Análisis de la evolución de consultas atendidas en los servicios deurgencias españoles durante la primera ola pandémica / Analysis of the evolution of patients attended in Spanish emergency departments during the first wave of the pandemic

Fundamento: Describir el número de consultas, total y porCOVID-19, atendidas en servicios de urgencias hospitalarios(SUH) españoles durante marzo y abril de 2020, compararlocon el mismo periodo del año anterior, cuantificar el cambiode actividad asistencial e investigar la posible influencia deltamaño del hospital y de la seroprevalencia provincial deCOVID-19. Métodos: Estudio transversal. Se envió una encuesta a todoslos responsables de SUH españoles del sistema público de salud sobre el número de consultas atendidas durante marzo yabril de 2019 y de 2020. Se calculó el cambio de actividad asistencial por comunidad autónoma, y se comparó en función deltamaño del hospital y del impacto provincial de la pandemia.Resultados: Participaron el 66 % de los 283 SUH. Se observó undescenso del 49,2 % de las consultas totales (solo los SUH deCastilla-La Mancha mostraron un descenso inferior al 30 %) ydel 60 % de las consultas no-COVID-19 (solo los SUH de Asturias y Extremadura mostraron un descenso inferior al 50 %). elcambio de actividad asistencial no difirió en función del tamaño del hospital, pero sí en relación al impacto provincial de lapandemia, con una correlación directa respecto al descensode actividad no-COVID-19 (a mayor impacto, mayor descenso;R2 = 0,05; p = 0,002) e inversa en relación a la actividad global (amayor impacto, menor descenso; R2 = 0,05; p = 0,002).Conclusiones: Durante la primera ola pandémica descendió elnúmero de consultas en los SUH, si bien dicho descenso nose explica únicamente por la incidencia local de la pandemia.(AU)

Background: To describe the number of visits (total and perCOVID-19) attended by the Spanish hospital emergency departments (EDs) during March and April 2020 compared to thesame period in 2019, and to calculate the quantitative changesin healthcare activity and investigate the possible influence ofhospital size and regional COVID-19 seroprevalence. Method: Cross-sectional study that analyzes the number ofvisits to Spanish public EDs, reported through a survey ofED chiefs during the study periods. Changes in healthcareactivity were described in each autonomous community andcompared according to hospital size and the regional impactof the pandemic. Results: The 66% of the 283 Spanish EDs participated in thestudy. The total number of patients attended decreased to49.2 % (< 30 % in the Castilla-La Mancha region), with a 60 %reduction in non-COVID-19 patients (reduction < 50 % only inthe regions of Asturias and Extremadura). While there wereno differences in changes of healthcare activity according tothe size of the hospital, there were differences in relation tothe regional impact of the pandemic, with a direct correlationrelated to the decrease in non-COVID-19 activity (the greaterthe impact, the greater the decrease; R2 = 0.05; p = 0.002) andan inverse correlation to the overall activity (the greater theimpact, the lesser the decrease; R2 = 0.05; p = 0.002). Conclusion: There was a very significant decrease in the numberof ED visits during the first pandemic wave, although this decreasecannot be explained solely by the local incidence of the pandemic.(AU)

[Analysis of the evolution of patients attended in Spanish emergency departments during the first wave of the pandemic].

BACKGROUND: To describe the number of visits (total and per COVID-19) attended by the Spanish hospital emergency departments (EDs) during the first wave of the pandemic (March-April 2020) compared to the same period in 2019, and to calculate the quantitative changes in healthcare activity and investigate the possible influence of hospital size and COVID-19 seroprevalence. METHOD: Cross-sectional study that analyzes the number of visits to Spanish public EDs, reported through a survey of ED chiefs during the study periods. Changes in healthcare activity were described in each autonomous community and com-pared according to hospital size and the provincial impact of the pandemic. RESULTS: A total of 187 (66?%) of the 283 Spanish EDs participated in the study. The total number of patients attended de-creased to 49.2?% (

Comparación de las características demográficas y comorbilidad de los pacientes con COVID-19 fallecidos en hospitales españoles, en función de si ingresaron o no en Cuidados Intensivos / Comparison of the demographic characteristics and comorbidities of patients with COVID-19 who died in Spanish hospitals based on whether they were or were not admitted to an intensive care unit

