-167 months after the diagnosis (median duration, 89 months), while one received chemotherapy for 20 months. Five patients exhibited mental retardation, and one patient experienced normal development after surgical removal of his choroid plexus papilloma. Diencephalic syndrome developed in one patient with pilomyxoid astrocytoma that necessitated hormone replacement therapy, and bodyweight over +2 SD was observed in two patients. The remaining five patients died 11-111 months after diagnosis (median duration, 24 months)., Conclusion: The prognosis of infantile brain tumor with regard to mortality and developmental outcome remains poor. Furthermore, survivors require comprehensive medical and social support for an extended period.

Background: Pilomyxoid astrocytoma (PMA) shows a higher rate of recurrence and cerebrospinal fluid (CSF) dissemination than does pilocytic astrocytoma (PA). In this article, we discuss the treatment of PMA., Materials and Methods: Between 1992 and 2007, the authors treated 5 patients. Two of these were male, three female. Their ages ranged from 3 months to 11 years., Results: Three patients showed CSF dissemination on the initial radiographic examination. All patients received chemotherapy; the most commonly used combination drugs were cisplatin (CDDP)/carboplatin (CBDCA) and etoposide. When these drugs were unsuccessful, they were changed or other drugs added to the combination. After chemotherapy, four patients showed remarkable tumor regression. Nevertheless, one patient died 22 months after initial diagnosis, due to tumor progression., Conclusion: While our series was limited to a small number of patients, we have a positive impression of the value of chemotherapy. Even if initial chemotherapy is ineffective, we recommend continued CDDP/CBDCA-based chemotherapy with new drug combinations.

A 13-day-old female infant was admitted with hydrocephalus that had been diagnosed on prenatal ultrasound at 33 weeks' gestation. She was delivered by Caesarean section at 34 weeks with an Apgar score of 10. On admission, she weighed 2,103 g. The head circumference was 32.3 cm, and the fontanelle was tense. T(1)- and T(2)-weighted MR images revealed an isointense mass occupying the fourth ventricle with multiple cysts in the vermis. The mass was not enhanced after gadolinium administration. CT showed no definite calcification in the lesion. Preoperatively, vermian tumors, including medulloblastoma, ependymoma, astrocytoma, and hamartomas, were considered in the differential diagnosis. Hamartoma was strongly suspected due to the lack of enhancement on MRI. After a suboccipital midline craniotomy, subtotal resection of a soft grayish tumor with areas of hematoma was carried out. The pathological diagnosis was medulloblastoma. Despite chemotherapy, CSF dissemination resulted in death at 11 months. We report this case of congenital medulloblastoma with atypical MRI findings and discuss the clinical characteristics of this lesion.

Of 11 children with juvenile myelomonocytic leukemia (JMML) carrying RAS mutations (8 with NRAS mutations, 3 with KRAS2 mutations), 5 had a profound elevation in either or both the white blood cells and spleen size at diagnosis. Three patients had no or modest hepatosplenomegaly and mild leukocytosis at presentation but subsequently showed a marked increase in spleen size with or without hematologic exacerbation, for which nonintensive chemotherapy was initiated. The other three patients with NRAS or KRAS2 glycine to serine substitution received no chemotherapy, but hematologic improvement has been observed during a 2- to 4-year follow up. In the third group, all hematopoietic cell lineages analyzed had the RAS mutations at the time of hematologic improvement, whereas DNA obtained from the nails had the wild type. Additionally, numbers of circulating granulocyte-macrophage progenitors were significantly reduced during the clinical course. Thus, some patients with JMML with specific RAS mutations may have spontaneously improving disease.

Early diagnosis is an important factor in a better prognosis in patients with Wiskott-Aldrich syndrome (WAS), but it is not always easy to distinguish between WAS and immune thrombocytopenic purpura on clinical grounds. To confirm or to exclude a WAS diagnosis promptly for children with thrombocytopenia, the authors performed flow cytometric screening of Wiskott-Aldrich syndrome protein (WASP) for 10 children with thrombocytopenia of an unknown etiology. Five children were diagnosed with WAS, and the remaining 5 were diagnosed as having non-WAS causes of thrombocytopenia. There were no ambiguous results, and these were confirmed by genetic analysis. The authors conclude that screening by flow cytometry for WASP is recommended for boys with persistent thrombocytopenia of an unknown etiology.

