Parkinsonian motor impairment predicts personality domains related to genetic risk and treatment outcomes in schizophrenia

Identifying endophenotypes of schizophrenia is of critical importance and has profound implications on clinical practice. Here we propose an innovative approach to clarify the mechanims through which temperament and character deviance relates to risk for schizophrenia and predict long-term treatment outcomes. We recruited 61 antipsychotic naïve subjects with chronic schizophrenia, 99 unaffected relatives, and 68 healthy controls from rural communities in the Central Andes. Diagnosis was ascertained with the Schedules of Clinical Assessment in Neuropsychiatry; parkinsonian motor impairment was measured with the Unified Parkinson\u27s Disease Rating Scale; mesencephalic parenchyma was evaluated with transcranial ultrasound; and personality traits were assessed using the Temperament and Character Inventory. Ten-year outcome data was available for ~40% of the index cases. Patients with schizophrenia had higher harm avoidance and self-transcendence (ST), and lower reward dependence (RD), cooperativeness (CO), and self-directedness (SD). Unaffected relatives had higher ST and lower CO and SD. Parkinsonism reliably predicted RD, CO, and SD after correcting for age and sex. The average duration of untreated psychosis (DUP) was over 5 years. Further, SD was anticorrelated with DUP and antipsychotic dosing at follow-up. Baseline DUP was related to antipsychotic dose-years. Further, \u27explosive/borderline\u27, \u27methodical/obsessive\u27, and \u27disorganized/schizotypal\u27 personality profiles were associated with increased risk of schizophrenia. Parkinsonism predicts core personality features and treatment outcomes in schizophrenia. Our study suggests that RD, CO, and SD are endophenotypes of the disease that may, in part, be mediated by dopaminergic function. Further, SD is an important determinant of treatment course and outcome

Parkinsonian motor impairment predicts personality domains related to genetic risk and treatment outcomes in schizophrenia

Identifying endophenotypes of schizophrenia is of critical importance and has profound implications on clinical practice. Here we propose an innovative approach to clarify the mechanims through which temperament and character deviance relates to risk for schizophrenia and predict long-term treatment outcomes. We recruited 61 antipsychotic naïve subjects with chronic schizophrenia, 99 unaffected relatives, and 68 healthy controls from rural communities in the Central Andes. Diagnosis was ascertained with the Schedules of Clinical Assessment in Neuropsychiatry; parkinsonian motor impairment was measured with the Unified Parkinson’s Disease Rating Scale; mesencephalic parenchyma was evaluated with transcranial ultrasound; and personality traits were assessed using the Temperament and Character Inventory. Ten-year outcome data was available for ~40% of the index cases. Patients with schizophrenia had higher harm avoidance and self-transcendence (ST), and lower reward dependence (RD), cooperativeness (CO), and self-directedness (SD). Unaffected relatives had higher ST and lower CO and SD. Parkinsonism reliably predicted RD, CO, and SD after correcting for age and sex. The average duration of untreated psychosis (DUP) was over 5 years. Further, SD was anticorrelated with DUP and antipsychotic dosing at follow-up. Baseline DUP was related to antipsychotic dose-years. Further, ‘explosive/borderline’, ‘methodical/obsessive’, and ‘disorganized/schizotypal’ personality profiles were associated with increased risk of schizophrenia. Parkinsonism predicts core personality features and treatment outcomes in schizophrenia. Our study suggests that RD, CO, and SD are endophenotypes of the disease that may, in part, be mediated by dopaminergic function. Further, SD is an important determinant of treatment course and outcome

A new family of soluble epoxide hydrolase inhibitors: in vivo evaluation in a murine model of chemotherapy-induced neuropathic pain

