Biomarcadores séricos y riesgo vascular en la enfermedad de Parkinson esporádica y familiar

La enfermedad de Parkinson (EP) es una enfermedad neurodegenerativa cuya etiopatogenia aún se desconoce en su totalidad. Sin embargo, se conoce que influyen tanto factores ambientales como genéticos. Las formas familiares de EP más frecuentes son aquellas asociadas a variantes patogénicas en los genes que codifican para la proteína glucocerebrosidasa (GBA), para la proteína leucine-rich repeat kinase 2 (LRRK2) y para la proteína parkina (PRKN). Diversos mecanismos fisiopatológicos (como el estrés oxidativo, neuroinflamación o alteración del metabolismo lipídico, entre otros) se han planteado como implicados en la neurodegeneración acaecida en la EP. A su vez, se ha descrito un mayor riesgo de ictus isquémico en general en la población de pacientes EP, sin embargo, se desconoce si este riesgo varía en los diferentes subtipos de EP o si depende de otros factores distintos a los factores de riesgo vascular clásicos. Nuestro objetivo con este trabajo fue analizar si biomarcadores séricos relacionados con el estrés oxidativo como la bilirrubina total diferían entre pacientes con EP y controles sanos; así como analizar si existía un perfil lipídico y un riesgo vascular diferente en las formas familiares y esporádicas de la enfermedad. Se evidenció que los niveles de bilirrubina total sérica diferían entre los pacientes con EP y controles sanos, siendo mayores en los pacientes EP tras ajustar por posibles factores de confusión. Específicamente, eran aquellos pacientes EP con menor severidad clínica (estadios Hoehn & Yahr ≤ 3) los que exhibían mayores niveles de bilirrubina total sérica. Adicionalmente, se encontró una correlación leve negativa entre los niveles de bilirrubina sérica y la duración de la enfermedad. Sin embargo, no se evidenció una relación entre los niveles de bilirrubina sérica y el tipo de terapia dopaminérgica o la dosis equivalente de levodopa diaria de los pacientes. En nuestro trabajo se confirmó por primera vez que el perfil lipídico sérico difería entre las formas esporádicas y las principales formas familiares de EP. Concretamente, los pacientes con EP asociada a mutaciones en GBA (EP-GBA) mostraron un perfil lipídico con unos niveles inferiores, tanto de colesterol total como de lipoproteína de baja densidad, comparados con el resto de los subtipos de EP y los controles sanos. Estas diferencias fueron estadísticamente significativas al compararlas frente a controles sanos y pacientes con EP asociada a mutaciones en LRRK2 (EP-LRRK2), mostrando una tendencia a la significación frente a la EP esporádica. Finalmente, evidenciamos que el riesgo de ictus isquémico era diferente entre las principales formas familiares de EP y la EP esporádica al compararlo frente a controles, sin evidenciarse diferencias en el riesgo de cardiopatía isquémica. Los pacientes con EP-LRRK2 mostraban un incremento significativo del riesgo de ictus isquémico comparado con controles. El incremento de riesgo de ictus isquémico en los pacientes EP-LRRK2 comparado con controles se asoció con una menor edad en el momento del evento cerebrovascular en los análisis de supervivencia. Cuando se consideraron los eventos isquémicos tanto clínicos como radiológicos, tanto el grupo EP-LRRK2 como EP esporádica mostraron un incremento de riesgo de evento frente a controles sanos. Sin embargo, ni los pacientes con EP-GBA ni con EP asociada a mutaciones en PRKN (EPPRKN) mostraron un riesgo cerebrovascular diferente a los controles. Por todo ello, concluimos que las concentraciones de bilirrubina total sérica son mayores en pacientes EP, describiéndose por primera vez que este incremento está relacionado con los años iniciales de la enfermedad. Estos hallazgos en estadios iniciales de la EP pueden traducir la sobre-expresión de enzimas implicadas en el mantenimiento del equilibrio redox en el sistema nervioso y en el metabolismo de la bilirrubina. A su vez, nuestros resultados muestran que los pacientes con EP-GBA presentan un perfil lipídico diferente, y ello apoya la hipótesis de la alteración del metabolismo lipídico como uno de los principales mecanismos patogénicos de estas formas de EP. Finalmente, nuestros hallazgos sugieren que los pacientes con EP-LRRK2 muestran