Theoretical Study of the Function of the IP3 Receptor/BK Channel Complex in a Single Neuron / Estudio Teórico de la Función del Complejo Receptor-IP3/Canales BK en Neurona Única

ABSTRACT Large conductance calcium-activated potassium (BK) channels carry out many functions in the central nervous system. These channels open in response to increased cytosolic calcium ([Ca2+]cyt) concentration. The influx of calcium ions to the cytosol can occur through voltage-gated calcium channels (VGCCs) on the plasma membrane and/ or through IP3 receptors (IP3-Rs) and ryanodine receptors (RyRs) on the endoplasmic reticulum membrane. The BK channel/IP3-R/RyR interaction has been widely reported in smooth muscle but scarcely investigated in relation to neurons. The aim of this study was to theoretically explore the function of the BK/IP3-R complex by means of a computational model of a neuron that replicates the interaction between the release of Ca2+ from the endoplasmic reticulum (through IP3-Rs) and the opening of the BK channels. The mathematical models are based on the Hodgkin-Huxley formalism and the Goldbeter model. These models were implemented on Visual Basic® and differential equations were solved numerically. Distinct conditions were contemplated for BK conductance and the efflux of endoplasmic Ca2+ to the cytosol. An abrupt rise in [Ca2+]cyt (≥ 5 μM) and short duration (spark) was found to activate BK channels and either pause or stop the action potential train.

RESUMEN Los canales de potasio activados por calcio de gran conductancia (canales BK) cumplen múltiples funciones en el sistema nervioso central. Estos canales se abren en respuesta al incremento de la concentración de calcio citosólico ([Ca2+]cyt). La entrada de Ca2+ puede ocurrir a través de canales de calcio dependientes de voltaje (VGCCs) localizados en la membrana plasmática y por eflujo de Ca2+ del retículo endoplásmico (ER) causado por 1,4,5-Trifosfato (IP3) o rianodina (RyR). La interacción BK/IP3/RyR ha sido ampliamente estudiada en músculo liso, pero escasamente en neuronas. El objetivo de este estudio fue explorar teóricamente la función del complejo BK/IP3-R mediante un modelo computacional de una neurona que replica la interacción entre la liberación de Ca2+ del retículo endoplásmico (a través de IP3-Rs) y la apertura de los canales BK. Los modelos matemáticos se basan en el formalismo de Hodgkin-Huxley y el modelo de Goldbeter. Estos modelos fueron implementados en Visual Basic® y las ecuaciones diferenciales fueron resueltas por métodos numéricos. Se contemplaron distintas condiciones para la conductancia del canal BK y la salida de Ca2+ endoplásmico al citosol. Los resultados muestran que un incremento abrupto de [Ca2+] cyt (≥ 5 μM) y de corta duración (spark) activa los canales BK y producen una pausa o detiene el tren de potenciales de acción.

Prevención de extubación no programada en pacientes con ventilación mecánica invasiva / Prevention of non-programed tube-extractions among patients with invasive mechanical ventilation / Prevenção de extubação não programada em pacientes com ventilação mecânica invasiva

Introducción Las extubaciones no programadas constituyen un evento adverso frecuente y de alto impacto, en la mayoría de los casos la presencia de este evento se relaciona con factores como la vía aérea, ventilación mecánica, nivel de sedación, estado y actividad mental del paciente, entre otros también prevenibles. Por ello, se establece un indicador de calidad para prevenir extubaciones no programadas en pacientes con ventilación mecánica invasiva y tubo endotraqueal. Objetivo Realizar la validación de contenido del indicador y describir el nivel de cumplimiento para la prevención de extubaciones no programadas en pacientes con ventilación mecánica invasiva en un hospital de tercer nivel de la Ciudad de México, con el propósito de dar a conocer nuevos aportes en materia de prevención. Metodología Estudio cuantitativo y descriptivo, con una muestra no probabilística a conveniencia conformada por 46 procesos observados durante el turno matutino en tres servicios de hospitalización. Resultados Se encontró que el 96% de los procesos observados arrojaron un nivel de prevención medio para las extubaciones no programadas. Al evaluar el índice de eficiencia global del indicador, se obtuvo un resultado del 59.8%, lo cual muestra que las acciones para prevenir una extubación no programada se cumplen en un porcentaje muy bajo. Conclusiones Se detectó una omisión de funciones por los profesionales de la salud en la prevención de este evento, por lo que se propuso un plan de mejora para la institución con el propósito de disminuir los eventos relacionados a las extubaciones.