OBJETIVO: Describir las características demográficas y de comorbilidad de los pacientes con COVID-19 fallecidos en hospitales españoles durante el brote pandémico de 2020 y compararlas según si ingresaron o no en una Unidad de Cuidados Intensivos (UCI) antes del fallecimiento. MÉTODOS: Análisis secundario de los pacientes de la cohorte SIESTA (formada por pacientes COVID de 62 hospitales españoles) fallecidos durante la hospitalización. Se recogieron sus características demográficas y comorbilidades, individuales y globalmente, estimadas mediante el índice de comorbilidad de Charlson (ICC). Se identificaron los factores independientes relacionados con ingreso en UCI, y se realizaron diversos análisis de sensibilidad para contrastar la consistencia de los hallazgos del análisis principal. RESULTADOS: Se incluyeron los 338 pacientes de la cohorte SIESTA fallecidos; de ellos, 77 (22,8%) accedieron a una UCI previamente al fallecimiento. En el análisis multivariable, tres de las 20 características basales analizadas se asociaron independientemente con ingreso en UCI de los pacientes fallecidos: demencia (no hubo pacientes fallecidos con demencia que ingresasen en UCI; OR = 0, IC 95% = no calculable), cáncer activo (OR = 0,07, IC 95% = 0,02-0,21) y edad (< 70 años: OR = 1, referencia; 70-74 años: OR = 0,21, IC 95% = 0,08-0,54; 75-79 años: OR = 0,21, IC 95% = 0,08-0,54; ≥ 80 años: OR = 0,02, IC 95% = 0,01-0,05). La probabilidad de ingreso en UCI de los pacientes que fallecieron disminuyó significativamente al aumentar el ICC, incluso tras ajustarla por edad (ICC 0 puntos: OR = 1, referencia; ICC 1 punto: OR = 0,36, IC 95% = 0,16-0,83; ICC 2 puntos: OR = 0,36, IC 95% = 0,16-0,83; ICC > 2 puntos: OR = 0,09, IC 95% = 0,04-0,23). Los análisis de sensibilidad no mostraron diferencias destacables respecto al análisis principal. CONCLUSIONES: El perfil de los pacientes COVID fallecidos sin ingresar en UCI se ajustó a lo observado en la práctica médica habitual antes de la pandemia, y las características basales que limitaron su ingreso fueron la edad y la carga de comorbilidad global, especialmente la demencia y el cáncer activo

OBJECTIVE: To describe and compare the demographic characteristics and comorbidities of patients with COVID-19 who died in Spanish hospitals during the 2020 pandemic based on whether they were or were not admitted to an intensive care unit (ICU) prior to death. METHODS: We performed a secondary analysis of COVID-19 patients who died during hospitalization included by 62 Spanish emergency departments in the SIESTA cohort. We collected the demographic characteristics and comorbidities, determined both individually and estimated globally by the Charlson index (ChI). Independent factors related to ICU admission were identified and different analyses of sensitivity were performed to contrast the consistency of the findings of the principal analysis. RESULTS: We included the 338 patients from the SIESTA cohort that died during hospitalization. Of these, 77 (22.8%) were admitted to an ICU before dying. After multivariate adjustment, 3 out of the 20 basal characteristics analyzed in the present study were independently associated with ICU admission: dementia (no patients with dementia who died were admitted to the ICU: OR = 0, 95%CI = not calculable), active cancer (OR = 0.07; 95%CI = 0.02-0.21) and age (< 70 years: OR = 1, reference; 70-74 years: OR = 0.21; 95%CI = 0.08-0.54; 75-79 years: OR = 0.21; 95%CI = 0.08-0.54; ≥ 80 years: OR = 0.02; 95%CI = 0.01-0.05). The probability of ICU admission significantly increased in parallel to the ChI, even after adjustment for age (ChI 0 points: OR = 0, reference; ChI 1 point: OR = 0.36; 95%CI = 0.16-0.83; ChI 2 points: OR = 0.36; 95%CI = 0.16-0.83; ChI >2 points: OR = 0.09; 95%CI = 0.04-0.23). The sensitivity analyses showed no gross differences compared to the principal analysis. CONCLUSIONS: The profile of COVID-19 patients who died without ICU admission is similar to that observed in the usual medical practice before the pandemic. The basal characteristics limiting their admission were age and global burden due to comorbidity, especially dementia and active cancer

