Chromosome biorientation requires Aurora B's spatial separation from its outer kinetochore substrates, but not its turnover at kinetochores.

For correct chromosome segregation in mitosis, sister kinetochores must interact with microtubules from opposite spindle poles (biorientation). For this, aberrant kinetochore-microtubule interaction must be resolved (error correction) by Aurora B kinase. Once biorientation is formed, tension is applied on kinetochore-microtubule interaction, stabilizing this interaction. The mechanism for this tension-dependent process has been debated. Here, we study how Aurora B localizations at different kinetochore sites affect the biorientation establishment and maintenance in budding yeast. Without the physiological Aurora B-INCENP recruitment mechanisms, engineered recruitment of Aurora B-INCENP to the inner kinetochore, but not to the outer kinetochore, prior to biorientation supports the subsequent biorientation establishment. Moreover, when the physiological Aurora B-INCENP recruitment mechanisms are present, an engineered Aurora B-INCENP recruitment to the outer kinetochore, but not to the inner kinetochore, during metaphase (after biorientation establishment) disrupts biorientation, which is dependent on the Aurora B kinase activity. These results suggest that the spatial separation of Aurora B from its outer kinetochore substrates is required to stabilize kinetochore-microtubule interaction when biorientation is formed and tension is applied on this interaction. Meanwhile, Aurora B exhibits dynamic turnover on the centromere/kinetochore during early mitosis, a process thought to be crucial for error correction and biorientation. However, using the engineered Aurora B-INCENP recruitment to the inner kinetochore, we demonstrate that, even without such a turnover, Aurora B-INCENP can efficiently support biorientation. Our study provides important insights into how Aurora B promotes error correction for biorientation in a tension-dependent manner.

Aurora B-INCENP Localization at Centromeres/Inner Kinetochores Is Required for Chromosome Bi-orientation in Budding Yeast.

For proper chromosome segregation in mitosis, sister kinetochores must interact with microtubules from opposite spindle poles (chromosome bi-orientation) [1, 2]. To promote bi-orientation, Aurora B kinase disrupts aberrant kinetochore-microtubule interactions [3-6]. It has long been debated how Aurora B halts this action when bi-orientation is established and tension is applied across sister kinetochores. A popular explanation for it is that, upon bi-orientation, sister kinetochores are pulled in opposite directions, stretching the outer kinetochores [7, 8] and moving Aurora B substrates away from Aurora-B-localizing sites at centromeres (spatial separation model) [3, 5, 9]. This model predicts that Aurora B localization at centromeres is required for bi-orientation. However, this notion was challenged by the observation that Bir1 (yeast survivin), which recruits Ipl1-Sli15 (yeast Aurora B-INCENP) to centromeres, can become dispensable for bi-orientation [10]. This raised the possibility that Aurora B localization at centromeres is dispensable for bi-orientation. Alternatively, there might be a Bir1-independent mechanism for recruiting Ipl1-Sli15 to centromeres or inner kinetochores [5, 9]. Here, we show that the COMA inner kinetochore sub-complex physically interacts with Sli15, recruits Ipl1-Sli15 to the inner kinetochore, and promotes chromosome bi-orientation, independently of Bir1, in budding yeast. Moreover, using an engineered recruitment of Ipl1-Sli15 to the inner kinetochore when both Bir1 and COMA are defective, we show that localization of Ipl1-Sli15 at centromeres or inner kinetochores is required for bi-orientation. Our results give important insight into how Aurora B disrupts kinetochore-microtubule interaction in a tension-dependent manner to promote chromosome bi-orientation.

A conserved Polϵ binding module in Ctf18-RFC is required for S-phase checkpoint activation downstream of Mec1.

