Curing hemoglobinopathies : challenges and advances of conventional and new gene therapy approaches

Inherited hemoglobin disorders, including beta-thalassemia (BT) and sickle-cell disease (SCD), are the most common monogenic diseases worldwide, with a global carrier frequency of over 5%.1 With migration, they are becoming more common worldwide, making their management and care an increasing concern for health care systems. BT is characterized by an imbalance in the \u3b1/\u3b2-globin chain ratio, ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hemopoietic expansion.1 Globally, there are over 25,000 births each year with transfusion-dependent thalassemia (TDT). The currently available treatment for TDT is lifelong transfusions and iron chelation therapy or allogenic bone marrow transplantation as a curative option. SCD affects 300 million people worldwide2 and severely impacts the quality of life of patients who experience unpredictable, recurrent acute and chronic severe pain, stroke, infections, pulmonary disease, kidney disease, retinopathy, and other complications. While survival has been dramatically extended, quality of life is markedly reduced by disease- and treatment-associated morbidity. The development of safe, tissue-specific and efficient vectors, and efficient gene-editing technologies has led to the development of several gene therapy trials for BT and SCD. However, the complexity of the approach presents its hurdles. Fundamental factors at play include the requirement for myeloablation on a patient with benign disease, the age of the patient, and the consequent bone marrow microenvironment. A successful path from proof-of-concept studies to commercialization must render gene therapy a sustainable and accessible approach for a large number of patients. Furthermore, the cost of these therapies is a considerable challenge for the health care system. While new promising therapeutic options are emerging,3,4 and many others are on the pipeline,5 gene therapy can potentially cure patients. We herein provide an overview of the most recent, likely potentially curative therapies for hemoglobinopathies and a summary of the challenges that these approaches entail

Effect of preweanling methylphenidate exposure on the induction, extinction and reinstatement of morphine-Induced conditioned place preference in rats

This study examined the effect of preweanling methyphenidate exposure on later drug reward. We examined the induction, extinction, and reinstatement of morphine induced conditioned place preference (CPP) in rats that received methylphenidate pretreatment during the preweanling period

Three essays on the comovement of financial assets

In this thesis I study the effects of institutional trading on the comovementof financial assets. In the first chapter, joint work with Christopher Polk, we connect stocks through common active mutual fund ownership, and use these connections to forecast cross-sectional variation in return covariance, controlling for similarity in style and other pair characteristics. We argue this covariance is due to contagion based on return decomposition evidence, cross-sectional heterogeneity in the extent of the effect, and the magnitude of average abnormal returns to a cross-stock reversal trading strategy exploiting information in these connections. We show that the typical long/short hedge fund covaries negatively with this strategy suggesting that hedge funds may potentially exacerbate the price dislocation we document. In the second chapter I study the sources of change in the systematic risks of stocks added to the S&P 500 index. Firstly, using vector autoregressions (VARs) and a two-beta decomposition, I find that I cannot reject the hypothesis that all of the well-known change in beta comes from the cash-flow news component of a firm's return. Secondly, I study fundamentals of included firms directly to reduce any concerns that the VAR-based results are sensitive to my particular speciffcation. As ownership structure cannot directly influence fundamentals, these results challenge previous findings, as they are consistent with the change in beta being due to a selection effect. In the third chapter, joint work with Daniel Bergstresser, we explore index-based comovement in the market for Credit Default Swaps (CDS). We exploit the additions of individual CDS contracts in the Markit CDX Index, a major credit derivative benchmark. We find that for single name CDS contracts, comovement increases after inclusion in the index. Comparing movements in the CDS spreads to movements of the bonds of the same issuers, the CDS spread comovement increases significantly more than the bond spread comovement. This pattern of evidence is consistent with the excess comovement in equity markets documented by Barberis et al (2005) and others

Doing More with Less : Innovation Input and Output in Family Firms

International audienceFamily firms are often portrayed as an important yet conservative form of organization that is reluctant to invest in innovation; however, simultaneously, evidence has shown that family firms are flourishing and in fact constitute many of the world’s most innovative firms. Our study contributes to disentangling this puzzling effect. We argue that family firms—owing to the family’s high level of control over the firm, wealth concentration, and importance of nonfinancial goals—invest less in innovation but have an increased conversion rate of innovation input into output and, ultimately, a higher innovation output than nonfamily firms. Empirical evidence from a meta-analysis based on 108 primary studies from 42 countries supports our hypotheses. We further argue and empirically show that the observed effects are even stronger when the CEO of the family firm is a later-generation family member. However, when the CEO of the family firm is the firm’s founder, innovation input is higher and, contrary to our initial expectations, innovation output is lower than that in other firms. We further show that the family firm–innovation input–output relationships depend on country-level factors; namely, the level of minority shareholder protection and the education level of the workforce in the country.<br/

Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective

This Report has a number of inter-related general purposes. One is to explore the extent to which food, nutrition, physical activity, and body composition modify the risk of cancer, and to specify which factors are most important. To the extent that environmental factors such as food, nutrition, and physical activity influence the risk of cancer, it is a preventable disease. The Report specifies recommendations based on solid evidence which, when followed, will be expected to reduce the incidence of cancer

Synchrotron-based characterization of mechanobiological effects on the nanoscale in musculoskeletal tissues

Collagen is the main organic building block of musculoskeletal tissues. Despite collagen being their smallest load bearing unit, these tissues differ significantly in mechanical function and properties. A major factor behind these differences is their hierarchical organization, from the collagen molecule up to the organ scale. It is thus of high importance to understand the characteristics of each level, as well as how they interact and relate to each other. With such knowledge, improved prevention and rehabilitation of musculoskeletal pathologies may be achieved.Both mineralized and soft collagenous tissues respond to their mechanical loading environment according to specific mechanobiological principles. During prenatal development, immobilization can cause dramatic effects on the developing skeleton, causing the newly formed bones to be smaller, deformed and more prone to fracture. But how immobilization affects the deposition, structure and composition of the developing bones is still unclear. In tendons, both insufficient and excessive mechanical loading increases the risk of injury. After rupture, reduced mechanical loading results in altered collagen structure and cell activity, thus influencing the mechanical properties of the healing tendon. How the loading environment affects the structure of intact and ruptured tendons is still debated.The work presented in this thesis aims to thoroughly characterize the mechanobiological effects on the mineralization process in developing bones as well as the collagen structure and multiscale mechanical response of intact and healing tendons. This is achieved through a multimodal approach including a range of high-resolution synchrotron- and lab-based techniques, in combination with mechanical testing.In the first part of the thesis, humeri from “muscle-less” embryonic mice and their healthy littermates at development stages from start of mineralization to shortly before birth were investigated. The multimodal approach revealed a highly localized spatial pattern of Zinc during normal development to sites of ongoing mineralization, accompanied by larger mineral particles. Healthy bones also showed signs of remodeling at later time points. In the absence of skeletal muscle, it was revealed that the developing bones exhibited a delayed but increased mineral deposition and growth, with no signs of remodeling.In the second part of the thesis, intact Achilles tendons from rats subjected to either full in vivo loading through free cage activity or unloading by Botox injections combined with cast immobilization were investigated. It was shown that the nanoscale fibrils in the Achilles tendon respond to the applied tissue loads and exhibit viscoelastic responses. It was revealed that in vivo unloading results in a more disorganized microstructure and an impaired viscoelastic response. Unloading also altered the nanoscale fibril mechanical response, possibly through alterations in the strain partitioning between hierarchical levels.In the third part of the thesis, Achilles tendons were transected and allowed to heal while subjected to either full in vivo loading, reduced loading through Botox injections or unloading. In vivo unloading during the early healing process resulted in a delayed and more disorganized collagen structure and a larger presence of adipose tissue. Unloading also delayed the remodeling of the stumps as well as callus maturation. Additionally, the nanoscale fibril mechanical response was altered, with unloaded tendons exhibiting a low degree of fibril recruitment as well as a decreased ability for fibril extension.The work in this thesis further illustrates the important role of the mechanical environment on the nanostructure of musculoskeletal tissues. It also highlights the power of combining high-resolution tissue characterization techniques into a multimodal and multiscale approach, allowing us to study the effects on several hierarchical length scales simultaneously and as a result be able to elucidate the intricate connection between hierarchical scales

Impacto da reabilitação pulmonar sobre a capacidade funcional avaliada pelo teste de sentar e levantar em adultos com doença pulmonar avançada listados para transplante de pulmão