[Comparison of the demographic characteristics and comorbidities of patients with COVID-19 who died in Spanish hospitals based on whether they were or were not admitted to an intensive care unit]. / Comparación de las características demográficas y comorbilidad de los pacientes con COVID-19 fallecidos en hospitales españoles, en función de si ingresaron o no en Cuidados Intensivos.

OBJECTIVE: To describe and compare the demographic characteristics and comorbidities of patients with COVID-19 who died in Spanish hospitals during the 2020 pandemic based on whether they were or were not admitted to an intensive care unit (ICU) prior to death. METHODS: We performed a secondary analysis of COVID-19 patients who died during hospitalization included by 62 Spanish emergency departments in the SIESTA cohort. We collected the demographic characteristics and comorbidities, determined both individually and estimated globally by the Charlson index (ChI). Independent factors related to ICU admission were identified and different analyses of sensitivity were performed to contrast the consistency of the findings of the principal analysis. RESULTS: We included the 338 patients from the SIESTA cohort that died during hospitalization. Of these, 77 (22.8%) were admitted to an ICU before dying. After multivariate adjustment, 3 out of the 20 basal characteristics analyzed in the present study were independently associated with ICU admission: dementia (no patients with dementia who died were admitted to the ICU: OR = 0, 95%CI = not calculable), active cancer (OR = 0.07; 95%CI = 0.02-0.21) and age (< 70 years: OR = 1, reference; 70-74 years: OR = 0.21; 95%CI = 0.08-0.54; 75-79 years: OR = 0.21; 95%CI = 0.08-0.54; ≥ 80 years: OR = 0.02; 95%CI = 0.01-0.05). The probability of ICU admission significantly increased in parallel to the ChI, even after adjustment for age (ChI 0 points: OR = 0, reference; ChI 1 point: OR = 0.36; 95%CI = 0.16-0.83; ChI 2 points: OR = 0.36; 95%CI = 0.16-0.83; ChI >2 points: OR = 0.09; 95%CI = 0.04-0.23). The sensitivity analyses showed no gross differences compared to the principal analysis. CONCLUSIONS: The profile of COVID-19 patients who died without ICU admission is similar to that observed in the usual medical practice before the pandemic. The basal characteristics limiting their admission were age and global burden due to comorbidity, especially dementia and active cancer.

[Comparison of different strategies for short-term death prediction in the infected older patient]. / Comparación de distintas estrategias para la predicción de muerte a corto plazo en el paciente anciano infectado.

OBJECTIVE: The aim of this study was to determine the utility of a post hoc lactate added to SIRS and qSOFA score to predict 30-day mortality in older non-severely dependent patients attended for infection in the Emergency Department (ED). METHODS: We performed an analytical, observational, prospective cohort study including patients of 75 years of age or older, without severe functional dependence, attended for an infectious disease in 69 Spanish ED for 2-day three seasonal periods. Demographic, clinical and analytical data were collected. The primary outcome was 30-day mortality after the index event.The antimicrobial susceptibility data and extended-spectrum beta-lactamase (ESBL) production in isolates recovered from intra-abdominal (IAI) (n=1,429) and urinary tract (UTI) (n=937) infections during the 2016- 2017 SMART study in 10 Spanish hospitals were analysed. RESULTS: We included 739 patients with a mean age of 84.9 (SD 6.0) years; 375 (50.7%) were women. Ninety-one (12.3%) died within 30 days. The AUC was 0.637 (IC 95% 0.587-0.688; p<0.001) for SIRS ≥ 2 and 0.698 (IC 95% 0.635-0.761; p<0.001) for qSOFA ≥ 2. Comparing receiver operating characteristic (ROC) there was a better accuracy of qSOFA vs SIRS (p=0.041). Both scales improve the prognosis accuracy with lactate inclusion. The AUC was 0.705 (IC95% 0.652-0.758; p<0.001) for SIRS plus lactate and 0.755 (IC95% 0.696-0.814; p<0.001) for qSOFA plus lactate, showing a trend to statistical significance for the second strategy (p=0.0727). Charlson index not added prognosis accuracy to SIRS (p=0.2269) or qSOFA (p=0.2573). CONCLUSIONS: Lactate added to SIRS and qSOFA score improve the accuracy of SIRS and qSOFA to predict short-term mortality in older non-severely dependent patients attended for infection. There is not effect in adding Charlson index.

