Scn1a haploinsufficiency in the prefrontal cortex engages to cognitive impairment and depressive phenotype.

Altered development and function of the prefrontal cortex (PFC) during adolescence is implicated in the origin of mental disorders. Deficits in the GABAergic system prominently contribute to these alterations. Nav1.1 is a voltage-gated Na+ channel critical for normal GABAergic activity. Here, we studied the role of Nav1.1 in PFC function and its potential relationship with the aetiology of mental disorders. Dysfunction of Nav1.1 activity in the medial PFC (mPFC) of adolescent mice enhanced the local excitation/inhibition ratio, resulting in epileptic activity, cognitive deficits and depressive-like behaviour in adulthood, along with a gene expression profile linked to major depressive disorder (MDD). Additionally, it reduced extracellular serotonin concentration in the dorsal raphe nucleus and brain-derived neurotrophic factor expression in the hippocampus, two MDD-related brain areas beyond the PFC. We also observed alterations in oscillatory activity and impaired hippocampal-mPFC coherence during sleep. Finally, we found reduced expression levels of SCN1A, the gene encoding Nav1.1, in post-mortem PFC samples from human MDD subjects. Collectively, our results provide a novel mechanistic framework linking adolescence-specific alterations in Nav1.1 function in the PFC to the pathogenesis of epilepsy and comorbidities such as cognitive impairment and depressive disorders.

Estudio transversal multicéntrico sobre la prevalencia de delirium en unidades de ortogeriatría: protocolo de «Estudio DELFRA 24» / Multicenter cross-sectional study on the prevalence of delirium in orthogeriatric units: «DELFRA 24 study» protocol

Introducción El delirium es la complicación perioperatoria más frecuente en el adulto mayor con fractura de cadera (FC) conllevando un impacto catastrófico en su recuperación funcional y su estado cognitivo. Actualmente se desconoce la prevalencia real de este síndrome ya que no está protocolizada su detección y abordaje en la práctica clínica habitual. Métodos Se realizará un estudio observacional multicéntrico de tipo transversal a nivel nacional en el que participarán distintas unidades de ortogeriatría de España. Se evaluará la prevalencia de delirium con la escala 4AT, así como las características de este y su relación con otros síndromes geriátricos, variables sociodemográficas, características de la cirugía y parámetros analíticos. Resultados La recogida de datos se llevará a cabo el próximo día mundial del delirium (miércoles 13 de marzo de 2024), por lo que los resultados se esperan durante el segundo o tercer trimestre del año 2024. Conclusiones Conocer la prevalencia real y las características del delirium en mayores con FC podría contribuir a sensibilizar en la detección sistemática, la prevención y el abordaje protocolizado del delirium en servicios quirúrgicos, disminuyendo el impacto de sus consecuencias. (AU)

Introduction Delirium is the most common perioperative complication in older adults with hip fracture (HF), leading to a catastrophic impact on their functional recovery and cognitive status. Currently, the true prevalence of this syndrome is unknown as its detection and management are not standardized in clinical practice. Methods A multicenter observational cross-sectional study will be conducted nationwide, involving different orthogeriatric units in Spain. The prevalence of delirium will be assessed using the 4AT scale, along with its characteristics and its relationship with other geriatric syndromes, sociodemographic variables, surgical characteristics, and laboratory parameters. Results Data collection is scheduled to take place on World Delirium Day (Wednesday, March 13, 2024), and therefore, the results are expected during the second or third quarter of 2024. Conclusions Understanding the real prevalence and characteristics of delirium in older adults with HF could contribute to the development of strategies for its detection and management, reducing the impact of its consequences. (AU)

Estudio transversal multicéntrico sobre la prevalencia de delirium en unidades de ortogeriatría: protocolo de «Estudio DELFRA 24» / Multicenter cross-sectional study on the prevalence of delirium in orthogeriatric units: «DELFRA 24 study» protocol