Introduction Non-programed extubation, constitute a frequent high impact adverse event involving issues on the airway, mechanical ventilation, sedation level, patient´s mental activity, among others. Because of this, a quality indicator is established in order to help prevent non-programed extubation among patients with invasive mechanical ventilation and endotracheal tube. Objective To perform a validation of content on this indicator in a third level hospital of the City of Mexico, and describe the level of adherence to its components in order to prevent non-programed extubation among patients with invasive mechanical ventilation and endotracheal tube, and share the resulting contributions in the area of prevention. Methodology This is a quantitative and descriptive study with a non-probabilistic sample by convenience of 46 processes which were observed during the morning shifts in three hospitalization services. Results It was found that 96% of the processes observed showed an insufficient level of prevention of non-programed extubation. The assessment of the efficiency related to indicator´s components showed a 59.8% compliance, suggesting that the actions to prevent non-programed extubation are not sufficiently taken. Conclusions An important related omission by health professionals regarding the prevention of this kind of adverse events was detected, and thus, a corresponding improvement plan for the institution was proposed.

Introdução As extubaçãos não programadas constituem um evento adverso frequente e de alto impacto, na maioria dos casos, a presença deste evento relaciona-se com fatores como a via aérea, ventilação mecânica, nível de sedação, estado e atividade mental do paciente, entre outros, também preveníeis. Por isso, estabelece-se um indicador de qualidade para prevenir extubaçãos não programadas em pacientes com ventilação mecânica invasiva e tubo endotraqueal. Objetivo Realizar a validação de conteúdo do indicador e descrever o nível de cumprimento para a prevenção de extubaçãos não programadas em pacientes com ventilação mecânica invasiva em um hospital de terceiro nível da Cidade do México, com o propósito de dar a conhecer novas contribuições em matéria de prevenção. Metodologia Estudo quantitativo e descritivo, com uma amostra não probabilística a conveniência, conformada por 46 processos observados durante o turno matutino em três serviços de hospitalização. Resultados Encontrou-se que o 96% dos processos observados revelaram um nível de prevenção médio para as extubaçãos não programadas. Avaliando o índice de eficiência global do indicador, obteve-se um resultado do 59.8%, o qual mostra que as ações para prevenir uma extubação não programada cumprem-se em uma porcentagem muito baixa. Conclusões Identificou-se uma omissão de funções pelos profissionais da saúde na prevenção deste evento, pelo que se propus um plano de melhora para a instituição com o propósito de diminuir os eventos relacionados às extubaçãos.

Desarrollo de un Simulador de los Experimentos Clásicos y Actualizados de Fijación de Voltaje de Hodgkin y Huxley / Developing a simulation program for classic and updated Hodgkin and Huxley's voltage clamp experiments

Resumen: Los estudios de Hodgkin y Huxley fueron el punto de partida de la generación de modelos matemáticos que explican, reproducen y predicen los resultados experimentales del comportamiento de los canales iónicos sensibles a voltaje del axón. Los altos costos de estos experimentos impiden su implementación en la práctica docente de licenciatura. Una alternativa didáctica son los experimentos virtuales mediante simuladores computacionales. En este trabajo se presenta el desarrollo de un simulador que reproduce paso a paso los experimentos clásicos de Hodgkin y Huxley sobre las conductancias de los canales dependientes de voltaje del axón gigante de calamar. El simulador fue desarrollado en lenguaje Visual Basic ver 5.0 para ambiente Wiindows® . Está formado de cuatro módulos: (1) simulación de corrientes iónicas; (2) experimentos clásicos de Hodgkin y Huxley; (3) versión actual del modelo; (4) potenciales de acción. Consta de pantallas de interfaz que permiten simular y calcular los valores de las variables relacionadas con la conductancia de los canales. El usuario puede realizar una cantidad ilimitada de experimentos virtuales que le facilitarán la comprensión del tema.

Abstract: Hodgkin and Huxley ́s works were the starting point to generating mathematical models for explain, reproduce the experimental results and predict the behavior of voltage-sensitive ion channels in the axon. The high costs of these experiments avoid its implementation in teaching degree. An educational alternative is virtual experiments using computer simulations. In this work the development of a simulator that reproduces step by step the classic experiments of Hodgkin and Huxley on the conductance of voltage-dependent channels in squid giant axon is presented. The simulator was developed in Visual Basic language, ver 5.0 for Windows environment. It consists of four modules: (1) ionic currents simulation; (2) classical Hodgkin and Huxley ́s experiments; (3) current version model; (4) action potentials. It comprises connecting interface screens that allow simulate and compute the values of the variables associated with the channel conductance. The user can perform an unlimited number of virtual experiments that will facilitate the understanding of the subject.

Treatment of childhood acute lymphoblastic leukemia in central America: a lower-middle income countries experience.