Perforin gene (PRF1) mutations appear to occur in about 30% of patients with haemophagocytic lymphohistiocytosis (HLH). We tested perforin expression and gene mutations in 14 HLH patients and six patients with Epstein-Barr virus-associated HLH (EBV-HLH) in Japan. Five of the 14 HLH patients had perforin abnormalities. The presence of PRF1 genetic abnormality correlated well with the lack of perforin expression as determined by flow cytometry. Sequencing showed that four patients had a compound heterozygous mutation while the fifth patient had a homozygous mutation. Three of the mutations we detected were novel. In contrast, none of the six EBV-HLH patients showed perforin abnormalities. Our data, combined with the PRF1 mutations in three previously reported Japanese patients, suggest that the 1090-1091delCT and 207delC mutations of the perforin gene are frequently present in Japanese HLH patients (62.5% and 37.5% respectively). Examination of the geographical origins of the ancestors in the perforin-mutant HLH patients revealed that they mostly came from the Western part of Japan, suggesting that the present-day cases may largely derive from a common ancestor.

Although primary haemophagocytic lymphohistiocytosis (HLH) is a genetic disorder of T lymphocytes, it remains unclear why T lymphocytes of primary HLH patients preferentially infiltrate the central nervous system and peripheral blood, in addition to the reticuloendothelial systems. We engrafted Herpesvirus saimiri (HVS)-immortalized T-lymphocyte lines established from primary HLH patients into severe combined immunodeficient (scid) mice and examined their capacity to infiltrate mouse organs. A diffuse infiltration of human T lymphocytes was detected in each organ of scid mice treated with 1 x 10(6) T lymphocytes from all four primary HLH patients assessed, whereas no infiltration of T lymphocytes from healthy individuals was observed in any organ. The infiltration of T lymphocytes was mainly observed in the lung, brain and peripheral blood, in association with haemophagocytosis. These cells were positive for HLA-DR, CD3 and either CD8 or CD4, but negative for CD68. Certain markers of proliferation and apoptotic activities were highly positive in these cells. There was no difference between the infiltration pattern of T lymphocytes of primary HLH patients with a perforin deficiency and those without. By Southern blot analysis, T lymphocytes infiltrating mouse organs were observed to be polyclonal. These findings suggest that our murine model implementing HVS-immortalized human T lymphocytes is suitable to clarify the pathogenesis of primary HLH.

Although the cytotoxic mechanisms of murine CTLs have been investigated extensively using various mutant and knockout mice, those of human CTLs, especially CD4+ CTLs, are still obscure. To clarify the roles of perforin in Ag-specific cytotoxicity mediated by human CD4+ CTLs, alloantigen-specific and HSV-specific human CD4+ T lymphocyte bulk lines and clones were established from a patient with hereditary perforin deficiency and her healthy father, and their cytotoxic activities were investigated. Alloantigen-specific CD4+ T lymphocytes expressing perforin exerted cytotoxicity against Fas-negative as well as Fas-positive allogeneic B lymphoblastoid cell lines established from members of a family with hereditary Fas deficiency. Perforin-deficient, but not perforin-expressing, CD4+ T lymphocytes failed to show strong cytotoxicity against HSV-infected autologous B lymphoblastoid cells. Perforin-deficient CD4+ T lymphocytes could exert relatively low level cytotoxicity against allogeneic IFN-gamma-treated keratinocytes. Although cytotoxicity mediated by perforin-expressing CD4+ CTLs was almost completely inhibited by concanamycin A, a potent inhibitor of the perforin-mediated cytotoxic pathway, cytotoxicity against IFN-gamma-treated keratinocytes mediated by perforin-deficient CD4+ T lymphocytes was inhibited only partially by concanamycin A, but was inhibited significantly by antagonistic anti-Fas Ab and anti-Fas ligand Ab. The combination of perforin-deficient effector T lymphocytes and Fas-negative target cells used in the present study provides a novel experimental system for studying the detailed mechanisms of human CTL-mediated cytotoxicity. The present data demonstrate that perforin-negative CD4+ CTLs can exert cytotoxicity against Fas-sensitive target cells; however, perforin plays essential roles in Ag-specific cytotoxicity mediated by human CD4+ as well as CD8+ CTLs.