Introducción El delirium es la complicación perioperatoria más frecuente en el adulto mayor con fractura de cadera (FC) conllevando un impacto catastrófico en su recuperación funcional y su estado cognitivo. Actualmente se desconoce la prevalencia real de este síndrome ya que no está protocolizada su detección y abordaje en la práctica clínica habitual. Métodos Se realizará un estudio observacional multicéntrico de tipo transversal a nivel nacional en el que participarán distintas unidades de ortogeriatría de España. Se evaluará la prevalencia de delirium con la escala 4AT, así como las características de este y su relación con otros síndromes geriátricos, variables sociodemográficas, características de la cirugía y parámetros analíticos. Resultados La recogida de datos se llevará a cabo el próximo día mundial del delirium (miércoles 13 de marzo de 2024), por lo que los resultados se esperan durante el segundo o tercer trimestre del año 2024. Conclusiones Conocer la prevalencia real y las características del delirium en mayores con FC podría contribuir a sensibilizar en la detección sistemática, la prevención y el abordaje protocolizado del delirium en servicios quirúrgicos, disminuyendo el impacto de sus consecuencias. (AU)

Introduction Delirium is the most common perioperative complication in older adults with hip fracture (HF), leading to a catastrophic impact on their functional recovery and cognitive status. Currently, the true prevalence of this syndrome is unknown as its detection and management are not standardized in clinical practice. Methods A multicenter observational cross-sectional study will be conducted nationwide, involving different orthogeriatric units in Spain. The prevalence of delirium will be assessed using the 4AT scale, along with its characteristics and its relationship with other geriatric syndromes, sociodemographic variables, surgical characteristics, and laboratory parameters. Results Data collection is scheduled to take place on World Delirium Day (Wednesday, March 13, 2024), and therefore, the results are expected during the second or third quarter of 2024. Conclusions Understanding the real prevalence and characteristics of delirium in older adults with HF could contribute to the development of strategies for its detection and management, reducing the impact of its consequences. (AU)

[Multicenter cross-sectional study on the prevalence of delirium in orthogeriatric units: «DELFRA 24 study¼ protocol]. / Estudio transversal multicéntrico sobre la prevalencia de delirium en unidades de ortogeriatría: protocolo de «Estudio DELFRA 24¼.

INTRODUCTION: Delirium is the most common perioperative complication in older adults with hip fracture (HF), leading to a catastrophic impact on their functional recovery and cognitive status. Currently, the true prevalence of this syndrome is unknown as its detection and management are not standardized in clinical practice. METHODS: A multicenter observational cross-sectional study will be conducted nationwide, involving different orthogeriatric units in Spain. The prevalence of delirium will be assessed using the 4AT scale, along with its characteristics and its relationship with other geriatric syndromes, sociodemographic variables, surgical characteristics, and laboratory parameters. RESULTS: Data collection is scheduled to take place on World Delirium Day (Wednesday, March 13, 2024), and therefore, the results are expected during the second or third quarter of 2024. CONCLUSIONS: Understanding the real prevalence and characteristics of delirium in older adults with HF could contribute to the development of strategies for its detection and management, reducing the impact of its consequences.

Lesiones cutáneas por síndrome de disfunción multiorgánica: caso clínico / Skin injuries associated with multiple organ dysfunction syndrome: clinical case

Se presenta el caso de una mujer de 95 años, derivada a urgencias por presentar de forma súbita lesiones necróticas parcheadas en cuero cabelludo, que tras realización de analítica y pruebas complementarias se identifica como un cuadro de sepsis de origen multifactorial. Posteriormente, se realiza preparación del lecho de las heridas con desbridamiento cortante con bisturí, aplicando posteriormente colagenasa e hidrogel para continuar con desbridamiento enzimático y autolítico. La paciente fallece a las 4 h tras realizar el desbridamiento. Dado el cuadro de sepsis de origen multifactorial, muy probablemente se trate de lesiones cutáneas por compromiso vital grave, y dentro de ellas de lesiones cutáneas por síndrome de disfunción multiorgánica, que se puede confundir con lesiones por presión, pero dada la localización de las lesiones y el cuadro de sepsis de origen multifactorial, se descarta esta etiología. Los pacientes que sufren este tipo de lesiones tienen una condición clínica irreversible (AU)

