Estudio poblacional forense de la muerte súbita inexplicada en la epilepsia en niños y jóvenes durante el periodo 1991-2021 / Forensic population study of sudden unexplained death in epilepsy in children and young people during the period 1991–2021

Introducción la muerte súbita inexplicada en la epilepsia (MSIEP) es una causa importante de mortalidad en los pacientes epilépticos jóvenes; sin embargo, su existencia es poco conocida en el ámbito forense. El objetivo del trabajo es analizar la frecuencia y características clínico-patológicas de la MSIEP en los epilépticos menores de 35 años. Métodos estudio observacional de todas MSIEP ocurridas en personas de 1-35 años en Bizkaia (periodo 1991-2021) y Sevilla (2004-2021) investigadas en los servicios de patología forense (SPF). Además, se examinaron las muertes por epilepsia de los registros de mortalidad. Resultados se registraron 101 muertes por epilepsia en los registros de mortalidad y 46 MSIEP en los SPF, representando el 6% de las muertes súbitas en esta edad. Se registró una alta frecuencia de casos de epilepsia postraumática (n = 5), o con anomalías cerebrales (n = 5) o asociadas a trastornos del desarrollo (n = 4) o retraso mental (n = 3). El estudio toxicológico fue positivo en el 75%, destacando la presencia de fármacos antiepilépticos (n = 26). Se detectaron drogas ilegales en 5 jóvenes, principalmente cocaína (n = 3). La muerte fue no presenciada en la mayoría de los sujetos (85%) y sucedió por la noche (n = 63%) durante el sueño. Conclusiones la MSIEP en los niños y los jóvenes es infrecuente, pero constituye una causa importante de mortalidad en los epilépticos. Aunque los mecanismos de la MSIEP no son bien conocidos, se recomienda reforzar el control médico de la epilepsia en la juventud, principalmente en los pacientes con epilepsia postraumática o posquirúrgica o en aquellos con trastornos del desarrollo o retraso mental asociados. (AU)

Introduction Sudden unexpected death in epilepsy (SUDEP) is a major cause of mortality in young epileptic patients. The objective of the work is to analyze its frequency and clinical-pathological characteristics as a cause of sudden death in epileptics under 35 years of age. Methods Retrospective population study of all SUDEP in people aged 1–35 years in Bizkaia (period 1991–2021) and Seville (2004–2021) investigated in the Forensic Pathology Services (FPS). In each case, a complete autopsy was carried out with histopathological and toxicological studies, and review of clinical and circumstantial data. Data from the Mortality Registry for deaths by epilepsy were examined. Results 101 deaths due to epilepsy were registered in the Mortality Registries and 46 SUDEP cases in the FPS, representing 6% of forensic sudden deaths in this age population. A high frequency of post-traumatic epilepsy cases (n = 5), brain abnormalities (n = 5) or epilepsy associated to developmental disorders (n = 4) or mental retardation (n = 3) was observed. The toxicological analysis was positive in 75%, highlighting the presence of antiepileptic drugs (n = 26). Illegal drugs were detected in 5 young people, mainly cocaine (n = 3). Death was unwitnessed in most subjects (85%) and occurred at night (n = 63%) while sleeping. Conclusions SUDEP in children and young people is infrequent, however it is an important cause of mortality in epileptics. Although the mechanisms are not well understood, it is recommended to strengthen the medical control of epilepsy in youth, mainly in patients with post-traumatic or post-surgical epilepsy or in those who have associated developmental disorders or mental retardation. (AU)

Effect of antipsychotic drugs on group II metabotropic glutamate receptor expression and epigenetic control in postmortem brains of schizophrenia subjects.

Antipsychotic-induced low availability of group II metabotropic glutamate receptors (including mGlu2R and mGlu3R) in brains of schizophrenia patients may explain the limited efficacy of mGlu2/3R ligands in clinical trials. Studies evaluating mGlu2/3R levels in well-designed, large postmortem brain cohorts are needed to address this issue. Postmortem samples from the dorsolateral prefrontal cortex of 96 schizophrenia subjects and matched controls were collected. Toxicological analyses identified cases who were (AP+) or were not (AP-) receiving antipsychotic treatment near the time of death. Protein and mRNA levels of mGlu2R and mGlu3R, as well as GRM2 and GRM3 promoter-attached histone posttranslational modifications, were quantified. Experimental animal models were used to compare with data obtained in human tissues. Compared to matched controls, schizophrenia cortical samples had lower mGlu2R protein amounts, regardless of antipsychotic medication. Downregulation of mGlu3R was observed in AP- schizophrenia subjects only. Greater predicted occupancy values of dopamine D2 and serotonin 5HT2A receptors correlated with higher density of mGlu3R, but not mGlu2R. Clozapine treatment and maternal immune activation in rodents mimicked the mGlu2R, but not mGlu3R regulation observed in schizophrenia brains. mGlu2R and mGlu3R mRNA levels, and the epigenetic control mechanisms did not parallel the alterations at the protein level, and in some groups correlated inversely. Insufficient cortical availability of mGlu2R and mGlu3R may be associated with schizophrenia. Antipsychotic treatment may normalize mGlu3R, but not mGlu2R protein levels. A model in which epigenetic feedback mechanisms controlling mGlu3R expression are activated to counterbalance mGluR loss of function is described.