The exact nature of the desmoplastic small round cell tumor (DSRCT) remains controversial. More detailed analyses might be facilitated by the establishment of permanent DSRCT cell lines. To date, however, no human DSRCT cell line has been reported. In this study, we report the establishment of a new human cell line, JN-DSRCT-1, from the pleural effusion of a 7-year-old boy with pulmonary metastasis from a typical intra-abdominal DSRCT. JN-DSRCT-1 cells were small round or spindle shaped with oval nuclei and have been maintained continuously in vitro for over 190 passages during more than 40 months. Histologic features of the heterotransplanted tumors in severe combined immunodeficiency mouse were essentially the same as those of the original DSRCT, revealing nests or clusters of small round cells embedded in an abundant desmoplastic stroma. Both in vitro and in vivo, the cells exhibited immunopositive reactions for vimentin, desmin, cytokeratins (AE1/AE3 and CAM 5.2), epithelial membrane antigen, neuron-specific antigen, and CD57 (Leu-7). JN-DSRCT-1 cells exhibited a pathognomonic t(11;22)(p13;q12) translocation by cytogenetic analysis. In addition, RT-PCR and sequencing analysis revealed a chimeric transcriptional message of the Ewing's sarcoma gene exon 10 fused to the Wilms' tumor gene exon 8. To our knowledge, this is the first permanent human DSRCT cell line. The JN-DSRCT-1 cell line, which exhibits the unique morphologic and genetic characteristics of DSRCT, will be extremely useful for a variety of important studies such as the pathogenic mechanism, biologic behavior, and therapeutic model of human DSRCT.

Background: In our previous studies, the outcome of high-risk ALL was still poor. In the present study, all children with ALL were classified into three groups and treated with a new regimen (AL90)., Patients and Methods: Between 1990 and 1996, 220 children with ALL, treated with the AL90 regimen, were classified into three risk groups: low, intermediate, and high: LR, IR, and HR, respectively. The protocol consisted of three- to five-drug induction, consolidation with intermediate-dose methotrexate and/or cytarabine, mercaptopurine and cyclophosphamide, four-drug intensification, and sequential maintenance therapies. Only intrathecal chemotherapy was used for CNS prophylaxis in the LR group, whereas cranial irradiation was added for the IR and HR groups., Results: The number of eligible patients was 91: LR group, 71: IR group, and 58: HR group. Complete remission (CR) was obtained in > 98% of the LR and IR groups, while only 88% achieved CR in the HR group. The 5-year event-free survival (EFS) rate was 67.4% in all patients: 70.4% in the LR group, 71.7% in the IR group, and 57.5% in the HR group. With respect to the previous study, EFS in the HR group who showed positive residual leukemia at 14 days was improved, whereas EFS in boys versus girls was significantly lower (48.8% : 85.7%, P = 0.02)., Conclusions: In high-risk ALL, the rate of induction failure was high and boys had a worse outcome, calling for improvements in induction therapy and a specific approach for boys., (Copyright 2001 Wiley-Liss, Inc.)