Defects during chromosome replication in eukaryotes activate a signaling pathway called the S-phase checkpoint, which produces a multifaceted response that preserves genome integrity at stalled DNA replication forks. Work with budding yeast showed that the 'alternative clamp loader' known as Ctf18-RFC acts by an unknown mechanism to activate the checkpoint kinase Rad53, which then mediates much of the checkpoint response. Here we show that budding yeast Ctf18-RFC associates with DNA polymerase epsilon, via an evolutionarily conserved 'Pol ϵ binding module' in Ctf18-RFC that is produced by interaction of the carboxyl terminus of Ctf18 with the Ctf8 and Dcc1 subunits. Mutations at the end of Ctf18 disrupt the integrity of the Pol ϵ binding module and block the S-phase checkpoint pathway, downstream of the Mec1 kinase that is the budding yeast orthologue of mammalian ATR. Similar defects in checkpoint activation are produced by mutations that displace Pol ϵ from the replisome. These findings indicate that the association of Ctf18-RFC with Pol ϵ at defective replication forks is a key step in activation of the S-phase checkpoint.

Rad53 is essential for a mitochondrial DNA inheritance checkpoint regulating G1 to S progression.

The Chk2-mediated deoxyribonucleic acid (DNA) damage checkpoint pathway is important for mitochondrial DNA (mtDNA) maintenance. We show in this paper that mtDNA itself affects cell cycle progression. Saccharomyces cerevisiae rho(0) cells, which lack mtDNA, were defective in G1- to S-phase progression. Deletion of subunit Va of cytochrome c oxidase, inhibition of F(1)F(0) adenosine triphosphatase, or replacement of all mtDNA-encoded genes with noncoding DNA did not affect G1- to S-phase progression. Thus, the cell cycle progression defect in rho(0) cells is caused by loss of DNA within mitochondria and not loss of respiratory activity or mtDNA-encoded genes. Rad53p, the yeast Chk2 homologue, was required for inhibition of G1- to S-phase progression in rho(0) cells. Pif1p, a DNA helicase and Rad53p target, underwent Rad53p-dependent phosphorylation in rho(0) cells. Thus, loss of mtDNA activated an established checkpoint kinase that inhibited G1- to S-phase progression. These findings support the existence of a Rad53p-regulated checkpoint that regulates G1- to S-phase progression in response to loss of mtDNA.

Mitochondrial inheritance is required for MEN-regulated cytokinesis in budding yeast.

Mitochondrial inheritance, the transfer of mitochondria from mother to daughter cell during cell division, is essential for daughter cell viability. The mitochore, a mitochondrial protein complex containing Mdm10p, Mdm12p, and Mmm1p, is required for mitochondrial motility leading to inheritance in budding yeast. We observe a defect in cytokinesis in mitochore mutants and another mutant (mmr1Delta gem1Delta) with impaired mitochondrial inheritance. This defect is not observed in yeast that have no mitochondrial DNA or defects in mitochondrial protein import or assembly of beta-barrel proteins in the mitochondrial outer membrane. Deletion of MDM10 inhibits contractile-ring closure, but does not inhibit contractile-ring assembly, localization of a chromosomal passenger protein to the spindle during early anaphase, spindle alignment, nucleolar segregation, or nuclear migration during anaphase. Release of the mitotic exit network (MEN) component, Cdc14p, from the nucleolus during anaphase is delayed in mdm10Delta cells. Finally, hyperactivation of the MEN by deletion of BUB2 restores defects in cytokinesis in mdm10Delta and mmr1Delta gem1Delta cells and reduces the fidelity of mitochondrial segregation between mother and daughter cells in wild-type and mdm10Delta cells. Our studies identify a novel MEN-linked regulatory system that inhibits cytokinesis in response to defects in mitochondrial inheritance in budding yeast.

