Postmortem genetic testing should be recommended in sudden cardiac death cases due to thoracic aortic dissection.

BACKGROUND: Acute thoracic aortic dissections and ruptures, the main life-threatening complications of the corresponding aneurysms, are an important cause of sudden cardiac death. Despite the usefulness of the molecular diagnosis of these conditions in the clinical setting, the corresponding forensic field remains largely unexplored. The main goal of this study was to explore and validate a new massive parallel sequencing candidate gene​ assay as a diagnostic tool for acute thoracic aortic dissection autopsy cases. MATERIALS AND METHODS: Massive parallel sequencing of 22 thoracic aortic disease candidate genes performed in 17 cases of thoracic aortic dissection using AmpliSeq and Ion Proton technologies. Genetic variants were filtered by location, type, and frequency at the Exome Aggregation Consortium and an internal database and further classified based on the American College of Medical Genetics and Genomics (ACMG) recommendations published in 2015. All prioritized results were confirmed by traditional sequencing. RESULTS: From the total of 10 potentially pathogenic genetic variants identified in 7 out of the 17 initial samples, 2 of them were further classified as pathogenic, 2 as likely pathogenic, 1 as possibly benign, and the remaining 5 as variants of uncertain significance, reaching a molecular autopsy yield of 23%, approximately. CONCLUSIONS: This massive parallel sequencing candidate gene approach proved useful for the molecular autopsy of aortic dissection sudden cardiac death cases and should therefore be progressively incorporated into the forensic field, being especially beneficial for the anticipated diagnosis and risk stratification of any other family member at risk of developing the same condition.

Deregulated hepatic microRNAs underlie the association between non-alcoholic fatty liver disease and coronary artery disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) appears to be a new risk factor for the development of coronary artery disease (CAD). Members of a class of non-coding RNAs, termed microRNAs (miRNAs), have been identified as post-transcriptional regulators of cholesterol homoeostasis and can contribute to the development of NAFLD. The aims of this study were to (i) to assess the relationship between NAFLD and sudden cardiac death (SCD) from severe CAD in forensic autopsies and (ii) to quantify several hepatic miRNAs previously associated with lipid metabolism and NAFLD to correlate their expression with the presence of NAFLD, CAD, obesity parameters and postmortem lipid profile. METHODS: A total of 133 cases of autopsies with SCD and established CAD (patient group, CAD-SCD) and 106 cases of non-CAD sudden death (control group, non-CAD-SD) were included. miRNAs were quantified in frozen liver tissues. RESULTS: Males predominated in both groups. Patients more frequently exhibited NAFLD and necroinflammatory steatohepatitis (NASH) than controls (62% vs 26%, P = 0.001 and 42% vs 26%, P = 0.001 respectively). In both groups, the presence of NAFLD correlated with body mass index and abdominal circumference (P < 0.05). An increase in miR-34a-5p and a decrease in miR-122-5p and -29c-3p in patients with NASH vs controls without NAFLD were observed (P < 0.05). Finally, significant correlations between miR-122-5p and unfavourable lipid profile and also hs-CRP and miR-34a-5p were noted. CONCLUSIONS: CAD is associated with NAFLD and NASH. The hepatic miRNAs studied appear to be associated with NAFLD severity and may promote CAD through lipid metabolism alteration and/or promotion of the systemic inflammation.

Acute and chronic kidney disease and risk of hospital mortality during COVID-19 pandemic waves in the pre-vaccination era.

Background: Chronic kidney disease (CKD) is a risk factor for death from coronavirus disease 2019 (COVID-19), and COVID-19 may cause acute kidney injury (AKI) which also influences outcomes. There is little information on the independent contribution of CKD and AKI to the risk of death in COVID-19 on different waves, as CKD is a key risk factor for AKI. Methods: We have studied the epidemiology of CKD and AKI in 2878 patients hospitalized for COVID-19 and their independent association with in-hospital mortality in the two largest pre-vaccination COVID-19 waves in Madrid, Spain. Hospitalized COVID-19 patients were grouped into four mutually exclusive categories: previous-CKD, community-acquired AKI (CA-AKI), hospital-acquired AKI (HA-AKI) and normal renal function throughout hospitalization. Results: Pre-existent or acquired kidney involvement was observed in 35.5% and 36.8% of COVID-19 patients in the 1st and 3rd waves, respectively. Overall, 13.9% of patients with normal kidney function on arrival developed HA-AKI. In the 3rd wave, CA-AKI was more common than in the 1st wave. Overall, 9%-20% of CKD cases and 22%-40% of AKI cases remained undiagnosed in the discharge report. CKD, CA-AKI and HA-AKI were independently associated with risk of death in multivariate analysis, with HA-AKI, which was usually mild, being the most relevant independent risk factor for in-hospital mortality. A model including kidney involvement category, age, Charlson index, admission lactate dehydrogenase and lymphocytes predicted death with a receiver operating characteristic area under the curve of 0.898. Conclusion: In conclusion, CKD and AKI were common in pre-vaccination waves among hospitalized COVID-19 patients and were independent risk factors for death, even when AKI was mild to moderate, and despite improvements in treatment.

