Rhumatologie. Une nouvelle option thérapeutique dans la prise en charge de l'inflammation chronique en rhumatologie: les inhibiteurs des janus kinases [A new therapeutical option for chronic inflammation in rheumatology: janus kinases inhibitors (JAK)].

In the last 15 years, the therapeutical options for the treatment of chronic inflammatory diseases in rheumatology have increased a lot. Nevertheless, some patients do not respond or respond partially to the current therapies--including to the biologics therapy. Tofacitinib (Xeljanz) is now on the Swiss market. It inhibits the JAK pathway. Tofacitinib--as monotherapy or with methotrexate--improves the control of rheumatoid arthritis (RA). In a comparative study, tofacitinib was as effective as adalimumab. Further, tofacitinib reduced structural damages in RA and is considered as an alternative, in case of non-response, to anti-TNF and probably to other biologics therapy. The side effects are upper respiratory tract and opportunist infections and tuberculosis. Blood count, lipids, kidney function, liver tests, CK and blood pressure have to be monitored.

Neuronal autophagy as a mediator of life and death: contrasting roles in chronic neurodegenerative and acute neural disorders.

Autophagy is a cellular mechanism for degrading proteins and organelles. It was first described as a physiological process essential for cellular health and survival, and this is its role in most cells. However, it can also be a mediator of cell death, either by the triggering of apoptosis or by an independent "autophagic" cell death mechanism. This duality is important in the central nervous system, where the activation of autophagy has recently been shown to be protective in certain chronic neurodegenerative diseases but deleterious in acute neural disorders such as stroke and hypoxic/ischemic injury. The authors here discuss these distinct roles of autophagy in the nervous system with a focus on the role of autophagy in mediating neuronal death. The development of new therapeutic strategies based on the manipulation of autophagy will need to take into account these opposing roles of autophagy.

A next step in adeno-associated virus-mediated gene therapy for neurological diseases: regulation and targeting.

Recombinant adeno-associated virus (rAAV) vectors mediating long term transgene expression are excellent gene therapy tools for chronic neurological diseases. While rAAV2 was the first serotype tested in the clinics, more efficient vectors derived from the rh10 serotype are currently being evaluated and other serotypes are likely to be tested in the near future. In addition, aside from the currently used stereotaxy-guided intraparenchymal delivery, new techniques for global brain transduction (by intravenous or intra-cerebrospinal injections) are very promising. Various strategies for therapeutic gene delivery to the central nervous system have been explored in human clinical trials in the past decade. Canavan disease, a genetic disease caused by an enzymatic deficiency, was the first to be approved. Three gene transfer paradigms for Parkinson's disease have been explored: converting L-dopa into dopamine through AADC gene delivery in the putamen; synthesizing GABA through GAD gene delivery in the overactive subthalamic nucleus and providing neurotrophic support through neurturin gene delivery in the nigro-striatal pathway. These pioneer clinical trials demonstrated the safety and tolerability of rAAV delivery in the human brain at moderate doses. Therapeutic effects however, were modest, emphasizing the need for higher doses of the therapeutic transgene product which could be achieved using more efficient vectors or expression cassettes. This will require re-addressing pharmacological aspects, with attention to which cases require either localized and cell-type specific expression or efficient brain-wide transgene expression, and when it is necessary to modulate or terminate the administration of transgene product. The ongoing development of targeted and regulated rAAV vectors is described.

Targeting IL-1β and IL-17A driven inflammation during influenza-induced exacerbations of chronic lung inflammation.

For patients with chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), exacerbations are life-threatening events causing acute respiratory distress that can even lead to hospitalization and death. Although a great deal of effort has been put into research of exacerbations and potential treatment options, the exact underlying mechanisms are yet to be deciphered and no therapy that effectively targets the excessive inflammation is available. In this study, we report that interleukin-1β (IL-1β) and interleukin-17A (IL-17A) are key mediators of neutrophilic inflammation in influenza-induced exacerbations of chronic lung inflammation. Using a mouse model of disease, our data shows a role for IL-1β in mediating lung dysfunction, and in driving neutrophilic inflammation during the whole phase of viral infection. We further report a role for IL-17A as a mediator of IL-1β induced neutrophilia at early time points during influenza-induced exacerbations. Blocking of IL-17A or IL-1 resulted in a significant abrogation of neutrophil recruitment to the airways in the initial phase of infection or at the peak of viral replication, respectively. Therefore, IL-17A and IL-1β are potential targets for therapeutic treatment of viral exacerbations of chronic lung inflammation.