Permissive epigenetic regulatory mechanisms at the histone level are enhanced in postmortem dorsolateral prefrontal cortex of individuals with schizophrenia.

BACKGROUND: Susceptibility to schizophrenia is determined by interactions between genes and environment, possibly via epigenetic mechanisms. Schizophrenia has been associated with a restrictive epigenome, and histone deacetylase (HDAC) inhibitors have been postulated as coadjuvant agents to potentiate the efficacy of current antipsychotic drugs. We aimed to evaluate global histone posttranslational modifications (HPTMs) and HDAC expression and activity in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. METHODS: We used postmortem DLPFC samples of individuals with schizophrenia and controls matched for sex, age, and postmortem interval. Schizophrenia samples were classified into antipsychotic-treated or antipsychotic-free subgroups according to blood toxicology. Expression of HPTMs and HDAC was quantified by Western blot. HDAC activity was measured with a fluorometric assay. RESULTS: H3K9ac, H3K27ac, and H3K4me3 were globally enhanced in the DLPFC of individuals with schizophrenia (+24%-42%, p < 0.05). HDAC activity (-17%, p < 0.01) and HDAC4 protein expression (-20%, p < 0.05) were downregulated in individuals with schizophrenia. Analyses of antipsychotic-free and antipsychotic-treated subgroups revealed enhanced H3K4me3 and H3K27ac (+24%-49%, p < 0.05) and reduced HDAC activity in the antipsychotic-treated, but not in the antipsychotic-free subgroup. LIMITATIONS: Special care was taken to control the effect of confounding factors: age, sex, postmortem interval, and storage time. However, replication studies in bigger cohorts might strengthen the association between permissive HPTMs and schizophrenia. CONCLUSION: We found global HPTM alterations consistent with an aberrantly permissive epigenome in schizophrenia. Further studies to elucidate the significance of enhanced permissive HPTMs in schizophrenia and its association with the mechanism of action of antipsychotic drugs are encouraged.

Toxicology Screening in Sports-Related Sudden Cardiac Death: A Multinational Observational Study.

BACKGROUND: Knowledge of toxicological findings among sports-related sudden cardiac death (SrSCD) is scarce. OBJECTIVES: This study aimed to describe postmortem toxicology findings in a multinational cohort of young SrSCD. METHODS: Patients with sudden cardiac death (SCD) aged 12 to 49 years with a complete post mortem were included from Denmark, Spain, and Australia. Postmortem findings were compared between SrSCD and non-SrSCD, and toxicology findings in SrSCD were assessed. RESULTS: We included 3,189 SCD, of which 219 (7%) were sports-related. SrSCD patients were younger (36 years vs 41 years; P < 0.001) and of male predominance (96% vs 75%; P < 0.001), and their death was more often caused by structural cardiac disease (68% vs 61%; P = 0.038). Positive toxicology screenings were significantly less likely among SrSCD than non-SrSCD (12% vs 43%; P < 0.001), corresponding to 82% lower odds of a positive toxicology screening in SrSCD. Patient characteristics were similar between SrSCDs with positive and negative toxicology screenings, but deaths were more often unexplained (59% vs 34%). Nonopioid analgesics were the most common finding (3%), and SCD-associated drugs were detected in 6% of SrSCD. SUD was more prevalent among the SrSCD with positive toxicology (59% vs 34%). CONCLUSIONS: Sports-related SCD mainly occurred in younger men with structural heart disease. They had a significantly lower prevalence of a positive toxicology screening compared with non-SrSCD, and detection of SCD-associated drugs was rare.

Ethanol and illicit drugs acute use and abuse as risk factors for suicide: A case-control study based on forensic autopsies in the Basque Country, Spain.

INTRODUCTION: Abuse/dependence and acute use of ethanol and illicit drug are considered risk factors for suicide. The risk is also influenced by demographic conditions and/or psychiatric comorbidity. The aim of the study was to test the association between presence of ethanol, illicit substances and prescribed drugs in suicide decedents and controls. MATERIALS AND METHODS: Case-control study of autopsies performed in the Biscay Forensic Pathology Service, Basque Country, Spain from 01/01/2010 to 30/06/2021 in subjects between 15 and 55 years old. Suicide deaths (n=481) with completed autopsy were evaluated. Concurrent natural deaths were chosen as controls (n=330). The risk for suicide according to demographic, toxicological and psychiatric variables was analyzed using logistic regression. RESULTS: Ethanol was present in 21% and illicit drugs, mainly cannabis, cocaine and amphetamine, in 27% of suicide deaths. Illicit drugs were more frequent among males. In 63% of suicide cases, prescribed psychotropic drugs were detected. In a multivariate analysis, the main risk factors for suicide were psychiatric diagnosis of illicit drug abuse/dependence (OR=5.56, 95% CI 2.74-11.30) or another mental disease as mood or psychotic disorders (OR=13.05, 95% CI 8.79-19.37). Acute presence of ethanol (OR=4.22, 95% CI 2.52-7.08), recent use of cocaine (OR=2.52, 95% CI 1.05-6.07) and age <35 years (OR=2.50, 95% CI 1.62-3.87) were also associated with suicide deaths. CONCLUSIONS: The presence of drugs of abuse in suicide deaths of people ≤55 years old is high. Recent use of ethanol and cocaine is significantly associated with an increased suicide risk. Specific prevention strategies against exposition to substances of abuse should be promoted, especially in psychiatric patients.

