Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism

Inflammation is a predominant aspect of neurodegenerative diseases, manifested by glia activation and expression of pro-inflammatory mediators. Studies on animal models of Parkinson’s disease (PD) suggest that sustained neuroinflammation exacerbates degeneration of the dopaminergic (DA) nigro-striatal pathway. Therefore, insights into the inflammatory mechanisms of PD may help the development of novel therapeutic strategies against this disease. As extracellular matrix metalloproteinases (MMPs) could be major players in the progression of Parkinsonism, we investigated, in the substantia nigra and striatum of mice acutely injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), changes in mRNA expression, protein levels, and cell localization of MMP-9. This protease is mainly neuronal, but early after MPTP injection its mRNA and protein levels, as well as the number of MMP-9-expressing microglia and astrocytes, increase concomitantly to a prominent inflammation. Neuroinflammation and MMP-9+ glia begin to decline within 2 weeks, although protein levels remain higher than control, in association with a partial recovery of DA nigro-striatal circuit. Comparable quantitative studies on MMP-9 knock-out mice, show a significant decrease in both glia activation and loss of DA neurons and fibers, with respect to wild-type. Moreover, in a parallel study on chronically MPTP-injected macaques, we observed that perpetuation of inflammation and high levels of MMP-9 are associated to DA neuron loss. Our data suggest that MMP-9 released by injured neurons favors glia activation; glial cells in turn reinforce their reactive state via autocrine MMP-9 release, contributing to nigro-striatal pathway degeneration. Specific modulation of MMP-9 activity may, therefore, be a strategy to ameliorate harmful inflammatory outcomes in Parkinsonism

Evidence of oligodendrogliosis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism

Aims: Mice and nonhuman primates administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) represent elective experimental models of Parkinsonism, in which degeneration of the nigrostriatal dopaminergic pathway is associated with prominent neuroinflammation, characterized by activated microglia and astrocytes in both substantia nigra (SN) and striatum. To date, it is unknown whether oligodendrocytes play a role in these events. Methods: We performed a detailed qualitative and quantitative analysis of oligodendrocyte-associated changes induced by acute and chronic MPTP treatment, in the SN and striatum of mice and macaques respectively. Oligodendrocytes were immunolabelled by cell-specific markers and analysed by confocal microscopy. Results: In both experimental models, MPTP treatment induces an increase in oligodendrocyte cell number and average size, as well as in the total area occupied by this cell type per tissue section, accompanied by evident morphological changes. This multifaceted array of changes, herein referred to as oligodendrogliosis, significantly correlates with the reduction in the level of dopaminergic innervation to the striatum. Conclusions: This event, associated with early damage of the dopaminergic neurone axons and of the complex striatal circuits of which they are part, may result in an important, although neglected, aspect in the onset and progression of Parkinsonism

Intervención no farmacológica como estrategia para favorecer el control de la hipertensión arterial y mejorar el cumplimiento antihipertensivo

