Extensive and bilateral anterior cerebral stroke mimicking basilar artery occlusion. / Infarto extenso y bilateral de la arteria cerebral anterior que imita una oclusión de la arteria basilar.

TITLE: Infarto extenso y bilateral de la arteria cerebral anterior que imita una oclusión de la arteria basilar.

Titer and Distribution of 'Candidatus Phytoplasma pruni' in Prunus avium.

'Candidatus Phytoplasma pruni' infection in cherries causes small, misshapen fruit with poor color and taste, rendering the fruit unmarketable. However, this is a disease with a long development cycle and a scattered, nonuniform symptom distribution in the early stages. To better understand the biology as well as the relationship between pathogen titer and disease expression, we carried out seasonal, spatial, and temporal examinations of 'Ca. P. pruni' titer and distribution in infected orchard-grown trees. Sequential sampling of heavily infected trees revealed marked seasonal patterns, with differential accumulation in woody stem and leaf tissues and, most notably, within fruit in the early stages of development from bloom to pit hardening. Furthermore, mapping phytoplasma distribution and titer in trees at different stages of infection indicated that infection proceeds through a series of stages. Initially, infection spreads basipetally and accumulates in the roots before populating aerial parts of the trees from the trunk upward, with infection of specific tissues and limbs followed by an increasing phytoplasma titer. Finally, we observed a correlation between phytoplasma titer and symptom severity, with severe symptom onset associated with three to four orders of magnitude more phytoplasma than mild symptoms. Cumulatively, these data aid in accurate sampling and management decision-making and furthers our understanding of disease development.

Relevancia clínica de la interacción entre posaconazol y digoxina: a propósito de un caso / Clinical relevance of the pharmacokinetic interaction between posaconazol and digoxin: a case report

El posaconazol es un inhibidor de la glicoproteína P (P-gp), un transportador dependiente del ATP que desempeña un papel importante en la absorción, distribución y eliminación de múltiples medicamentos. Varios estudios in vitro han demostrado que la digoxina es un sustrato de la P-gp, por lo que su administración concomitante puede dar lugar a un aumento de la absorción intestinal y/o a una disminución de la depuración renal, con el consiguiente riesgo de toxicidad digitálica. Se presenta el caso clínico de una intoxicación digitálica como consecuencia de la interacción entre posaconazol y digoxina en un paciente con fibrilación auricular, insuficiencia cardiaca y múltiples episodios de pancitopenia postquimioterapia por leucemia mieloide aguda. El paciente tuvo que ser hospitalizado por bradicardia de 30 l.p.m. Ambos medicamentos fueron suspendidos de inmediato y el paciente se recuperó sin incidencias. (AU)

Posaconazole is an inhibitor of glycoprotein P (P-gp), an ATP-dependent transporter with a role in drug absorption, distribution and elimination. Several in vitro studies have shown that digoxin is a substrate of P-gp, so concomitant administration may result in increased intestinal absorption and/or decreased renal clearance, with a consequent risk of digitalic toxicity. The clinical case of digitalis intoxication as a consequence of the interaction between posaconazole and digoxin in a patient with atrial fibrillation, congestic heart failure and multiple episodes of post chemotherapy pancytopenia due to acute myeloid leukemia is weighed. The patient had to be hospitalized for bradicardia of 30 l.p.m. Both medicines were immediately suspended and the patient recovered without major issues. (AU)

Dual T1/ T2 Nanoscale Coordination Polymers as Novel Contrast Agents for MRI: A Preclinical Study for Brain Tumor.

In the last years, extensive attention has been paid on designing and developing functional imaging contrast agents for providing accurate noninvasive evaluation of pathology in vivo. However, the issue of false-positives or ambiguous imaging and the lack of a robust strategy for simultaneous dual-mode imaging remain to be fully addressed. One effective strategy for improving it is to rationally design magnetic resonance imaging (MRI) contrast agents (CAs) with intrinsic T1/ T2 dual-mode imaging features. In this work, the development and characterization of one-pot synthesized nanostructured coordination polymers (NCPs) which exhibit dual mode T1/ T2 MRI contrast behavior is described. The resulting material comprises the combination of different paramagnetic ions (Fe3+, Gd3+, Mn2+) with selected organic ligands able to induce the polymerization process and nanostructure stabilization. Among them, the Fe-based NCPs showed the best features in terms of colloidal stability, low toxicity, and dual T1/ T2 MRI contrast performance overcoming the main drawbacks of reported CAs. The dual-mode CA capability was evaluated by different means: in vitro phantoms, ex vivo and in vivo MRI, using a preclinical model of murine glioblastoma. Interestingly, the in vivo MRI of Fe-NCPs show T1 and T2 high contrast potential, allowing simultaneous recording of positive and negative contrast images in a very short period of time while being safer for the mouse. Moreover, the biodistribution assays reveals the persistence of the nanoparticles in the tumor and subsequent gradual clearance denoting their biodegradability. After a comparative study with commercial CAs, the results suggest these nanoplatforms as promising candidates for the development of dual-mode MRI CAs with clear advantages.