Enterocolitis neutropénica en el niño con cáncer: nuestra casuistica y revisión de la literatura / Neutropenic enterocolitis in the child with cancer: our casuistics and review of the literature

Introducción: La enterocolitis neutropénica o tiflitis es una alteración de la región ileocecal con ausencia de infiltrado inflamatorio o tumoral y diferentes grados de afectación de la pared intestinal, típica de pacientes con tumores hematológicos afectos de neutropenia grave o prolongada secundaria a la quimioterapia. Objetivos: Revisar los casos de enterocolitis neutropénica diagnosticados en niños con cáncer del Hospital Universitario de Canarias (HUC) durante los últimos 6 años y medio y realizar una revisión actualizada de la literatura sobre el tema. Pacientes y métodos: Revisión retrospectiva de historias clínicas de los niños que padecieron tiflitis. Se analizaron las siguientes variables: edad, sexo, tipo de neoplasia, protocolo de quimioterapia, y al diagnóstico de la tiflitis; número de días desde el último ciclo de quimioterapia (quimioterápicos recibidos), días de neutropenia, síntomas, método diagnóstico (grosor máximo de la pared intestinal), tratamiento y evolución. Resultados: De los 41 casos de tumores malignos tratados con quimioterapia, el 7,3% (n = 3) presentaron uno o más episodios de enterocolitis neutropénica (todos afectos de leucemia aguda; dos mieloblásticas y una linfoblástica).Todos eran varones, con una edad media de 11 años y medio. La clínica predominante fue dolor abdominal en el contexto de una neutropenia febril postquimioterapia. La confirmación diagnóstica se realizó mediante ecografía abdominal en dos casos y tomografía computarizada (TC) en los otros dos (media del grosor intestinal máximo: 11,5 mm). El tratamiento instaurado en todos los casos fue conservador, logrando una recuperación clínico-radiológica en el 100% de los pacientes. Conclusión: En todo niño con cáncer en tratamiento quimioterápico, especialmente en afectos de leucemia aguda, con neutropenia febril que además refiera dolor abdominal persistente, vómitos y/o diarrea, se debe sospechar una enterocolitis neutropénica, solicitar una ecografía y/o una TC abdominal urgente para confirmarla, e instaurar lo antes posible el tratamiento recomendado, logrando, así, una reducción significativa de la morbimortalidad que conlleva esta grave complicación (AU)

Background: Neutropenic enterocolitis or thyphlitis is a lesion of the ileocecal arca with lack of inflammatory or tumoral infiltration and different degrees of affection on the bowel wall. It is typical in patients with hematologic malignancies with prolonged or severe neutropema alter intensive chemotherapy. Objectives: Revise all neutropenic enterocolitis diagnosed at Hospital Universitario de Canarias (HUC) in the last six and a half years in children with cancer, and carry out an up today literature review. Patients and methods: Retrospective review of the medical histories to the children who had thyplitis. We analyzed the following data: age, sex, cancer type and chemotherapy protocol, and when thyplitis was diagnosed; days from the last cytotoxic chemotherapy cycle (anticancer drugs used), days of neutropenia, symptoms, diagnosis method used (maximum thickness on the bowel wall), treatment and evolution. Results: Forty one cases of malignant neoplasms were treated with chemotherapy and 7,3% (n = 3) had one or more episodes of neutropenic enterocolitis (all of them with acute leukemia, two myelogenus and one lymphoblastic). All of them were male, with an average age of 11 years and 6 months. The symptom more frequently seen was abdominal pain in a child with a febrile neutropenia alter intensive chemotherapy. The diagnosis confirmation was with abdominal ultrasonography (US) in two cases, and computed tomography (CT) in the other two ones (average thickness on the bowel wall was 11,5 mm). All the children recovered without problems with medical treatment. Conclusion: Any child with cancer treated with chemotherapy, especially with acute leukaemia, and febrile neutropenia associated with persistent abdominal pain, vomiting and/or diarrhea, we must suspect neutropenic enterocolitis, ask for an urgent abdominal US and/or CT to confirm the diagnosis, and start as far as possible the recommended treatment, achieving as that a significative morbimortality reduction so common in this severe complication (AU)

Puf3p, a Pumilio family RNA binding protein, localizes to mitochondria and regulates mitochondrial biogenesis and motility in budding yeast.