Evolución epidemiológica y causas de muerte súbita en lactantes: estudio poblacional desde 1991 a 2020 en Bizkaia / Epidemiological changes and causes of sudden unexpected death in infancy: A 30-year population-based study in Basque Country

Introducción: la muerte súbita del lactante (MSL) representa un grave problema de salud pública. El objetivo del trabajo es analizar sus características epidemiológicas y clínico-patológicas. Método: estudio retrospectivo poblacional de la MSL en Bizkaia entre 1991–2020. Se examinaron datos del Registro de Mortalidad y Servicio de Patología Forense. Resultados: se registraron 1.109 defunciones en menores de un año. En 107 se efectuó autopsia forense: 61 síndromes de muerte súbita del lactante (SMSL) y 23 MSL de causa explicada. En otros 10 casos se codificó el SMSL como causa de muerte sin autopsia forense. La incidencia del SMSL fue de 0,26/1.000 recién nacidos/año y descendió desde 0,74 (quinquenio 1991–1995) a 0,07 (quinquenios 2011–2020). El porcentaje del SMSL en relación a la mortalidad total decreció del 11,2 al 2,5%. En el SMSL predominó la categoría IB de San Diego (67%) y los lactantes entre 1–4 meses (63%). Un «ambiente de sueño inseguro» se detectó en 6 SMSL. El 56,5% de las MSL explicadas fueron infecciosas. De los 84 casos de MSL autopsiados, el 70% no tenía enfermedades previas y el 15% eran prematuros y/o recién nacidos de bajo peso. En el 32% existieron síntomas prodrómicos, principalmente infección de vías respiratorias. Hallazgos microscópicos sugestivos de infección respiratoria se diagnosticaron en 10 SMSL. Conclusiones: la incidencia del SMSL en Bizkaia es baja y ha disminuido notablemente en los últimos 30 años. La sintomatología prodrómica y los signos histopatológicos sugestivos de infección son relativamente frecuentes. En el futuro serían deseables investigaciones prospectivas multidisciplinares y multicéntricas.(AU)

Introduction: Sudden unexpected deaths in infancy (SUDI) represents a serious public health problem. The objective of this work is to analyze its epidemiological and clinical-pathological characteristics. Method: Retrospective population study of SUDI in Bizkaia between 1991–2020. Data from the Mortality Registry and Forensic Pathology Service were examined. Results: 1,109 deaths in children under one year were recorded. A forensic autopsy was performed in 107: 61 cases of sudden infant death syndrome (SIDS) and 23 SUDI of explained cause. In other 10 cases SIDS was coded as cause of death without forensic autopsy. The incidence of SIDS was 0.26/1000/year and decreased from 0.74 (1991–1995 five-year period) to 0.07 (2011–15 and 2016–20 periods). The percentage of SIDS in relation to total mortality decreased from 11.2 to 2.5%. In SIDS, category IB from San Diego (67%) and infants between 1 and 4 months (63%) predominated. An “unsafe sleep environment” was detected in 6 SIDS. 56.5% of the explained SUDI were infectious. Of the 84 autopsied SUDI cases, 70% had no pre-existing disease and 15% were premature and/or low birth weight infants. In 32% there were prodromal symptoms, mainly respiratory tract infection. Microscopic findings suggestive of respiratory infection were diagnosed in 10 SIDS. Conclusions: The incidence of SIDS in Bizkaia is low and has decreased notably in the last 30 years. Prodromal symptoms and histopathological signs suggestive of infection are relatively common. Forensic studies provide relevant data, although prospective multidisciplinary and multicenter research would be desirable.(AU)

Factores de riesgo del suicidio consumado en los jóvenes y los adultos de mediana edad: estudio poblacional forense / Risk factors for completed suicide in young people and middle-aged adults: Population forensic study

Introducción: El suicidio es un problema importante de salud pública. El objetivo del estudio es analizar las características demográficas, clínicas y toxicológicas, y los métodos del suicidio en jóvenes y adultos de mediana edad.MétodoEl estudio fue retrospectivo poblacional del suicidio consumado en sujetos de 14-55 años que fueron objeto de autopsia forense en Bizkaia entre 2016-2018.ResultadosSe registraron 272 suicidios. La incidencia global fue de 7,8/100.000 habitantes/año. Ciento veintisiete tenían entre 14 y 55 años. La tasa fue 3 veces superior en los varones y se incrementó con la edad. En el 72% se recogió algún factor de riesgo clínico, predominando los trastornos mentales (59%): del estado de ánimo (23%), por abuso de sustancias (20,5%) y psicóticos (14%). El 38% de los adictos tenía otro trastorno mental. La enfermedad física (23%) y el intento de suicidio (20,5%) fueron los factores relevantes. El 41% fueron positivos para sustancias de abuso: etanol (22%), cannabis (16%), cocaína (11%) y anfetamina (8%). Este porcentaje fue del 79% en los adictos a sustancias. Los trastornos por abuso de sustancias (25% vs. 6,5%; p = 0,03) y la presencia de alcohol y/o drogas (49% vs. 16%; p = 0,001) fueron más prevalentes en los varones.ConclusionesLa incidencia del suicidio en Bizkaia es más baja que la media europea. El suicidio es un problema complejo asociado a factores demográficos, clínicos (principalmente, trastornos depresivos y abuso de sustancias) y al consumo reciente de alcohol y drogas ilegales. Para identificar los factores de riesgo y orientar las medidas preventivas se requieren investigaciones prospectivas multidisciplinares y multicéntricas. (AU)