Dynamic damage in carbon-fibre composites.

The Taylor test is used to determine damage evolution in carbon-fibre composites across a range of strain rates. The hierarchy of damage across the scales is key in determining the suite of operating mechanisms and high-speed diagnostics are used to determine states during dynamic loading. Experiments record the test response as a function of the orientation of the cylinder cut from the engineered multi-ply composite with high-speed photography and post-mortem target examination. The ensuing damage occurs during the shock compression phase but three other tensile loading modes operate during the test and these are explored. Experiment has shown that ply orientations respond to two components of release; longitudinal and radial as well as the hoop stresses generated in inelastic flow at the impact surface. The test is a discriminant not only of damage thresholds but of local failure modes and their kinetics. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'.

[Cost-effectiveness analysis of aflibercept in combination with FOLFIRI in the treatment of patients with metastatic colorectal cancer]. / Análisis coste-efectividad de aflibercept en combinación con FOLFIRI en el tratamiento de pacientes con cáncer colorrectal metastásico.

OBJECTIVES: To estimate the incremental cost per life-year gained (LYG) of aflibercept in combination with FOLFIRI as second-line treatment in metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. METHODS: Based on clinical trial VELOUR results, a three-state Markov model (stable disease, progression and death) with 2-week cycle duration was designed. Transition to health state «progression¼ implied the interruption of second-line treatment and administration of a third-line treatment (post-second line chemotherapy). Cost estimation included disease management cost (pharmaceutical, adverse event management, administration costs, etc.). Both cost and outcomes were discounted (3% annually). Sensitivity analyses (SA) were performed to test model robustness. RESULTS: Administration of aflibercept + FOLFIRI as second-line treatment provided 1.78 LYG (21 life-months gained). With FOLFIRI 1.43 LYG (17 months) were obtained. The cost of the clinical management of aflibercept + FOLFIRI implied an additional investment of Euros 13,564 compared with FOLFIRI for a lifetime horizon, being total costs for aflibercept + FOLFIRI of Euros 38,346, compared to Euros 24,782 with FOLFIRI. In the cost-effectiveness analysis Euros 38,931/LYG was obtained with aflibercept in combination with FOLFIRI versus FOLFIRI. CONCLUSION: Aflibercept in combination with FOLFIRI increased overall survival versus FOLFIRI, so it is an effective strategy in the treatment of patients with mCRC. Aflibercept in combination with FOLFIRI is an efficient strategy for second-line mCRC treatment from the National Health System perspective.

OBJETIVOS: Estimar el coste incremental por año de vida ganado (AVG) de la utilización de aflibercept en combinación con FOLFIRI como tratamiento de 2ª línea en pacientes con cáncer colorrectal metastásico (CCRm) previamente tratados con oxaliplatino. MATERIAL Y MÉTODOS: Basándose en los resultados del ensayo clínico VELOUR, se utilizó un modelo de Markov con 3 estados de salud (enfermedad estable, progresión y muerte) y ciclos de 2 semanas. La transición al estado de salud «progresión¼ implicaba interrumpir el tratamiento en 2ª línea y administrar una 3ª línea de tratamiento. La estimación de costes incluyó costes del manejo de la enfermedad (farmacológicos, acontecimientos adversos, administración, etc.). Costes y resultados en salud fueron descontados al 3% anualmente. Para probar la robustez del modelo se realizaron análisis de sensibilidad determinístico y probabilístico. RESULTADOS: La administración de aflibercept + FOLFIRI como 2ª línea de quimioterapia aporta 1,78 AVG (21 meses de vida ganados). Con FOLFIRI se consiguen 1,43 AVG (17 meses). El coste del manejo clínico de aflibercept + FOLFIRI supone una inversión adicional de 13.564 frente a FOLFIRI a lo largo de toda la vida del paciente, siendo el coste total de 38.346 para aflibercept + FOLFIRI y 24.782 para FOLFIRI. Se obtiene un RCEI (ratio coste efectividad incremental) de 38.931 /AVG con aflibercept + FOLFIRI frente a FOLFIRI. CONCLUSIÓN: Aflibercept en combinación con FOLFIRI incrementa la supervivencia global frente a FOLFIRI, lo que supone una estrategia efectiva en el tratamiento de pacientes con CCRm. La relación coste-efectividad incremental de aflibercept en combinación con FOLFIRI supone una estrategia eficiente, coste-efectiva, para el Sistema Nacional de Salud.