Introdução: Pacientes candidatos à transplante de pulmão (TxP) apresentam sintomas que limitam as atividades, perda funcional, intolerância ao exercício e redução da qualidade de vida. A reabilitação pulmonar (RP) pode melhorar estes desfechos. O papel do teste de sentar e levantar de 30 segundos (TSL30) na avaliação da resposta à RP não está definido. Objetivos: Avaliar a resposta do TSL em candidatos à TxP submetidos à RP e identificar os fatores associados com esta resposta. Material e Métodos: Estudo retrospectivo, foram coletados dados de pacientes adultos em lista de espera para TxP, que completaram o protocolo de reabilitação de 24 sessões pré TxP, e que realizaram TSL30 e teste da caminhada de 6 minutos (TC6m) antes e após a RP. Dados sobre sintomas, qualidade de vida avaliada pelo Short-Form-36 (SF-36), pressões respiratórias máximas, força do quadríceps e da preensão palmar e exames funcionais pré e pós RP foram recuperados do banco de dados do programa de RP. Resultados: Foram incluídos 29 pacientes, com média de idade de 46±17 anos, 69% do sexo feminino. As doenças de base mais prevalentes foram fibrose pulmonar idiopática (FPI) e doença pulmonar obstrutiva crônica (DPOC). Houve melhora da dispneia, dos sintomas depressivos, do domínio estado geral de saúde do SF-36, das pressões respiratórias máximas e da força muscular periférica (p<0,05) com a RP. A RP induziu aumento de 2,8 repetições no TSL30 (11,1 ± 2,2 repetições vs. 13,9 ± 2,9 repetições, p<0,0001) e de 14 ± 55 m (p=0,189) na distância do TC6m. Melhora clinicamente significativa no TSL30 foi observada em 19 pacientes e no TC6m em 11 pacientes. O número de repetições no TSL30 após a RP se associou com as pressões respiratórias máximas. Conclusões: Houve melhora no TSL30 com a RP e o número de repetições após a intervenção se associou com as pressões respiratórias máximas em pacientes candidatos à TxP. O TSL30 foi mais sensível que o TC6m para identificar os benefícios da RP, sugerindo que o mesmo possa ser usado adicionalmente ao TC6m nos programas de RP. Estudos adicionais são necessários para determinar os fatores associados ao desempenho no TSL30, assim como para identificar o potencial prognóstico do teste.Introduction: Patients who are candidates for lung transplantation (LTx) have symptoms that limit activities, functional loss, exercise intolerance and reduced quality of life. Pulmonary rehabilitation (PR) can improve these outcomes. The role of the sit-to-stand test (STS) in assessing response to PR is not defined. Objectives: To evaluate STS response in TxP candidates undergoing PR and to identify factors associated with this response. Material and Methods: Retrospective study, data were collected from adult patients on the waiting list for LTx, who completed the 24-session rehabilitation protocol pre LTx, and who performed the 30 seconds STS (STS30) and 6-minute walk test (6MWT) before and after PR. Data on symptoms, quality of life assessed by the Short-Form-36 (SF-36), maximal respiratory pressures, quadriceps and handgrip strength, and pre- and post-RP functional exams were retrieved from the PR program database. Results: Twenty nine patients were included, with a mean age of 46±17 years, 69% female. The most prevalent underlying diseases were idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). There was an improvement in dyspnea, depressive symptoms, the general health status domain of the SF-36, maximum respiratory pressures and peripheral muscle strength (p<0.05) with PR. The PR induced an increase of 2.8 repetitions in the STS30 (11.1 ± 2.2 repetitions vs. 13.9 ± 2.9 repetitions, p<0.0001) and of 14 ± 55 m (p=0.189) in the distance of the TC6m. Clinically significant improvement in STS30 was observed in 19 patients and in 6MWT in 11 patients. The number of repetitions in the STS30 after PR was associated with maximum respiratory pressures. Conclusions: There was an improvement in STS30 with PR and the number of repetitions after the intervention was associated with maximum respiratory pressures in candidates for Ltx. The STS30 was more sensitive than the 6MWT to identify the benefits of PR, suggesting that it can be used in addition to the 6MWT in PR programs. Additional studies are needed to determine the factors associated with performance on the STS30, as well as to identify the test's prognostic potential

Chemoprevention of Lung Carcinogenesis: Aerosol Administration and Deposition in the Mouse Lung