BACKGROUND: Five Asociación de Hemato-Oncología de Centroamérica (AHOPCA) countries have used an adapted BFM-based protocol for childhood acute lymphoblastic leukemia (ALL). PROCEDURE: In the AHOPCA-ALL 2008 protocol, patients were stratified by age, white blood cell count, immunophenotype, central nervous system involvement, day 8 prednisone response, and morphologic bone marrow response to induction therapy. Patients at Standard Risk (SR) received a three-drug induction regimen, a reinduction phase, and maintenance with protracted intrathecal therapy. Those at Intermediate (IR) and High Risk (HR) received, in addition, daunorubicin during induction therapy, a consolidation phase and two or three reinduction phases respectively. RESULTS: From August 2008 through July 2012, 1,313 patients were enrolled: 353 in SR, 548 in IR, 412 in HR. During induction therapy, 3.0% of patients died, 2.7% abandoned treatment, 1.1% had resistant ALL, and 93.2% achieved morphological complete remission (CR). Deaths and abandonment in first CR occurred in 2.7% and in 7.0% of patients, respectively. The relapse rate at a median observation time of 2.1 years was 15.0%. At 3 years, the event-free survival (EFS) and overall survival (OS), with abandonment considered as an event, were 59.4% (SE 1.7) and 68.2% (SE 1.6). Three-year EFS was 68.5% (SE 3.0), 62.1% (SE 2.6), and 47.8% (SE 3.2) for SR, IR, and HR groups. Adolescents had a significantly higher relapse rate (P = 0.001). CONCLUSIONS: This experience shows that common international studies are feasible in lower-middle income countries. Toxic deaths, abandonment of treatment, and relapses remain major obstacles to the successful treatment. Alternative treatment strategies may be beneficial.

Proceso de formación para el liderazgo en un programa de enfermería: concepciones de estudiantes y docentes / Process for leadership training program in nursing: concepts of students and teachers / Processos de formação para liderança em programa de emfermagem: conceitos de estudantes e professores

[{"text": "Esta investigación cualitativa se realizó con el objetivo de caracterizar las concepciones de estudiantes y docentes \r\nsobre el proceso de formación en liderazgo en un programa de enfermería de una universidad de Bogotá. Se partió \r\ndel concepto de liderazgo en enfermería como "el proceso que promueve la mejora de las condiciones de salud y vida \r\nde la población, el logro de objetivos de cuidado propios de la profesión y el alcance de las metas propuestas en los \r\nservicios de salud" (1).\r\nMediante entrevista semiestructurada realizada a cuatro estudiantes de último año y cuatros docentes, se concluyó \r\nque los estudiantes reconocen que la formación en el pregrado de alguna manera contribuye al desarrollo del liderazgo \r\nmediante diferentes actividades y metodologías pedagógicas como trabajos en grupo y estudios de casos, entre otras, \r\ny consideran las prácticas formativas como el escenario por excelencia para lograrlo. Ellos también valoran de manera \r\npositiva estrategias extracurriculares como las asesorías psicológicas y las realizadas por algunos docentes, así como \r\nla oportunidad de ser representantes de grupo. Señalan que el proyecto de vida, que se desarrolla transversalmente en \r\nel plan de estudios, es un apoyo que ha incidido de una manera importante en el logro de este objetivo. Todas estas \r\nestrategias están encaminadas, en su gran mayoría, al fortalecimiento del liderazgo personal. Aunque los estudiantes \r\nreconocen su influencia, creen que deben fortalecerse de una forma intencionada para mejorar su impacto. Por su parte \r\nlos docentes reconocen, además de las prácticas formativas, la actitud y el ejemplo docente como lo más importante \r\nen la formación para el liderazgo. Sin embargo, estas posturas educativas no fueron reconocidas por los estudiantes.", "_i": "es"}, {"text": "Qualitative research was conducted with the aim of \r\ncharacterizing the views of students and teachers about \r\nthe process of leadership training in a nursing program in \r\na University of Bogotá. We considered nursing leadership \r\nas "the process that promotes the improvement of health \r\nand living conditions of the population, the achievement \r\nof the objectives related to professional care, and the \r\nreaching of the proposed targets in health services" (1).\r\nThrough semi-structured interviews with four seniors \r\nand four teachers, it was concluded that students recog\r\n-\r\nnize that undergraduate training in some degree has \r\nhelped in the development of leadership, by means of \r\ndifferent activities and teaching methods such as group \r\nwork and case studies, among others. Formative prac\r\n-\r\ntice is considered by the students the best way to achieve \r\nthat purpose. The students identified and considered that \r\nsome non-pedagogical strategies, such as the psycholo\r\n-\r\ngical counseling done by some teachers, as well as the \r\nopportunity to be representatives of the group, are very \r\nimportant. They also indicate among these strategies \r\nthe project of life that is carried across the curriculum, \r\nas a support that helps to achieve positive results. All of \r\nthese measures strengthen personal leadership. Although \r\nthe students recognized their influence, they considered \r\nthat these strategies should be strengthened intentionally \r\nin order to enhance their impact. Meanwhile, teachers \r\nrecognize that besides the formative practices, the atti\r\n-\r\ntude and example of the teacher is the most important \r\naspect in a leadership formation. However the students \r\ndid not recognize this educational stance.", "_i": "en"}, {"text": "Uma investigação qualitativa foi realizada com objetivo \r\nde caracterizar os conceitos de estudantes e professores\r\nsobre o processo de formação e liderança em um programa \r\nde enfermagem de uma universidade de Bogotá. Parte do \r\nconceito de liderança de enfermagem o "processo que \r\npromove a melhora das condições de saúde e vida da \r\npopulação, o alcance de objetivos de cuidados próprios \r\nda profissão e o alcance das metas propostas nos serviços \r\nde saúde" (1).\r\nPerante entrevista semi-estruturada realizada com \r\n4 estudantes do último ano e 4 professores, pode-se \r\nconcluir que os alunos reconhecem que a graduação \r\ntem contribuído de certa forma com o desenvolvimento \r\nde liderança. Desde atividades diferentes, metodologias \r\npedagógicas como trabalhos em grupos e estudos de \r\ncasos, até outras que praticas construtivas, são excelentes \r\ncenários para esta formação. Há também estratégias \r\nnão pedagógicas consideradas de grande importância, \r\ncomo assessorias psicológicas realizadas por alguns \r\ndocentes, e a oportunidade de representar um grupo. \r\nTambém identificam dentro destas o projeto de vida que \r\né levado transversalmente no Plano de Estudos, como \r\num apoio que tem sido muito importante para esse \r\nobjetivo. A maioria dessas medidas são encaminhadas \r\nao fortalecimento de liderança pessoal. Apesar de ter a \r\ninfluência reconhecida, acreditam que ainda devem ser \r\naprimorados para melhorar seu impacto. Ademais, os \r\nprofessores mencionam práticas além das citadas acima: \r\na atitude e o exemplo docente, como o mais importante \r\npara a formação de liderança. Entretanto, essas posturas \r\neducativas não foram reconhecidas pelos estudantes.", "_i": "pt"}]