Análisis coste-efectividad de aflibercept en combinación con FOLFIRI en el tratamiento de pacientes con cáncer colorrectal metastásico / Cost-effectiveness analysis of aflibercept in combination with FOLFIRI in the treatment of patients with metastatic colorectal cancer

Objetivos: Estimar el coste incremental por año de vida ganado (AVG) dela utilización de aflibercept en combinación con FOLFIRI como tratamiento de 2ª línea en pacientes con cáncer color rectal metastásico (CCRm) previamente tratados con oxaliplatino. Material y métodos: Basándose en los resultados del ensayo clínico VELOUR, se utilizó un modelo de Markov con 3 estados de salud (enfermedad estable, progresión y muerte) y ciclos de 2 semanas. La transición al estado de salud «progresión» implicaba interrumpir el tratamiento en 2ªlínea y administrar una 3ª línea de tratamiento. La estimación de costes incluyó costes del manejo de la enfermedad (farmacológicos, acontecimientos adversos, administración, etc.). Costes y resultados en salud fueron descontados al 3% anualmente. Para probar la robustez del modelo se realizaron análisis de sensibilidad determinístico y probabilístico. Resultados: La administración de aflibercept + FOLFIRI como 2ª línea de quimioterapia aporta 1,78 AVG (21 meses de vida ganados). Con FOLFIRI se consiguen 1,43 AVG (17 meses). El coste del manejo clínico de aflibercept + FOLFIRI supone una inversión adicional de 13.564 Euros frente a FOLFIRI a lo largo de toda la vida del paciente, siendo el coste total de 38.346 Euros para aflibercept + FOLFIRI y 24.782 Euros para FOLFIRI. Se obtiene un RCEI (ratio coste efectividad incremental) de 38.931 Euros/AVG con aflibercept + FOLFIRI frente a FOLFIRI. Conclusión: Aflibercept en combinación con FOLFIRI incrementa la supervivencia global frente a FOLFIRI, lo que supone una estrategia efectiva en el tratamiento de pacientes con CCRm. La relación coste-efectividad incremental de aflibercept en combinación con FOLFIRI supone una estrategia eficiente, coste-efectiva, para el Sistema Nacional de Salud (AU)

Objectives: To estimate the incremental cost per life-year gained (LYG) of aflibercept in combination with FOLFIRI as second-line treatment inmetastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. Methods: Based on clinical trial VELOUR results, a three-state Markovmodel (stable disease, progression and death) with 2-week cycle duration was designed. Transition to health state «progression» implied the interruption of second-line treatment and administration of a third-line treatment(post-second line chemotherapy). Cost estimation included disease management cost (pharmaceutical, adverse event management, administration costs, etc.). Both cost and outcomes were discounted (3% annually).Sensitivity analyses (SA) were performed to test model robustness. Results: Administration of aflibercept + FOLFIRI as second-line treatment provided 1.78 LYG (21 life-months gained). With FOLFIRI 1.43 LYG (17months) were obtained. The cost of the clinical management of aflibercept+ FOLFIRI implied an additional investment of Euros 13,564 compared with FOLFIRI for a lifetime horizon, being total costs for aflibercept + FOLFIRI of Euros 38,346, compared to Euros 24,782 with FOLFIRI. In the cost-effectiveness analysis Euros 38,931/LYG was obtained with aflibercept in combination with FOLFIRI versus FOLFIRI. Conclusion: Aflibercept in combination with FOLFIRI increased overall survival versus FOLFIRI, so it is an effective strategy in the treatment of patients with mCRC. Aflibercept in combination with FOLFIRI is an efficient strategy for second-line mCRC treatment from the National Health System perspective (AU)

Assessing the repair of critical size bone defects performed in a goat tibia model using tissue-engineered constructs cultured in a bidirectional flow perfusion bioreactor.