Prognostic accuracy of SIRS criteria, qSOFA score and GYM score for 30-day-mortality in older non-severely dependent infected patients attended in the emergency department.

The aim of this study was to determine the accuracy of systemic inflammatory response syndrome (SIRS), quick Sepsis-related Organ Failure Assessment (qSOFA) score and GYM score to predict 30-day mortality in older non-severely dependent patients attended for an episode of infection in the emergency department (ED). We performed an analytical, observational, prospective cohort study including patients 75 years of age or older, without severe functional dependence, attended for an infectious process in 69 Spanish EDs for 2-day three-seasonal periods. Demographic, clinical and analytical data were collected. The primary outcome was 30-day mortality after the index event. We included 1071 patients, with a mean age of 83.6 [standard deviation (SD) 5.6] years; 544 (50.8%) were men. Seventy-two patients (6.5%) died within 30 days. SIRS criteria ≥ 2 had a sensitivity of 65% [95% confidence interval (CI) 53.1-75.9] and a specificity of 49% (95% CI 46.0-52.3), a qSOFA score ≥ 2 had a sensitivity of 28% (95% CI 18.2-39.8) and a specificity of 94% (95% CI 91.9-95.1), and a GYM score ≥ 1 had a sensitivity of 81% (95% CI 69.2-88.6) and a specificity of 45% (95% CI 41.6-47.9). A GYM score ≥ 1 and a qSOFA score ≥ 2 were the cut-offs with the highest sensitivity (p < 0.001) and specificity (p < 0.001), respectively. The area under the curve (AUC) was 0.73 (95% CI 0.66-0.79; p < 0.001) for the GYM score, 0.69 (95% CI 0.61-0.76; p < 0.001) for the qSOFA score and 0.65 (95% CI 0.59-0.72; p < 0.001) for SIRS. A GYM score ≥ 1 may be the most sensitive score and a qSOFA score ≥ 2 the most specific score to predict 30-day mortality in non-severely dependent older patients attended for acute infection in EDs.

Documento de consenso y recomendaciones sobre el uso de los péptidos natriuréticos en la práctica clínica / Consensus document and recommendations on the use of natriuretic peptides in clinical practice

Los péptidos natriuréticos son una herramienta de laboratorio útil en el diagnóstico, pronóstico y tratamiento de los pacientes con insuficiencia cardiaca. Su uso involucra a diferentes ámbitos sanitarios (consultas, urgencias, hospitalización, laboratorio) y a muy diferentes profesionales de la Atención Primaria o especializada. Sin embargo, su incorporación a la práctica asistencial aún es escasa y desigual. Para un correcto uso e interpretación en la práctica clínica se necesita un mínimo de conocimientos preanalíticos (fisiopatología), analíticos (métodos) y postanalíticos (interpretación e integración con los datos clínicos). Este documento de consenso elaborado por varias sociedades científicas tiene como objetivo actualizar los conceptos y conocimientos necesarios sobre los péptidos natriuréticos que permitan su aplicación para el diagnóstico, pronóstico y tratamiento de la insuficiencia cardiaca, en los diferentes ámbitos sanitarios (AU)

Natriuretic peptides are a useful laboratory tool for the diagnosis, prognosis and treatment of patients with heart failure. Natriuretic peptides are used in various healthcare settings (consultations, emergency department, hospitalization, laboratory) and by various primary care and specialised professionals. However, their use in clinical practice is still scare and uneven. Properly using and interpreting natriuretic peptides in clinical practice requires a minimum of prelaboratory (pathophysiology), laboratory (methods) and postlaboratory (interpretation and integration of clinical data) expertise. The objective of this consensus document, developed by several scientific societies, is to update the necessary concepts and expertise on natriuretic peptides that enable its application in the diagnosis, prognosis and treatment of heart failure, in various healthcare environments (AU)

Consensus document and recommendations on the use of natriuretic peptides in clinical practice. / Documento de consenso y recomendaciones sobre el uso de los péptidos natriuréticos en la práctica clínica.