Puf3p binds preferentially to messenger RNAs (mRNAs) for nuclear-encoded mitochondrial proteins. We find that Puf3p localizes to the cytosolic face of the mitochondrial outer membrane. Overexpression of PUF3 results in reduced mitochondrial respiratory activity and reduced levels of Pet123p, a protein encoded by a Puf3p-binding mRNA. Puf3p levels are reduced during the diauxic shift and growth on a nonfermentable carbon source, conditions that stimulate mitochondrial biogenesis. These findings support a role for Puf3p in mitochondrial biogenesis through effects on mRNA interactions. In addition, Puf3p links the mitochore, a complex required for mitochondrial-cytoskeletal interactions, to the Arp2/3 complex, the force generator for actin-dependent, bud-directed mitochondrial movement. Puf3p, the mitochore, and the Arp2/3 complex coimmunoprecipitate and have two-hybrid interactions. Moreover, deletion of PUF3 results in reduced interaction between the mitochore and the Arp2/3 complex and defects in mitochondrial morphology and motility similar to those observed in Arp2/3 complex mutants. Thus, Puf3p is a mitochondrial protein that contributes to the biogenesis and motility of the organelle.

[Neonatal neoplasms: a single-centre experience]. / Neoplasias neonatales: experiencia de un centro.

INTRODUCTION: Malignant tumors are uncommon in the neonatal period and benign tumors may have malignant potential. OBJECTIVES: To describe the neoplasms diagnosed and treated in newborns (

[Study of the introduction of the European Credit Transfer System (ECTS) in pediatrics and modification of the teaching methodology]. / Estudio sobre la introducción del Sistema de Transferencia de Créditos Europeo en Pediatría y modificaciones de la metodología docente.

INTRODUCTION: Spanish medical faculties have initiated the new curriculum reform process within the framework of the European Higher Education Area and are required to incorporate the European Credit Transfer System (ECTS) to new syllabi before 2010. OBJECTIVES: To test the introduction of the ECTS in pediatrics and modify the teaching methodology. STUDY DESIGN: The theoretical and practical programs were adapted; academic objectives and a student evaluation system were established. Students were surveyed on starting the second term of the 2004-05 academic year before the theory examination and again on terminating the academic year: a 5-point Likert-type scale was used for responses. Priorities for generic and specific competencies selected by students were compared with those selected by the National Deans Conference (NDC). The results were analyzed using non-parametric tests. RESULTS: Fifteen credits became 11 ECTS, with 297 student working hours. The theory program was reduced from 80 to 52 lessons. The students prepared 14 tutor-supervised case presentations. The teaching staff considered that learning of theory was similar to previous years (66 %) and that practical learning improved (73.3 %). The students thought the program should continue (73.2 %) but 98.8 % considered the workload excessive. The students believed that their practical training and their ability to prepare and make case presentations significantly improved during the semester. Academic performance was significantly higher than that in students of the previous year. Students agreed with NDC priorities for 9/9 general and 4/17 specific competencies. Estimation of workload by students was significantly higher than that by staff, and 73.3 % of the students believed that workload should be reduced and the examination system improved. CONCLUSIONS: Introducing the ECTS improved academic performance, practical training, and self-directed learning. The project was satisfactory for staff and students. Student workload was underestimated.

Neoplasias neonatales: experiencia de un centro / Neonatal neoplasms: a single-centre experience