un mayor riesgo de ictus isquémico. Adicionalmente, las formas esporádicas de la EP podrían presentar un mayor riesgo cerebrovascular que los controles; sin evidenciarse en ninguno grupo un mayor riesgo de cardiopatía isquémica. En estos pacientes, otros mecanismos distintos a los factores de riesgo vascular clásicos podrían estar implicados en el mayor riesgo cerebrovascular. Por el contrario, los pacientes con EP-GBA y EPPRKN muestran un riesgo vascular similar a los sujetos control. Son necesarios estudios prospectivos y con cohortes mayores para confirmar estos hallazgos e incorporarlos a nuestra práctica clínica diaria.Parkinson’s disease (PD) is the second most common neurodegenerative disorder, and its pathophysiology still remains unclear. Both environmental as well as genetic factors may play a key role in the neurodegeneration of these patients. The main familial forms of PD are those related to pathogenic variants in the glucocerebrosidase (GBA) gene, the leucine-rich repeat kinase 2 (LRRK2) gene and the parkin (PRKN) gene. Several pathogenic mechanisms (such as oxidative stress, neuroinflammation or altered lipid metabolism, among others) are described as related to the neurodegeneration of PD. Additionally, a higher risk of ischemic stroke has been described in the overall PD population. However, little is known about the specific vascular risk of PD subtypes such as the main monogenic forms of the disease. This work aims to determine whether serum bilirubin levels (a possible oxidative stress biomarker) differ among PD patients and healthy subjects. Also, it aims to explore the specific serum lipid profile and vascular risk among sporadic and familial forms of PD. Bilirubin levels were significantly higher in PD patients than in controls, especially in early to moderate PD stages (Hoehn & Yahr stage ≤ 3). In PD patients, we demonstrated a negative correlation between bilirubin levels and disease duration (p<0.05). However, no relationship between bilirubin and treatment was found, neither in the type of treatment nor in the levodopa equivalent daily dose. In our work, we showed for the first time that familial and sporadic forms of PD might have different serum lipid profiles. Multivariate analyses revealed significant differences among groups within cholesterol and LDL levels. GBA- associated PD patients had significantly lower levels of total cholesterol and LDL compared to LRRK2- associated PD patients and healthy controls; being these differences marginally significant compared with sporadic PD. The prevalence of ischemic stroke differed significantly between sporadic and familial forms of PD and controls, after multivariate analyses. However, no differences were found in coronary artery disease risk among PD groups and controls. LRRK2-associated PD patients showed a significantly increased risk of symptomatic stroke. This increased risk was associated with a younger age at stroke within the LRRK2-associated PD group in the survival analysis. Sporadic PD patients also showed a marginally significant higher risk of cerebrovascular events. Conversely, patients with GBA-PD and PRKN-PD showed a similar vascular risk to controls. For all the above, we conclude that increased bilirubin levels are particularly related to the first years of PD. Overexpression of oxidative enzymes could play an important role in PD etiology, leading to higher bilirubin levels in the early stages of PD. Secondly, the different serum cholesterol levels in GBA-associated PD might be related to diverse pathogenic mechanisms within this specific subtype of PD. Our results support the hypothesis of lipid metabolism disruption as one of the main PD pathogenic mechanisms in patients with GBA-associated PD. Finally, our results suggest that patients with LRRK2-associated PD may show an increased risk of ischemic stroke as well as the sporadic forms of PD. Despite this finding, no differences in cardiovascular events were shown between PD subtypes and controls. Mechanisms other than classical vascular risk factors might be involved in the cerebrovascular disease of those patients. Due to the preliminary nature of our results, prospective and larger studies are needed to confirm these last findings and incorporate them into standard clinical practice