Of flies, mice and men: a systematic approach to understanding the early life origins of chronic lung disease.

Despite intensive research efforts, the aetiology of the majority of chronic lung diseases (CLD) in both, children and adults, remains elusive. Current therapeutic options are limited, providing only symptomatic relief, rather than treating the underlying condition, or preventing its development in the first place. Thus, there is a strong and unmet clinical need for the development of both, novel effective therapies and preventative strategies for CLD. Many studies suggest that modifications of prenatal and/or early postnatal lung development will have important implications for future lung function and risk of CLD throughout life. This view represents a fundamental change of current pathophysiological concepts and treatment paradigms, and holds the potential to develop novel preventative and/or therapeutic strategies. However, for the successful development of such approaches, key questions, such as a clear understanding of underlying mechanisms of impaired lung development, the identification and validation of relevant preclinical models to facilitate translational research, and the development of concepts for correction of aberrant development, all need to be solved. Accordingly, a European Science Foundation Exploratory Workshop was held where clinical, translational and basic research scientists from different disciplines met to discuss potential mechanisms of developmental origins of CLD, and to identify major knowledge gaps in order to delineate a roadmap for future integrative research.

Cardiovascular disease and the changing face of global public health : a focus on low and middle income countries

Eighty percent of the global 17 million deaths due to cardiovascular disease (CVD) occur in low and middle income countries (LMICs). The burden of CVD and other noncommunicable diseases (NCDs) is expected to markedly increase because of the global aging of the population and increasing exposure to detrimental lifestyle-related risk in LMICs. Interventions to reduce four main risks related to modifiable behaviors (tobacco use, unhealthy diet, low physical activity and excess alcohol consumption) are key elements for effective primary prevention of the four main NCDs (CVD, cancer, diabetes and chronic pulmonary disease). These behaviors are best improved through structural interventions (e.g., clean air policy, taxes on cigarettes, new recipes for processed foods with reduced salt and fat, urban shaping to improve mobility, etc.). In addition, health systems in LMICs should be reoriented to deliver integrated cost-effective treatment to persons at high risk at the primary health care level. The full implementation of a small number of highly cost effective, affordable and scalable interventions ("best buys") is likely to be the necessary and sufficient ingredient for curbing NCDs in LMICs. NCDs are both a cause and a consequence of poverty. It is therefore important to frame NCD prevention and control within the broader context of social determinants and development agenda. The recent emphasis on NCDs at a number of health and economic forums (including the September 2011 High Level Meeting on NCDs at the United Nations) provides a new opportunity to move the NCD agenda forward in LMICs.

Disease profiles of detainees in the Canton of Vaud in Switzerland: gender and age differences in substance abuse, mental health and chronic health conditions.

BACKGROUND: Literature on the disease profile of prisoners that differentiates by age and gender remains sparse. This study aimed to describe the health of correctional inmates in terms of substance abuse problems and mental and somatic health conditions, and compare it by gender and age. METHODS: This study examined cross-sectional data from the Canton of Vaud in Switzerland on the health conditions of detainees who were in prison on January 1, 2011 or entered prison in 2011. Health conditions validated by physician examination were reported using the International Classification of Diseases (ICD) version 10. The analyses were descriptive by groups of prisoners: the entire sample (All), Men, Older adults and Women. RESULTS: A total of 1,664 individuals were included in the analysis. Men comprised 91.5 % of the sample and had a mean age of 33 years. The other 8.5 % were women and had an average age of 39. Older adults (i.e., age 50 and older) represented 7 % of the total sample. Overall, 80 % of inmates were non-Swiss citizens, but the proportion of Swiss prisoners was higher among the older adults (51 %) and women (29 %). Overall, 41 % of inmates self-reported substance abuse problems. Of those, 27 % were being treated by psychiatrists for behavioral disorders related to substance abuse. Chronic infectious diseases were found in 9 % of the prison population. In addition, 27 % of detainees suffered from serious mental health conditions. Gender and age had an influence on the disease profile of this sample: compared to the entire prison population, the older inmates were less likely to misuse illegal drugs and to suffer from communicable infections but exhibited more problems with alcohol and a higher burden of chronic health conditions. Female prisoners were more disposed to mental health problems (including drug abuse) and infectious diseases. In terms of chronic diseases, women suffered from the same conditions as men, but the diseases were more prevalent in women. CONCLUSION: It is important to understand the different disease profiles of prisoners by gender and age, as it helps identify the needs of different groups and tailor age-and gender-specific interventions.