Natriuretic peptides are a useful laboratory tool for the diagnosis, prognosis and treatment of patients with heart failure. Natriuretic peptides are used in various healthcare settings (consultations, emergency department, hospitalization, laboratory) and by various primary care and specialised professionals. However, their use in clinical practice is still scare and uneven. Properly using and interpreting natriuretic peptides in clinical practice requires a minimum of prelaboratory (pathophysiology), laboratory (methods) and postlaboratory (interpretation and integration of clinical data) expertise. The objective of this consensus document, developed by several scientific societies, is to update the necessary concepts and expertise on natriuretic peptides that enable its application in the diagnosis, prognosis and treatment of heart failure, in various healthcare environments.

Guía práctica para el manejo de la hemorragia digestiva alta no varicosa / Clinical practice guidelines for managing nonvariceal upper gastrointestinal bleeding

La hemorragia digestiva alta no varicosa (HDANV) es una emergencia médica frecuente que se asocia a una considerable morbilidad y mortalidad. En los últimos años se han producido importantes avances en el manejo de la HDANV, que han permitido disminuirla recidiva hemorrágica y la mortalidad en estos pacientes. El objetivo del presente documento es ofrecer una guía de manejo de la HDANV eminentemente práctica basada en la evidencia científica y en las recomendaciones de los recientes consensos. Lostres puntos clave del manejo de la HDANV son: a) la reanimación hemodinámica precozy la prevención de las complicaciones de la patología cardiovascular de base, quees frecuente en pacientes con HDANV; b) el tratamiento endoscópico de las lesiones con alto riesgo de recidiva; y c) el uso de inhibidores de la bomba de protones a dosis altas pre y postendoscopia. La combinación de estas medidas permite reducir la recidiva y la mortalidad de la HDANV (AU)

Nonvariceal upper gastrointestinal (GI) bleeding is a common medical emergency associated with appreciable morbidity and mortality. The significant advances made in managing this condition in recent years have reduced the rates of rebleeding and mortality. These clinical guidelines for managing this emergency are intended to be highly practical, evidence-based, and take recent consensus statements into account. The 3 keys to managing nonvariceal upper GIbleeding are a) early restoration of fluids and blood pressure and the prevention of underlying cardiovascular disease, which is common in these patients; b) endoscopy to treat lesions at high risk of rebleeding; and c) medical therapy with high doses of proton pump inhibitors before and after endoscopy. These 3 measures, used in combination, reduce upperGI rebleeding and mortality rates (AU)

Expression and cell localization of brain-derived neurotrophic factor and TrkB during zebrafish retinal development.

Brain-derived neurotrophic factor (BDNF) signaling through TrkB regulates different aspects of neuronal development, including survival, axonal and dendritic growth, and synapse formation. Despite recent advances in our understanding of the functional significance of BDNF and TrkB in the retina, the cell types in the retina that express BDNF and TrkB, and the variations in their levels of expression during development, remain poorly defined. The goal of the present study is to determine the age-dependent changes in the levels of expression and localization of BDNF and TrkB in the zebrafish retina. Zebrafish retinas from 10 days post-fertilization (dpf) to 180 dpf were used to perform PCR, Western blot and immunohistochemistry. Both BDNF and TrkB mRNAs, and BDNF and full-length TrkB proteins were detected at all ages sampled. The localization of these proteins in the retina was very similar at all time points studied. BDNF immunoreactivity was found in the outer nuclear layer, the outer plexiform layer and the inner plexiform layer, whereas TrkB immunoreactivity was observed in the inner plexiform layer and, to a lesser extent, in the ganglion cell layer. These results demonstrate that the pattern of expression of BDNF and TrkB in the retina of zebrafish remains unchanged during postembryonic development and adult life. Because TrkB expression in retina did not change with age, cells expressing TrkB may potentially be able to respond during the entire lifespan of zebrafish to BDNF either exogenously administered or endogenously produced, acting through paracrine mechanisms.