Introduction: Suicide is a major public health problem. The objective of this study is to analyze the demographic, clinical and toxicological characteristics and the mechanisms of suicide in young people and middle-aged adults.MethodRetrospective population study of completed suicide in subjects aged 14-55 who were subjected to a forensic autopsy in Bizkaia between 2016-2018.Results272 suicides were recorded. The global incidence was 7.8/100.00 inhabitants/year. 127 were 14-55 years old. The rate was 3 times higher in men and increased with age. In 72%, some clinical risk factor was collected, mainly mental disorders (59%): mood disorders (23%), substance abuse (20.5%) and psychotic disorders (14%). 38% of addicts had another mental disorder. Physical illness (23%) and suicide attempt (20.5%) were also relevant factors. 41% were positive for alcohol and/or illicit drugs: ethanol (22%), cannabis (16%), cocaine (11%) and amphetamine (8%). This percentage was 79% in substance addicts. Substance abuse disorders (25% vs. 6.5%; p = 0.03) and presence of alcohol and/or drugs (49% vs. 16%; p = 0.001) were more prevalent in men. The most commonly used methods were fall from heights (35%) and hanging (31%).ConclusionsThe incidence of suicide in Bizkaia is lower than the European average. Suicide is a complex problem associated with demographic and clinical factors (mainly depressive and substance abuse disorders) and recent use of alcohol and illicit drugs. Prospective multidisciplinary and multicenter researches are required in order to identify risk factors and to guide preventive measures. (AU)

Differential brain ADRA2A and ADRA2C gene expression and epigenetic regulation in schizophrenia. Effect of antipsychotic drug treatment.

Postsynaptic α2A-adrenoceptor density is enhanced in the dorsolateral prefrontal cortex (DLPFC) of antipsychotic-treated schizophrenia subjects. This alteration might be due to transcriptional activation, and could be regulated by epigenetic mechanisms such as histone posttranslational modifications (PTMs). The aim of this study was to evaluate ADRA2A and ADRA2C gene expression (codifying for α2-adrenoceptor subtypes), and permissive and repressive histone PTMs at gene promoter regions in the DLPFC of subjects with schizophrenia and matched controls (n = 24 pairs). We studied the effect of antipsychotic (AP) treatment in AP-free (n = 12) and AP-treated (n = 12) subgroups of schizophrenia subjects and in rats acutely and chronically treated with typical and atypical antipsychotics. ADRA2A mRNA expression was selectively upregulated in AP-treated schizophrenia subjects (+93%) whereas ADRA2C mRNA expression was upregulated in all schizophrenia subjects (+53%) regardless of antipsychotic treatment. Acute and chronic clozapine treatment in rats did not alter brain cortex Adra2a mRNA expression but increased Adra2c mRNA expression. Both ADRA2A and ADRA2C promoter regions showed epigenetic modification by histone methylation and acetylation in human DLPFC. The upregulation of ADRA2A expression in AP-treated schizophrenia subjects might be related to observed bivalent chromatin at ADRA2A promoter region in schizophrenia (depicted by increased permissive H3K4me3 and repressive H3K27me3) and could be triggered by the enhanced H4K16ac at ADRA2A promoter. In conclusion, epigenetic predisposition differentially modulated ADRA2A and ADRA2C mRNA expression in DLPFC of schizophrenia subjects.

Muerte súbita relacionada con la actividad deportiva en España. Estudio poblacional multicéntrico forense de 288 casos / Sports-related sudden cardiac death in Spain. A multicenter, population-based, forensic study of 288 cases

Introducción y objetivos Conocer la incidencia, características clínico-patológicas, hábitos tóxicos y actividad deportiva relacionadas con la muerte súbita en la actividad deportiva en España.MétodosEstudio poblacional retrospectivo y multicéntrico, basado en autopsias forenses realizadas en 25 provincias durante 8 años (2010-2017).ResultadosSe investigaron 288 casos (el 98,6% varones; media de edad, 43,8±14,4 años). La incidencia fue de 0,38 casos/100.000 hab./año (0,82 entre deportistas habituales), la mayoría (54%) varones entre 35 y 54 años. Los deportes más frecuentes (el 96% recreativos) fueron ciclismo (28%), fútbol (18%) y carrera a pie (17%). La muerte fue de origen cardiovascular en el 99%: cardiopatía isquémica (63%), miocardiopatías (21%) y síndrome de muerte súbita arrítmica (6%). En los jóvenes, las miocardiopatías (38%) y la cardiopatía isquémica (30%), presente a partir de los 20 años, fueron las más prevalentes. La enfermedad se había diagnosticado en vida en 23 casos; se observaron antecedentes clínicos relevantes en 30 casos y factores de riesgo cardiovascular, principalmente obesidad, en 95. El análisis toxicológico detectó sustancias cardiotóxicas en el 7%, y destaca la relación entre cannabis y cardiopatía isquémica aguda.ConclusionesLa muerte súbita asociada a la actividad deportiva en España tiene una incidencia muy baja, afecta a varones de mediana edad que realizan deporte recreativo, principalmente ciclismo, fútbol y carrera, y es de origen cardiovascular, con aparición temprana de la cardiopatía isquémica. Los datos clínicos y los hábitos tóxicos deben tenerse en cuenta para desarrollar estrategias de prevención. (AU)