Introducción Los tumores malignos en el período neonatal son poco frecuentes y los benignos pueden tener un potencial de malignización. Objetivos Revisar las neoplasias diagnosticadas y tratadas en recién nacidos (≤ 28 días de vida) en el Hospital Universitario de Canarias, su asociación con anomalías congénitas y valorar el diagnóstico prenatal. Pacientes y métodos Se revisaron de forma retrospectiva las historias clínicas de las neoplasias diagnosticadas durante la época neonatal en los últimos 25 años en nuestro centro. Se analizaron las siguientes variables: el porcentaje de neoplasias neonatales sobre el total de las registradas en niños menores de 14 años y su incidencia, sexo, año de diagnóstico, edad al diagnóstico clínico y si se había hecho diagnóstico prenatal, tipo de tumor (diagnóstico histológico), asociación a síndromes u otras malformaciones congénitas, tratamiento recibido y evolución posterior. Resultados Del total de 260 tumores diagnosticados en nuestra unidad desde 1980, 16 (6,1 %) han sido en la etapa neonatal, con una incidencia de 276,5 casos por 10 6 recién nacidos vivos. El 43,8 % eran varones y el 56,2 % mujeres, con una edad media al diagnóstico de 5,5 días de vida (límites entre 1 a 28 días). El diagnóstico fue prenatal en 5 neonatos (31,2 %), de los cuales hasta un 60 % se hizo en los últimos 7 años. Otros 5 recién nacidos fueron diagnosticados en la primera exploración neonatal. Los diagnósticos histopatológicos fueron: neuroblastoma (n = 5; 31,2 %), teratoma/tumor de células germinales (n = 4; 25 %), sarcoma de partes blandas (1 fibrosarcoma de muslo y 2 hemangiopericitomas, de espalda y cardíaco; 18,8 %), un nefroma mesoblástico, un caso de tumor cerebral (ependimoblastoma), un melanoma (asociado a un nevo melanocítico congénito gigante), y una leucemia aguda (asociada a síndrome de Down). El tratamiento recibido fue: sólo cirugía (n = 10; 62,5 %), cirugía más quimioterapia (n =5; 31,2 %) y uno sin tratamiento. La supervivencia global actuarial es del 87,5 %. De los supervivientes hasta un 33,3 % presentan algún tipo de secuela. Conclusiones Las neoplasias más frecuentemente diagnosticadas en el período neonatal fueron tumores sólidos como el neuroblastoma y teratomas/tumores de células germinales. El 12,5 % estuvieron asociadas con síndromes u anomalías congénitas. En los últimos 7 años se observa un avance en su diagnóstico prenatal. La mayoría respondieron a la terapia instaurada, principalmente cirugía, con un buen pronóstico a largo plazo

Introduction Malignant tumors are uncommon in the neonatal period and benign tumors may have malignant potential. Objectives To describe the neoplasms diagnosed and treated in newborns (≤ 28 days of life) in the Hospital Universitario de Canarias and their association with congenital abnormalities and to evaluate prenatal diagnosis of these tumors. Patients and methods The medical records of patients with neoplasms diagnosed during the neonatal period in the previous 25 years in our hospital were retrospectively reviewed. The variables analyzed were the percentage of neonatal neoplasms among the total number of cancer cases in children aged less than 14 years, their incidence among all the newborns in our hospital, sex, year of diagnosis, age at clinical diagnosis, the presence or absence of prenatal diagnosis, type of tumor (histologic diagnosis), association with syndromes or other congenital anomalies, treatment, and long-term outcome. Results Of 260 neoplasms diagnosed in our unit from 1980, 16 (6.1 %) were diagnosed in the neonatal period. The incidence of neonatal neoplasms was estimated to be 276.5 per million live births. Males accounted for 43.8 % and females for 56.2 %, with a mean age at diagnosis of 5.5 days (range 1-28 days). Five neonates (31.2 %) had a prenatal diagnosis, 60 % of which were made in the last 7 years of the study period. A further five newborns were diagnosed at the initial neonatal examination. Histologic diagnoses were neuroblastoma (n = 5; 31.2 %), teratoma/ germ cell tumor (n = 4; 25 %), soft tissue sarcoma (one fibrosarcoma of the thigh and two hemangiopericytoma of the back and heart; 18.8 %), and one case each of mesoblastic nephroma, cerebral tumor (ependymoblastoma), melanoma (associated with giant congenital melanocytic nevi), and acute leukemia (associated with Down syndrome). Treatment consisted of surgery alone (n = 10; 62.5 %) and surgery plus chemotherapy (n = 5; 31.2 %); one patient received no treatment. The overall actuarial survival rate was 87.5 %. Sequelae were observed in 33.3 % of survivors. Conclusions The neoplasms most frequently diagnosed in the neonatal period were solid tumors, mainly neuroblastoma and teratomas/germ cell tumors; 12.5 % were associated with syndromes or congenital anomalies. In the last 7 years, the prenatal diagnosis of these entities has improved. Most of the neoplasms responded to therapy, mainly surgery, and long-term outcome was favorable