Trabajo presentado en el 22nd European Symposium on Organic Chemistry, celebrado en Ghent (Bélgica), del 9 al 13 de julio de 2023Thisworkwasfundedbythethe Grant PID2020-118127RB-I00 fundedbyMCIN/AEI/10.13039/501100011033andby“ERDFAwayofmakingEurope”toS.V.,andthe Xunta de Galicia (ED431G2019/02andED431C2018/21).PartialsupportwasprovidedbyNIH-NIEHSRiverAwardR35ES03443,NIH-NIEHSSuperfundProgramP42ES004699,NINDSR01DK107767,andNIDDKR01DK103616toB.D.H

In vivo evaluation of soluble epoxide hydrolase inhibitors in murine models of allodynia, chemotherapy-induced neuropathic pain and visceral pain

Trabajo presentado en el IX EFMC International Symposium on Advances in Synthetic and Medicinal Chemistry, celebrado en Zagreb (Croacia), del 3 al 7 de septiembre de 2023Soluble epoxide hydrolase inhibitors (sEHI) are a new class of non-opioid analgesics, with a representative compound, EC5026, currently in clinical trials for the management of neuropathic pain [1]. Our group has recently designed, synthesized and pharmacologically evaluated novel series of potent benzohomoadamantane-based sEHI [2]. Herein, we report further medicinal chemistry around the abovementioned polycyclic scaffold to improve the potency and, particularly, the DMPK properties of previous hits. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, three candidates were selected for in vivo studies. Two compounds evaluated in a murine model of capsaicin-induced allodynia displayed potent anti-allodynic effect in a dose-dependent manner. Next, the most potent compound was evaluated in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain, presenting robust analgesic efficacy [3]. Finally, considering that chemotherapy-induced neuropathic pain (CINP), a severe side effect of several anticancer agents, is a largely unmet medical need [4], our third candidate was evaluated in a murine model of paclitaxel-induced neuropathic pain. CINP was performed by a daily injection of paclitaxel via i.p. (2 mg/kg), for 5 consecutive days. Mice developed neuropathic mechanical allodynia, which peaked on day 10 after the first paclitaxel administration ¿time when the acute effects of sEHI were tested. Subcutaneous administration of this candidate (2.5-5 mg/kg) completely reversed in a dose dependent manner the sensory hypersensitivity. Additionally, administration of the sEHI (5 mg/kg, s.c.) 30 min before each paclitaxel injection completely prevented the development of neuropathic allodynia. Collectively, these results suggest interstitial cystitis/pain bladder syndrome and CINP as possible new indications for sEHI. Acknowledgements: This work was funded by the Grant PID2020-118127RB-I00 funded by MCIN/AEI/10.13039/501100011033 and by ¿ERDF A way of making Europe¿ to S.V

Synthesis, in Vitro Profiling, and in Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field

Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer's Disease

With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer's disease (AD), which remains inefficiently treated, the advent of multitarget drug discovery has brought a new breath of hope. Here, we disclose a class of 6-chlorotacrine (huprine)‒TPPU hybrids as dual inhibitors of the enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), a multitarget profile to provide cumulative effects against neuroinflammation and memory impairment. Computational studies confirmed the gorge-wide occupancy of both enzymes, from the main site to a secondary site, including a so far non-described AChE cryptic pocket. The lead compound displayed in vitro dual nanomolar potencies, adequate brain permeability, aqueous solubility, and human microsomal stability and lack of neurotoxicity, and rescued memory, synaptic plasticity and neuroinflammation in an AD mouse model, after low dose chronic oral administration

Transformación agraria en los valles templados de Jujuy: la situación de los productores campesinos en finca El Pongo, 1980-2015

