Teriflunomide-induced Raynaud's phenomenon: a serious adverse event, previously unreported

Teriflunomide, sold under the brand name Aubagio®, is an immunomodulatory drug inhibiting pyrimidine de novo synthesis by blocking the enzyme dihydroorotate dehydrogenase. It has been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of patients with remitting relapsing multiple sclerosis (rrMS) (1). This drug exhibits a favourable safety profile and is well tolerated by most patients (2). Most common adverse events include hair thinning, mild lymphocytopenia and headache (2). We report the first case of teriflunomide-associated Raynau's phenomeno

Análise espacial de acidente vascular cerebralisquêmico na Espanha: os papéis da acessibilidade à saúde e do desenvolvimento econômico

Ischemic Stroke (IS) is a major cause of mortality worldwide; however, few studies have been carried out to measure the impact of the distribution of healthcare services on IS lethality.The aim of this study was to explore the relationship between three IS outcomes (incidence, mortality, and lethality) and accessibility to hospitals in Spain, considering the economic development.A cross sectional ecological study was performed using data capturing all hospital admissions and mortality due to IS during 2016–2018. Gross Geographic Product per capita (GGPpc) was calculated and a healthcare accessibility index was created. A Besag-York-Molliè autoregressive spatial model was used to estimate the magnitude of association between IS outcomes and economic development and healthcare accessibility. GGPpc showed a geographical gradient from southwest to northeast in Spain. Mortality and lethality rates due to IS were higher in the south of the country in both women and men aged 60+ years. In women and men aged 20-59 years a 1,000 € increase in GGPpc was associated with decreases in mortality of 5% and 4%, respectively. Lethality decreased 3-4% with each 1,000 euro increase of GGPpc in both sexes and in the 20-59 and 60+ age groups. Decreased healthcare accessibility was associated with higher lethality in the population aged 60+.Economic development in southwest Spain would not only improve employment opportunities but also reduce mortality due to IS. New health related strategies to improve hospital accessibility should be considered in regions more sparsely populated or with worse transport and/or healthcare infrastructure.El ictus isquémico es una de las principales causas de mortalidad en todo el mundo; sin embargo, pocos estudios han medido el impacto de la distribución de los servicios de salud sobre la letalidad del ictus isquémico. Este estudio exploró la relación entre tres desenlaces del ictus isquémico (incidencia, mortalidad y letalidad) y la accesibilidad a los hospitales en España, teniendo en cuenta el desarrollo económico. Se realizó un estudio ecológico transversal utilizando datos que captan todas las hospitalizaciones y la mortalidad por ictus isquémico durante el período 2016-2018. Se calculó el producto geográfico bruto (PGB) per cápita y se creó un índice de accesibilidad a la salud. Se utilizó un modelo espacial autorregresivo de Besag-YorkMollié para estimar la magnitud de la asociación entre los desenlaces del ictus isquémico y el desarrollo económico y la accesibilidad a la salud. El PGB per cápita mostró un gradiente geográfico de suroeste a noreste en España. Las tasas de mortalidad y letalidad por ictus isquémico fueron mayores en el sur del país, tanto en mujeres como en hombres mayores de 60 años. En mujeres y hombres de 20 a 59 años, un aumento de EUR 1.000 en el PGB per cápita se asoció con una disminución en la mortalidad del 5% y del 4%, respectivamente. La letalidad disminuyó 3-4% por cada EUR 1.000 de aumento del PGB per cápita en ambos sexos y en los rangos de edad de 20-59 y mayores de 60 años. La disminución del acceso a la salud se asoció con una mayor mortalidad en la población mayor de 60 años. El desarrollo económico en el suroeste de España no solo mejoraría las oportunidades de empleo, sino que también reduciría la mortalidad por ictus isquémico. Se deben considerar nuevas estrategias relacionadas con la salud para mejorar la accesibilidad hospitalaria en regiones menos pobladas o con peor infraestructura de transporte o salud.O acidente vascular cerebral isquêmico (AVC) é uma das principais causas de mortalidade no mundo; no entanto, poucos estudos têm mensurado o impacto da distribuição dos serviços de saúde sobre a letalidade do AVC. Este estudo explorou a relação entre três desfechos do AVC (incidência, mortalidade e letalidade) e a acessibilidade à hospitais na Espanha, considerando o desenvolvimento econômico. Um estudo ecológico transversal foi realizado usando dados que capturam todas as internações e mortalidade por AVC durante 2016-2018. Calculou-se o produto geográfico bruto (PGB) per capita e criou-se um índice de acessibilidade à saúde. Um modelo espacial autorregressivo de Besag-York-Mollié foi utilizado para estimar a magnitude da associação entre os desfechos do AVC e o desenvolvimento econômico e a acessibilidade à saúde. O PGB per capita mostrou um gradiente geográfico de sudoeste para nordeste na Espanha. As taxas de mortalidade e letalidade por AVC foram maiores no sul do país, tanto em mulheres quanto em homens com mais de 60 anos. Em mulheres e homens com idades entre 20 e 59 anos, um aumento de EUR 1.000 no PGB per capita foi associado a diminuições na mortalidade de 5% e 4%, respetivamente. A letalidade diminuiu 3-4% a cada aumento de EUR 1.000 no PGB per capita em ambos os gêneros e nas faixas etárias de 20-59 e 60+. A diminuição do acesso à saúde foi associada à maior letalidade na população 60+. O desenvolvimento econômico no sudoeste da Espanha não só melhoraria as oportunidades de emprego, mas também reduziria a mortalidade devido ao AVC. Novas estratégias relacionadas à saúde devem ser consideradas para melhorar a acessibilidade hospitalar em regiões menos povoadas ou com pior infraestrutura de transporte e/ou saúde.Fil: Leveau, Carlos Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Lanus. Departamento de Desarrollo Productivo y Tecnologico. Instituto de Produccion, Economia y Trabajo; ArgentinaFil: Riancho, Javier. Universidad de Cantabria; EspañaFil: Shaman, Jeffrey. Columbia University; Estados UnidosFil: Santurtún, Ana. Universidad de Cantabria; Españ