Disease profiles of detainees in the Canton of Vaud in Switzerland: gender and age differences in substance abuse, mental health and chronic health conditions.

BACKGROUND: Literature on the disease profile of prisoners that differentiates by age and gender remains sparse. This study aimed to describe the health of correctional inmates in terms of substance abuse problems and mental and somatic health conditions, and compare it by gender and age. METHODS: This study examined cross-sectional data from the Canton of Vaud in Switzerland on the health conditions of detainees who were in prison on January 1, 2011 or entered prison in 2011. Health conditions validated by physician examination were reported using the International Classification of Diseases (ICD) version 10. The analyses were descriptive by groups of prisoners: the entire sample (All), Men, Older adults and Women. RESULTS: A total of 1,664 individuals were included in the analysis. Men comprised 91.5 % of the sample and had a mean age of 33 years. The other 8.5 % were women and had an average age of 39. Older adults (i.e., age 50 and older) represented 7 % of the total sample. Overall, 80 % of inmates were non-Swiss citizens, but the proportion of Swiss prisoners was higher among the older adults (51 %) and women (29 %). Overall, 41 % of inmates self-reported substance abuse problems. Of those, 27 % were being treated by psychiatrists for behavioral disorders related to substance abuse. Chronic infectious diseases were found in 9 % of the prison population. In addition, 27 % of detainees suffered from serious mental health conditions. Gender and age had an influence on the disease profile of this sample: compared to the entire prison population, the older inmates were less likely to misuse illegal drugs and to suffer from communicable infections but exhibited more problems with alcohol and a higher burden of chronic health conditions. Female prisoners were more disposed to mental health problems (including drug abuse) and infectious diseases. In terms of chronic diseases, women suffered from the same conditions as men, but the diseases were more prevalent in women. CONCLUSION: It is important to understand the different disease profiles of prisoners by gender and age, as it helps identify the needs of different groups and tailor age-and gender-specific interventions.

The role of cathepsin K in lung development and newborn chronic lung injury.

Chronic lung diseases, specifically bronchopulmonary dysplasia (BPD), are still causing mortality and morbidity amongst newborn infants. High protease activity has been suggested to have a deleterious role in oxygen-induced lung injuries. Cathepsin K (CatK) is a potent protease found in fetal lungs, degrading collagen and elastin. We hypothesized that CatK may be an important modulator of chronic lung injury in newborn infants and neonatal mice. First we measured CatK protein levels in repeated tracheal aspirate fluid samples from 13 intubated preterm infants during the first two weeks of life. The amount of CatK at 9-13 days was low in infants developing chronic lung disease. Consequently, we studied CatK mRNA expression in oxygen-exposed wild-type (WT) rats at postnatal day (PN) 14 and found decreased pulmonary mRNA expression of CatK in whole lung samples. Thereafter we demonstrated that CatK deficiency modifies lung development by accelerating the thinning of alveolar walls in newborn mice. In hyperoxia-exposed newborn mice CatK deficiency resulted in increased number of pulmonary foam cells, macrophages and amount of reduced glutathione in lung homogenates indicating intensified pulmonary oxidative stress and worse pulmonary outcome due to CatK deficiency. Conversely, transgenic overexpression of CatK caused slight enlargement of distal airspaces with increased alveolar chord length in room air in neonatal mice. While hyperoxic exposure inhibited alveolarization and resulted in enlarged airspaces in wild-type mice, these changes were significantly milder in CatK overexpressing mice at PN7. Finally, we showed that the expression of macrophage scavenger receptor 2 (MSR2) mRNA was down-regulated in oxygen-exposed CatK-deficient mice analyzed by microarray analysis. Our results demonstrate that CatK seems to participate in normal lung development and its expression is altered during pulmonary injury. In the presence of pulmonary risk factors, like high oxygen exposure, low amount of CatK may contribute to aggravated lung injury while sustained or slightly elevated amount of CatK may even protect the newborn lungs from excessive injury. Besides collagen degrading and antifibrotic function of CatK in the lungs, it is obvious that CatK may affect macrophage activity and modify oxidative stress response. In conclusion, pulmonary proteases, specifically CatK, have distinct roles in lung homeostasis and injury development, and although suggested, broad range inhibition of proteases may not be beneficial in newborn lung injury.