INTRODUCTION Chemoprevention is the use of natural or synthetic agents to inhibit either the initial development or the further progression of early lesions. Chemoprevention of lung cancer aims to decrease lung cancer morbidity and mortality, especially for former smokers. Many synthetic and natural compounds have been investigated for their potential chemopreventive efficacy. Conventional administration of these compounds: especially oral administration) is convenient, but may potentially result in adverse side effects. Aerosol delivery, on the other hand, offers many advantages over conventional routes of administration for diseases of the respiratory tract and the lungs. These advantages include the extensive pulmonary surface area available for drug deposition, the avoidance of first-pass metabolic degradation by the liver and/or intestines, the noninvasive nature of administration, and the localized effect of low doses of drugs, all of which lead to a rapid response with fewer systemic side effects. The efficacy of a given drug via aerosol administration depends on many factors such as particle size distribution, total particle mass concentration, and the physiochemical properties of drug particles. Genetically-engineered mice play an important role in drug screening and preclinical studies. However, because mice have much smaller lungs than those of human beings, the lung deposition data attained for humans cannot be applied to the mouse. Hence few studies have focused on particle deposition in the mouse lung. It is thus necessary to measure the mass deposition of particles in the mouse lung. METHOD A spray-drying process was used to study the inhibitory effects of potential chemopreventive agents on carcinogen-induced tumors in the A/J mouse. The carcinogen in the studies was benzo[a]pyrene, unless otherwise specified. Synthetic and natural compounds were investigated individually or in combination. The compounds were aerosolized with a custom-built Collison atomizer. The resultant drug aerosols were delivered to the mice that were retained in a nose-only exposure chamber. Four small molecular inhibitors: gefitinib, erlotinib, lapatinib and wortmannin), and four natural agents: resveratrol, caffeine, anthocyanins, and protocatechuic acid), were considered as examples of single agents. Gefitinib and erlotinib were delivered in an aerosol form to reduce the cutaneous side effects. Lapatinib and wortmannin were each administered both via aerosol and oral gavage to compare the efficacy and toxicity as they were administered via different routes. Resveratrol was evaluated in two models with either vinyl carbamate or benzo[a]pyrene as the carcinogen. It was delivered via aerosol to avoid fast clearance in the blood before it reached the lung. Caffeine was delivered in aerosol to assess only its inhibitory effects and to avoid its negative effects on body weight. Anthocyanins were delivered via aerosol due to their poor bioavailability. Protocatechuic acid is a metabolite of anthocyanins and was also delivered via aerosol for comparison with anthocyanins. The combinations of aerosolized budesonide: a synthetic glucocorticoid) and dietary polyphenon E: a well-defined mixture of green tea extract) was discussed as one example of the combinational treatment. In addition to the bioassays, drug deposition in the mouse lung was evaluated for both polydispersed and monodispersed drug particles for a better understanding of the delivery process and for future applications. Gefitinib was selected as the model agent. Polydispersed gefitinib particles were generated with the Collison atomizer used in the animal studies. Monodispersed particles were generated using the single-capillary electrospray technique. Lung and blood samples were harvested immediately after the aerosol treatment. The lung and plasma levels of gefitinib were measured with varied solution concentrations, exposure durations, and particle sizes. The aerial mass concentration in the chamber was also measured to estimate the doses. RESULTS Aerosolized erlotinib: 5 mg/ml) did not inhibit tumor multiplicity but reduced tumor load by 63.8%: P \u3c 0.05). Aerosolized gefitinib in three separate doses: 5, 10, and 15 mg/ml) inhibited tumor multiplicity by ~30% for all three doses when the tumors were induced by one dose of benzo[a]pyrene: 100 mg/kg body weight), but the results were not statistically significant. Aerosolized gefitinib showed consistent inhibitory effects on tumor load, and the inhibition rate increased as the dose increased. The tumor load was reduced by 39.0%, 46.2%, and 56.4%: P \u3c 0.05) for 5, 10, and 15 mg/ml gefitinib solutions, respectively. The highest dose: 15 mg/ml) of