Natural history of pyuria and microhematuria after prostate surgery.

OBJECTIVE: Urinalysis alterations are common after prostatic surgery. However, time to normalization has not been established. Presence of pyuria and microhematuria can lead to unnecessary diagnostic procedures. The objective of this study is to determine the time to normalization for both parameters. MATERIAL AND METHODS: We reviewed medical records of patients who underwent prostatic surgery without infectious complications during follow-up. We included patients who underwent transurethral resection of the prostate (TURP) with either monopolar or bipolar energy, or open prostatectomy (OP). Kaplan-Meier curves were used to determine the time of persistence of both parameters. ANOVA was used to compare the 3 groups according to the type of surgery. We analyzed the impact of preoperative use of 5-α-reductase inhibitors, and searched for a correlation between the weight of resected tissue and persistence of both parameters. RESULTS: 85 patients were analyzed: 44 underwent monopolar TURP, 27 bipolar TURP, and 14 OP. Persistence of pyuria was significantly longer than microhematuria with a median of 274 days vs. 176 days. Neither the use of monopolar or bipolar energy, nor the use of preoperative 5α-reductase inhibitors affected the persistence time. We found a positive correlation between the resected tissue weight and the persistence of leukocyturia after endoscopic surgery: 23 g was the best cut-off point. CONCLUSIONS: Pyuria persists longer than microhematuria regardless of the type of surgery. There is a correlation between the resected tissue weight and the persistence of pyuria. The presence of pyuria and microhematuria after prostatic surgery is not always a pathological finding.

Economía del tabaco / Tobacco economics

La ciencia ha demostrado inequívocamente que el consumo de tabaco y la exposición al humo de este, son causa de mortalidad, morbilidad y discapacidad y representan un riesgo inminente para la salud pública a nivel mundial. Muchos gobiernos dudan en adoptar medidas legales y políticas necesarias para disminuir el consumo de tabaco, por temor a las consecuencias económicas negativas que tales medidas podrían implicar. La producción, exportación e importación de tabaco son una parte ínfima de la economía costarricense. El control estricto del tabaco no produciría una pérdida neta de empleos; la teoría económica dicta que se verificaría un cambio en los patrones de consumo, el cual implicaría un aumento de empleos en otras áreas de la economía nacional. Existe evidencia de países de alto, mediano y bajo ingreso, que demuestra que el aumento del precio de los cigarrillos por medio del incremento de impuestos induce a la disminución en el consumo y previene el inicio del fumado, especialmente en la población joven. Además, se genera un aumento en ingresos fiscales como consecuencia de los impuestos. La evidencia prueba que el contrabando de tabaco está íntimamente relacionado con el nivel de corrupción existente en el país, por eso con el aumento o disminución de impuestos, los cambios en el contrabando no son significativos. Hay evidencia de que no existen pérdidas económicas por ventas, ni disminución en empleos en hoteles, bares y restaurantes, al implementar la ley de espacios 100 por ciento libres de humo.