The africanismo castrense: a bibliographical review

RESUMEN: El propósito de este artículo es realizar un estado de la cuestión del africanismo castrense, un grupo militar forjado en el contexto colonial de las Campañas de Marruecos (1909-1927) y decisivo para comprender la historia contemporánea española del siglo xx. Para ello se ha procedido a una revisión sistemática de la bibliografía existente en torno al tema para estudiar su tratamiento a lo largo de los últimos años. De esta forma se pretenden desgranar las diferentes características que se atribuyen a estos militares para observar los puntos débiles de la situación actual de las investigaciones. A la par se propondrán algunas posibles vías de estudio y tratamiento del tema.ABSTRACT: The purpose of this article is to outline a state of the art about africanismo castrense, a Spanish military group forged in the colonial context of Moroccan Campaigns (1909-1927) and decisive for understanding Spanish contemporary history of the 20th century. To that end, a systematic review of existing bibliography has been made to study its treatment along recent years. In this way, the paper seeks to narrow down different characteristics that have been attributed to these soldiers in order to uncover current research weaknesses. At the same time, some possible ways forwards will be proposed

africanismo castrense

The purpose of this article is to outline a state of the art about africanismo castrense, a Spanish military group forged in the colonial context of Moroccan Campaigns (1909-1927) and decisive for understanding Spanish contemporary history of the 20th century. To that end, a systematic review of existing bibliography has been made to study its treatment along recent years. In this way, the paper seeks to narrow down different characteristics that have been attributed to these soldiers in order to uncover current research weaknesses. At the same time, some possible ways forwards will be proposed.El propósito de este artículo es realizar un estado de la cuestión del africanismo castrense, un grupo militar forjado en el contexto colonial de las Campañas de Marruecos (1909-1927) y decisivo para comprender la historia contemporánea española del siglo xx. Para ello se ha procedido a una revisión sistemática de la bibliografía existente en torno al tema para estudiar su tratamiento a lo largo de los últimos años. De esta forma se pretenden desgranar las diferentes características que se atribuyen a estos militares para observar los puntos débiles de la situación actual de las investigaciones. A la par se propondrán algunas posibles vías de estudio y tratamiento del tema

An efficient and accurate linearization approach for hydraulically actuated multibody systems with holonomic and nonholonomic constraints

Hydraulics is often used to actuate mechanisms in the applications of heavy machinery. In this work, a linearization approach for hydraulically driven multibody systems is presented. The approach allows linearizing the equations of motion of general multibody systems with holonomic and nonholonomic constraints, augmented with the hydraulic equations of the hydraulic subsystem. The derivation of this linearization approach is of interest in many applications, such as the performance of linear stability analyses. The procedure is tested with a three-dimensional multibody model of a hydraulically actuated four-bar mechanism. The validation of the approach is performed by means of the forward dynamics simulation of the linear and nonlinear systems. The results show the power of the approach, obtaining the linearized equations of motion around the equilibrium position of the four-bar mechanism multibody model in terms of the mechanical and hydraulic parameters. A comparison of the proposed procedure with a conventional counterpart approach is included, demonstrating the great accuracy and computational efficiency of the approach developed in this work

Women caregivers of dependent relatives and health: Effects of the participation in a stress management workshop

Las tareas de cuidado a dependientes merecen ser objeto de estudio y atención por representar un factor de riesgo para la salud. Por ello analizamos los efectos de ser cuidadora familiar y asistir a un curso de control del estrés, así como la incidencia de dos covariables consideradas relevantes, como son los pensamientos disfuncionales y el tiempo prestando cuidados. Analizamos una muestra de 219 asistentes a talleres psicoeducativos a la que se aplicaron tres instrumentos: cuestionario sociodemográfico, cuestionario de salud general (GHQ28) y pensamientos disfuncionales (CPD). El análisis univariante mostró que ser cuidadora familiar repercute negativamente (p< .001) en todas las escalas del GHQ y que realizar un curso de estrés tiene efectos claramente positivos (p< .05) en la salud general, la somatización y la función social. Asimismo, el análisis de la covarianza mostró que los efectos de ser cuidadora y haber realizado un curso de estrés se mantienen incluso si se consideran los pensamientos disfuncionales y el tiempo cuidando.Dependent care tasks deser ve a special study and attention because of being a health risk factor. That is the reason why we analyzed the effects of working as a family caregiver and of attending a stress management workshop and the impact of two relevant covariables, i.e., dysfunctional thoughts and the time spent providing care. We analyzed a sample of 219 participants attending psychoeducational workshops. Three instruments were applied: A socio-demographic questionnaire, the General Health Questionnaire (GHQ28), and the Dysfunctional Thoughts Questionnaire (CPD). Univariate analysis showed that working as a family caregiver has a negative impact (p< .001) on all GHQ scales and that attending a stress management workshop has a positive effect (p< .05) on general health, somatization and social function. Furthermore, covariance analysis showed that the effects of working as a caregiver and attending a stress management workshop remained significant even when the two covariables (dysfunctional thoughts and time providing care) were considered