Differential localization of Acid-sensing ion channels 1 and 2 in human cutaneus pacinian corpuscles.

Acid-sensing ion channels (ASICs) are the members of the degenerin/epithelial sodium channel (Deg/ENaC) superfamily which mediate different sensory modalities including mechanosensation. ASICs have been detected in mechanosensory neurons as well as in peripheral mechanoreceptors. We now investigated the distribution of ASIC1, ASIC2, and ASIC3 proteins in human cutaneous Pacinian corpuscles using immunohistochemistry and laser confocal-scanner microscopy. We detected different patterns of expression of these proteins within Pacinian corpuscles. ASIC1 was detected in the central axon co-expressed with RT-97 protein, ASIC2 was expressed by the lamellar cells of the inner core co-localized with S100 protein, and ASIC3 was absent. These results demonstrate for the first time the differential distribution of ASIC1 and ASIC2 in human rapidly adapting low-threshold mechanoreceptors, and suggest specific roles of both proteins in mechanotransduction.

The lamellar cells in human Meissner corpuscles express TrkB.

Cutaneous Meissner corpuscles depend for development and survival exclusively on the NT system TrkB/BDNF/NT-4 unlike other types of sensory corpuscles and nerve endings, which have very complex neuronal and growth factor dependence. However, the pattern of expression of TrkB in human Meissner corpuscles is not known. The experiments in these studies were designed to pursue further findings that suggest that BDNF and NT-4 have critical roles in the development and maintenance of Meissner corpuscles by analyzing the pattern of expression of TrkB, their high-affinity receptor, in human glabrous skin. These experiments showed that TrkB is expressed in different patterns by the lamellar cells of Meissner corpuscles and not by the axon. The studies also show that while the percentage of Meissner corpuscles that express TrkB remains constant from birth till 50-year old cases, it decreases approximately 3-fold in subjects older than 50 years. These results are important since the study of Meissner corpuscles from cutaneous biopsies to diagnose some neurological diseases has rapidly become of high interest and therefore the proteins expressed in these corpuscles are potential diagnostic tools.

The expression of ENa(+)C and ASIC2 proteins in Pacinian corpuscles is differently regulated by TrkB and its ligands BDNF and NT-4.

Pacinian corpuscles are innervated by large myelinated Aalpha-beta axons from the large- and intermediate-sized sensory neurons of dorsal root ganglia. These neurons express different members of the degenerin/epithelial Na(+) channel (DEG/ENa(+)C) superfamily of proteins with putative mechanosensory properties, whose expression is regulated by the TrkB-BDNF system. Thus, we hypothesized that BDNF and/or NT-4 signalling through activation of TrkB may regulate the expression of molecules supposed to be necessary for the mechanosensory function of Pacinian corpuscles. To test this hypothesis we analyzed the expression and distribution of ENa(+)C subunits and acid-sensing ion channel 2 (ASIC2) in Pacinian corpuscles from 25 days old mice deficient in TrkB, BDNF and NT-4. Pacinian corpuscles in these animals are normal in number, structure, and expression of several immunohistochemical markers. Using immunohistochemistry we observed that the beta-ENa(+)C and gamma-ENa(+)C subunits, but not the alpha-ENa(+)C subunit, were expressed in wild-type animals, and they were always found in the central axon. ASIC2 immunoreactivity was found in both the central axon and the inner core cells. The absence of TrkB or BDNF abolished expression of beta-ENa(+)C and ASIC2, whereas expression of gamma-ENa(+)C did not change. Expression of beta-ENa(+)C and gamma-ENa(+)C subunits in NT-4 deficient mice was found in the axons but also in the inner core cells whereas levels of expression of ASIC2 were increased in these animals. This study suggests that expression in Pacianian corpuscles of some potential mechanosensory proteins is regulated by BDNF, NT-4 and TrkB.

TrkB is necessary for the normal development of the lung.