Two Japanese patients were newly diagnosed as having B subunit (XIIIB) deficiency of factor XIII (former type I deficiency). Both patients have a previously described one-base deletion at the boundary between intron A/exon II in the XIIIB gene, heterozygously or homozygously. A founder effect was proposed for this mutation because 3 unrelated patients with XIIIB deficiency also share 2 3'-polymorphisms. In one patient heterozygous for the above mutation, a novel mutation was also identified: a deletion of guanosine in exon IX (delG) of the XIIIB gene. To understand the molecular and cellular pathology of the delG mutation, expression studies were performed using a cultured mammalian cell line. Pulse-chase experiments showed that a resultant truncated XIIIB remained inside the cells and could not be secreted into the culture medium. Furthermore, immunocytochemical examinations by epifluorescence, confocal, and electron microscopes indicated impaired intracellular transportation of the truncated XIIIB from the endoplasmic reticulum to the Golgi apparatus. No mutations in the gene for the A subunit (XIIIA) were identified in this patient. Therefore, secretion of the truncated XIIIB must also be impaired in vivo, leading to a secondary XIIIA deficiency. These results support a previous conclusion that genetic defects of XIIIB are the basis for the former type I factor XIII deficiency.

We analyzed the long-term outcome and late effects of treatment in 187 patients with childhood acute lymphoblastic leukemia (ALL) diagnosed between 1984 and 1990. Overall survival and event-free survival rates were 68.2% +/- 3.7% and 63.2% +/- 3.6% at 15 years, respectively. Of 55 patients who relapsed after achieving the first complete remission (CR), only 17.4% were rescued by salvage therapy. The advantage of stem cell transplantation over chemotherapy was observed only in those patients with bone marrow relapse during therapy. The SD for score height in patients maintaining the first CR significantly decreased at the time of final follow-up compared with that at diagnosis: 0.059 to -0.800 (P < .0001). The decrease was remarkable in patients younger than 5 years at diagnosis. Other late effects included mild liver dysfunction in 18% and hepatitis C virus infection in 9%. Congestive heart failure was observed in only 2.9% of patients despite the high cumulative dose of daunorubicin (450 mg/m2). Although the survival rates of patients on our protocols were comparable to those of other study groups, some modification, including reduction in dose of cranial irradiation and/or anticancer drugs, should be considered to reduce late adverse effects in survivors of childhood ALL.

To identify the role of T cells in chronic active Epstein-Barr virus (EBV) infection, EBV and cytokine gene expression was quantified by use of real-time polymerase chain reaction (PCR) among 6 patients who fulfilled the diagnostic criteria for chronic active EBV infection. Four of these patients showed clonal expansion of EBV-infected T cells. Quantitative PCR for EBV DNA in peripheral blood of patients with symptomatic chronic active EBV infection showed higher copy numbers of virus (mean, 1.45 x 10(5) copies/mL) than were seen in blood from patients with infectious mononucleosis (3.08 x 10(3) copies/mL) or with EBV-associated hemophagocytosis (2.95 x 10(4) copies/mL). Fractionated CD3(+) HLA-DR(+) cells from patients with chronic active EBV infection contained higher copy numbers than did CD3(+) HLA-DR(-) cells. Quantitative PCR for cytokines revealed that interferon-gamma, interleukin (IL)-2, IL-10, and transforming growth factor-beta genes were expressed at higher levels in HLA-DR(+) than in HLA-DR(-) T cells. These results suggest that activated T cells in chronic active EBV infection expressed high levels of EBV DNA and both Th1 and Th2 cytokines. EBV-infected T cells may contribute to the unbalanced cytokine profiles of chronic mononucleosis.

A total of 64 newly diagnosed acute myelogenous leukemia patients (except FAB M3 and/or Down syndrome) under 18 years of age were consecutively enrolled into the study. Patients having an HLA-identical sibling (allo group) were assigned to undergo allogeneic bone marrow transplantation (allo BMT) in the first complete remission (CR). Others (non-allo group) were assigned to undergo autologous peripheral blood stem cell transplantation (PBSCT) or autologous BMT (auto BMT). Conditioning regimen was busulfan + melphalan for all transplantation. Of 64 patients (allo group 24; non-allo group 40), 59 (92.2%) achieved a CR. Eighteen relapses occurred (allo group 4; non-allo group 14) and 6 died during the first CR. The 5-year event-free survival (EFS) rate was 53.3 +/- 6.4% at a median follow-up period of 45 months. The 5-year EFS rates of allo and non-allo groups were 70.8 +/- 9.3% and 43.0 +/- 8.1%, respectively (p = .08). The EFS rates at 5 years post-transplant for allo BMT from an HLA-identical sibling (n = 18), PBSCT (11), and auto BMT (6) were 88.1 +/- 7.9%, 41.6 +/- 19.7%, and 83.3 +/- 15.2%, respectively. The outcome of allo BMT was superior to that of autograft. Auto BMT rather than PBSCT might contribute to a long-term survival in case of no available HLA-identical siblings.