Gestación heterotópica en dos casos de embarazos espontáneos / Spontaneous heterotopic pregnancy

Gestación heterotópica se define como la coexistencia entre gestación intra y extrauterina. Su incidencia es baja en embarazos espontáneos, aumentando con las técnicas de reproducción asistida, por lo tanto, su diagnóstico precisa de un alto índice de sospecha. Presentamos dos casos, sin antecedentes de importancia, con gestación actual espontánea, que consultaron por dolor hipogástrico y goteo hemático. En la ecografía se objetivaron una gestación intrauterina detenida y una masa anexial compatible con gestación tubárica. Tras la sospecha de gestación heterotópica se realizó salpingectomía laparoscópica y legrado evacuador. La anatomía patológica confirmó el diagnóstico en las pacientes.

Heterotopic pregnancy consists of simultaneous intra and extra uterine pregnancy. The incidence is low in spontaneous pregnancies, but these pregnancies are more common when assisted reproductive technologies are used; therefore, diagnosis requires a high index of suspicion. We report two cases with no history of interest and a spontaneous pregnancy, who presented with hipogastric pain and spotting. An ultrasound scan showed an intrauterine gestational sac and adnexal mass consistent with ectopic pregnancy. As a heterotopic pregnancy was suspected, laparoscopic salpingectomy and curettage of the miscarriage were performed. Pathological analysis confirmed the diagnosis.

Comparative analysis of enzyme and pathway engineering strategies for 5FC-mediated suicide gene therapy applications.

Bacterial- and yeast- encoded cytosine deaminases (bCD and yCD, respectively) are widely investigated suicide enzymes used in combination with the prodrug 5-fluorocytosine (5FC) to achieve localized cytotoxicity. Yet characteristics such as poor turnover rates of 5FC (bCD) and enzyme thermolability (yCD) preclude their full therapeutic potential. We previously applied regio-specific random mutagenesis and computational design to create novel bCD and yCD variants with altered substrate preference (bCD(1525)) or increased thermostability (yCD(double), yCD(triple)) to aid in overcoming these limitations. Others have utilized pathway engineering in which the microbial enzyme uracil phosphoribosyltransferase (UPRT) is fused with its respective CD, creating bCD/bUPRT or yCD/yUPRT. In this study, we evaluated whether the overlay of CD mutants onto their respective CD/UPRT fusion construct would further enhance 5FC activation, cancer cell prodrug sensitivity and bystander activity in vitro and in vivo. We show that all mutant fusion enzymes allowed for significant reductions in IC(50) values relative to their mutant CD counterparts. However, in vivo the CD mutants displayed enhanced tumor growth inhibition capacity relative to the mutant fusions, with bCD(1525) displaying the greatest tumor growth inhibition and bystander activity. In summary, mutant bCD(1525) appears to be the most effective of all bacterial or yeast CD or CD/UPRT enzymes examined and as such is likely to be the best choice to significantly improve the clinical outcome of CD/5FC suicide gene therapy applications.

Fusion enzymes containing HSV-1 thymidine kinase mutants and guanylate kinase enhance prodrug sensitivity in vitro and in vivo.

Herpes simplex virus thymidine kinase (HSVTK) with ganciclovir (GCV) is currently the most widely used suicide gene/prodrug system in cancer gene therapy. A major limitation in this therapy is the inefficient activation of GCV by HSVTK to its active antimetabolites. We described earlier two strategies to overcome this limitation: (1) generation of HSVTK mutants with improved GCV activation potential and (2) construction of a fusion protein encoding HSVTK and mouse guanylate kinase (MGMK), the second enzyme in the GCV activation pathway. As a means to further enhance GCV activation, two MGMK/HSVTK constructs containing the HSVTK mutants, mutant 30 and SR39, were generated and evaluated for their tumor and bystander killing effects in vitro and in vivo. One fusion mutant, MGMK/30, shows significant reduction in IC(50) values of approximately 12 500-fold, 100-fold, and 125-fold compared with HSVTK, mutant 30 or MGMK/HSVTK, respectively. In vitro bystander analyses show that 5% of MGMK/30-expressing cells are sufficient to induce 75% of tumor cell killing. In an xenograft tumor model, MGMK/30 displays the greatest inhibition of tumor growth at a GCV concentration (1 mg kg(-1)) that has no effect on wild-type HSVTK-, MGMK/HSVTK-, or mutant 30-transfected cells. Another fusion construct, MGMK/SR39, sensitizes rat C6 glioma cells to GCV by 2500-fold or 25-fold compared with HSVTK or MGMK/HSVTK, respectively. In vitro analyses show similar IC(50) values between cells harboring SR39 and MGMK/SR39, although MGMK/SR39 seems to elicit stronger bystander killing effects in which 1% of MGMK/SR39-transfected cells result in 60% cell death. In a xenograft tumor model, despite observable tumor growth inhibition, no statistical significance in tumor volume was detected between mice harboring SR39- and MGMK/SR39-transfected cells when dosed with 1 mg kg(-1) GCV. However, at a lower dose of GCV (0.1 mg kg(-1)), MGMK/SR39 seems to have slightly greater tumor growth inhibition properties compared with SR39 (P< or =0.05). In vivo studies indicate that both mutant fusion proteins display substantial improvements in bystander killing in the presence of 1 mg kg(-1) GCV, even when only 5% of the tumor cells are transfected. Such fusion mutants with exceptional prodrug converting properties will allow administration of lower and non-myelosuppressive doses of GCV concomitant with improved tumor killing and as such are promising candidates for translational gene therapy studies.