Normal development of the lung requires coordinated activation of cascades of signaling pathways initiated by growth factors signaling through their receptors. TrkB and its ligands, brain-derived neurotrophic factor (BDNF) and neurotrophin-4, belong to the neurotrophin family of growth factors, which are expressed in a large variety of non-neuronal tissues including the lung. Aberrant neurotrophin signaling underlies the pathogenesis of several lung-related pathologies, including asthma and lung cancer, however, little is known about the role of neurotrophins in the embryonic development of the lung. To fill this gap in knowledge, we analyzed the pattern of TrkB expression in the murine lung and we observed that TrkB is expressed in alveolar macrophages, type II pneumocytes, neuroepithelial bodies and nerves. Analysis of the structure of lung from mice deficient in TrkB revealed that absence of TrkB signaling results in thinner bronchial epithelium and apparent larger air space, and, more importantly, lack of neuroepithelial bodies, an important reduction in the density of nerve fibres in the bronchial smooth muscle, submucous plexus in bronchioles, and pulmonary artery walls. These findings suggest TrkB is essential for the normal development of the lung and the nervous system in the lung.

Enteric glial cells express full-length TrkB and depend on TrkB expression for normal development.

The embryonic development of the enteric nervous system (ENS) from neural crest precursor cells requires neurotrophic signaling. Neurotrophins (NTs) are a family of growth factors that bind Trk receptors to signal diverse functions, including development and maintenance of different cell populations in the peripheral nervous system. In this study we investigated the expression and cell localization of TrkB, the high affinity receptor for brain-derived neurotrophic factor and NT-4, in the murine ENS using Western blot and immunohistochemistry. The results demonstrate that enteric glial cells within the ENS express full-length TrkB at all stages tested. The ENS of TrkB deficient mice have reduced expression of glial cell markers, and a disarrangement of glial cells and the plexular neuropil. These results strongly suggest TrkB has essential roles in the normal development and maintenance of glial cells in the ENS.

Characterization of sensory deficits in TrkB knockout mice.

The sensory deficit in TrkB deficient mice was evaluated by counting the neuronal loss in lumbar dorsal root ganglia (DRG), the absence of sensory receptors (cutaneous--associated to the hairy and glabrous skin - muscular and articular), and the percentage and size of the neurocalcin-positive DRG neurons (a calcium-binding protein which labels proprioceptive and mechanoceptive neurons). Mice lacking TrkB lost 32% of neurons, corresponding to the intermediate-sized and neurocalcin-positive ones. This neuronal lost was accomplished by the absence of Meissner corpuscles, and reduction of hair follicle-associated sensory nerve endings and Merkel cells. The mutation was without effect on Pacinian corpuscles, Golgi's organs and muscle spindles. Present results further characterize the sensory deficit of the TrkB-/- mice demonstrating that the intermediate-sized neurons in lumbar DRG, as well as the cutaneous rapidly and slowly adapting sensory receptors connected to them, are under the control of TrkB for survival and differentiation. This study might serve as a baseline for future studies in experimentally induced neuropathies affecting TrkB positive DRG neurons and their peripheral targets, and to use TrkB ligands in the treatment of neuropathies in which cutaneous mechanoreceptors are primarily involved.

The Trk tyrosine kinase inhibitor K252a regulates growth of lung adenocarcinomas.

The neurotrophin family of growth factors and their receptors support the survival of several neuronal and non-neuronal cell populations during embryonic development and adult life. Neurotrophins are also involved in malignant transformation. To seek the role of neurotrophin signaling in human lung cancer we studied the expression of neurotrophin receptors in human lung adenocarcinomas and investigated the effect of the neurotrophin receptor inhibitor K252a in A549 cell survival and colony formation ability in soft agar. We showed that human lung adenocarcinomas express TrkA and TrkB, but not TrkC; A549 cells, derived from a human lung adenocarcinoma, express mRNA transcripts encoding nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), TrkA, TrkB, and p75, and high protein levels of TrkA and TrkB. Stimulation of cells using NGF or BDNF activates the anti-apoptotic protein Akt. Interestingly, inhibition of neurotrophin receptor signaling using K252a prevents Akt activation in response to NGF or BDNF, induces apoptotic cell death, and diminishes the ability of A549 cells to growth in soft agar. The data suggest that neurotrophin signaling inhibition using k252a may be a valid therapy to treat patients with lung adenocarcinomas.