A total of 62 patients with standard-risk acute lymphoblastic leukemia received three-drug induction consisting of vincristine, prednisolone, and L-asparaginase (l-Asp) followed by consolidation therapy with intermediate-dose methotrexate (MTX), intrathecal MTX, and 18 Gy of cranial irradiation. Maintenance therapy consisting of 6 drugs including daunorubicin (DNR, 450 mg/m2 in total) was continued for 3 years. Patients were randomized and half of them received weekly l-Asp during maintenance therapy as a late intensification. Complete remission (CR) was achieved in 61/62 (98.4%), and 11 of 61 patients relapsed. At 10 years, the event-free survival (EFS) was 80.6 +/- 5.0% and overall survival was 88.7 +/- 4.0%; median follow-up time was 9.3 years. The 10-year EFS of patients with additional l-Asp (84.8 +/- 6.2%) was superior to that without l-Asp (75.9 +/- 7.9%), although it was not statistically significant. No patients who received a full dose of DNR and maintained CR developed heart failure, although the shortening fraction decreased from 41.0% at diagnosis to 35.2% (median). The protocol AL841 provided good long-term disease control without severe late cardiac dysfunction.

We report here that a defect of the interleukin common gamma subunit (gamma c) in X-linked severe combined immunodeficiency (XSCID) previously known as a missense mutation resulted instead in exon skipping in a Japanese XSCID patient. The phenotype of the patient was consistent with that of typical XSCID, and his Epstein-Barr virus-transformed B cells accordingly entirely lacked surface expression of gamma c . On analysis by the reverse transcription-polymerase chain reaction (RT-PCR), a single but small gamma c mRNA species was detected. Exon 6, which encodes the transmembrane domain of gamma c, was skipped in the mRNA. A G to A mutation was found at the last nucleotide of exon 6 of the gamma c gene (868G-->A). The predicted consequence of the exon skipping is a frameshift resulting in a premature stop codon, and the mutated gamma c presumably loses association with the cell membrane. In XSCID, this mutation (868G-->A) is known as a missense mutation that results in R285Q [corrected]. Previously reported patients with the same mutation apparently had no aberrant or alternative splicing but did have the R285Q [corrected] exchange. Similar mutations at the last nucleotide of an outskipped exon have been reported. However, such mutations do not always cause exon skipping. Analyses of RNA structural changes induced by the mutations supported the variability of consequences of the mutations. Taken together, our findings suggest that the 868G-->A mutation of the gamma c gene may affect gamma c transcripts differently, i.e., generating missense or exon skipping, in XSCID patients with the same mutation. Patient-specific variation in splicing thus appears to occur.