Autoimmune diseases in the TH17 era

A new subtype of CD4+ T lymphocytes characterized by the production of interleukin 17, i.e., TH17 cells, has been recently described. This novel T cell subset is distinct from type 1 and type 2 T helper cells. The major feature of this subpopulation is to generate significant amounts of pro-inflammatory cytokines, therefore appearing to be critically involved in protection against infection caused by extracellular microorganisms, and in the pathogenesis of autoimmune diseases and allergy. The dynamic balance among subsets of T cells is important for the modulation of several steps of the immune response. Disturbances in this balance may cause a shift from normal immunologic physiology to the development of immune-mediated disorders. In autoimmune diseases, the fine balance between the proportion and degree of activation of the various T lymphocyte subsets can contribute to persistent undesirable inflammatory responses and tissue replacement by fibrosis. This review highlights the importance of TH17 cells in this process by providing an update on the biology of these cells and focusing on their biology and differentiation processes in the context of immune-mediated chronic inflammatory diseases.

Clinical and genetic markers in disease progression – a study among subjects with obstructive lung diseases

Asthma, COPD, and asthma and COPD overlap syndrome (ACOS) are chronic pulmonary diseases with an obstructive component. In COPD, the obstruction is irreversible and the disease is progressive. The aim of the study was to define and analyze factors that affected disease progression and patients’ well-being, prognosis and mortality in Chronic Airway Disease (CAD) cohort. The main focus was on COPD and ACOS patients. Retrospective data from medical records was combined with genetic and prospective follow-up data. Smoking is the biggest risk factor for COPD and even after the diagnosis of the disease, smoking plays an important role in disease development and patient’s prognosis. Sixty percent of the COPD patients had succeeded in smoking cessation. Patients who had managed to quit smoking had lower mortality rates and less psychiatric diseases and alcohol abuse although they were older and had more cardiovascular diseases than patients who continued smoking. Genetic polymorphism rs1051730 in the nicotinic acethylcholine receptor gene (CHRNA3/5) associated with heavy smoking, cancer prevalence and mortality in two Finnish independent cohorts consisting of COPD patients and male smokers. Challenges in smoking cessation and higher mortality rates may be partly due to individual patient’s genetic composition. Approximately 50% of COPD patients are physically inactive and the proportion was higher among current smokers. Physically active and inactive patients didn’t differ from each other in regard to age, gender or comorbidities. Bronchial obstruction explained inactivity only in severe disease. Subjective sensation of dyspnea, however, had very strong association to inactivity and was also associated to low health related quality of life (HRQoL). ACOS patients had a significantly lower HRQoL than either the patients with asthma or with COPD even though they were younger than COPD patients, had better lung functions and smaller tobacco exposure.

Riesgo asociado a la cirugía cardíaca mayor en pacientes octogenarios : una revisión sistemática de la literatura.

Introducción: La enfermedad cardiovascular es la principal causa de muerte a nivel mundial, afectando principalmente la salud pública de países pobres con economías emergentes. La transición epidemiológica en Colombia ha incrementado la proporción de pacientes ancianos con enfermedad cardiovascular y que requieren cirugía cardíaca. Sin embargo, no existe consenso sobre la conducta para la selección de pacientes añosos para este tipo de intervenciones. El objetivo de este estudio fue definir el riesgo mortalidad asociado a cirugía cardíaca en este grupo de pacientes, basados en una revisión sistemática de la literatura. Materiales y Métodos: Se diseñó una revisión sistemática empleando las plataformas PubMed (Medline), EBSCO Discovery Service, Ovid SP-EBMR, Sciverse y MDConsult. Los términos de búsqueda fueron “Aged”, “Cardiac surgery” and “Mortality”, conjugados de acuerdo con el lenguaje de cada buscador. Las publicaciones fueron seleccionadas por consenso. Los resultados se analizaron en un modelo de Mantel-Haenszel. Resultados: La búsqueda arrojó un total de 8.565 publicaciones. Los datos analizados en el modelo incluyeron 81.547 pacientes (7.855 octogenarios y 73.692 más jóvenes). El riesgo de mortalidad asociado a cirugía cardíaca en octogenarios fue de 125% (OR=2,35, IC 95% [2,15 - 2,57]). Discusión: El sometimiento de pacientes octogenarios a cirugías cardíacas mayores es una decisión que requiere un juicio clínico minucioso en el que es importante destacar que la probabilidad de un resultado francamente desfavorable es alta. Se necesitan más estudios diseñados que permitan aumentar la solidez de la evidencia actual en cuanto al riesgo aquí encontrado.