gefitinib was repeated in mice whose tumors were induced by two doses of benzo[a]pyerene: 100 mg/kg body weight, one week apart) and it inhibited both tumor multiplicity: by 49.8%, P \u3c 0.001) and tumor load: by 57.0%, P \u3c 0.001). No visible skin alteration was observed in mice treated with aerosolized gefitinib or erlotinib. Both aerosolized lapatinib: 50 mg/ml) and orally-administered lapatinib: 100 mg/kg body weight) showed inhibitory effects. Aerosolized lapatinib reduced tumor multiplicity by 39.6%: P \u3c 0.05) and tumor load by 41.7%: P \u3c 0.05). Orally-dosed lapatinib reduced tumor multiplicity by 37.6%: not significant) and tumor load by 42.4%: P \u3c 0.05). At the current doses of lapatinib, no adverse side effect was observed in either the aerosol group or the orally-dosed group. Wortmannin showed striking inhibitory effects via aerosol inhalation and per os. Oral wortmannin: 1.0 mg/kg body weight) inhibited tumor multiplicity by 85.5%: P \u3c 0.001) and tumor load by 77.9%: P \u3c 0.05). In the same model, aerosolized wortmannin: 2.0 mg/ml) inhibited tumor multiplicity by 50.8%: P \u3c 0.05) and tumor load by 79.7%: P \u3c 0.05). Despite the efficacy of oral wortmannin, the accompanying systemic adverse effects were not negligible. Reduced body weight and death were observed in the orally-dosed mice, but not in the aerosol treated mice. Thus, aerosolized wortmannin was evaluated a second time in the bioassay with two doses of benzo[a]pyrene, and it was found to reduce tumor multiplicity and tumor load by 66.7%: P \u3c 0.001) and 80.4%: P \u3c 0.0001), respectively, with a slight decrease in body weight. Resveratrol inhibited the proliferation of cells in the human lung cancer cell lines A549 and H1129, which indicates that resveratrol could possibly be an effective inhibitor of human lung cancer. Aerosolized resveratrol was shown to inhibit the tumor load in both vinyl carbamate- and benzo[a]pyrene-induced models. The decrease in tumor load was 26.3%: P \u3c 0.05) and 36.0%: P \u3c 0.01) for 7.5 and 15 mg/ml solutions, respectively, in the vinyl carbamate-induced model. In the benzo[a]pyrene-induced model, aerosolized resveratrol: 15 mg/ml) significantly reduced tumor multiplicity by 37.1%: P \u3c 0.05) and tumor load by 72.0%: P \u3c 0.01). Pharmacokinetic studies showed that more resveratrol was delivered to the lung by aerosol inhalation than by oral gavage. Aerosolized caffeine: 10 mg/ml) inhibited tumor multiplicity by 31.9%: P \u3c 0.05) and tumor load by 44.3%: P \u3c 0.05) without causing a reduction in the body weight gain, in contrast to the orally-administered caffeine, which did cause body weight loss. Aerosolized protocatechuic acid: 12 mg/ml) reduced tumor multiplicity by 47.8%: P \u3c 0.05) and tumor load by 44.9%: P \u3c 0.05). However, the inhibitory effects of anthocyanins: 5 mg/ml, extracted from black raspberries) were marginal: 14.5% on the tumor multiplicity and 30.4% on the tumor load, not significant). The particle deposition in the mouse lung was estimated using gefitinib as the model compound. For the Collison atomizer, the aerosol mass concentration in the exposure chamber increased linearly from 12.3 to 179.8 μg/L as the solution concentration increased from 1 to 50 mg/ml. The lung and plasma levels of gefitinib increased monotonically with increased solution concentration and exposure time, and the concentration in the lung was much higher than that in the plasma. The deposition efficiency is defined as the ratio of the mass deposited in the lung to the dose, and it is a function of particle size. In general, monodispersed particles have a higher delivery efficiency than polydispersed particles. For polydispersed particles, the 2.5 mg/ml solution: with a mass mean aerodynamic diameter, MMAD, at 120 nm) had the highest efficiency. For monodispersed particles, 100 nm particles showed the highest deposition efficiency. CONCLUSIONS Aerosol delivery is a promising approach for the chemoprevention of lung cancer. Many natural and synthetic compounds showed inhibitory effects on benzo[a]pyrene-induced lung tumorigenesis in A/J when they are delivered via aerosol inhalation. In contrast to oral administration, aerosol delivery of the agents mitigated systemic toxicities with comparable inhibitory effects and improved the efficacy of some agents by increasing their bioavailability in the lung. The current aerosol delivery system was characterized and the mass deposition in the mouse lung was positively correlated with both the solution concentration and the exposure time. Aerosols with an MMAD around 100 nm may have the highest delivery efficiency, for both polydispersed and monodispersed distributions