A total of 125 children, who were diagnosed as having high-risk acute lymphoblastic leukemia (ALL), were treated with two consecutive protocols designated as AL851 (1985-1988) and ALHR88 (1988-1990). All patients received induction therapy consisting of vincristine (VCR), prednisolone (PSL), daunorubicin (DNR), and I-asparaginase (I-Asp). In the ALHR88 protocol, the patients whose blasts in the bone marrow (BM) were > or = 25% on day 14 of induction therapy and who were classified into T-cell type received additional cytosine arabinoside (AraC). After consolidation with intermediate-dose methotrexate (MTX), reinduction therapy including VCR, dexamethasone, and adriamycin followed by high-dose AraC was done for all patients. Intrathecal MTX and 24Gy of cranial irradiation were used to prevent central nervous system leukemia. A maintenance therapy consisting of 6-mercaptopurine, cyclophosphamide, MTX, DNR, VCR, and AraC was administered for 3 years after achieving a complete remission (CR). CR was achieved in 51/55 (92.7%) for AL851 and 68/70 (97.1%) for ALHR88. The 5-year event-free survival rates were 49.1 +/- 6.7% in AL851 and 62.5 +/- 6.1% in ALHR88. The factors related to a poor prognosis were a high initial leukocyte count of greater than 50 x 10(9)/L (P < 0.001), an L2 morphology of leukemic cells by FAB classification (P = 0.009), the chromosomal abnormality (P = 0.004) and high residual leukemic cells in BM (> or = 25%) on day 14 of induction therapy (P < 0.001). Taking these factors into consideration, more intensive protocols were started in 1990 for the patients with high-risk ALL.

We evaluated the efficacy and toxicity of aclarubicin for acute non-lymphocytic leukemia (ANLL) refractory to daunorubicin in childhood. Twenty-four patients were treated with aclarubicin and prednisolone with or without 6-mercaptopurine and behenoyl-cytosine arabinoside daily for 5 to 14 days. Of 21 evaluable patients, 14 (67%) responded: 12 obtained complete remission and 2 partial remission. The median time to reach complete remission was 37 days (range, 16 to 60 days), and the median duration of complete remission was 5.5 months (range, 2 to 41 months). The cumulative dose of anthracycline administered before the study was not considered significant for the response. The only major complication was severe bone marrow suppression; infectious episodes occurred in 14 patients (58%) and three died of sepsis and/or bleeding. The observed non-hematologic toxicities included hematuria, an elevation of serum amylase, nausea/vomiting, and angitis. In addition, one patient showed abnormal cardiac function. Aclarubicin is therefore considered a highly active drug for remission reinduction of previously treated children suffering from ANLL with an acceptable toxicity.

Since October 1984, children with acute lymphoblastic leukemia (ALL) were treated with six protocols of the Kyushu-Yamaguchi Children's Cancer Study Group (KYCCSG). We reviewed cases in whom the first relapse sites of ALL were CNS, testis and ovary. Between October 1984 and July 1993, 302 children with ALL were registered. Ten children (3.3%) developed CNS-L. After treatment for CNS-L, four cases were alive, however one of them has had several episodes of CNS-L. Testicular relapse occurred in 8 boys and three of them are alive. One girl developed ovarian and uterine involvement 7 months after completion of treatment and she survived after intensive chemotherapy for an additional 3 years. Before September 1990, children with ALL received 18Gy cranial irradiation in standard risk group and 24Gy in high risk group. Since October 1990, children with ALL received no cranial irradiation in low risk group, 15Gy in intermediate risk group and 18Gy in high risk group. Incidence of CNS-L has not increased in children treated with protocols, in which cranial irradiation was reduced.

Fifty five children diagnosed as having high-risk acute lymphoblastic leukemia (ALL) between 1985 and 1988 were treated with protocol AL851. The agents used in the protocol were as follows: induction therapy: vincristine (VCR), prednisolone, daunorubicin (DNR) and l-asparaginase, consolidation therapy: an intermediate-dose methotrexate (MTX), central nervous system (CNS) leukemia prophylaxis: intrathecal MTX and 24Gy cranial irradiation, reinduction therapy: VCR, adriamycin, dexamethasone and high dose cytarabine (AraC), maintenance therapy: 6-mercaptopurine, cyclophosphamide, MTX, DNR, VCR and AraC. Patients received chemotherapy for 3 years after achieving complete remission (CR). CR was obtained in 51 patients (92.7%). Twenty-four of them relapsed after achieving CR (bone marrow 16, CNS 3 and testis 5). At median follow-up of 79 (range 64-102) months, the estimated 8-year disease free survival rate was 49.1 +/- 6.7%. Four patients relapsed at bone marrow during the first 6 months of the treatment, indicating that more intensive combination chemotherapy should be included in earlier stage of the protocol. The high incidence of testicular relapse (14.3% in boys) suggests that high-dose MTX or AraC should be needed for improvement of the prognosis of high-risk ALL patients.