Pleiotrophin disrupts calcium-dependent homophilic cell-cell adhesion and initiates an epithelial-mesenchymal transition.

Regulation of the levels of tyrosine phosphorylation is essential to maintain the functions of proteins in different signaling pathways and other cellular systems, but how the steady-state levels of tyrosine phosphorylation are coordinated in different cellular systems to initiate complex cellular functions remains a formidable challenge. The receptor protein tyrosine phosphatase (RPTP)beta/zeta is a transmembrane tyrosine phosphatase whose substrates include proteins important in intracellular and transmembrane protein-signaling pathways, cytoskeletal structure, cell-cell adhesion, endocytosis, and chromatin remodeling. Pleiotrophin (PTN the protein and Ptn the gene) is a ligand for RPTPbeta/zeta; PTN inactivates RPTPbeta/zeta, leaving unchecked the continued endogenous activity of tyrosine kinases that increase phosphorylation of the substrates of RPTPbeta/zeta at sites dephosphorylated by RPTPbeta/zeta in cells not stimulated by PTN. Thus, through the regulation of the tyrosine phosphatase activity of RPTPbeta/zeta, the PTN/RPTPbeta/zeta signaling pathway coordinately regulates the levels of tyrosine phosphorylation of proteins in many cellular systems. We now demonstrate that PTN disrupts cytoskeletal protein complexes, ablates calcium-dependent homophilic cell-cell adhesion, stimulates ubiquitination and degradation of N-cadherin, reorganizes the actin cytoskeleton, and induces a morphological epithelial-mesenchymal transition (EMT) in PTN-stimulated U373 cells. The data suggest that increased tyrosine phosphorylation of the different substrates of RPTPbeta/zeta in PTN-stimulated cells alone is sufficient to coordinately stimulate the different functions needed for an EMT; it is possible that PTN initiates an EMT in cells at sites where PTN is expressed in development and in malignant cells that inappropriately express Ptn.

Thymocyte depletion affects neurotrophin receptor expression in thymic stromal cells.

Thymocytes and thymic stromal cells cross-talk in a bidirectional manner within the thymus, thus contributing to the generation of mature T-cells. The thymic stromal cells in the rat express the high- (TrkA, TrkB) and low-affinity (p75NTR) receptors for neurotrophins. In this study we analysed the regulation of TrkA, TrkB and p75NTR expression in the rat thymus by thymocytes. We induced thymocyte apoptosis by administration of corticoids in rats, and then analysed the expression and distribution of these receptors 1, 4 and 10 days later. Thymocyte death was assessed by the activation of caspase-3 in cells undergoing apoptosis. We observed massive thymocyte apoptosis 1 day after injection and, to a lesser extent, after 4 days, which was parallel with a reduction in the density of thymic epithelial cells normally expressing TrkA and p75NTR. Furthermore, TrkA expression was found in cortical thymic epithelial cells, which normally lack this receptor. The expression of TrkB was restricted to a subset of macrophage-dendritic cells, and remained unchanged with treatment. The normal pattern of neurotrophin receptor expression was almost completely restored by day 10. The results demonstrate that the expression of neurotrophin receptors by thymic epithelial cells, but not by macrophage-dendritic cells, is regulated by thymocytes.

APP processing and the APP-KPI domain involvement in the amyloid cascade.

Alternative APP mRNA splicing can generate isoforms of APP containing a Kunitz protease inhibitor (KPI) domain. KPI is one of the main serine protease inhibitors. Protein and mRNA KPI(+)APP levels are elevated in Alzheimer's disease (AD) brain and are associated with increased amyloid beta deposition. In the last years increasing evidence on multiple points in the amyloid cascade where KPI(+)APP is involved has been accumulated, admitting an outstanding position in the pathogenesis of AD to the KPI domain. This review focuses on the APP processing, the molecular activity of KPI and its physiological and pathological roles and the KPI involvement in the amyloid cascade through the nerve growth factor, the lipoprotein receptor-related protein, the tumor necrosis factor-alpha converting enzyme and the Notch1 protein.