Lenguaje y conflicto: ¿imperativo necesario? / Language and conflict: ¿imperative need?

El lenguaje se constituye en una evidencia cierta de la evolución de la humanidad. A lo largo de los años ha participado en los cambios de la humanidad y de una u otra forma ha influido en los conflictos existentes, así como en sus soluciones. En este artículo de reflexión queremos plantear algunas ideas que permiten ver cómo el lenguaje, al igual que el hombre, ha ido evolucionando hasta tal punto que se ha ido posicionando cada vez más en las decisiones que afectan el desarrollo del individuo. También queremos mostrar, cómo a través del lenguaje se puede, no sólo entender el conflicto, sino aprender y construir con él.

Language constitutes a true evidence of human evolution. Through the years, it has participated in the changes of mankind and in some way it has influenced the existing conflicts and their solutions. In this article, we want to raise some ideas that allow us to see how the language, as well as the human being, co-evolved to the point that it has been slowly positioned in the decisions affecting the development of the individual. We also want to show how through the language, it can be possible not only to understand the conflict, but to learn and build up with it.

Incidence and predictors of treatment-related mortality in paediatric acute leukaemia in El Salvador.

Survival rates among children with leukaemia in low-income countries are lower than those in high-income countries. This has been attributed in part to higher treatment-related mortality (TRM). We examined the demographics, treatment, and outcomes of paediatric patients in El Salvador with acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) to determine the incidence, causes, and risk factors for TRM. Two trained data managers collected data prospectively; no patients were excluded. Biological, socioeconomic and nutritional predictors were examined. A total of 469 patients with ALL and 78 patients with AML were included. The 2-year cumulative incidence of TRM was significantly higher among children with AML (35.4+/-6.4%) than those with ALL (12.5+/-1.7%; P<0.0001). However, the proportion of deaths attributable to the toxicity of treatment did not differ significantly between AML (25/47, 53.2%) and ALL (55/107, 51.4%; P=0.98). Among children with ALL, low monthly income (P=0.04) and low parental education (P=0.02) significantly increased the risk of TRM. Among children with AML, biological, socioeconomic, and nutritional variables were not associated with TRM. In this low-income country, toxic death significantly contributes to mortality in both ALL and AML. A better understanding of the effect of socioeconomic status on TRM may suggest specific strategies for patients with ALL.

Clinical epidemiology of childhood cancer in Central America and Caribbean countries.

BACKGROUND: Countries with scarce resources have the right to appropriate essential health care but very few reports discuss how this can be achieved. We assessed the survival of a large cohort of pediatric oncological patients to provide hard data on which to base realistic evaluation and planning schemes. PATIENTS AND METHODS: This multicenter retrospective survey covered consecutively diagnosed and treated patients admitted to eight national level hospitals in seven countries in Central America and the Caribbean. The research protocol was discussed extensively, so the data to be collected and the criteria for their evaluation were clearly pre-defined. We analysed 2214 patients diagnosed between 1996 and 1999 with various cancers, classified as hemato-oncological disorders (70%) and solid tumors (30%). RESULTS: Three-year overall survival was 48.4% [standard error (SE) 1.3]. Detailed analysis of acute lymphoblastic leukemia highlighted the wide intercountry variability: 3-year survival was 62.2% (SE 5.3) in Cuba, 74.2% (SE 3.3) in Costa Rica, 61.7% (SE 4.9) in Nicaragua, and lower in the other four countries. CONCLUSIONS: The yield of diagnostic-therapeutic protocols depends largely on the context of care in which they are applied. This paper documents the importance of including epidemiological research in interventions for cooperation in complex health areas such as pediatric oncology.