A 95-year-old woman, brought to emergency department who suddenly present patchy necrotic skin injuries on the scalp, after performing laboratory tests and complementary tests, is associated with sepsis of multifactorial origin. Subsequently, the wound bed was prepared with sharp debridement with a scalpel, applying collagenase and hydrogel to continue with enzymatic and autolytic debridement. The patient died 4 h after debridement. Given the picture of sepsis of multifactorial origin, it is very likely to be skin injuries associated with serious life threatening situations, and within them skin injuries associated with multiple organ dysfunction syndrome, which could be confused with pressure skin injuries, but given the location of skin injuries and sepsis of multifactorial origin, this etiology is ruled out. Patients who suffer this type of skin injuries have an irreversible clinical condition (AU)

Utilización del sevoflurano de forma tópica en úlceras de la extremidad inferior: revisión sistematizada / Use of sevoflurane topically on leg ulcers: systematized review

Las úlceras de la extremidad inferior siguen siendo en la actualidad un problema global. Las opciones analgésicas para el control del dolor se basan generalmente en medidas farmacológicas con acción local y/o sistémica. El sevoflurano es un anestésico general inhalatorio, asociado a sus efectos sobre el sistema nervioso central, y tradicionalmente no se emplea por otras vías que no sea inhalado. Sin embargo, hoy en día se le conoce una acción analgésica a nivel central y también periférico. Actualmente, su uso clínico ha llevado a algunos autores a considerar la posibilidad de nuevos efectos del sevoflurano a través de la vía tópica. OBJETIVO: Sintetizar las evidencias científicas disponibles sobre el uso del sevoflurano aplicado de forma tópica en úlceras de la extremidad inferior. METODOLOGÍA: Revisión sistematizada de la literatura científica, siguiendo la guía PRISMA. La búsqueda de estudios se realizó en las principales bases de datos bibliográficas, sin límite de fechas ni de idiomas. También se realizó una búsqueda incluyendo resúmenes de congresos. RESULTADOS: Se obtuvieron un total de 120 referencias. Finalmente, ocho de ellas correspondían a los estudios incluidos para la síntesis cualitativa. En la mayoría de los estudios se encontró una disminución del dolor de 8 a 2 puntos en las escalas empleadas. CONCLUSIONES: Los escasos estudios parecen sugerir un importante efecto analgésico aplicado de forma tópica, un probable efecto antibacteriano y un posible efecto promotor de la cicatrización. Sin embargo, son necesarios más estudios comparativos con un tamaño de muestra mayor, con mejor calidad en sus diseños

Leg ulcers are a global problem daily. The analgesic options for pain control are generally based on pharmacological measures with local and / or systemic action. Sevoflurane is a general inhalation anesthetic, associated with its effects on the central nervous system, its use not being traditional by other routes that are not inhaled. However, today it is known an analgesic action at the central level and at the peripheral level. Actually, the clinical use of this product has led some authors to consider the possibility of new effects of Sevoflurane topically. OBJECTIVE: To synthesize the available scientific evidences about the use of Sevoflurane topically on leg ulcers. METHODOLOGY: Systematized review of the scientific literature, following the PRISMA guide. The main bibliographic databases were searched without date or language limits. Also references lists and congress abstracts were searched. RESULTS: 120 references were identified. Finally, 8 of them were selected for qualitative synthesis. In most studies, was found a decrease in pain of 8 to 2 points in the scales used. CONCLUSIONS: The few studies suggest an analgesic effect applied topically, a probable antibacterial effect and a possible healing promoting effect. However, comparative studies of large sample are needed, with a better quality designs

Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics.

A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.

Selective up-regulation of cannabinoid CB1 receptor coupling to Go-proteins in suicide victims with mood disorders.