This work evaluated in vivo performance of a tissue-engineered bone-like matrix obtained by culturing cell-scaffold constructs in a flow perfusion bioreactor, designed to enable culture of large constructs, envisioning the regeneration of critical-sized defects. A blend of starch with polycaprolactone scaffolds was seeded with goat bone marrow stromal cells (GBMSCs) cultured in the perfusion bioreactor for 14 days using osteogenic medium. Cell seeded scaffolds cultured in static conditions acted as controls. After 14 days, constructs (42 mm length and 16 mm in diameter) were implanted in critical size defects performed in the tibial bone of six adult goats from which the bone marrow had been collected previously. Explants were retrieved after six and 12 weeks of implantation and characterized using scanning electron microscopy, energy-dispersive spectroscopy, micro-computed tomography and radiographic analysis to assess tissue morphology and calcification. Explants were histologically analyzed, using Hematoxylin & Eosin and Masson Trichrome staining. Results provided relevant information about the performance and functionality of starch with polycaprolactone-goat bone marrow stromal cell constructs in a critical size orthotopic defect performed in a large animal model and demonstrated that culture of the starch with polycaprolactone scaffolds with the autologous cells in perfusion culture provide a good therapy for the healing and regenerative process of bone defects.

[Efficiency of oncologic treatments for solid tumours in Spain]. / Eficiencia de tratamientos oncológicos para tumores sólidos en España.

OBJECTIVE: To provide estimates of the efficiency for chemotherapy strategies used in Spain. METHODS: Published reports of the phase-III clinical trials for chemotherapies used for the most prevalent solid tumours in Spain were retrieved. The incremental cost-effectiveness ratio (ICER) was calculated for each strategy compared to the control group in the clinical trial, with the National Health System perspective. The total cost (?, 2012) including only drug cost (exfactory price) was estimated based on the total units of each drug required for administration (no vial wastage), with the dosification and number of cycles specified in the publication for each treatment arm. Effectiveness was measured as month of overall survival (OS) and/or month of progression free survival (PFS). RESULTS: A total of 40 chemotherapies for 13 different advanced or metastatic tumours were assessed. OS ranged from 5.3 to 33.3 months for the 34 therapies that included the information with hazard ratios (HR) values from 0.49 to 1.15 when compared with its control group. PFS ranged, from 39 therapies with these data, between 1.5 to 12.4 months, with HR from 0.33 to 1.52. ICERs were between ?2,142.57 and ?60,996.37 per each OS month gained, and from ?2,102.54 to ?661,845.27 per PFS month gained. CONCLUSION: The variety and heterogenicity of survival and ICERs results, suggest disparity of criteria in the price and reimbursement process of drugs in Spain. The continuous advances in oncology seem to require economic revaluations of drugs.

Objetivo: Proporcionar estimadores de la eficiencia de esquemas oncológicos empleados en España. Métodos: Se seleccionaron las publicaciones de ensayos clínicos en fase III usados para indicación de las terapias oncológicas de alto impacto empleadas para tratamiento de tumores sólidos en estadíos III-IV. Para cada esquema se calculó la relación costeeficacia incremental (RCEI) respecto al comparador del ensayo, con la perspectiva del Sistema Nacional de Salud. El coste (?, 2012) farmacológico, en PVL, de cada esquema y comparador se estimó con las unidades de medicamento requeridas en cada administración (aprovechamiento máximo de viales) considerando la posología y el número de ciclos especificado en el ensayo para cada una de las ramas. La efectividad se expresó en meses de supervivencia global (SG) y/o supervivencia libre de progresión (SLP). Resultados: Se analizaron 40 esquemas oncológicos para trece tumores metastásicos. La SG osciló entre 5,3 y 33,3 meses para las 34 terapias que incluían esa información, con valores de Hazard ratio (HR) respecto a sus comparadores de 0,49 a 1,15. La SLP osciló entre 1,5 y 12,4 meses para las 39 terapias con este dato, con HR de 0,33 a 1,52. Los valores de RCEI oscilaron entre 2.142,57 ?-60.996,37 ?/mes de SG adicional y entre 2.102,54 ?-661.845,27 ?/mes de SLP adicional. Conclusión: La dispersión y heterogeneidad de la supervivencia y RCEI estimadas, sugieren disparidad de criterios en la decisión de precio y financiación de las terapias, en España. Los continuos avances en terapias oncológicas parecen requerir reevaluaciones económicas de los medicamentos.