Acute lymphoblastic leukemia in a developing country: preliminary results of a nonrandomized clinical trial in El Salvador.

PURPOSE: To improve outcome and study biology of childhood acute lymphoblastic leukemia (ALL) in El Salvador. PATIENTS AND METHODS: Between January 1994 and December 1996, 153 children of El Salvador had newly diagnosed ALL treated in a collaborative program between Hospital Benjamin Bloom and St. Jude Children's Research Hospital (SJCRH). Therapy was based on a modified SJCRH protocol, with uniform remission induction (prednisone, vincristine, L-asparaginase) followed-up by consolidation with teniposide/cytarabine and/or high-dose methotrexate. Continuation treatment was risk-stratified: 123 patients assigned to the high-risk group received weekly rotational drug pairs, and 16 assigned to the standard-risk group received daily 6-mercaptopurine, weekly methotrexate, and monthly pulses of vincristine plus dexamethasone. High risk was defined as: DNA index < 1.16, age 12 months or younger, white blood cell count > or = 50 x 10(9)/L, T-cell immunophenotype, anterior mediastinal mass, central nervous system leukemia at diagnosis, or t(4;11), t(1;19), or t(9;22). Duration of the continuation treatment was 2.5 years in both groups. The median age at diagnosis of all patients was 4.8 (range I d-17 yrs), median leukocyte count was 15 (range 1-766) x 10(9)/L, and sex distribution was equal. RESULTS: Immunophenotypes were early beta-progenitor in 79%, T-cell in 3.9%, and inconclusive in 17% of cases. DNA index was <1.16 in 80.5% and was > or = 1.16 in 19.5% of the 123 known cases. For the analyzes, patients who refused therapy (abandoned treatment) were considered to have treatment failure as of their last follow-up dates. Complete remission was achieved in 126 of 151 (82.4%) patients (11 abandoned therapy during induction). The overall 4-year event-free survival (EFS) rate +/- 1 standard error was 48 +/- 6%. The 4-year EFS rates in patients at high-risk and standard-risk were 46 +/- 7% (n = 121) and 69 +/- 15% (n = 16), respectively (P = 0.20). When patients who refused further treatment are censored, the corresponding 4-year estimates of EFS are 51 +/- 8% and 75 +/- 14%, respectively. CONCLUSIONS: These results suggest that the biology of childhood ALL in El Salvador appears to be similar to that seen in the United States. Risk-directed chemotherapy can successfully be used in developing countries, but risk factors must be carefully determined and applied.

Effect of malnutrition at the time of diagnosis on the survival of children treated for cancer in El Salvador and Northern Brazil.

PURPOSE: To investigate the relationship between survival and malnutrition at the time of diagnosis among children treated for cancer in two developing countries. PATIENTS AND METHODS: We studied 443 children treated for cancer between 1995 and 1998 at two centers in San Salvador, El Salvador, and Recife, Brazil. Median age at diagnosis was 4.9 years; 283 children had leukemia and 160 had solid tumors. Z-scores were calculated for weight for age (WAZ), height for age (HAZ), and weight for height (WHZ) at diagnosis. Z scores <-2 indicated malnutrition. Patients were also stratified by low-risk disease (solid tumors: stage I, stage II, or localized; acute lymphocytic leukemia: white blood cell count <25,000/microL, no central nervous system involvement, no mediastinal mass and age >1 and <10 yrs) and high-risk disease (all other patients, including those with acute or chronic myelocytic leukemia). RESULTS: Z-scores indicated malnutrition in 23.5% (WAZ), 22.8% (HAZ), and 15.7% (WHZ) of patients. Z-score was not significantly related to overall survival rates, to survival rates analyzed by type of malignancy or risk status, or to survival rates at the end of the first month of treatment. CONCLUSIONS: We found no relationship between nutritional status and survival in these patients. This implies that future protocols for use in developing countries can be designed to provide optimal treatment intensity despite the high incidence of malnutrition.

Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.

Congenital neutropenia and cyclic neutropenia are disorders of neutrophil production predisposing patients to recurrent bacterial infections. Recently the locus for autosomal dominant cyclic neutropenia was mapped to chromosome 19p13.3, and this disease is now attributable to mutations of the gene encoding neutrophil elastase (the ELA2 gene). The authors hypothesized that congenital neutropenia is also due to mutations of neutrophil elastase. Patients with congenital neutropenia, cyclic neutropenia, or Shwachman-Diamond syndrome were referred to the Severe Chronic Neutropenia International Registry. Referring physicians provided hematologic and clinical data. Mutational analysis was performed by sequencing polymerase chain reaction (PCR)-amplified genomic DNA for each of the 5 exons of the neutrophil ELA2 gene and 20 bases of the flanking regions. RNA from bone marrow mononuclear cells was used to determine if the affected patients expressed both the normal and the abnormal transcript. Twenty-two of 25 patients with congenital neutropenia had 18 different heterozygous mutations. Four of 4 patients with cyclic neutropenia and 0 of 3 patients with Shwachman-Diamond syndrome had mutations. For 5 patients with congenital neutropenia having mutations predicted to alter RNA splicing or transcript structure, reverse transcriptase-PCR showed expression of both normal and abnormal transcripts. In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the opposite face was predominantly affected by the mutations found in congenital neutropenia. This study indicates that mutations of the gene encoding neutrophil elastase are probably the most common cause for severe congenital neutropenia as well as the cause for sporadic and autosomal dominant cyclic neutropenia.