In the on-going study of men retiring from the Self-Defense Forces in Japan, we previously reported that serum total cholesterol was not related to colorectal adenomas but that men with low levels of serum high-density lipoprotein (HDL) cholesterol had an elevated adenoma risk. We examined whether the previous observation was reproducible in a different set of data accrued subsequently in the study. Serum total cholesterol, HDL-cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were compared between 138 cases of colorectal adenomas at the depth of 60 cm or less from the anus and 909 controls with normal sigmoidoscopy in the period from October 1988 to December 1990. There was virtually no relation between adenoma risk and any of the serum lipids studied with or without adjustment for smoking, alcohol use, and body mass index. In the analysis combining the earlier and present data, however, men with large adenomas (> or = 10 mm, n = 25) tended to have lower levels of total cholesterol and LDL-cholesterol compared with controls (n = 1,612); adjusted mean differences were -0.21 mmol/l (P = 0.24) and -0.26 mmol/l (P = 0.13), respectively. These findings are inconclusive, but hypocholesterolemia may be associated with the growth of colorectal adenoma.

The relation of dietary factors to the risk of adenomas of the sigmoid colon was examined in men receiving a retirement health examination at the Self-Defense Forces Fukuoka Hospital between October 1986 and 1990. A total of 187 adenoma cases and 1557 controls with normal colonoscopy were identified in the series. Cases were further classified into small-adenoma (< 5 mm, n = 78) and large-adenoma (> or = 5 mm, n = 67) groups. The consumptions of selected foods and beverages were ascertained before colonoscopy by means of a self-administered questionnaire. After adjustment for smoking, alcohol use, rank and body mass index, low rice consumption and high meat intake were independently associated with an increased risk of large adenomas. The risk of small adenomas was not related to either rice consumption or meat intake. Adjusted odds ratios of large adenomas for the low, intermediate and high consumption levels of rice were estimated to be 1.0 (referent), 0.83 and 0.43, respectively (trend P = 0.08), and the corresponding figures for meat consumption were 1.0 (referent), 1.58 and 2.38, respectively (trend P = 0.02). The findings suggest that low rice consumption and high meat intake may promote the growth of colon adenomas, thereby increasing the risk of colon cancer.

METHODS. The relation between green tea consumption and serum lipid concentrations was examined using cross-sectional data on 1,306 males who received the retirement health examination at the Self-Defense Forces Fukuoka Hospital between October 1986 and December 1988. RESULTS. After adjustment for rank, smoking, alcohol use, physical activity, and body mass index, serum total cholesterol levels were found to be inversely related to the consumption of green tea while no association was noted with serum triglycerides and high-density lipoprotein cholesterol. Adjusted mean concentrations of total cholesterol were 8 mg/dl lower in men drinking nine cups or more per day than in those consuming zero to two cups per day. Serum cholesterol levels were inversely associated with traditional Japanese dietary habits (intake of rice and soy bean paste soup) and positively associated with Westernized habits. Additional adjustment for these dietary variables did not alter the inverse relation between green tea and total cholesterol.

Evidence on determinants of BP is mostly derived from studies in western populations. The relationship of BP with lifestyle variables and glucose tolerance was studied in 1,302 male self-defence officials aged 49-56 years who received a health examination before retirement at the Self-Defense Forces Fukuoka Hospital from October 1986 to December 1988. Those with treated hypertension or diabetes mellitus and those with conditions affecting BP levels were excluded from the study. In multiple regression analysis, alcohol use, body mass index and glucose intolerance were strongly associated with elevated BP while there was an inverse relation between cigarette smoking and BP. Physical activity expressed as the time spent in vigorous exercise was not associated with either systolic or diastolic BP. These findings indicate that alcohol use, obesity and glucose intolerance are also important determinants of BP in male Japanese, and that cigarette smoking is a potential covariate in the study of BP.