Brain endocannabinoid system is proposed to play a role in the pathogenesis of affective disorders. In the present study, we analyzed the functionality of the cannabinoid receptor type 1 (CB1 receptor) at different transduction levels in prefrontal cortex (PFC) of depressed suicide victims. We examined stimulation of [35S]GTPγS binding, activation of Gα protein subunits and inhibition of adenylyl cyclase by the cannabinoid agonist WIN55,212-2, as well as [3H]CP55,940 binding, in PFC homogenates from suicide victims with major depression (MD) and matched control subjects. CB1 receptor-stimulated [35S]GTPγS binding was significantly greater in the PFC of MD compared with matched controls (23%, p < 0.05). This increase was most evident in the PFC from MD subgroup with negative blood test for antidepressants (AD) at the time of death (AD-free) (38%, p < 0.05), being absent when comparing the AD-treated MD cases with their controls. The density of CB1 receptors and their coupling to adenylyl cyclase were similar between MD and control cases, regardless of the existence of AD intake. Analysis of [35S]GTPγS-labelled Gα subunits allowed for the detection of upregulated CB1 receptor coupling to Gαo, but not to Gαi1, Gαi2, Gαi3, Gαz subunits, in the PFC from AD-free MD suicides. These results suggest that increased CB1 receptor functionality at the Gαi/o protein level in the PFC of MD subjects is due to enhanced coupling to Gαo proteins and might be modulated by AD intake. These data provide new insights into the role of endocannabinoid neurotransmission in the pathobiology of MD and suggest its regulation by ADs.

Disfagia y estado nutricional en ancianos institucionalizados / Dysphagia and nutritional status in institutionalized elderly population

La disfagia es un síndrome geriátrico por su alta prevalencia en ancianos (mayor en la población institucionalizada) que favorece la desnutrición y compromete la seguridad, debido al riesgo de aspiración de alimentos. Objetivos: Conocer el estado nutricional de los ancianos institucionalizados que presentan disfagia, residentes en instituciones sociosanitarias de carácter público de la provincia de Toledo. Metodología: Estudio descriptivo y transversal (enero-febrero 2015). Población de estudio: personas de 65 años o más, residentes en instituciones sociosanitarias públicas de Toledo con disfagia. Criterios de exclusión: nutrición enteral o parenteral y situación terminal. Variables: edad, sexo, valoración antropométrica, dieta, restricciones dietéticas, suplemento nutricional y estado nutricional con Mini Nutritional Assessment (MNA). Resultados: Un total de 33 ancianos. Media de edad: 86,73 años (DT 7,74). Mujeres: 84,84%. MNA medio: 13,85 (DT = 3,5), riesgo de desnutrición: 18,18% y desnutrición: 78,78%. IMC: bajo peso 36,36%. Un 51,51% no sabe si ha perdido peso, un 96,97% con deterioro cognitivo, un 81,82% toma 4 fármacos o más, un 39,4% toma menos de 3 comidas diarias completas, un 27,27% toma frutas o verduras menos de 2 veces al día, un 78,79% menos de 6 vasos de líquidos al día. Un 90,9% solo movilidad cama-sillón y un 78,79% necesita ayuda para alimentarse. Dieta túrmix: 90,9%, sin restricciones dietéticas: 84,84%. Sin suplementos nutricionales: 75,75%. Diferencias estadísticamente significativas: MNA-independencia en movilidad (p = 0,008), MNA-problemas neuropsicológicos (p = 0,01), MNA-independencia en alimentación (p = 0,001) y MNA-suplementos nutricionales (p = 0,028). MNA-polimedicación: tendencia a sufrir desnutrición (p = 0,903). Conclusiones: En la valoración nutricional de la población mayor institucionalizada con disfagia se concluye la existencia de una gran proporción de ancianos con un estado nutricional deficitario, asociada a demencia y mayor dependencia en movilidad y alimentación