ResumenObjetivoComprobar la eficacia de una intervención mediante una revista educacional en el cumplimiento antihipertensivo de la hipertensión arterial (HTA) no controlada.DiseñoEstudio clínico controlado, aleatorizado y multicéntrico.EmplazamientoOchenta y siete Centros de Salud de España.ParticipantesSe incluyeron 450 pacientes hipertensos diagnosticados de HTA no controlada.IntervenciónSe formaron 2 grupos con 225 individuos: a) grupo de intervención (GI), los que recibieron una revista educacional domiciliaria bimensual y b) grupo de control (GC), que tuvieron práctica clínica habitual.Mediciones principalesEl cumplimiento se midió mediante monitores electrónicos (MEMS-Aardex). Se calculó el porcentaje de cumplimiento, el porcentaje de cumplidores del total de dosis y de días en los que tomaba una dosis y el NNT (number needed to treat 'número de pacientes que es necesario tratar'). Se definió cumplidor un consumo del 80 al 110%. Se calculó la presión arterial media y los porcentajes de los controlados.ResultadosConcluyeron 393 individuos (edad: 62,4 años [desviación estándar de 11,6 años]), 196 pacientes del GI y 197 pacientes del GC. Ciento ochenta y cuatro eran varones (46,8%).Fueron cumplidores del total de las dosis tomadas el 83,2% en el GI (del 78 al 88,4%) y el 49,2% del GC (IC del 95%: del 42,2 al 56,2%) (p=0,0001) y fueron cumplidores diarios el 74% del GI (IC del 95%: del 67,9 al 80,1%) y el 42,6% del GC (IC del 95%: del 35,7 al 49,5%) (p=0,0001).El control de la HTA fue del 81,6% en el GI (IC del 95%: del 76,2 al 86,5%) y del 56,3% en el GC (IC del 95%: del 49,4 al 63,2%). El NNT con la intervención fue de 3,3 pacientes.ConclusionesEl incumplimiento del tratamiento fue muy alto. La revista educacional es una estrategia eficaz para disminuir el incumplimiento y mejorar el grado de control de la HTA.AbstractObjetiveTo evaluate the efficacy of an intervention by means of an educational magazine on treatment compliance in uncontrolled arterial hypertension (AHT).DesignControlled, randomised clinical trial.Setting87 primary care centres. Spain.ParticipantsA total of 450 patients with uncontrolled hypertension were included.InterventionTwo groups of 225 patients were formed: 1) Control group (CG): standard health intervention; 2) Intervention Group (IG): received a twice monthly educational magazine at home.Main measurementsCompliance was measured using the Medication Event Monitoring System (MEMS-Aardex). Compliance rate (CR) was recorded. Compliers were defined as individuals with a treatment compliance of 80–110%. The percentage of compliers, the mean percentage of doses taken and the percentage of patients taking the medication at the correct times were estimated. The mean blood pressures (BPs) and the percentage of controlled patientswere calculated. The number needed to treat (NNT) was calculated.ResultsA total of 393 individuals were evaluable (Age: 62.4 years), 196 in the IG and 197 in the CG. There were 83.2% (95% CI 78–88.4) and 49.2% (95% CI 42.2–56.2) (P=0.0001) of overall compliers in the IG and CG, respectively and 74% (95% CI: 67.9–80.1) and 42.6% (95% CI=35.7–49.5) (P=0.0001) of correct times compliers. A total of 81.6% (95% CI=76.2–86.5%)) were controlled in the IG and 56.3% (95% CI=49.4–63.2) in the CG. The NNT was 3.3 patients.ConclusionsTherapeutic non-compliance was very high. The educational magazine is an effective strategy to improve the compliance and degree of control of the AHT

Persistent phagocytic characteristics of microglia in the substantia nigra of long-term Parkinsonian macaques

Patients with Parkinson's disease show persistent microglial activation in the areas of the brain where the degeneration of dopaminergic neurons takes place. The reason for maintaining this activated state is still unknown, but it is thought that this persistent microglial activation may contribute to the degeneration of dopaminergic neurons. In this study, we report the microanatomical details of microglia and the relationship between microglia and neurons in the substantia nigra pars compacta of Parkinsonian monkeys years after insult with MPTP. We observed that microglial cells appear polarized toward dopaminergic neurons in MPTP-treated macaques compared to untreated animals and present clear phagocytic characteristics, such as engulfing gliaptic contacts, an increase in Golgi apparatus protein machinery and ball-and-chain phagocytic buds. These results demonstrate that activated microglia maintain phagocytic characteristics years after neurotoxin insult, and phagocytosis may be a key contributor to the neurodegenerative process

ROCK/Cdc42-mediated microglial motility and gliapse formation lead to phagocytosis of degenerating dopaminergic neurons in vivo

The role of microglial motility in the context of adult neurodegeneration is poorly understood. In the present work, we investigated the microanatomical details of microglia-neuron interactions in an experimental mouse model of Parkinson’s disease following the intraperitoneal injection of MPTP. The specific intoxication of dopaminergic neurons induces the cellular polarization of microglia, leading to the formation of body-to-body neuron-glia contacts, called gliapses, which precede neuron elimination. Inhibiting ROCK/Cdc42-mediated microglial motility in vivo blocks the activating features of microglia, such as increased cell size and number of filopodia and diminishes their phagocyting/secreting domains, as the reduction of the Golgi apparatus and the number of microglia-neuron contacts has shown. High-resolution confocal images and three-dimensional rendering demonstrate that microglia engulf entire neurons at one-to-one ratio, and the microglial cell body participates in the formation of the phagocytic cup, engulfing and eliminating neurons in areas of dopaminergic degeneration in adult mammals