Introduction and objectives To determine the incidence of sports-related sudden cardiac death in Spain, and to identify the clinical-pathological characteristics, substance abuse, and sports activity associated with this entity.MethodsRetrospective, population-based, multicenter study of forensic autopsies conducted in 25 provinces during an 8-year period (2010-2017).ResultsWe investigated 288 cases (98.6% occurred in men with a mean age of 43.8±14.4 years). The incidence in the general population was 0.38 cases out of 100 000 inhabitants per year (0.82 among regular athletes), and most cases (54%) occurred in persons aged between 35 and 54 years. The most frequent sports (96% recreational) were cycling (28%), football (18%), and jogging (17%). Death was of cardiovascular origin in 99%. The main causes were ischemic heart disease (63%), cardiomyopathies (21%), and sudden arrhythmic death syndrome (6%). In young people, cardiomyopathies (38%) and ischemic heart disease (30%), present after the age of 20 years, were the most prevalent. The disease was diagnosed during life in 23 cases, relevant clinical antecedents were observed in 30 cases, and cardiovascular risk factors, mainly obesity, in 95 cases. Toxicological analysis detected cardiotoxic substances in 7%, highlighting the association between cannabis and acute ischemic heart disease.ConclusionsSports-related sudden cardiac death in Spain has a very low incidence and affects middle-aged men practicing recreational sports, mainly cycling, football, and jogging. This entity is of cardiovascular origin with early onset of ischemic heart disease. Clinical data and substance abuse should be taken into account to develop preventive strategies. (AU)

Sports-related sudden cardiac death in Spain. A multicenter, population-based, forensic study of 288 cases.

INTRODUCTION AND OBJECTIVES: To determine the incidence of sports-related sudden cardiac death in Spain, and to identify the clinical-pathological characteristics, substance abuse, and sports activity associated with this entity. METHODS: Retrospective, population-based, multicenter study of forensic autopsies conducted in 25 provinces during an 8-year period (2010-2017). RESULTS: We investigated 288 cases (98.6% occurred in men with a mean age of 43.8±14.4 years). The incidence in the general population was 0.38 cases out of 100 000 inhabitants per year (0.82 among regular athletes), and most cases (54%) occurred in persons aged between 35 and 54 years. The most frequent sports (96% recreational) were cycling (28%), football (18%), and jogging (17%). Death was of cardiovascular origin in 99%. The main causes were ischemic heart disease (63%), cardiomyopathies (21%), and sudden arrhythmic death syndrome (6%). In young people, cardiomyopathies (38%) and ischemic heart disease (30%), present after the age of 20 years, were the most prevalent. The disease was diagnosed during life in 23 cases, relevant clinical antecedents were observed in 30 cases, and cardiovascular risk factors, mainly obesity, in 95 cases. Toxicological analysis detected cardiotoxic substances in 7%, highlighting the association between cannabis and acute ischemic heart disease. CONCLUSIONS: Sports-related sudden cardiac death in Spain has a very low incidence and affects middle-aged men practicing recreational sports, mainly cycling, football, and jogging. This entity is of cardiovascular origin with early onset of ischemic heart disease. Clinical data and substance abuse should be taken into account to develop preventive strategies.

Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia.

The mechanistic target of rapamycin (also known as mammalian target of rapamycin) (mTOR)-dependent signaling pathway plays an important role in protein synthesis, cell growth, and proliferation, and has been linked to the development of the central nervous system. Recent studies suggest that mTOR signaling pathway dysfunction could be involved in the etiopathogenesis of schizophrenia. The main goal of this study was to evaluate the status of mTOR signaling pathway in postmortem prefrontal cortex (PFC) samples of subjects with schizophrenia. For this purpose, we quantified the protein expression and phosphorylation status of the mTOR downstream effector ribosomal protein S6 as well as other pathway interactors such as Akt and GSK3ß. Furthermore, we quantified the status of these proteins in the brain cortex of rats chronically treated with the antipsychotics haloperidol, clozapine, or risperidone. We found a striking decrease in the expression of total S6 and in its active phosphorylated form phospho-S6 (Ser235/236) in the brain of subjects with schizophrenia compared to matched controls. The chronic treatment with the antipsychotics haloperidol and clozapine affected both the expression of GSK3ß and the activation of Akt [phospho-Akt (Ser473)] in rat brain cortex, while no changes were observed in S6 and phospho-S6 (Ser235/236) protein expression with any antipsychotic treatment. These findings provide further evidence for the involvement of the mTOR-dependent signaling pathway in schizophrenia and suggest that a hypofunctional S6 may have a role in the etiopathogenesis of this disorder.