Eficiencia de tratamientos oncológicos para tumores sólidos en España / Efficiency of oncologic treatments for solid tumours in Spain

OBJETIVO: Proporcionar estimadores de la eficiencia de esquemas oncológicos empleados en España. MÉTODOS: Se seleccionaron las publicaciones de ensayos clínicos en fase III usados para indicación de las terapias oncológicas de alto impacto empleadas para tratamiento de tumores sólidos en estadíos III-IV. Para cada esquema se calculó la relación coste-eficacia incremental (RCEI) respecto al comparador del ensayo, con la perspectiva del Sistema Nacional de Salud. El coste (€, 2012) farmacológico, en PVL, de cada esquema y comparador se estimó con las unidades de medicamento requeridas en cada administración (aprovechamiento máximo de viales) considerando la posología y el número de ciclos especificado en el ensayo para cada una de las ramas. La efectividad se expresó en meses de supervivencia global (SG) y/o supervivencia libre de progresión (SLP). RESULTADOS: Se analizaron 40 esquemas oncológicos para trece tumores metastásicos. La SG osciló entre 5,3 y 33,3 meses para las 34 terapias que incluían esa información, con valores de hazard ratio (HR) respecto a sus comparadores de 0,49 a 1,15. La SLP osciló entre 1,5 y 12,4 meses para las 39 terapias con este dato, con HR de 0,33 a 1,52. Los valores de RCEI oscilaron entre 2.142,57 €-60.996,37 €/mes de SG adicional y entre 2.102,54 €-661.845,27 €/mes de SLP adicional. CONCLUSIÓN: La dispersión y heterogeneidad de la supervivencia y RCEI estimadas, sugieren disparidad de criterios en la decisión de precio y financiación de las terapias, en España. Los continuos avances en terapias oncológicas parecen requerir reevaluaciones económicas de los medicamentos (AU)

OBJECTIVE: To provide estimates of the efficiency for chemotherapy strategies used in Spain. METHODS: Published reports of the phase-Ill clinical trials for chemotherapies used for the most prevalent solid tumours in Spain were retrieved. The incremental cost-effectiveness ratio (ICER) was calculated for each strategy compared to the control group in the clinical trial, with the National Health System perspective. The total cost (€, 2012) including only drug cost (ex-factory price) was estimated based on the total units of each drug required for administration (no vial wastage), with the dosification and number of cycles specified in the publication for each treatment arm. Effectiveness was measured as month of overall survival (OS) and/or month of progression free survival (PFS). RESULTS: A total of 40 chemotherapies for 13 different advanced or metastatic tumours were assessed. OS ranged from 5.3 to 33.3 months for the 34 therapies that included the information with hazard ratios (HR) values from 0.49 to 1.15 when compared with its control group. PFS ranged, from 39 therapies with these data, between 1.5 to 12.4 months, with HR from 0.33 to 1.52. ICERs were between €2,142.57 and €60,996.37 per each OS month gained, and from €2,102.54 to €661,845.27 per PFS month gained. CONCLUSION: The variety and heterogenicity of survival and ICERs results, suggest disparity of criteria in the price and reimbursement process of drugs in Spain. The continuous advances in oncology seem to require economic revaluations of drugs (AU)

Cost-effectiveness analyses of docetaxel versus paclitaxel once weekly in patients with metastatic breast cancer in progression following anthracycline chemotherapy, in Spain