Dysphagia is a geriatric syndrome due to its high prevalence in the elderly (higher in the institutionalized population) favoring malnutrition and compromising safety because of choking risk by food intake. Objective: To know the nutritional status of institutionalized elderly people with dysphagia, residents in public nursing homes of Toledo. Methodology: Descriptive and transversal study (January February 2015). Sample: people aged ≥ 65 years with dysphagia from Toledo, residents in public nursing homes. Exclusion criteria: enteral-parenteral nutrition and terminal illness. Variables: age, gender, anthropometric assessment, diet, dietary restrictions, nutritional supplement and nutritional status with Mini Nutritional Assessment (MNA). Results: 33 adults, aged: 86.73 years (SD 7.74). 84.84% women. MNA (average): 13.85 (SD = 3.5), risk of malnutrition: 18.18%, malnutrition: 78.78%. BMI: underweight 36.36%. 51.51% do not know if he/she has lost weight, 96.97% dementia, 81.82% ≥4 drugs, 39.4% < 3 full meals daily, 27,27% fruits or vegetables < 2 times daily, 78.79% 6 glasses daily. 90.9% mobility bed to chair and 78.79% help to feed. Turmix diet: 90.9%, without dietary restrictions: 84.84%. No nutritional supplements: 75.75%. Statistically significant differences: MNA-independent to mobilize (p=0.008), MNA-dementia (p=0.01), MNA independent to feed (p=0.001), MNA-nutritional supplements (p=0.028). MNA-polypharmacy: tend to malnutrition (p=0.903). Conclusions: In the nutritional assessment of institutionalized elderly population with dysphagia is concluded that the existence of a large proportion of elderly patients with a deficient nutritional status, associated with dementia and increased reliance on mobility and feed

Biased Agonism of Three Different Cannabinoid Receptor Agonists in Mouse Brain Cortex.

Cannabinoid receptors are able to couple to different families of G proteins when activated by an agonist drug. It has been suggested that different intracellular responses may be activated depending on the ligand. The goal of the present study was to characterize the pattern of G protein subunit stimulation triggered by three different cannabinoid ligands, Δ9-THC, WIN55212-2, and ACEA in mouse brain cortex. Stimulation of the [35S]GTPγS binding coupled to specific immunoprecipitation with antibodies against different subtypes of G proteins (Gαi1, Gαi2, Gαi3, Gαo, Gαz, Gαs, Gαq/11, and Gα12/13), in the presence of Δ9-THC, WIN55212-2 and ACEA (submaximal concentration 10 µM) was determined by scintillation proximity assay (SPA) technique in mouse cortex of wild type, CB1 knock-out, CB2 knock-out and CB1/CB2 double knock-out mice. Results show that, in mouse brain cortex, cannabinoid agonists are able to significantly stimulate not only the classical inhibitory Gαi/o subunits but also other G subunits like Gαz, Gαq/11, and Gα12/13. Moreover, the specific pattern of G protein subunit activation is different depending on the ligand. In conclusion, our results demonstrate that, in mice brain native tissue, different exogenous cannabinoid ligands are able to selectively activate different inhibitory and non-inhibitory Gα protein subtypes, through the activation of CB1 and/or CB2 receptors. Results of the present study may help to understand the specific molecular pathways involved in the pharmacological effects of cannabinoid-derived drugs.

Gi protein coupling to adenosine A1-A2A receptor heteromers in human brain caudate nucleus.

Pharmacological characterization of adenosine A(1) and A(2A) receptors in human brain caudate nucleus membranes led to non-cooperative binding of radiolabelled ligands. In human caudate nucleus but not in cortex, the agonist binding to A(1) receptors was modulated by the agonist binding to A(2A) receptors indicating a functional negative cross-talk. Accordingly, the A(1) receptor-activation-mediated G(i)-dependent guanosine 5'-o-(3-[(35)S]thio-triphosphate) binding was modulated by agonist binding to A(2A) receptors. A(2A) receptors occupation led to a decrease in the potency of A(1) receptor agonists. These results indicate that A(1) but not A(2A) receptors activation, likely occurring at low adenosine concentrations, engages a G(i)-mediated signaling; however, when both receptors are occupied by adenosine, there is an A(2A) receptor-mediated impairment of G(i)-operated transducing units. These findings are relevant to get insight into the complex relationships derived from co-expression of multiple neurotransmitter/neuromodulator receptors subtypes that individually are coupled to different G proteins. A further finding was the demonstration that the A(2A) receptor agonist, CGS 21680, at high concentrations able to significantly bind to the A(1) receptor, behaved as a partial agonist of the later receptor. This fact might be taken into account when characterizing CGS 21680 actions in human cells expressing A(1) receptors when the compound is used at micromolar concentrations.