Piezoelectric composite cements: Towards the development of self-powered and self-diagnostic materials

Piezoresistivity is the most commonly used sensing principle in cement-based smart composites for strainmonitoring applications. Nonetheless, the need for external electric power to conduct electrical resistivity measurements restricts the scalability of this technology, especially when implemented in remote structures. To address this issue, this manuscript thoroughly analyses the piezoelectric properties of cement composites doped with reduced graphene oxide (rGO) and evaluates their potential as self-powered strain sensors. To do so, a comprehensive methodology involving voltammetry measurements, open circuit potential determination, and uniaxial compression testing is developed to determine the piezoelectric coefficients of charge �33 and voltage �33. Furthermore, a novel circuital model for signal processing of the electromechanical response is developed and experimentally validated in terms of time series of output voltage, resistance, and the generated electric power. The developed methodology is applied to laboratory samples manufactured following two different filler dispersion methods. The presented results evidence that samples prepared by ultrasonic cleaner dispersion achieve optimal properties, with a piezoelectric charge coefficient of 1122.28 ± 246.67 pC/N, about 47 times greater than previously reported composites in the literature. Unlike piezoresistive cement-based composites, a remarkable nonlinear correlation between the fractional change in the intrinsic resistance of the material and the applied mechanical strain has been observed. Instead, a considerable linearity (R 2 = 0.96) between the externally applied mechanical strain and the generated (piezoelectric) electric power has been found, which suggests the great potential of the latter for conducting off-the-grid strain monitoring applications

Effective medium electrical response model of carbon nanotubes cement-based composites

The electrical properties of carbon nanotubes (CNT) cement-based composites have been modeled in previous works by circuit models or homogenization theories. An alternative approach is the use of an effective medium theory with induced polarization: In this work, a new model based on the generalized effective medium theory of induced polarization (GEMTIP) with cylindrical inclusions is proposed. The presented results and discussion show its applicability to interpret the electrical impedance spectra of cylindrical cement samples doped with multi-walled CNTs (MWCNTs). The MWCNTs were dispersed in different media: one nonionic surfactant, two superplasticizers, a cationic type polycarboxylate ether, and an anionic type naphthalene sulfonate. Particle dispersion and their sizes were analyzed by Ultraviolet–Visible (UV–Vis) spectroscopy, and Scanning Electron Microscopy (SEM) measurements. Two electrode electrical impedance spectra were measured and analyzed by circuital models and the proposed GEMTIP model. The results demonstrate the efficiency of the proposed model in describing the Alternating Current (AC) response of cement/CNT composites irrespective of the dispersant agent used to elaborate the samples.CBUAConsejería de Transformación Económica, Conocimiento, Empresas Universidades de la Junta de Andalucía P18-RT-3128MinCiencias 82779Piezoresistividad en Pasta de Cemento con Adición de Nanopartículas de Oro o Materiales CarbonososUniversidad de GranadaInstituto Colombiano de Crédito Educativo y Estudios Técnicos en el Exterio

Actitudes y percepciones sobre la violencia de género del personal docente y administrativo y de servicios de Manta: estudio del Colegio 5 de Junio (2014)