OBJECTIVES: Our aim was to evaluate the cost-effectiveness of docetaxel versus weekly paclitaxel regimen in patients with metastatic breast cancer previously treated with anthracycline from the Spanish National Health Service (NHS) perspective. METHODS: A Markov model with a 21-day cycle duration was developed to estimate total treatment-related costs and clinical benefits over 5 years of docetaxel (100 mg/m²) and weekly paclitaxel (80 mg/m²). Patient data were obtained from the Randomized Phase III Study of Docetaxel Compared with Paclitaxel in Metastatic Breast Cancer (TAX- 311) and Anglo-Celtic IV trials. Utilities were obtained from literature, and unitary costs (€2009) from a Spanish health-cost database and the Catalogue of Medicines. Cost and benefits [life-years gained (LYG) and quality-adjusted life years (QALY)] were discounted at 3%. Sensitivity analyses were performed. RESULTS: Docetaxel yields higher health benefits (1.83 LYG; 1.08 QALY) than paclitaxel (1.46 LYG; 0.84 QALY). Global costs (treatment, concomitant medication, adverse events management, progression, best supportive care, and end of life phase) per patient were €20,052 and €9,982 with docetaxel and paclitaxel, respectively. Incremental cost-effectiveness ratio (ICER) of docetaxel versus paclitaxel was €190/LYG and €295/QALY. Based on a €30,000/QALY threshold, docetaxel has 99% probability of being cost-effective. ICER was mostly sensitive to hazard ratio (HR) (when varied from 1.46 to 1.09; €3,517/ QALY), discount over the ex-lab price of Taxol® (75%; €6,396/QALY) and granulocyte colony-stimulating factor (G-CSF) prophylactic treatment (when administered in 60% of cycles instead of 100%; cost saving). Variations in other inputs, such as time horizon (3-10 years), discount rate (0-5%), or adverse event cost (± 25%) were shown not to have relevant influence on the results. CONCLUSION: Compared to weekly paclitaxel, docetaxel therapy is cost effective for treating metastatic breast cancer patient (AU)

Polymeric piezoelectric actuator substrate for osteoblast mechanical stimulation.

Bone mass distribution and structure are dependent on mechanical stress and adaptive response at cellular and tissue levels. Mechanical stimulation of bone induces new bone formation in vivo and increases the metabolic activity and gene expression of osteoblasts in culture. A wide variety of devices have been tested for mechanical stimulation of cells and tissues in vitro. The aim of this work was to experimentally validate the possibility to use piezoelectric materials as a mean of mechanical stimulation of bone cells, by converse piezoelectric effect. To estimate the magnitude and the distribution of strain, finite numerical models were applied and the results were complemented with the optical tests (Electronic Speckle Pattern Interferometric Process). In this work, osteoblasts were grown on the surface of a piezoelectric material, both in static and dynamic conditions at low frequencies, and total protein, cell viability and nitric oxide measurement comparisons are presented.

Ontogeny of the immune system of fish.

Information on the ontogeny of the fish immune system is largely restricted to a few species of teleosts (e.g., rainbow trout, catfish, zebrafish, sea bass) and has previously focused on morphological features. However, basic questions including the identification of the first lympho-hematopoietic sites, the origin of T- and B-lymphocytes and the acquisition of full immunological capacities remain to be resolved. We review these three main topics with special emphasis on recent results obtained from the zebrafish, a new experimental model particularly suitable for study of the ontogeny of the immune system because of its rapid development and easy manipulation. This species also provides an easy way of creating mutations that can be detected by various types of screens. In some teleosts (i.e., angelfish) the first blood cells are formed in the yolk sac. In others, such as zebrafish, the first hematopoietic site is an intraembryonic locus, the intermediate cell mass (ICM), whereas in both killifish and rainbow trout the first blood cells appear for a short time in the yolk sac but later the ICM becomes the main hematopoietic area. Erythrocytes and macrophages are the first blood cells to be identified in zebrafish embryos. They occur in the ICM, the duct of Cuvier and the peripheral circulation. Between 24 and 30 hour post-fertilization (hpf) at a temperature of 28 degrees C a few myeloblasts and myelocytes appear between the yolk sac and the body walls, and the ventral region of the tail of 1-2 day-old zebrafish also contains developing blood cells. The thymus, kidney and spleen are the major lymphoid organs of teleosts. The thymus is the first organ to become lymphoid, although earlier the kidney can contain hematopoietic precursors but not lymphocytes. In freshwater, but not in marine, teleosts the spleen is the last organ to acquire that condition. We and other authors have demonstrated an early expression of Rag-1 in the zebrafish thymus that correlates well with the morphological identification of lymphoid cells. On the other hand, the origins and time of appearance of B lymphocytes in teleosts are a matter of discussion and recent results are summarized here. The functioning rather than the mere morphological evidence of lymphocytes determines when the full immunocompetence in fish is attained. Information on the histogenesis of fish lymphoid organs can also be obtained by analysing zebrafish mutants with defects in the development of immune progenitors and/or in the maturation of non-lymphoid stromal elements of the lymphoid organs. The main characteristics of some of these mutants will also be described.