Fil: Calvó, María Eugenia. Universidad Nacional de Córdoba. Facultad de Ciencias Sociales. Centro de Estudios Avanzados; ArgentinaEn este libro, analizo la situación de los productores campesinos en los valles templados de Jujuy. Abordo procesos específicos que impactan sobre la producción y población agrícola de la zona: ¿Cuáles son las propuestas que surgen de los productores campesinos de la zona? ¿Cómo viven y producen? ¿Con qué otros sujetos sociales agrarios se encuentran y qué lugar ocupan en la estructura agraria y económica de la región? ¿Cuáles son las características que se expresan en el desarrollo agrario en los valles templados? El período de análisis va desde 1980 a 2015. En los años 80, la estructura agraria de los valles templados que se venía definiendo desde la década del 30 ya estaba consolidada. La ocupación del espacio por el capital mantiene un carácter de baja concentración de los recursos naturales, particularmente la tierra, y la producción está en manos, principalmente, de productores de pequeña y mediana escala. El corte que representa el año 2015 puede parecer arbitrario, pero en ese año se promulgó la Ley Nacional 27118 de “Reparación Histórica de la Agricultura Familiar para la construcción de una nueva ruralidad en la Argentina”, que respondía a la larga demanda por parte de organizaciones campesinas y de agricultores familiares nucleados en diferentes espacios. Esta ley no llegó a aplicarse debido a los cambios en la gestión del gobierno nacional que instaló en la presidencia de la Nación a Mauricio Macri en diciembre de 2015 y a Gerardo Morales como gobernador de la provincia de Jujuy. Los cambios en las políticas de Estado pronto mostraron el nuevo rumbo que asumiría la cuestión agraria en la Argentina: el Ministerio de Agricultura pasó a denominarse Ministerio de Agroindustria, evidenciando la línea de trabajo que fomentaría a partir de allí el Estado. La Secretaría de Agricultura Familiar (SAF), único organismo del Estado que atiende exclusivamente al sector campesino, con un despliegue territorial en todo el país y con técnicos de campo en todas las provincias, sufrió un proceso de desmantelamiento, con despidos masivos de trabajadores y sin financiamiento para la atención del sector.Fil: Calvó, María Eugenia. Universidad Nacional de Córdoba. Facultad de Ciencias Sociales. Centro de Estudios Avanzados; Argentin

Altruism and social integration

We develop a two-stage experimental protocol by which i) we elicit the social network within a group of undergraduate students and ii) we measure their altruistic attitudes by way of a standard Dictator game. We observe that more socially integrated subjects are also more altruistic, as betweenness centrality and reciprocal degree are positively correlated with the level of giving, even after controlling for the effect of social distance, which has been shown to affect giving. Our findings suggest that social distance and network position are complementary determinants of altruistic behavior

Estudio MESGI50: descripción de una cohorte sobre la madurez y el envejecimiento satisfactorio

Objetivo: Describir las principales características demográficas, de salud y socioeconómicas de los participantes en el Estudio sobre la Madurez y el Envejecimiento Satisfactorio en Girona (estudio MESGI50). Métodos: Estudio epidemiológico poblacional vinculado a la Survey of Health, Ageing, and Retirement in Europe (SHARE). La población de referencia fueron los habitantes de la provincia de Girona de 50 y más años de edad. Se utilizó un muestreo probabilístico por conglomerados bietápico estratificado según el número de habitantes y el grado de envejecimiento de la población. Resultados: Se seleccionaron aleatoriamente 28 municipios según su tipo (demográficamente envejecidos o jóvenes) y estratificados según el número de habitantes. La tasa de respuesta fue del 65%, con una media de 1,7 sujetos elegibles por hogar y una muestra final de 2065 hogares y 3331 participantes. El efecto del diseño fue de 1,27. El 52,9% eran mujeres y la media de edad era de 66,9 años (desviación estándar: 11,5). La salud autorreferida, la fuerza de agarre manual, la limitación en las actividades de la vida diaria y la sintomatología depresiva aumentaron con la edad y de forma más acusada en las mujeres. Se observaron diferencias en el consumo de alcohol y en los patrones de alimentación según el ámbito de residencia. Conclusiones: Las características demográficas, de salud y socioeconómicas durante el proceso de envejecimiento son distintas según los grupos de edad, el sexo y el ámbito de residencia