Ecuador presenta unas cifras alarmantes relativas a la violencia de género: seis de cada diez mujeres sostienen haber padecido algún tipo de violencia, según datos oficiales. En ese sentido, la región de Manabí, con un 36,1% de casos, se erige como la provincia ecuatoriana con una menor incidencia de mujeres que han vivido algún tipo de violencia de género. Este bajo índice de denuncias podría estar vinculado a factores contextuales, como el temor a las fuerzas públicas, el temor al agresor, e incluso la escasez de relaciones formales o de vínculos religiosos en las relaciones interpersonales. En este artículo presentamos una encuesta dirigida a los docentes y al personal administrativo y de servicios del Colegio Nacional 5 de Junio, radicado en la ciudad de Manta (Ecuador),un centro paradigmático con más de seis décadas de existencia donde se han dado casos de violencia extrema en las aulas. Los resultados de la encuesta confirman de manera preocupante el turbulento estado del imaginario ecuatoriano sobre la violencia de género. Dada la gravedad de la situación, los autores recomiendan a las autoridades gubernamentales emprender análisis de mayor profundidad sobre el mismo objeto de estudio.Ecuador presents some alarming figures on domestic violence: six out of ten women say they have suffered some form of violence, according to official data. In that sense, the region of Manabí, with 36.1% of cases, stands as the Ecuadorian province with a lower incidence of women who have experienced some form of domestic violence. This under-reporting could be linked to contextual factors, such as fear of public forces, fear the attacker, and even the lack of formal relations or religious ties in interpersonal relationships. In this paper we present a survey of teachers and administrative and service staff of the National College June 5, based in the city of Manta (Ecuador), a paradigm center with over six decades of existence where there have been cases of extreme violence in the classroom. The results of the survey confirm worryingly the turbulent state of the Ecuadorian imagination about gender violence. Given the gravity of the situation, the authors recommend that government authorities undertake further analysis on the same subject matter

Levodopa-Induced Dyskinesia in Parkinson Disease Specifically Associates with Dopaminergic Depletion in Sensorimotor-Related Functional Subregions of the Striatum

[Purpose] To determine whether the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) specifically relates to dopaminergic depletion in sensorimotor-related subregions of the striatum.[Methods] Our primary study sample consisted of 185 locally recruited PD patients, of which 73 (40%) developed LID. Retrospective 123I-FP-CIT SPECT data were used to quantify the specific dopamine transporter (DAT) binding ratio within distinct functionally defined striatal subregions related to limbic, executive, and sensorimotor systems. Regional DAT levels were contrasted between patients who developed LID (PD + LID) and those who did not (PD-LID) using analysis of covariance models controlled for demographic and clinical features. For validation of the findings and assessment of the evolution of LID-associated DAT changes from an early disease stage, we also studied serial 123I-FP-CIT SPECT data from 343 de novo PD patients enrolled in the Parkinson Progression Marker’s Initiative using mixed linear model analysis.[Results] Compared with PD-LID, DAT level reductions in PD + LID patients were most pronounced in the sensorimotor striatal subregion (F = 5.99, P = 0.016) and also significant in the executive-related subregion (F = 5.30, P = 0.023). In the Parkinson Progression Marker’s Initiative cohort, DAT levels in PD + LID (n = 161, 47%) were only significantly reduced compared with PD-LID in the sensorimotor striatal subregion (t = −2.05, P = 0.041), and this difference was already present at baseline and remained largely constant over time.[Conclusion] Measuring DAT depletion in functionally defined sensorimotor-related striatal regions of interest may provide a more sensitive tool to detect LID-associated dopaminergic changes at an early disease stage and could improve individual prognosis of this common clinical complication in PD.Peer reviewe

NR4A2 Mutations Can Cause Intellectual Disability and Language Impairment With Persistent Dystonia-Parkinsonism

TheNR4A2/NURR1gene (MIM*601828) has recently been associated with autosomal-dominantearly-onset dystonia-parkinsonism with intellectual disability.1NR4A2codifies for a nuclear tran-scription factor and is expressed mainly in the substantia nigra, ventral tegmental area, and limbicareas.2To date, 14 different alterations inNR4A2have been described associated with variousclinical phenotypes, mainly with neurodevelopment disorders (table e-1, links.lww.com/NXG/A371). We describe here an interesting case suffering a persistent dystonia-parkinsonism syndrome(DPS) with motor tics, which expands the clinical phenotype ofNR4A2-associated DPS