Are the anterior negativities to grammatical violations indexing working memory?

Anterior negativities obtained when a grammatical rule is violated may reflect highly automatic first-pass parsing processes, the detection of a morphosyntactic mismatch, and/or the inability to assign the incoming word to the current phrase structure. However, for some theorists these negativities rather reflect some aspect of working memory processes. Event-related brain potentials (ERPs) obtained for word category and morphosyntactic violations were directly compared with effects obtained when working memory is particularly demanded (embedding subject- or object-relative clauses), yielding a significant dissociation in terms of topography. Even though, the anterior negativities for grammatical violations vanished when relative clauses were embedded, suggesting that the processes reflected by anterior negativities related to grammatical violations and those related to working memory manipulations, even if different, are placing demands on a common pool of limited resources.

Caregiver physical and mental health predicts reactions to caregiving.

Self-reported health and reactions to providing care to older adults with cognitive or physical impairments were examined. Health status was examined on a single occasion in 177 persons (aged 63-94 years) referred to programs within a comprehensive set of geriatric care services and the 133 family members involved in their care (ages 31-96 years). The five-scale Caregiver Reaction Assessment (CRA) was administered to the family members. Reliability analyses revealed that the CRA had good internal consistency. Being older was related to experiencing greater health problems in the caregiver role. Greater health problems from providing care were reported by caregivers in worse physical health and also when the care recipient had more physical pain. Caregivers who reported fewer health problems attributed to caregiving reported better mental health and less depressive symptomatology. Caregivers with health problems may be at increased risk of suffering from stress from caregiving.

[Variability in Epstein-Barr virus serological markers in adult kidney transplant recipients]. / Variabilidad en los marcadores serológicos del virus de Epstein-Barr en receptores adultos de trasplante renal.

Epstein-Barr virus (EBV) infection is associated with the development of post-transplant lymphoproliferative disorders (PTLD). However, the clinical relevance and criteria for EBV serological reactivation in EBV-seropositive transplant recipients is unclear. EBV-specific antibodies: viral capsid immunoglobulm G [IgG (VCA)], nuclear antigen (EBNA) IgG, immunoglobulin M [IgM (VCA)] and early antigen IgG (EA) were prospectively analyzed in 71 adult kidney transplant recipients, before starting immunosuppression, when they were uraemic, and after transplantation. A total of 351 serum samples were tested. Relevance of different EBV reactivation-related variables were analyzed using the chi-square test. In 37 of 71 (52.1%) patients IgM (VCA) or IgG (EA) were detected when they were uraemic. EBV reactivation occurred in 25 of 71 (35.2%) patients, with clinical symptoms (fever, leukopenia, kidney function impairment, and increase in transaminases) in nine cases. One of 71 patients developed a PTLD, without detection of serologically EBV reactivation, but with an increase in EBV viral load. Absence of mycophenolate mofetil, that inhibits lymphocyte proliferation and antibody production, in immunosuppression was statistically significantly associated with EBV reactivation (p = 0.015). Serological diagnosis of EBV reactivation should be based on strict criteria (IgM (VCA) seroconversion, four-fold increase in IgM (VCA) or IgG (EA), or four-fold decrease in IgG (EBNA) titers and on analysis of serial samples. Some EBV-seropositive patients at high risk of developing PTLD could benefit from this diagnostic methodology.

Variabilidad en los marcadores serológicos del virus de Epstein-Barr en receptores adultos de trasplante renal / Variability in epstein-barr virus serological markers in adult kidney transplant recipients