Valoración forense integral del maltrato infantil intrafamiliar / Child abuse due to domestic violence: Integral forensic assessment

El abordaje del maltrato infantil intrafamiliar (MII) es uno de los más complejos en medicina forense. Los objetivos periciales son la evaluación del daño físico-psíquico y de los indicadores de MII, el análisis de credibilidad del testimonio y el estudio de la dinámica familiar. En este artículo se revisa la sistemática de abordaje del MII (fuentes de documentación, evaluación psíquica, recogida del relato y uso de pruebas psicológicas); se propone un modelo de exploración psíquico basado en bloques, se formulan pautas para la determinación del nexo causal entre hechos denunciados y daño detectado, y para el análisis de la credibilidad con el fin de concluir sobre la coherencia del relato. También se describen los principales indicadores de MII. Las conclusiones del informe forense se deben basar en evidencias sólidas ya que una peritación deficiente podría producir daños irreparables en víctimas menores y sus familias

The approach to child abuse due to domestic violence is one of the most complex in forensic medicine. The objectives are the evaluation of the physical-psychological damage and of the indicators of child abuse, the analysis of credibility of the testimony and the study of the family dynamics. In this article, the systematic approach to child abuse is reviewed: sources of documentation, psychological evaluation, story gathering and use of psychological tests. A model of psychological exploration based on blocks is proposed, guidelines for the determination of the causal relationship between allegation of ill-treatment and damage detected are formulated, and recommendations for the analysis of credibility in order to conclude on the coherence of the story are suggested. The main indicators of child abuse are also described. The conclusions of the forensic report must be based on solid evidence, since poor evaluation could cause irreparable damage to children and their families

Serotonin 5-HT2A receptor expression and functionality in postmortem frontal cortex of subjects with schizophrenia: Selective biased agonism via Gαi1-proteins.

Serotonin 5-HT2A receptors (5-HT2ARs) have been implicated in schizophrenia. However, postmortem studies on 5-HT2ARs expression and functionality in schizophrenia are scarce. The 5-HT2AR mRNA and immunoreactive protein expression were evaluated in postmortem tissue from dorsolateral prefrontal cortex (DLPFC) of antipsychotic-free (n = 18) and antipsychotic-treated (n = 9) subjects with schizophrenia, and matched controls (n = 27). Functional coupling of 5-HT2AR to G-proteins was tested by measuring the activation induced by the agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride ((±)DOI) in antibody-capture [35S]GTPγS scintillation proximity assays (SPA). In antipsychotic-free schizophrenia subjects, 5-HT2AR mRNA expression and protein immunoreactivity in total homogenates was similar to controls. In contrast, in antipsychotic-treated schizophrenia subjects, lower mRNA expression (60±9% vs controls) and a trend to reduced protein immunoreactivity (86±5% vs antipsychotic-free subjects) just in membrane-enriched fractions was observed. [35S]GTPγS SPA revealed a significant ~6% higher stimulation of Gαi1-protein by (±)DOI in schizophrenia, whereas activation of the canonical Gαq/11-protein pathway by (±)DOI remained unchanged. Expression of Gαi1- and Gαq/11-proteins did not differ between groups. Accordingly, in rats chronically treated with clozapine, but not with haloperidol, a 30-40% reduction was observed in 5-HT2AR mRNA expression, 5-HT2AR protein immunoreactivity and [3H]ketanserin binding in brain cortical membranes. Overall, the data suggest a supersensitive 5-HT2AR signaling through inhibitory Gαi1-proteins in schizophrenia. Together with previous results, a dysfunctional pro-hallucinogenic agonist-sensitive 5-HT2AR conformation in postmortem DLPFC of subjects with schizophrenia is proposed. Atypical antipsychotic treatment would contribute to counterbalance this 5-HT2AR supersensitivity by reducing receptor expression.

Sports-related sudden cardiac death due to myocardial diseases on a population from 1-35 years: a multicentre forensic study in Spain.

This is a multicentre forensic study that identifies all sports-related sudden deaths (SRSDs) in young people, due to myocardial diseases (MDs) that occurred in a large area of Spain. The aim of the study is to assess the epidemiology, causes of death, and sport activities associated with these fatalities. This is a retrospective study based on forensic autopsies performed in the provinces of Biscay, Seville, Valencia and in the jurisdiction covered by the National Institute of Toxicology and Forensic Sciences in Madrid (Spain). The retrospective study encompasses from 2010 to 2017. All sudden cardiac deaths (SCDs) in persons 1-35 years old were selected. The total number of SCDs were divided into death occurred during exercise (SRSD) and death during rest, sleep or normal activities (non-SRSD). Each of these two groups was subdivided according to the cause of death into MD (primary cardiomyopathies and myocarditis) and non-MD. Clinic-pathological, toxicological and genetic characteristics of SRSD due to MD were analysed. Over the 8-year study period, we identified 645 cases of SCD in the young: 75 SRSD (11.6%) and 570 non-SRSD (88.4%). MD was diagnosed in 33 (44.0%) of the SRSD and in 112 (19.6%) of the non-SRSD cases. All cases of SRSD due to MD were males (mean age (24.0 ± 7.6) years) practicing recreational sports (85%). SRSDs were more frequent in arrhythmogenic cardiomyopathy (ACM) (37%) and hypertrophic cardiomyopathy (HCM) (24%), followed by myocarditis (15%) and idiopathic left ventricular hypertrophy (ILVH) (9%). Only in five cases of SRSD the MD responsible of death (HCM) had been diagnosed in life. Cardiovascular symptoms related to the disease were present in other seven patients (six of them with ACM). Postmortem genetic studies were performed in 15/28 (54%) primary cardiomyopathies with positive results in 12 (80%) cases. The most frequent sports disciplines were football (49%) followed by gymnastics (15%) and running (12%). In Spain, SRSD in young people due to MDs occurs in males who perform a recreational activity. Compared with control group we observed a strong association between MDs and exertion. One in three SRSDs are due to cardiomyopathy, especially ACM, which reinforces the need for preparticipation screening to detect these pathologies in recreational sport athletes. Further studies are warranted to understand the causes and circumstances of sudden death to facilitate the development of preventive strategies.