Estudio sobre la introducción del Sistema de Transferencia de Créditos Europeo en Pediatría y modificaciones de la metodología docente / Study of the introduction of the european credit transfer system (ECTS) in pediatrics and modification of the teaching methodology

Introducción Las Facultades Médicas españolas han comenzado el nuevo proceso de reforma curricular en el marco del proceso de implantación del Espacio Europeo de Educación Superior y deben incorporar el Sistema de Transferencia de Créditos Europeo (ECTS) a los nuevos planes del estudio antes de 2010. Objetivos El objetivo del trabajo fue experimentar la introducción de los créditos ECTS en la asignatura de Pediatría y modificar la metodología docente. Diseño del estudio Adaptación del programa teórico y práctico, estableciendo unos objetivos docentes y un sistema de evaluación. Se realizaron encuestas a los alumnos al inicio del segundo cuatrimestre del curso 2004-2005, antes de realizar el examen teórico de la asignatura y al finalizar el curso académico, utilizando para las respuestas una escala de tipo Likert con 5 grados. Se comparó la priorización de las competencias genéricas y específicas de los alumnos con la de los profesionales médicos en la encuesta de la Conferencia Nacional de Decanos (CND). Para el análisis de los resultados se aplicaron pruebas no paramétricas. Resultados Los 15 créditos actuales se transformaron en 11 ECTS, con 297 h de trabajo para los alumnos. Se redujo el programa teórico de 80 a 52 lecciones. Los alumnos prepararon y presentaron 14 casos clínicos, bajo la supervisión de sus tutores. Los profesores consideraron que el aprendizaje teórico había sido similar al de cursos anteriores (66,6 %) y había sido mejor el práctico (73,3 %). Los alumnos opinaron que el proyecto debía continuar (73,2 %), pero el 98,8 % consideraron que la carga de trabajo había sido excesiva. Los alumnos apreciaron de forma estadísticamente significativa que mejoró la docencia práctica y su capacidad para preparar y presentar casos clínicos. El rendimiento académico de los alumnos fue significativamente mejor que el de los alumnos del curso anterior. Los estudiantes estuvieron de acuerdo con la prioridad de competencias de la CND para 9/9 de las generales y 4/17 de las específicas. La estimación de horas de trabajo de los alumnos fue mayor por los alumnos que por los profesores. El 73,3 % de los alumnos contestaron que el proyecto debía mejorarse, reduciendo la carga de trabajo de los alumnos y mejorando el sistema de evaluación. Conclusiones La introducción de los ECTS mejoró el rendimiento académico, la formación práctica y el autoaprendizaje de los alumnos. La experiencia fue satisfactoria para profesores y alumnos. La estimación de la carga de trabajo de los alumnos fue subestimada