Clonidina para el Tratamiento del Dolor Oncológico: una Revisión Sistemática de la Literatura

El dolor oncológico representa una de las principales causas de dolor crónico, siendo los opioides la primera línea de manejo, sin embargo 10% de los pacientes requieren estrategias analgésicas multimodales. La eficacia analgésica de la clonidina como coadyuvante ha sido demostrada para diversos modelos de dolor. Sin embargo no hay revisiones sistemáticas que validen su eficacia y seguridad en dolor crónico oncológico. Se realizó una revisión sistemática de la literatura a noviembre 26 de 2012, encontrando 15 trabajos (12 reportes de caso y tres ensayos clínicos controlados), n=138 pacientes. La intervención tuvo una eficacia entre 44,7 y 100%, mostrando mayor beneficio en pacientes con componente de dolor neuropático. La adición de clonidina fue bien tolerada, siendo la sedación y la disminución en tensión arterial y frecuencia cardiaca los efectos secundarios más frecuentes, con relación dosis dependiente, de resolución espontánea y en ninguno de los casos se documentó lesión secundaria en los pacientes. La vía de administración más frecuente fue neuroaxial (intratecal y peridural). La revisión sistemática no fue susceptible de metaanálisis por la heterogeneidad clínica de los estudios. Los resultados obtenidos sugieren que la adición de clonidina puede ser una opción terapeútica eficaz y segura en los pacientes con dolor crónico oncológico severo refractario a opioides a altas dosis asociado o no a infusión neuroaxial de anestésico local, en especial en presencia de componente neuropático. Sin embargo se identificó la necesidad de un mayor número de ensayos clínicos controlados aleatorios que permitan establecer conclusiones definitivas.

Influencia de las creencias religiosas cristianas en la decisión de realizar suicidio asistido al final de la vida

El suicidio asistido como una posible opción al final de la vida, es una idea que hasta ahora está siendo considerada, ya que existen argumentaciones a favor y en contra que han generado controvertidos debates a su alrededor. Algunos de los argumentos en contra están basados en los principios de las instituciones religiosas de orden cristiano, las cuales defienden el valor sagrado de la vida de las personas y la aceptación del sufrimiento como un acto de amor profundo y sumisión a los mandatos de Dios, el creador. Mientras del lado contrario, se encuentran quienes defienden el procedimiento, impulsando la autonomía y la autodeterminación que cada persona tiene sobre su vida. La revisión de la literatura realizada no sólo permite ampliar los argumentos de estas dos posiciones, sino que también permite conocer la historia del suicidio asistido, la posición que este procedimiento tiene en diferentes países del mundo, incluyendo a Colombia, y finalmente se presentan las contribuciones de la psicología entorno al procedimiento en discusión.

Factores de riesgo del comportamiento y readiness de aficionados inscritos a carreras atléticas de fondo de 18-64 años en Bogotá D.C., 2014”

La participación en carreras atléticas de calle ha aumentado; esto requiere detectar riesgos previos al esfuerzo físico. Objetivo. Identificar factores de riesgo del comportamiento y readiness de inscritos a una carrera. Método. Estudio transversal en aficionados de 18-64 años. Encuesta digital con módulos de IPAQ, PARQ+ y STEP. Muestreo aleatorio sistemático con n=510, para una inactividad física esperada de 35% (±5%). Se evaluó nivel de actividad física, consumo de alcohol (peligroso), de fruta, verdura, tabaco y sal, y readiness. Resultados. El cumplimiento de actividad física fue 97,4%; 2,4% consume nivel óptimo de fruta o verdura (diferencias por edad, sexo y estrato), 3,7% fuma y 44,1% consumo peligroso de alcohol. El 19,8% reportó PARQ+ positivo y 5,7% requiere supervisión. Hay diferencias por trabajo y estudio. Discusión. Los aficionados cumplen el nivel de actividad física; pero no de otros factores. Una estrategia de seguridad en el atletismo de calle es evaluar los factores de riesgo relacionados con el estilo de vida así como el readiness.