Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat. Relevance for anxiolytic actions.

Introduction: The amygdala is a limbic region of high value for understanding anxiety and its treatment. Dopamine D2 receptors (D2Rs) and oxytocin receptors (OXTRs) have both been shown to participate in modulating anxiety involving effects in the amygdala. The goal is to understand if D2R-OXTR heterocomplexes exist in the central amygdala and if, through enhancing allosteric receptor-receptor interactions, may enhance anxiolytic actions. Methods: The methods used involve the shock-probe burying test, the in situ proximity ligation assay (PLA), image acquisition and analysis, and the BRET2 assay. Bilateral cannulas were introduced into the amygdala, and the effects of the coadministration of oxytocin and the D2R-like agonist quinpirole into the amygdala were studied. Results: The combination treatment enhanced the anxiolytic effects compared to the single treatment. The D2R/D3R antagonist raclopride blocked the effects of the combination treatment of oxytocin and the D2R agonist, although oxytocin is regarded as a distinct modulator of fear-mediating anxiolytic effects. In situ PLA results indicate the existence of D2R-OXTR heteroreceptor complexes and/or the co-location of OXTR and D2R within the same cell membrane nanodomains in the central amygdala. With BRET2, evidence is given for the existence of D2R-OXTR heteromers in HEK293 cells upon co-transfection. Discussion: The enhanced behavioral effects observed upon co-treatment with OXTR and D2R agonists may reflect the existence of improved positive receptor-receptor interactions in the putative D2R-OXTR heterocomplexes in certain neuronal populations of the basolateral and central amygdala. The D2R-OXTR heterocomplex, especially upon agonist co-activation in the central amygdala, may open a new pharmacological venue for the treatment of anxiety.

Who judges medical practice?

Lawsuits due to patient perception of inappropriate medical actions are a growing reality in medical practice, which entails widespread concern in the medical community. Lawsuits often entail additional circumstances beyond the primary concern of preventing or sanctioning acts of medical negligence. CETREMI proposes various recommendations aimed at legal and medical professionals to improve this circumstance and avoid harming the doctor-patient relationship.

Las demandas judiciales por la percepción del paciente de una actuación médica inadecuada son una realidad creciente en la práctica médica, la cual entraña una preocupación extendida en el gremio médico. Las demandas judiciales frecuentemente conllevan circunstancias adicionales a la primaria preocupación de prevenir o sancionar actos de negligencia médica. CETREMI emite algunas recomendaciones a los profesionales jurídicos y médicos para mejorar esta situación y evitar daños en la relación médico-paciente.

¿Quién juzga la actuación médica? / Who judges medical practice?

Resumen Las demandas judiciales por la percepción del paciente de una actuación médica inadecuada son una realidad creciente en la práctica médica, la cual entraña una preocupación extendida en el gremio médico. Las demandas judiciales frecuentemente conllevan circunstancias adicionales a la primaria preocupación de prevenir o sancionar actos de negligencia médica. CETREMI emite algunas recomendaciones a los profesionales jurídicos y médicos para mejorar esta situación y evitar daños en la relación médico-paciente.

Abstract Lawsuits due to patient perception of inappropriate medical actions are a growing reality in medical practice, which entails widespread concern in the medical community. Lawsuits often entail additional circumstances beyond the primary concern of preventing or sanctioning acts of medical negligence. CETREMI proposes various recommendations aimed at legal and medical professionals to improve this circumstance and avoid harming the doctor-patient relationship.

Clinical Phenotypes and Mortality Biomarkers: A Study Focused on COVID-19 Patients with Neurological Diseases in Intensive Care Units.