Introduction Spanish medical faculties have initiated the new curriculum reform process within the framework of the European Higher Education Area and are required to incorporate the European Credit Transfer System (ECTS) to new syllabi before 2010. Objectives To test the introduction of the ECTS in pediatrics and modify the teaching methodology. Study design The theoretical and practical programs were adapted; academic objectives and a student evaluation system were established. Students were surveyed on starting the second term of the 2004-05 academic year before the theory examination and again on terminating the academic year: a 5-point Likert-type scale was used for responses. Priorities for generic and specific competencies selected by students were compared with those selected by the National Deans Conference (NDC). The results were analyzed using non-parametric tests. Results Fifteen credits became 11 ECTS, with 297 student working hours. The theory program was reduced from 80 to 52 lessons. The students prepared 14 tutor-supervised case presentations. The teaching staff considered that learning of theory was similar to previous years (66 %) and that practical learning improved (73.3 %). The students thought the program should continue (73.2 %) but 98.8 % considered the workload excessive. The students believed that their practical training and their ability to prepare and make case presentations significantly improved during the semester. Academic performance was significantly higher than that in students of the previous year. Students agreed with NDC priorities for 9/9 general and 4/17 specific competencies. Estimation of workload by students was significantly higher than that by staff, and 73.3 % of the students believed that workload should be reduced and the examination system improved. Conclusions Introducing the ECTS improved academic performance, practical training, and self-directed learning. The project was satisfactory for staff and students. Student workload was underestimated

Spontaneous speech events in two speech databases of human-computer and human-human dialogs in Spanish.

Previous works in English have revealed that disfluencies follow regular patterns and that incorporating them into the language model of a speech recognizer leads to lower perplexities and sometimes to a better performance. Although work on disfluency modeling has been applied outside the English community (e.g., in Japanese), as far as we know there is no specific work dealing with disfluencies in Spanish. In this paper, we follow a data driven approach in exploring the potential benefit of modeling disfluencies in a speech recognizer in Spanish. Two databases of human-computer and human-human dialogs are considered, which allow the absolute and relative frequencies of disfluencies in the two situations to be compared. The rate of disfluencies in human-human dialogs is found to be very close to that found for similar databases in English. Due to setup factors, the rate of disfluencies found in human-computer dialogs was remarkably higher than that reported for similar databases in English. In any case, from the point of view of speech recognition, the high frequencies of disfluencies and the distinct features of the acoustic events related to them support the need for explicit acoustic models. The regularities observed in the distribution of filled pauses and speech repairs reveal that including them in the language model of the speech recognizer may be also helpful. The extent to which the number of events depends on utterance length and on the speaker is also explored. Statistics are shown that follow previous studies for English, and a sizeable space is devoted to comparing our results with them. Finally, various possible cues for the automatic detection of speech repairs--a key issue from the point of view of speech understanding--are explored: silent pauses, filled pauses, lengthenings, cut off words and discourse markers. As previously observed for English, none of them was found to be reliable by itself. More information, especially at the acoustic-prosodic level, is no doubt needed to reliably detect speech repairs.

Cell integrity signaling activation in response to hyperosmotic shock in yeast.

Current progress highlights the role of the yeast cell wall as a highly dynamic structure that responds to many environmental stresses. Here, we show that hyperosmotic shock transiently activates the PKC signaling pathway, a response that requires previous activation of the HOG pathway. Phosphorylation of Slt2p under such conditions is related to changes in the glycerol turnover and is mostly Mid2p dependent, suggesting that changes in cell turgor, mediated by intracellular accumulation of glycerol, are sensed by PKC sensors to promote the cell integrity response. These observations, together with previous results, suggest that yeast cells respond to changes in cellular turgor by remodeling their cell walls.

Estudio de la enfermedad mínima residual en el cáncer infantil / Study of minimal residual disease of childhood cancer

El estudio de la enfermedad mínima residual (EMR), en distintas neoplasias infantiles, ha ido adquiriendo en los últimos años una importancia trascendental en la detección y seguimiento de pacientes con mayor probabilidad de recaída y como consecuencia, un mal pronóstico a largo plazo. Existen diferentes técnicas de estudio para determinar y cuantificar la EMR, según el tipo de neoplasia: la citometría de flujo, la inmunocitología y técnicas moleculares como la hibridación in situ con fluorescencia (FISH) y la transcripción inversa acoplada a la reacción en cadena de la polimerasa (RTPCR). En este artículo se repasan las diferentes técnicas utilzadas en busca de EMR durante y/o tras finalizar el tratamiento en leucemias agudas infantiles, neuroblastomas, rabdomiosarcomas y tumores de la familia del sarcoma de Ewing, así como su utilidad como factor pronóstico (AU)

[The role of molecular genetics in childhood cancer]. / Papel de la genética molecular en el cáncer infantil.