A genre approach to electronic rapid responses from the online British Medical Journal

El contínuo crecimiento de las comunicaciones electrónicas en las ciencias médicas ha creado nuevas esferas de interacción en las que sus participantes evalúan las contribuciones científicas realizadas por otros expertos. El presente estudio se aborda como caso práctico de Análisis de Discurso Comparativo. En la tradición del Análisis del Discurso, y del Análisis de Género, la presente tesis procede inicialmente a caracterizar cuantitativamente, en términos de frecuencia, un corpus de Respuestas Rápidas Electrónicas (e-RRs) en la revista British Medical Journal (thebmj.com) para, a continuación, proceder al estudio de las diferencias en la organización del discurso de dos subgéneros médicos presentes en la revista, Respuestas Rápidas Electrónicas a Editoriales (e-RREs) y Respuestas Rápidas Electrónicas a Artículos de Investigación (e-RRRAs). I. Objetivos de la Tesis Los objetivos de la presente tesis son estudiar la lengua de las respuestas rápidas electrónicas, en el caso de la revista electrónica British Medical Journal ,empleando las aportaciónes realizadas por la Lingüística Aplicada. Particularmente, se pretende observar similitudes y diferencias en los subcorpus de la revista online y describirlos en el marco proporcionado por la Lingüística Cuantitativa y el Análisis de Género. lo cual implica el empleo de la lingüística aplicada cuantitativa para la caracterización de los corpus del BMJ y el enfoque del análisis de género para analizar los subcorpus de e-RREs y e-RRRAs. En el plano cuantitativo, los objetivos de la presente tesis son estimar los siguientes estadísticos en los subcorpus de respuestas electrónicas en thebmj.com: (i) La actividad electrónica elicitada por los artículos del thebmj.com en términos de respuestas electrónicas (ii) El número de respuestas rápidas por género electrónico (iii) El número de palabras por tipo de respuesta electrónica (iv) Longitud de la oración y longitud de la respuesta rápida electrónica (v) Número de oraciones por tipo de respuesta (vi) El abanico de palabras más comunes en los tipos de respuesta electrónica En segundo lugar, la presente investigación se plantea el estudio e identificación de los elementos constitutivos de las respuestas electrónicas a artículos de investigación y editoriales. Por tanto, ofrece una descripción de las respuestas electrónicas basada en el análisis de corpus desde la perspectiva del análisis de género. En tercer lugar, se propone averiguar si hay asociaciónes, y si estas son significativas, entre las variables tipo de respuesta electrónica y propósito de respuesta electrónica; entre las variables tipo de respuesta y estructura en términos de movimientos y entre tipo de respuesta electrónica y abanico de estrategias identificadas en las respuestas rápidas electrónicas. Asímismo se plantea si las diferencias observadas son significativas. II. Metodología La metodología empleada, para obtener nuestros objetivos, hace uso de la presente en la tradición de la lingüística aplicada y el análisis de género. En ella enfatizamos nuestros esfuerzos por conseguir un corpus representativo, amplio y equilibrado. En primer lugar se hacen específicos los criterios para la selección del corpus; en segundo lugar se describen los subcorpus objecto de estudio cuantitativo y cualitativo; en tercer lugar se hace referencia al software empleado en el estudio cuantitativo; seguidamente se hace una descripción de los análisis cuantitativo y cualitativo de las respuestas rápidas en la revista BMJ y finalmente se ofrece el abanico de elementos constitutivos de ambos tipos de respuesta y se estudia la presencia de asociaciones y si las diferencias observadas son significativas mediante un modelo general lineal y Ji cuadrado. III. Resumen, conclusiones y sugerencias para futura investigación La presente tesis tiene por objeto caracterizar una selección de respuestas rápidas electrónicas en thebmj.com como género evaluativo online emergente (Hyland & Diani, 2009) en el ámbito médico. El Capítulo 1 es una presentación del locus de interés de este estudio en el amplio contexto de internet. Primero situa el presente estudio de respuestas electrónicas en la intersección del discurso médico, el discurso electrónico y los desarrollos y recursos electrónicos en medicina (e-health). En segundo lugar, enmarca las respuestas electrónicas en el contexto del movimiento de open access (acceso abierto), iniciativas recientes en la revision online por pares, y la revolucion electrónica en medicina. En tercer lugar describe la revista, su política de revisión y sus debates online postpublicación de artículos y editoriales. En cuarto lugar hace referencia al objeto del presente estudio, las respuestas rápidas electrónicas a editoriales y artículos de investigación. Y, finalmente, hace referencia a los objetivos de la presente investigación, las preguntas planteadas, las hipótesis básicas y el diseño de la investigación. El capítulo 2, titulado Revision de la literatura, proporciona los marcos teóricos para nuestro estudio de las respuestas electrónicas en thebmj.com; particularmente las tradiciones de Comunicación Mediada por Ordenador y el Análisis de Género. Se ha procedido a caracterizar en primer lugar las respuestas electrónicas rápidas como ejemplos de “comunicación mediada por ordenador” (Baron, 2008) e Inglés Electrónico para Medicina (Posteguillo, 2003), de naturaleza asincrónica y de casos de comunicación de uno a varios. Seguidamente han sido situadas en la tradición del “discurso electrónico” (Herring, 1996) debido a que los profesionales médicos emplean la lengua inglesa para comunicarse en el ciberespacio. La rápida expansión de internet ha proporcionado la base para la emergencia de nuevos géneros lingüísticos, y ha probado ser un contexto particularmente interesante en el que estudiar el empleo y desarrollo de los géneros. Hay elevados niveles de experimentación