Purpose: To identify clinical phenotypes and biomarkers for best mortality prediction considering age, symptoms and comorbidities in COVID-19 patients with chronic neurological diseases in intensive care units (ICUs). Subjects and Methods: Data included 1252 COVID-19 patients admitted to ICUs in Cuba between January and August 2021. A k-means algorithm based on unsupervised learning was used to identify clinical patterns related to symptoms, comorbidities and age. The Stable Sparse Classifiers procedure (SSC) was employed for predicting mortality. The classification performance was assessed using the area under the receiver operating curve (AUC). Results: Six phenotypes using a modified v-fold cross validation for the k-means algorithm were identified: phenotype class 1, mean age 72.3 years (ys)-hypertension and coronary artery disease, alongside typical COVID-19 symptoms; class 2, mean age 63 ys-asthma, cough and fever; class 3, mean age 74.5 ys-hypertension, diabetes and cough; class 4, mean age 67.8 ys-hypertension and no symptoms; class 5, mean age 53 ys-cough and no comorbidities; class 6, mean age 60 ys-without symptoms or comorbidities. The chronic neurological disease (CND) percentage was distributed in the six phenotypes, predominantly in phenotypes of classes 3 (24.72%) and 4 (35,39%); χ² (5) 11.0129 p = 0.051134. The cerebrovascular disease was concentrated in classes 3 and 4; χ² (5) = 36.63, p = 0.000001. The mortality rate totaled 325 (25.79%), of which 56 (17.23%) had chronic neurological diseases. The highest in-hospital mortality rates were found in phenotypes 1 (37.22%) and 3 (33.98%). The SSC revealed that a neurological symptom (ageusia), together with two neurological diseases (cerebrovascular disease and Parkinson's disease), and in addition to ICU days, age and specific symptoms (fever, cough, dyspnea and chilliness) as well as particular comorbidities (hypertension, diabetes and asthma) indicated the best prediction performance (AUC = 0.67). Conclusions: The identification of clinical phenotypes and mortality biomarkers using practical variables and robust statistical methodologies make several noteworthy contributions to basic and experimental investigations for distinguishing the COVID-19 clinical spectrum and predicting mortality.

Increased protein expression of VEGF-A, VEGF-B, VEGF-C and their receptors in the temporal neocortex of pharmacoresistant temporal lobe epilepsy patients.

The vascular endothelial growth factor (VEGF) system has been shown to play a crucial role in several neuropathological processes. Temporal lobe epilepsy (TLE) is the most common focal epilepsy type in adult humans. We assessed the protein expression levels of VEGF-A, VEGF-B, and VEGF-C, their specific receptors VEGFR-2 and -3, their accessory receptors neuropilins 1 and 2, and PI3 and Akt kinases, in temporal neocortex from pharmacoresistant TLE (PR-TLE) patients and control subjects by western blotting. All proteins were found to be significantly overexpressed in samples of PR-TLE patients, indicating that the VEGF system contributes to PR-TLE pathogenesis and should be further studied.

Dopamine D1 receptor activity is involved in the increased anxiety levels observed in STZ-induced diabetes in rats.

Epidemiological surveys have indicated that anxiety disorders are more frequent in diabetic patients than in the general population. Similar results have been shown in animal studies using the streptozotocin (STZ)-induced diabetes model. The mechanisms underlying this relationship are not clearly understood, but it has been suggested that alterations in the dopaminergic neurotransmission, which plays an important role in the amygdaloid modulation of fear and anxiety, may be involved. The aim of this study was to ascertain whether or not the amygdaloid DA D1 receptors are involved in the increase of anxiety-like behavior observed in "diabetic" animals. Adult Wistar male rats were injected with STZ (50mg/kg, i.p.) in two consecutive days and subjected to the Shock-Probe Burying Test 10days after the beginning of treatment. STZ-treated rats showed a significant increase in immobility/freezing behavior whereas no effects were elicited in latency to bury, burying behavior itself and the number of shocks received during testing as compared with non-diabetic controls. These results suggest the triggering of a passive coping response in the STZ-treated rats. Interestingly, immobility/freezing behavior was reversed following the intra-amygdaloid dopamine D1 receptor blockade by the local microinfusion of SCH23390 (100ng/side). Autoradiographic experiments showed a selective increase of [(3)H]-SCH23390 binding in the ventral intercalated paracapsular islands of STZ-treated rats when compared to the non-treated control group. Our results suggest that a hyperdopaminergic state involving DA D1 receptors within the amygdala may have a role in the increase of anxiety observed in diabetic rats.