Endocannabinoid system imbalance in the postmortem prefrontal cortex of subjects with schizophrenia.

BACKGROUND: The endocannabinoid system - comprising cannabinoid receptors, endocannabinoid ligands and their synthesis and inactivation enzymes - has been widely implicated in the pathophysiology of schizophrenia. However, little is known regarding the status of the different elements of the endocannabinoid system in the brain of schizophrenic patients. We have previously reported altered endocannabinoid levels in the postmortem brain of subjects with schizophrenia compared with matched controls. AIMS: Our aim was to further examine the status of the main elements of the endocannabinoid system in the postmortem prefrontal cortex of the same cohort of subjects. METHODS: Gene expression and function of the cannabinoid receptor type-1 (CB1) and the endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have been assessed. RESULTS: A significant decrease in CB1 mRNA levels in schizophrenia was found, without alteration of FAAH or MAGL mRNA expression. Moreover, positive correlations among mRNA expressions of the three genes studied were found in the prefrontal cortex of controls but not in schizophrenic subjects. No alteration was found in CB1 receptor mediated functional coupling to G-proteins, but a significant increase of FAAH activity was found in schizophrenic subjects compared with controls. 2-arachidonoylglycerol levels and MAGL activity were found to positively correlate in controls but not in schizophrenic subjects. CONCLUSIONS: The present findings reveal an imbalance in the expression and function of different elements of the endocannabinoid system in schizophrenia. This outcome highlights the relevance of the endocannabinoid system in the pathophysiology of schizophrenia and emphasises its elements as potential targets in the search for new therapeutic strategies.

Sudden cardiac death associated to substances of abuse and psychotropic drugs consumed by young people: A population study based on forensic autopsies.

BACKGROUND: Toxic substances are one of the main risk factors for sudden cardiac death (SCD) in young people. However, there is limited information about this matter based on clinical research. The aim of this study was to analyze the use of substances of abuse (legal and illicit) and prescribed psychotropic drugs in young people who died by SCD. METHODS: A population-based study performed in 15-35-year-olds who died by SCD in Biscay (Basque-Country) between 1991 and 2016. Cases were analyzed prospectively by a complete autopsy, toxicological and histopathological studies. A case was considered positive for exposure to cardiotoxic substances if smoking status was diagnosed or if toxicological analysis detected any drug associated with increased risk of SCD. RESULTS: There were 204 SCD; 98 (48%) were exposed to a cardiotoxic substance, including smoking status (n = 72) and/or positive toxicology (n = 58). Illicit drugs (n = 29, mainly cannabis and cocaine), ethanol (n = 25), and prescribed psychotropic drugs (n = 11) were detected. Positive cases were more frequent in males than in females (54% vs. 19%). They were also more common in subjects who died by acute (86%) and chronic (71%) ischemic heart disease than in myocardial diseases (33%) and sudden arrhythmic death syndrome (36%). All positive cases of illicit drugs were males. Smoking status was very high in deaths due to acute ischemic heart disease. CONCLUSIONS: The proportion of users of substances of abuse was unexpectedly high, even more prevalent than other cardiovascular risk factors. Toxic substances could play an important role as triggers of SCD in young people.

Assessing the level of credibility of allegations of physical torture.

BACKGROUND: No means exists to classify the overall credibility of physical torture allegations, which relies on qualitative forensic medical criteria. OBJECTIVES: To develop procedures for processing physical data from torture allegations in order to achieve robust credibility assessments. To assess inter-observer variation in semi-quantitative evaluations. To analyse the importance of physical aspects for the overall assessment of allegations of torture. To assess the correlation between a quantitative description of physical aspects of torture and the appraisal of credibility based on the semi-quantitative model. METHODS: We developed a semi-quantitative model to assess credibility of physical torture allegations and a model to describe allegations quantitatively. Information about physical aspects of ill-treatment in 202 extensive reports made by psychologists (part of a Basque Country Governmental project) was appraised individually and jointly by the two authors in the semi-quantitative model. Inter-observer variation was appraised. The assessed credibility based on physical details was compared with the psychologists' overall assessments and with the quantitative scoring of physical data. FINDINGS: The inter-observer agreement was substantial with kappa values of 0.64-0.77. Peer-reviewing revealed an error; using the defined criteria in the models facilitated achievement of common opinions. Comparison of credibility assessments found by different means suggests that physical data may be given a low priority in the overall assessment of torture allegations. There was a strong correlation (r=0,86, p<0.001) between the semi-quantitative credibility assessment and the quantitative scoring of physical aspects of torture, reinforcing the validity of both means. CONCLUSION: Peer-reviewing of physical aspects of torture based on a qualitative /semi-quantitative /quantitative multi-step analysis leads to robust assessments of credibility. A procedure is needed on how to merge the credibility assessments of the psychological and the physical data into an overall conclusion. We suggest that the highest level of the two evaluations should constitute the overall credibility assessment. LIMITATIONS: The examinations were done years after the detentions, they were not focused on physical details and the data we used was retrieved retrospectively.