con géneros potenciales (Crowston & Williams, 1997), entre los que podemos situar las respuestas electrónicas del thebmj.com como cartas electrónicas al editor. Las respuestas electrónicas pueden considerarse versiones digitales replicadas de las cartas al editor impresas, aunque el proceso de publicacion de la revista BMJ, primero online, puede sugerir cambios. Biber et al (1998) han servido de marco para nuestro enfoque de lingüística de corpus ya que caracterizan esta última como empírica, haciendo uso de corpus y software y dependiente de técnicas cuantitativas y cualitativas. El capítulo 3, Metodología, comprende la metodología empleada para responder a las preguntas planteadas en el presente estudio y para contrastar sus hipótesis. Dicha metodologia ha empleado los métodos característicos de la lingüística de corpus y el análisis de género, haciendo un esfuerzo por obtener un corpus representativo y equilibrado que posibilitara la fiabilidad y validez de procedimientos y resultados. En primer lugar se ha hecho referencia a los criterios para la selección del corpus: la relevancia de la revista BMJ, la representatividad y la accesibilidad del corpus. Las muestras son amplias (1750 textos para el estudio cuantitativo y 200 para el estudio cuantitativo), y representativas para el enfoque sincrónico que se ha adoptado en el estudio. En segundo lugar, se ha procedido a la descripción de los corpus que son objeto de estudio. En tercer lugar se ha indicado el software empleado en el estudio cuantitativo Wordsmith tools 6 (Scott, 2015). En cuarto lugar, se ofrece la descripción de los análisis cuantitativos y cualitativos de las respuestas electronicas en thebmj.com. En quinto lugar se proporciona el listado de respuestas electronicas por tipos y su análisis cualitativo. Por último, se indican las aportaciones de Swales (1990), Holmes (1997), Paltridge (1994) y Rasmenin (2006) que se han empleado en la realización de este estudio. El capítulo 4, Resultados cuantitativos, ha ofrecido respuesta a las preguntas planteadas en el capítulo 1. Se ha procedido al cálculo del número medio de respuestas electrónicas por editorial y artículo, seguido del número de palabras por tipo de respuesta, la longitud de la oración y la media de oraciones por tipo de respuesta. Seguidamente se muestra el abanico de palabras más frecuentes en los subcorpus de e-RREs y e-RRRAs. Nuestro estudio cuantitativo de las respuestas electrónicas de thebmj.com, muestra que los artículos de investigación reciben un mayor número de respuestas electrónicas que las editoriales. La presencia de respuestas rápidas puede servir al mantenimiento de relaciones personales como norma interaccional en el contexto médico internacional, sin embargo, puede tambien sugerir la presencia de competitividad y controversia en las ciencias médicas. La ausencia de respuestas electrónicas puede indicar la aceptación del contenido publicado, una estrategia de protección de imagen académica, o la preferencia por permanecer offline. En este sentido, la ausencia de respuestas puede contribuir a alcanzar un consenso en los debates medicos internacionales online. En segundo lugar, la longitud media de la oración en nuestro corpus es similar a la que caracteriza la literatura médica impresa. Finalmente, nuestro estudio de las palabras más frecuentes en ambos corpus revela la presencia de conceptos médicos, actividades de investigación, el género objeto de revisión (editoriales y artículos) y un determinado grado de personalización. Lo cual sugiere que las contribuciones electrónicas de los lectores de la revista online thebmj.com, reflejan las prácticas de la comunidad médica online, como indicado por parte de Androutsopoulos (2006). El capítulo 5, Estructura retórica de las respuestas electrónicas a editoriales online del BMJ, desarrolla nuestro análisis cualitativo del corpus de 100 respuestas rápidas a editoriales como ejemplos de comunicación entre expertos; se hace estudio de sus propósitos en el debate online posterior a la publicación de editoriales, y se procede al estudio de su estructura retórica. La identificación de la estructura genérica de las e-RREs en términos de movimientos (moves) parece tener origen en la tradición epistolar, con escasa presencia de los protocolarios apertura y cierre, y obligatorios título y cuerpo de la respuesta electrónica. Su análisis en términos de estrategias muestra que la mayoria de ellas son opcionales, aunque hace necesario un estudio de la posición en la que dichos elementos constituyentes puedan situarse. Conforme a los resultados obtenidos, el título es una estrategia obligatoria, mientras que el Reconocimiento social resulta ser convencional. El presente estudio revela una selección ad-hoc y escasa presencia de las restantes estrategias presentes en e-RREs;Indicación de Acuerdo/desacuerdo, Conocimientos marco, Consideración de evidencia científica, Crítica, Indicación de efectos (positivos y negativos), Palabras de advertencia, Indicación de problemas, Indicación de soluciones, Planteamiento de preguntas, Indicación de respuestas, Práctica clínica, Llamamiento al cambio, Situación, Experiencia propia, Indicación de oposición, Referencia o descripción de casos médicos, Indicacion de áreas faltas de investigación, Clarificación, Recurso a la propia investigación, Implicaciones, Interpretaciones, Extracción de conclusiones y Cierre de cortesía. El capítulo 6, Estructura retórica de las respuestas electrónicas a artículos de investigación online del BMJ, desarrolla nuestro análisis cualitativo del corpus de 100 respuestas rápidas a artículos como ejemplos de comunicación entre expertos; se hace estudio de sus propósitos en el debate online posterior a la publicación de artículos de investigación, y se procede al estudio de su estructura retórica. La identificación de la estructura genérica de las e-RRRAs en términos de movimientos (moves)también parece tener origen en la tradición epistolar, con escasa