A homolog of voltage-gated Ca(2+) channels stimulated by depletion of secretory Ca(2+) in yeast.

In animal cells, capacitative calcium entry (CCE) mechanisms become activated specifically in response to depletion of calcium ions (Ca(2+)) from secretory organelles. CCE serves to replenish those organelles and to enhance signaling pathways that respond to elevated free Ca(2+) concentrations in the cytoplasm. The mechanism of CCE regulation is not understood because few of its essential components have been identified. We show here for the first time that the budding yeast Saccharomyces cerevisiae employs a CCE-like mechanism to refill Ca(2+) stores within the secretory pathway. Mutants lacking Pmr1p, a conserved Ca(2+) pump in the secretory pathway, exhibit higher rates of Ca(2+) influx relative to wild-type cells due to the stimulation of a high-affinity Ca(2+) uptake system. Stimulation of this Ca(2+) uptake system was blocked in pmr1 mutants by expression of mammalian SERCA pumps. The high-affinity Ca(2+) uptake system was also stimulated in wild-type cells overexpressing vacuolar Ca(2+) transporters that competed with Pmr1p for substrate. A screen for yeast mutants specifically defective in the high-affinity Ca(2+) uptake system revealed two genes, CCH1 and MID1, previously implicated in Ca(2+) influx in response to mating pheromones. Cch1p and Mid1p were localized to the plasma membrane, coimmunoprecipitated from solubilized membranes, and shown to function together within a single pathway that ensures that adequate levels of Ca(2+) are supplied to Pmr1p to sustain secretion and growth. Expression of Cch1p and Mid1p was not affected in pmr1 mutants. The evidence supports the hypothesis that yeast maintains a homeostatic mechanism related to CCE in mammalian cells. The homology between Cch1p and the catalytic subunit of voltage-gated Ca(2+) channels raises the possibility that in some circumstances CCE in animal cells may involve homologs of Cch1p and a conserved regulatory mechanism.

Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy.

Granulocyte colony-stimulating factor (G-CSF) has had a major impact on management of "severe chronic neutropenia," a collective term referring to congenital, idiopathic, or cyclic neutropenia. Almost all patients respond to G-CSF with increased neutrophils, reduced infections, and improved survival. Some responders with congenital neutropenia have developed myelodysplastic syndrome and acute myeloblastic leukemia (MDS/AML), which raises the question of the role of G-CSF in pathogenesis. The Severe Chronic Neutropenia International Registry (SCNIR), Seattle, WA, has data on 696 neutropenic patients, including 352 patients with congenital neutropenia, treated with G-CSF from 1987 to present. Treatment and patient demographic data were analyzed. The 352 congenital patients were observed for a mean of 6 years (range, 0.1-11 years) while being treated. Of these patients, 31 developed MDS/AML, for a crude rate of malignant transformation of nearly 9%. None of the 344 patients with idiopathic or cyclic neutropenia developed MDS/AML. Transformation was associated with acquired marrow cytogenetic clonal changes: 18 patients developed a partial or complete loss of chromosome 7, and 9 patients manifested abnormalities of chromosome 21 (usually trisomy 21). For each yearly treatment interval, the annual rate of MDS/AML development was less than 2%. No significant relationships between age at onset of MDS/AML and patient gender, G-CSF dose, or treatment duration were found (P >.15). In addition to the 31 patients who developed MDS/AML, the SCNIR also has data on 9 additional neutropenic patients whose bone marrow studies show cytogenetic clonal changes but the patients are without transformation to MDS/AML. Although our data does not support a cause-and-effect relationship between development of MDS/AML and G-CSF therapy or other patient demographics, we cannot exclude a direct contribution of G-CSF in the pathogenesis of MDS/AML. This issue is unclear because MDS/AML was not seen in cyclic or idiopathic neutropenia. Improved survival of congenital neutropenia patients receiving G-CSF therapy may allow time for the expression of the leukemic predisposition that characterizes the natural history of these disorders. However, other factors related to G-CSF may also be operative in the setting of congenital neutropenia. (Blood. 2000;96:429-436)