Mecanismos de neurodegeneración en la epilepsia del lóbulo temporal / Mechanisms of neurodegeneration in temporal lobe epilepsy

Epilepsy affects 1 and 2 percent of the worldwide population, while temporal lobe epilepsy (TLE) covers 40 percent of all epilepsy cases. Controversy in defining epilepsy as a neurodegenerative disease exists because, no there is enough evidence to show seizures and status epilepticus (SE) as cause for irreversible neuronal damage. Epileptogenic insult at the beginning of the disease produces an acute and delayed neuronal death, resulting in gliosis, but also triggers compensatory processes such as angiogenesis, cell proliferation and reorganization of extracellular matrix as receptors, channels and drug transporter proteins. In neurogenesis and axonal regrowth, the age of onset is crucial for the formation of abnormal neurons and aberrant circuits as a result of seizures; approximately 30 percent begin in the temporal lobe. These disturbances continue in parallel or sequentially during the course of epilepsy, which implies a great challenge in the search of new treatments...

La epilepsia es una enfermedad que afecta entre el 1 al 2 por ciento de la población mundial, siendo la epilepsia del lóbulo temporal (ELT) la que abarca el 40 por ciento de todos los casos de epilepsia. La controversia en definir a la epilepsia como una enfermedad neurodegenerativa, se debe a que no hay pruebas suficientes que demuestren como las convulsiones y el estado de mal epiléptico (SE) provocan un daño neuronal irreversible. El insulto epileptógenico presente al inicio de la enfermedad genera la muerte neuronal aguda y tardía, para dar lugar a la gliosis; pero también se desencadenan procesos compensatorios como la angiogénesis, la proliferación celular y una reorganización tanto de la matriz extracelular como de los receptores, canales y proteínas transportadoras de fármacos. En el caso de la neurogénesis y recrecimiento axonal, la edad de inicio es determinante para la formación de neuronas anormales y circuitos aberrantes como consecuencia de las convulsiones, dónde aproximadamente un 30 por ciento comienzan en el lóbulo temporal. Estas alteraciones se continúan en paralelo o de forma secuencia! durante la evolución de la epilepsia, lo que implica un gran desafío en la búsqueda de nuevos tratamientos...

Inflammatory mediators in epilepsy.

All common contributing factors to epilepsy such as trauma, malignancies and infections are accompanied by different levels of central nervous system inflammation that in turn have been associated with the occurrence of seizure. Emerging data from human brain tissue and experimental models of epilepsy support the proposed involvement of inflammation in epilepsy. Key mediators of this process include, among others: interleukin (IL) -1ß, IL-6, tumor necrosis factor-α, adhesion molecules and component of complement. Recent advances suggest the involvement of specific inflammatory pathways in the pathogenesis of seizures in patients with pharmacoresistant temporal lobe epilepsy, highlighting the potential for new therapeutic strategies. This review provides an overview of the current knowledge on the relationship between inflammatory mediators and epilepsy. We also describe experimental and clinical evidence of inflammation in epilepsy with special emphasis on clinical aspects once the epileptogenic focus has been resected. Further insight into the complex role of inflammation in epileptogenesis may provide new treatment options.

Cambios electroencefalográficos y de la conducta producidos por derivados 5 Beta de la progesterona y su antagonismo por la 4-aminopiridina / Electroencephalographic and behavioral changes produced by 5 beta progestins and its antagonism by 4-aminopyridine

Se estudiaron en ratas en libre movimiento los cambios de la conducta y el EEG producidos por pregnandiona, pregnanolona y epipregnanolona, y su antagonismo por la 4-aminopiridina (4-AP). Las progestinas produjeron pérdida del reflejo de enderezamiento, ataxia, sedación, estado anestésico y aparición de husos en el EEG. La 4-AP produjo temblor y contracciones musculares, e incrementó la amplitud del EEG. La epipregnanolona fue más potente que la pregnandiona y la pregnanolona para producir los cambios en el EEG y la anestesia. El estado anestésico experimentó inversión por acción de la 4-AP en menos de tres minutos. Los animales despertaron temblorosos y, en algunos casos, con convulsiones. Sin embargo, la actividad del EEG permaneció sincronizada. La potencialización de la 4-AP por los derivados 5 ß de la progesterona refuerza la idea de un efecto bifásico de los últimos que podrían excitar más que deprimir algunas áreas cerebrales. Se concluye que la inversión por la 4-AP de la anestesia producida por los derivados de la 5 ß progesterona podría incluir efectos en la membrana neuronal, liberación de neurotransmisores y movimientos iónicos