In the last few years molecular genetic studies of childhood cancer have acquired great importance. Advances in these techniques have increased knowledge of the various genes involved in tumoral development. Genetic alterations can occur in three large groups of genes: oncogenes, tumor suppressor genes, and DNA repair genes. Cytogenetic analyses (karyotyping) are complemented by various molecular techniques, such as fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR) and spectral karyotyping (SKY). These are the most reliable techniques and improve the sensitivity of karyotyping. The present article reviews the most representative and best characterized genes involved in the molecular etiology of childhood cancer, both hematologic malignancies (leukemia and lymphoma) and solid tumors (brain tumors, neuroblastoma, Wilms' tumor, hepatoblastoma, rhabdomyosarcoma, Ewing's sarcoma and retinoblastoma). Molecular techniques have enabled more precise diagnosis as well as identification of new prognostic factors and the development of more effective treatments. These techniques can also be useful in identifying minimal residual disease during and after treatment for leukemias, neuroblastomas and sarcomas, with the aim of predicting recurrence.

Papel de la genética molecular en el cáncer infantil / In role of molecular genetics in chilhood cancer

Los estudios de genética molecular en el cáncer infantil han ido adquiriendo en los últimos años una importancia trascendental. Los avances en estas técnicas han permitido aumentar el conocimiento de distintos genes implicados en el desarrollo tumoral. Estas diferentes alteraciones génicas ocurren en tres grandes grupos de genes: oncogenes, genes supresores y genes reparadores de ADN. Los estudios citogenéticos (cariotipo) se complementan con diferentes técnicas moleculares como la hibridación in situ con fluorescencia (FISH), la transcripción inversa acoplada a la reacción en cadena de la polimerasa (RT-PCR) o el cariotipo espectral (SKY), como más fiables, mejorando su sensibilidad.En este artículo se repasan los genes más representativos y mejor estudiados implicados en la etiología molecular del cáncer pediátrico, tanto de neoplasias hematológicas (leucemias y linfomas) como de tumores sólidos (tumores cerebrales, neuroblastoma, tumor de Wilms, hepatoblastoma, rabdomiosarcoma, sarcoma de Ewing y retinoblastoma), y cómo su estudio, además de permitir alcanzar un diagnóstico más preciso, ha desarrollado nuevos factores pronóstico y tratamientos más efectivos. Estas técnicas también pueden utilizarse en busca de la enfermedad mínima residual, durante y tras finalizar el tratamiento en leucemias, neuroblastomas y sarcomas, con el fin de prevenir su reaparición (AU)

[Cutaneous involvement as the form of presentation in B-cell lymphoblastic leukemia/lymphoma]. / Nódulo cutáneo como forma de presentación de una leucemia/linfoma linfoblástico de estirpe B.

Primary cutaneous involvement in B-cell lymphoblastic leukemia/lymphoma is rare in childhood. We present the case of an eleven and a half year old girl who, five months prior to being referred to our center, had undergone surgery to remove a small gluteal tumor diagnosed histopathologically as lymphoid proliferation suggestive of large cell lymphoma. On examination the presence of small nodes close to the scar where the tumor had previously been removed was observed. Hemogram revealed 2.7 x 9/l white blood cells with 0.5 x 9/l neutrophils; the remaining series and complementary investigations were normal. Bone marrow aspiration revealed 52 % blastic cells with immunophenotype and morphological characteristics of common (B-cell) acute lymphoblastic leukemia with L2 subtype in the French-American-British (FAB) classification. Ten months after finishing polychemotherapy, the patient is now in complete remission. We would like to highlight that a small slow-growing cutaneous node could be the presenting form of lymphoblastic lymphoma or acute lymphoblastic leukemia.