Clinical and preclinical evidence of somatosensory involvement in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron neurodegenerative disease. Although it has been classically considered as a disease limited to the motor system, there is increasing evidence for the involvement of other neural and non-neuronal systems. In this review, we will discuss currently existing literature regarding the involvement of the sensory system in ALS. Human studies have reported intradermic small fibre loss, sensory axonal predominant neuropathy, as well as somatosensory cortex hyperexcitability. In line with this, ALS animal studies have demonstrated the involvement of several sensory components. Specifically, they have highlighted the impairment of sensory?motor networks as a potential mechanism for the disease. The elucidation of these ?non-motor? systems involvement, which might also be part of the degeneration process, should prompt the scientific community to re-consider ALS as a pure motor neuron disease, which may in turn result in more holistic research approaches

Why do motor neurons degenerate? Actualization in the pathogenesis of amyotrophic lateral sclerosis

Introducción: La esclerosis lateral amiotrófica (ELA) es la enfermedad degenerativa de las motoneuronas más frecuente. Aunque un peque?no porcentaje de los casos de ELA tienen un origen familiar y son secundarios a mutaciones en genes concretos, a la gran mayoría de ellos se les presupone un origen multifactorial, sin que su patogenia haya sido completamente aclarada. No obstante, en los últimos a?nos varios estudios han aumentado el conocimiento sobre la patogenia de la enfermedad, planteando la cuestión de si se trata de una proteinopatía, una ribonucleinopatía, una axonopatía o una enfermedad del microambiente neuronal. Desarrollo: En el presente artículo revisamos los trabajos publicados tanto en pacientes como en modelos animales de ELA y discutimos la implicación de los principales procesos celulares que parecen contribuir a su patogenia (procesamiento génico, metabolismo de proteínas, estrés oxidativo, transporte axonal y relación con el microambiente neuronal). Conclusiones: Aunque la patogenia de la ELA dista de estar aclarada, los estudios recientes apuntan a la idea de que hay unos desencadenantes iniciales que varían de unos sujetos a otros,y unas vías finales de degeneración de las motoneuronas que están implicadas en la mayor parte de los casos de enfermedad.Introduction: Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Although a small proportion of ALS cases are familial in origin and linked to mutations in specific genes, most cases are sporadic and have a multifactorial aetiology. Some recent studies have increased our knowledge of ALS pathogenesis and raised the question of whether this disorder is a proteinopathy, a ribonucleopathy, an axonopathy, or a disease related to the neuronal microenvironment. Development: This article presents a review of ALS pathogenesis. To this end, we have reviewed published articles describing either ALS patients or ALS animal models and we discuss how the main cellular pathways (gene processing, protein metabolism, oxidative stress, axonal transport, relationship with neuronal microenvironment) may be involved in motor neurons degeneration. Conclusions: ALS pathogenesis has not been fully elucidated. Recent studies suggest that although initial triggers may differ among patients, the final motor neurons degeneration mechanisms are similar in most patients once the disease is fully established

A time series analysis of the relationship between apparent temperature, air pollutants and ischemic stroke in Madrid, Spain

The understanding of the role of environment on the pathogenesis of stroke is gaining importance in the context of climate change. This study analyzes the temporal pattern of ischemic stroke (IS) in Madrid, Spain, during a 13-year period (2001-2013), and the relationship between ischemic stroke (admissions and deaths) incidence and environmental factors on a daily scale by using a quasi-Poisson regression model. To assess potential delayed and non-linear effects of air pollutants and Apparent Temperature (AT), a biometeorological index which represents human thermal comfort on IS, a lag non-linear model was fitted in a generalized additive model. The mortality rate followed a downward trend over the studied period, however admission rates progressively increased. Our results show that both increases and decreases in AT had a marked relationship with IS deaths, while hospital admissions were only associated with low AT. When analyzing the cumulative effects (for lag 0-14 days), with an AT of 1.7?°C (percentile 5%) a RR of 1.20 (95% CI, 1.05-1.37) for IS mortality and a RR of 1.09 (95% CI, 0.91-1.29) for morbidity is estimated. Concerning gender differences, men show higher risks of mortality in low temperatures and women in high temperatures. No significant relationship was found between air pollutant concentrations and IS morbi-mortality, but this result must be interpreted with caution, since there are strong spatial fluctuations of the former between nearby geographical areas that make it difficult to perform correlation analyses