La infección por el virus de Epstein-Barr (VEB) se asocia con el desarrollo desíndromes linfoproliferativos post-trasplante (SLPPT). Sin embargo, la relevancia clínicay el criterio para la reactivación serológica del VEB en pacientes seropositivospara el VEB no está clara. Se analizaron prospectivamente los anticuerpos específicosdel VEB: inmunoglubulina IgG frente al antígeno de la cápside viral [IgG(VCA)], IgG frente al antígeno nuclear [IgG (EBNA)], [IgM (VCA)] e IgG frente alantígeno precoz IgG (EA) en un grupo de 71 pacientes adultos trasplantados renales,antes de iniciar el tratamiento inmunosupresor, en uremia y después de efectuadoel trasplante. Se analizaron un total de 351 muestras de suero. Asimismose estudió la relevancia de distintas variables asociadas a la reactivación del VEBmediante el test de la chi-cuadrado.En 37 de 71 (52,1%) pacientes se detectaron anticuerpos IgM (VCA) o IgG(EA) en condiciones de uremia. La reactivación del VEB ocurrió en 25 de 71(35,2%) pacientes, con manifestaciones clínicas (fiebre, leucopenia, insuficienciarenal, e incremento en las transaminasas) en nueve casos. Uno de los 71 pacientesdesarrolló un SLPPT, con incremento en la carga viral pero sin evidencia de reactivacionserológica del VEB. Se encontró una asociación estadísticamente significativaentre la ausencia de micofenolato mofetil, que actúa inhibiendo la proliferaciónde los linfocitos y la producción de anticuerpos, en el protocoloinmunosupresor y la reactivación del VEB (p = 0,015).El diagnóstico serológico de la reactivación del VEB debería basarse en criteriosestrictos: seroconversión de IgM (VCA), incremento de cuatro veces en el títulode IgM (VCA) o IgG (EA), o disminución de cuatro veces en el título de IgG(EBNA) así como en el análisis de muestras seriadas de suero. Algunos pacientesseropositivos frente al VEB con un elevado riesgo de desarrollar SLPPT podrían beneficiarsede este método diagnóstico

Epstein-Barr virus (EBV) infection is associated with the development of posttransplantlymphoproliferative disorders (PTLD). However, the clinical relevanceand criteria for EBV serological reactivation in EBV –seropositive transplant recipientsis unclear. EBV– specific antibodies: viral capsid immunoglobulm G [IgG(VCA)], nuclear antigen (EBNA) IgG, immunoglobulin M [IgM (VCA)] and earlyantigen IgG (EA) were prospectively analyzed in 71 adult kidney transplant recipients,before starting immunosuppression, when they were uraemic, and aftertransplantation. A total of 351 serum samples were tested. Relevance of differentEBV reactivation-related variables were analyzed using the chi-square test.In 37 of 71 (52.1%) patients IgM (VCA) or IgG (EA) were detected when theywere uraemic. EBV reactivation occurred in 25 of 71 (35.2%) patients, with clinicalsymptoms (fever, leukopenia, kidney function impairment, and increase intransaminases) in nine cases. One of 71 patients developed a PTLD, without detectionof serologically EBV reactivation, but with an increase in EBV viral load.Absence of mycophenolate mofetil, that inhibits lymphocyte proliferation and antibodyproduction, in immunosuppression was statistically significantly associatedwith EBV reactivation (p = 0.015).Serological diagnosis of EBV reactivation should be based on strict criteria (IgM(VCA) seroconversion, four-fold increase in IgM (VCA) or IgG (EA), or four-folddecrease in IgG (EBNA) titers and on analysis of serial samples. Some EBV-seropositivepatients at high risk of developing PTLD could benefit from this diagnosticmethodology

[The possible role of acetaldehyde in the brain damage caused by the chronic consumption of alcohol]. / Posible papel del acetaldehído en el daño cerebral derivado del consumo crónico de alcohol.

AIMS: The purpose of this study is to collect and evaluate the experimental evidence suggesting that acetaldehyde, the first oxidative metabolite of ethyl alcohol (ethanol), plays a mediating role in the brain damage associated with the chronic consumption of this substance. DEVELOPMENT: Although the brain damage associated with the chronic consumption of ethanol is multifactorial and, possibly, dependent on the numerous actions of this substance on the central nervous system (CNS), there is data to suggest that the oxidative metabolism of ethanol and resulting substances are involved in the aetiology of such processes. Similarly, the generation of free radicals and the formation of adducts between the products of this metabolism and substrates contained in the CNS could be the main mediators in such pathological processes. This idea is supported by the fact that the adducts derived from the metabolism of ethanol are formed in the same areas of the brain as those which present structural and functional disorders in chronic consumers of alcohol. CONCLUSIONS: There are currently different experimental findings that appear to support the proposal that the substances resulting from the metabolism of ethanol can be important mediators in the brain damage associated with the chronic consumption of alcohol. Although more research is required, this theoretical proposal is very interesting, not just because of its relative novelty, but also because it is based on the same principles put forward to explain the toxic effects of alcohol consumption on organs and tissues.