Physical activity and dietary habits were compared between 80 men with adenomatous polyps of the sigmoid colon and 1148 men with normal colonoscopy among male retiring self-defense officials. Physical activity as expressed in terms of time spent doing strenuous activities during leisure time was inversely related to the risk of adenomatous polyps. Controlling for rank, smoking, alcohol and body mass index (BMI), odds ratios for the categories of 0, 1-59, 60-119 and greater than or equal to 120 minutes per week were 1.0, 0.88, 0.70 and 0.44, respectively (trend p = 0.015). Among a limited range of foods and beverages, the consumption of rice, green tea and instant coffee tended to be associated with a decreased risk of adenomatous polyps. Although the associations observed with dietary habits still need to be substantiated, the findings on physical activity lend further evidence to the hypothesis that physical activity may be protective in the development of colon cancer.

The drinking habits of 86 men with adenomatous polyps of the sigmoid colon were compared to those of 1184 men with normal colonoscopy among middle-aged male self-defence officials. After adjustment for rank, smoking history and rice consumption, total ethanol intake was positively associated with the risk of adenomatous polyps. The odds ratio (OR) was 2.4 (95% confidence interval (CI) 1.0-5.5) for men consuming at least 60 ml of ethanol per day. Among five alcoholic beverages (shochu, beer, sake, whiskey and wine), both sake and beer showed a dose-response relationship with the risk of adenomatous polyps although the association with beer was less striking. Shochu was the largest source of ethanol intake in the study population, but there was virtually no association between shochu consumption and adenomatous polyps. Men drinking wine had a significantly increased risk, but these men were too few to examine the relation in detail. The findings suggest that the consumption of specific alcoholic beverages rather than ethanol itself is associated with an increased risk of adenomatous polyps of the sigmoid colon.

Colorectal adenoma is regarded as a precursor lesion of adenocarcinoma. In view of the controversy on serum cholesterol and colorectal cancer, the risk of colorectal adenoma was examined in relation to serum total cholesterol, triglycerides and HDL-cholesterol. In the comparison of 88 men having adenoma and 1055 men with normal colonoscopy, there was no association between serum total cholesterol and colorectal adenoma. An increased risk of adenoma was observed at the highest quartile of triglycerides and at the lowest of HDL-cholesterol. When the three serum lipids were simultaneously examined, only the relation with HDL-cholesterol remained unchanged giving odds ratio of 1.7 at the lowest quartile compared with the upper three combined (p less than 0.05). The present study is consistent with the view that the inverse relation between serum total cholesterol and colorectal cancer is due to the effects of preclinical cancer. Further clarification is needed on low HDL-cholesterol and colorectal adenoma.

Human parvovirus B19 is known to cause aplastic crisis in patients with hemolytic anemias due to cytotoxic effect of the infection to erythroid progenitor cells. We report here the first case of aplastic crisis by B19 in a patient with glucose-6-phosphate dehydrogenase deficiency. A five-year-old boy was admitted to the hospital because of severe anemia, fever and jaundice. Four weeks after admission, he developed erythema infectiosum. B19 infection was confirmed using countercurrent immunoelectrophoresis, Southern blotting and hybridization method, and radioimmunoassay for B19 specific IgM. B19 virus antigen was detected by an indirect immunofluorescent method in both the cytoplasm and nucleus of large mononuclear cells that had no granules in bone marrow. On admission, the hemoglobin was 3.1 g/dl and no reticulocytes were detected in the peripheral blood smear. Bone marrow examination revealed a normocellular marrow with erythroid hypoplasia and M/E ratio of 7.38. Large basophilic erythroblasts containing vacuoles were also noticed. Elevation of indirect bilirubin and hemoglobinuria suggested intravascular hemolysis. Transient mild thrombocytopenia associated with increased PAIgG was observed. It is likely that B19 virus infection caused hemolysis which contributed to severe anemia.