An approach to the statistics of wild lagomorph captive rearing for releasing purposes in Spain

P. 49-56Despite the importance of rearing wild lagomorphs in captivity for hunting and predator conservation in Spain, little is known about this production sector. Taking official data into account, in this work the number and distribution of farms in Spain and the possible number of animals produced were analysed during the period 2005-2010. In 2010, 114 wild rabbit farms were widely distributed throughout the country (especially Cataluña, Galicia, Andalucía and Castilla La Mancha regions), while 21 hare farms were registered, the majority in Extremadura, Castilla La Mancha and Andalucía. A possible production figure of 225 000-265 000 rabbits and 1 034 hares was estimated in 2010. Game farms of wild lagomorphs are established in Spain and placement would be related to a high demand for hunting and predator conservation in certain regions. Although more research is needed, the number of animals produced would be an important part of the total animals released to the wild.S

Artículos publicados en el diario El País sobre Antonio Fernández Alba

Artículos publicados sobre Antonio Fernández Alba en el diario El Paí

The European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report 2016 : a summary

Background. This article summarizes the ERA-EDTA Registry's 2016 Annual Report, by describing the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 2016 within 36 countries. Methods. In 2017 and 2018, the ERA-EDTA Registry received data on patients undergoing RRT for ESRD in 2016 from 52 national or regional renal registries. In all, 32 registries provided individual patient data and 20 provided aggregated data. The incidence and prevalence of RRT and the survival probabilities of these patients were determined. Results. In 2016, the incidence of RRT for ESRD was 121 per million population (pmp), ranging from 29 pmp in Ukraine to 251 pmp in Greece. Almost two-thirds of patients were men, over half were aged >= 65 years and almost a quarter had diabetes mellitus as their primary renal diagnosis. Treatment modality at the start of RRT was haemodialysis for 84% of patients. On 31 December 2016, the prevalence of RRT was 823 pmp, ranging from 188 pmp in Ukraine to 1906 pmp in Portugal. In 2016, the transplant rate was 32 pmp, varying from 3 pmp in Ukraine to 94 pmp in the Spanish region of Catalonia. For patients commencing RRT during 2007-11, the 5-year unadjusted patient survival probability on all RRT modalities combined was 50.5%. For 2016, the incidence and prevalence of RRT were higher among men (187 and 1381 pmp) than women (101 and 827 pmp), and men had a higher rate of kidney transplantation (59 pmp) compared with women (33 pmp). For patients starting dialysis and for patients receiving a kidney transplant during 2007-11, the adjusted patient survival probabilities appeared to be higher for women than for men.Peer reviewe

La secuenciación masiva dirigida revela que los pacientes con leucemia linfática crónica y reordenamiento de igh presentan mutaciones en los genes POT1, EGR2, BRAF, IGLL5 Y MGA

Abstract [CO-081] Introducción: La traslocación de la región 14q32, que contiene el gen de la cadena pesada de las inmunoglobulinas (IGH), aparece en el 4-9% de pacientes de leucemia linfática crónica(LLC). Aunque algunos estudios le atribuyen a este subgrupo un pronóstico desfavorable, sus características clínicas y biológicas no se conocen en profundidad. La secuenciación masiva (NGS) ha mejorado notablemente el conocimiento de la heterogeneidad genética y clínica de la LLC, por lo que nos planteamos el análisis del perfil mutacional de estos pacientes para definir mejor su pronóstico. Métodos: Se analizaron 231 pacientes de LLC, de los cuales 42 presentaban traslocación de 14q32. En todos los casos se disponía de datos clínicos y FISH. Se diseñó un panel personalizado de 54 genes, seleccionados por su frecuencia e implicación en la patogenia de la enfermedad. La secuenciación se realizó en la plataforma NextSeq(Illumina). El panel cubre el 97% de las regiones (>100X) con una profundidad de 606 lecturas/base, permitiendo la detección de variantes presentes en >3% de las células..