The Loss of α- and ß-Tubulin Proteins Are a Pathological Hallmark of Chronic Alcohol Consumption and Natural Brain Ageing.

Repetitive excessive alcohol intoxication leads to neuronal damage and brain shrinkage. We examined cytoskeletal protein expression in human post-mortem tissue from Brodmann's area 9 of the prefrontal cortex (PFC). Brain samples from 44 individuals were divided into equal groups of 11 control, 11 alcoholic, 11 non-alcoholic suicides, and 11 suicide alcoholics matched for age, sex, and post-mortem delay. Tissue from alcoholic cohorts displayed significantly reduced expression of α- and ß-tubulins, and increased levels of acetylated α-tubulin. Protein levels of histone deacetylase-6 (HDAC6), and the microtubule-associated proteins MAP-2 and MAP-tau were reduced in alcoholic cohorts, although for MAPs this was not significant. Tubulin gene expressions increased in alcoholic cohorts but not significantly. Brains from rats administered alcohol for 4 weeks also displayed significantly reduced tubulin protein levels and increased α-tubulin acetylation. PFC tissue from control subjects had reduced tubulin protein expression that was most notable from the sixth to the eighth decade of life. Collectively, loss of neuronal tubulin proteins are a hallmark of both chronic alcohol consumption and natural brain ageing. The reduction of cytosolic tubulin proteins could contribute to the brain volumetric losses reported for alcoholic patients and the elderly.

Papel de las sustancias tóxicas en la muerte súbita cardiaca / The role of toxic substances in sudden cardiac death

El consumo de sustancias tóxicas constituye un factor de riesgo significativo para la muerte súbita cardiaca. Los tóxicos con mayor relevancia son las drogas ilegales (especialmente la cocaína), el alcohol y el tabaco, y en menor medida, las sustancias dopantes. Diversos medicamentos también incrementan el riesgo de muerte súbita cardiaca. En el presente artículo se hace una revisión sobre el mecanismo de acción y la patología inducida por estos tóxicos; se ofrece información epidemiológica, se destaca la trascendencia de una investigación forense protocolizada y se discuten las implicaciones de la patología forense en la prevención. La posibilidad de consumo de drogas de abuso debería ser tenida en cuenta en toda muerte súbita cardiaca de un adolescente, joven o adulto de edad mediana, principalmente en varones. En deportistas sería conveniente descartar el uso de sustancias dopantes; y en pacientes que toman psicofármacos valorar su influencia en el fallecimiento, aún con niveles terapéuticos (AU)

The use of toxic substances is a main risk factor for sudden cardiac death. The most relevant toxic substances are the illegal drugs (especially cocaine), ethanol, tobacco, and doping substances. Additionally, several therapeutic drugs are able to increase the risk for sudden cardiac death. The aim of the present paper is to review the mechanism of action and the main pathological problems induced by toxic substances. Moreover, we provide epidemiological information, underlie the importance of a standardised forensic investigation, and discuss the role of forensic pathology in the prevention of this phenomenon. The possibility of consumption of any drug of abuse should be considered in any case of sudden cardiac death in adolescents, young, or middle-age patients, especially in men. In athletes the use of doping substances should be ruled-out. In patients under psychopharmacological treatment, the putative influence of these drugs should be borne in mind (AU)

Detainees' perception of the doctors and the medical institution in Spanish police stations: An impediment in the fight against torture and ill-treatment.

BACKGROUND: As part of a program by the Basque Government (Spain) and the University of the Basque Country, persons who have alleged exposure to torture and ill-treatment have been examined by psychologists and psychiatrists according to the Istanbul Protocol (IP). Medical examinations of detainees with the aim, inter alia, to document abuses is fundamental for torture prevention. The IP prescribes how this should be done to ensure data collection and prevent reprisals for having reported ill-treatment to the doctor. OBJECTIVES: The objectives were to assess detainees' perception of the medical examinations which they underwent at different types of Spanish police institution and to compare practice between institutions; and, to compare information from the period 1969-1991 with that from 1992-2014. METHODS: All information about medical examinations of incommunicado detainees from 202 extensive IP reports was analysed according to a 19-item tool developed for the purpose dealing with the doctors' professional performance, the confidence of the detainees in the doctors, reprisals and procedural safeguards (Annex 1). All information was classified as acceptable, unacceptable /insufficient or totally unacceptable. FINDINGS: Very often the detainees perceived the doctors' professional performance as insufficient or totally unacceptable and the doctors did not instil their confidence. Threats of police reprisals and failure to observe procedural safeguards were often reported. There were no differences in the comparison between institutions. When comparing the two study periods an improvement was found over time. However, 64% of the scores came out as totally unacceptable or insufficient for the most recent period indicating that the medical institution in police stations where the detentions had taken place failed to constitute a preventive means against torture and ill-treatment. LIMITATIONS: Only 57% of the 202 reports assessed contained relevant information; data was retrieved retrospectively; the interviews were done years after detention without a particular focus on medical examinations.