presencia de los protocolarios apertura y cierre, y obligatorios título y cuerpo de la respuesta electrónica. Su análisis en términos de estrategias muestra, así mismo, que la mayoria de ellas son opcionales, aunque hace necesario un estudio de la posición en la que estos elementos constituyentes pueden situarse. Conforme a los resultados obtenidos, el título es una estrategia obligatoria, mientras que el Reconocimiento social resulta ser convencional. El presente estudio revela una selección ad-hoc y escasa presencia de las restantes estrategias presentes en e-RRRAs;Indicación de Acuerdo/desacuerdo, Conocimientos marco, Consideración de evidencia científica, Crítica, Indicación de efectos (positivos y negativos), Palabras de advertencia, Indicación de problemas, Indicación de soluciones, Planteamiento de preguntas, Indicación de respuestas, Llamamiento al cambio, Reconocimiento de limitaciones, Situación, Indicación de oposición, Experiencia propia, Indicacion de áreas faltas de investigación, Clarificación, Recurso a la propia investigación, Implicaciones, Interpretaciones, Extracción de conclusiones y Cierre de cortesía. Por último, el capítulo 7, denominado Estructuras de las respuestas rápidas electrónicas de thebmj.com aglutina dichos resultados, hace empleo de literatura relevante y ofrece respuestas a nuestras preguntas respecto a la presencia de asociaciones, y diferencias significativas, entre tipo de respuesta y su finalidad en debate online, entre tipo de respuesta y su estructura genérica en términos de movimientos, y entre tipo de respuesta y su estructura en términos de estrategias. En primer lugar, se revela, mediante chi cuadrado, la asociación entre tipo de respuesta rápida y la finalidad inferida. Desde un prisma más detenido se observa una mayor presencia de respuestas electrónicas en oposición a artículos en e-RRRAs y una mayor presencia de respuestas en apoyo de editoriales en e-RREs, y se revela que las diferencias observadas son significativas. En segundo lugar, se revela la no asociación entre tipo de respuesta rápida y estructura genérica de las respuestas rápidas en su estructura inferida de Título – Apertura – Cuerpo – Cierre, por lo que puede concluirse que se trata de una estructura genérica común a ambos tipos de respuesta. En tercer lugar, la identificación de los elementos constituyentes (estrategias) de la estructura retórica de los tipos de respuesta electrónica, ha revelado abanicos similares de estrategias, aunque se han observado algunas diferencias. Su estudio mediante un modelo general lineal y chi cuadrado ha mostrado la interacción/asociación entre el tipo de respuesta y su estructura retórica en términos de estrategias, también se revela que las diferencias observadas son significativas. La crítica parece ser más significativamente más frecuente en respuestas electrónicas a artículos de investigación, mientras que el recurso a los conocimientos marco y los llamamientos al cambio/acción han resultado ser significativamente más frecuentes en las respuestas rápidas a editoriales. La presente tesis proporciona evidencia en apoyo de la idea de que importantes factores contextuales influyen en los subgeneros médicos de online tales como las respuestas electrónicas en el caso de la revista thebmj.com. En conjunción con la materia, la finalidad, la audiencia internacional y el medio del discurso, el contenido de las e-RRs como subgéneros médicos evaluativos parece influído por importantes factores sociales como las normas científicas y el mantenimiento de relaciones sociales. En este sentido, la presente tesis contribuye a la tradición de investigación en variables sociales en el análisis de género y a la investigación en los géneros evaluativos en el ámbito médico.This study is undertaken as a practical instance of Comparative Discourse Analysis. Within Genre-Analysis, a field within the tradition of Discourse Analysis, this thesis first quantitatively characterizes word frequency in a corpus of Electronic Rapid Responses (e-RRs) in the British Medical Journal (thebmj.com). It then examines differences in the organization of discourse in two of the medical subgenres in the journal, Electronic Rapid Responses to Editorials (e-RREs) and Electronic Rapid Responses to Research Articles (e-RRRAs). The corpus for the quantitative study is comprised of 1750e-RRs retrieved in 2006; word frequency, text-type length, sentence number &sentence length are estimated. The corpus for the qualitative study comprises 200 texts, examples of expert-to-expert communication, 100 e-RREs and 100 e-RRRAs. The methodology employed in this study makes use of the contributions made by Swales (1990), Holmes (1997), Paltridge (1994) y Rasmenin (2006), in their approaches to corpus linguistics and genre analysis and Wordsmith tools 6 (Scott, 2015). Generalised linear models and Chi square tests are used to test the presence of associations between factors e-RR type and purpose, e-RR type and their structure, and to test whether the differences observed are significant. The cross-genre study yields subtle differences in terms of sentence length & text type length and qualitative differences in the most frequent words in the subcorpora. The analysis in the qualitative study shows a common generic structure for e-RREs and e-RRRAs, stemming from epistolary genres in the medical field with similar ranges of strategies, but significantly different at a strategy level. This thesis provides evidence to support the view that major contextual factors influence online medical subgenres such as thebmj.com e-RRs. Along with subject matter, purpose, an allegedly worldwide audience and medium of discourse, the content of e-RR s as review subgenres seems to be influenced by major social factors such as scientific norms, conversational maxims and an online context. In this sense, this thesis is a contribution to research in the field of social factors in genre analysis and in that of review genres in medicine