Genetic polymorphisms of the wint receptor LRP5 are differentially associated with trochanteric and cervical hip fractures

Producción CientíficaPurpose. Epidemiological studies suggest that cervical and trochanteric hip fractures have different pathogenesis. We planned to test the hypothesis that genetic factors have different influences on both types of fractures. Methods. Ten polymorphisms of genes known to play an important role in skeletal homeostasis (estrogen receptor alpha [ESR1], aromatase [CYP19A1], type I collagen [COL1A1], and lipoprotein receptor-related protein 5 [LRP5]) were analyzed in 471 Spanish patients with fragility hip fractures. Results. Two polymorphisms of the LRP5 gene (rs7116604 and rs3781600) were associated with the type of fracture (p-value 0.0085 and 0.0047, respectively). The presence of rare alleles at each locus was associated with trochanteric fractures over cervical fractures (OR 1.7 in individuals with at least one rare allele at rs7116604 or rs3781600 loci, in comparison with the common homozygotes). Considering individuals bearing the four common alleles as reference, the OR for trochanteric fractures was 1.6 in those with 1 or 2 rare alleles, and 7.5 in those with 3 or 4 rare alleles (p-value for trend 0.0074), which is consistent with an allele-dosage effect. There were no significant differences in the frequency distributions of the ESR1, CYP19A1 and COL1A1 genotypes between trochanteric and cervical fractures in either the original group or in an extended group of 818 patients. Conclusions. These results suggest LRP5 alleles influence the type of hip fractures. They support the view that different genetic factors are involved in cervical and trochanteric fractures, which should be taken into consideration in future genetic association studies

Satellite Glial Cells of the Dorsal Root Ganglion: A New ?Guest/Physiopathological Target? in ALS

Introduction: Amyotrophic lateral sclerosis (ALS) might not only be circumscribed to the motor system but also involves other neuronal systems including sensory abnormalities. In line with this notion, we aimed to assess the pathophysiology of sensory disturbances in the SOD1G93A mouse model of ALS, focusing on the satellite glial cells (SGCs) at the dorsal root ganglion (DRG) as a new potential target of the disease. MaterialandMethods: Thepresenceofsensorydisturbanceswasevaluatedusingvon Frey, hot plate, and hot water tail immersion tests at 75 days old, which represented the motor-pre-symptomatic stage. Cell biology analysis was performed at 75 and 95 days old and included conventional histology, immuno?uorescence, and electron microscopy of sensory neuron-SGC unit dissociates as a well as western blotting from DRG lysates. Results: At 75 days old, von Frey and hot plate tests demonstrated clear thermoalgesic disturbances in ALS transgenic mice. Histological studies of the SN-SGC units revealed abnormal SOD1 accumulation, which was associated with nitro-oxidative stress and biogenesis of lipid droplets in SGCs. Interestingly, these alterations led to a progressive lysosomal storage disorder and occasionally vacuolar degeneration in SGCs. Conclusions: SGCs emerge as a primary pathophysiological target in the SOD1 transgenic murine model of ALS, clearly reinforcing the pathogenic role of glial cells in motor neuron disease. Presymptomatic alterations of SGCs, might not only be responsibleofsensorydisturbancesinALS,butduetospinalcordsensory-motorcircuits could also contribute to anterior horn motor disturbance

Neuroprotective Effect of Bexarotene in the SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive weakness and muscle atrophy related to the loss of upper and lower motor neurons (MNs) without a curative treatment. There is experimental evidence suggesting that retinoids may be involved in ALS pathogenesis. Bexarotene (Bxt) is a retinoid-X receptor agonist used in the treatment of cutaneous lymphoma with a favorable safety profile whose effects have been recently investigated in other neurodegenerative diseases. In this study, we analyze the potential therapeutic effect of Bxt in the SOD1(G93A) mouse model of ALS. Mice were treated with Bxt or vehicle five times per week from day 60 onward. Survival, weight, and neuromuscular function studies together with histological and biochemical analyses were performed. Bxt significantly delayed motor function deterioration, ameliorated the loss of body weight, and extended mice survival up to 30% of the symptomatic period. Histological analyses of the lumbosacral spinal cord revealed that Bxt markedly delayed the early motor-neuron degeneration occurring at presymptomatic stages in ALS-transgenic mice. Bxt treatment contributed to preserve the MN homeostasis in the SOD1(G93A) mice. Particularly, it reduced the neuronal loss and the chromatolytic response, induced nucleolar hypertrophy, decreased the formation of ubiquitylated inclusions, and modulated the lysosomal response. As an agonist of the retinoic-X receptor (RXR) pathway, Bxt notably increased the nuclear expression of the RXRα throughout transcriptionally active euchromatin domains. Bxt also contributed to protect the MN environment by reducing reactive astrogliosis and preserving perisomatic synapsis. Overall, these neuroprotective effects suggest that treatment with Bxt could be useful in ALS, particularly in those cases related to SOD1 mutations