Arrhythmogenic cardiomyopathy with left ventricular involvement versus ischemic heart disease: lessons learned from the family study and the reviewed autopsy of a young male.

Ischemic heart disease (IHD) is the leading cause of sudden cardiac death (SCD) and often non-thrombosed severe coronary stenoses with or without myocardial scars are detected. Left dominant arrhythmogenic cardiomyopathy (LDAC) is a life-threating rare disease which has been more thoroughly studied in the last 10 years. The macroscopic study of an SCD victim was conducted and re-evaluated 9 years later. The cardiological work-up in his first-degree relatives initially comprised an electrocardiogram (ECG) and an echocardiogram. When they were re-evaluted 9 years later, a cardiac magnetic resonance, an ECG-monitoring, an exercise testing and a genetic study were performed and the pedigree was extended accordingly. In 2008, an IHD was suspected in the sports-triggered SCD of a 37-year-old man upon the postmortem (75% stenosis of the left main and circumflex coronary arteries; the subepicardial left ventricular fibrofatty infiltration with mild myocardial degeneration was assumed to be a past myocardial infarction). No cardiomyopathy was identified in any of the two proband's sisters. Nine years thereafter, distant relatives were diagnosed with LDAC due to a pathogenic desmoplakin mutation. The reanalysis of the two sisters showed ventricular arrhythmias in one of them without structural heart involvement and the reviewed postmortem of the proband was reclassified as LDAC based on the fibrofatty infiltration; both were mutation carriers. The completion of the family study on 19 family members yielded one SCD due to LDAC (the proband), three living patients diagnosed with LDAC (two with a defibrillator), one mutation carrier without structural ventricular involvement, and 14 healthy relatives (who were discharged) with a very good co-segregation of the mutation. Although rare, LDAC exists and sometimes its differential diagnosis with IHD has to be faced. Modifying previous postmortem misdiagnoses can help family screening to further prevent SCDs.

Thickness and an Altered miRNA Expression in the Epicardial Adipose Tissue Is Associated With Coronary Heart Disease in Sudden Death Victims.

INTRODUCTION AND OBJECTIVES: An increased epicardial adipose tissue (EAT) thickness has become a new risk factor for coronary heart disease (CHD). We aimed to study the role of EAT dysfunction as a CHD marker by focusing on its thickness and microRNA (miRNA) expression profile, and the potential factors possibly influencing them. METHODS: One hundred and fifty-five CHD sudden cardiac death victims and 84 non-CHD-sudden death controls were prospectively enrolled at autopsy. A representative subset underwent EAT thickness measurements and EAT miRNA expression profiling. RESULTS: Epicardial adipose tissue thickness was increased and allowed an accurate diagnosis of patient status (among other measurements, EAT score area under the curve 0.718, P < .001). Epicardial adipose tissue from patients showed 14 up- and 14 down-regulated miRNAs and miR-34a-3p, -34a-5p, -124-3p, -125a-5p, 628-5p, -1303 and -4286 were validated by quantitative real-time polymerase chain reaction. Patients exhibited higher EAT levels of miR-34a-3p and -34a-5p than controls (with a positive trend considering EAT from coronaries without stenosis, with stable stenosis and complicated plaques) and correlated with age only in controls. The mild positive correlation between liver and EAT miR-34a-5p levels in patients (r = 0.295, P = .020) dramatically increased in EAT from complicated plaques (r = 0.799, P = .017). Similar correlations were observed for high-sensitivity-C-reactive protein levels and miR-34a-5p levels both in EAT and liver extracts. CONCLUSIONS: Increased age-independent levels of miR-34a-3p and -34a-5p characterize the EAT miRNA expression profile of CHD regardless of EAT thickness, anthropometric parameters, and the presence of underlying atherosclerotic plaques.

Sellar xanthogranuloma.

We report the case of a 16-year-old girl with a history of idiopathic precocious puberty and normal results on pituitary imaging scan. Ten years later, a new cranial magnetic resonance imaging scan was performed due to worsening of episodes resembling Horton's headache and a lesion suggestive of pituitary bleeding was detected. The headaches diminished with glucocorticoid administration but a severe complication, steroid psychosis, occurred. Surgical treatment and pathological study of the lesion led to the differential diagnosis between craniopharyngyoma and xanthogranuloma of the sella turcica. The clinical progression of the tumor (not visualized 10 years previously), together with preservation of pituitary and visual function both before and after surgery, gross total removal of the tumor (difficult to achieve with craniopharyngioma) and the absence of recurrence provide strong support for the diagnosis of xanthogranuloma of the sella turcica.

Histological Features of Cerebellar Neuropathology in Patients With Alcoholic and Nonalcoholic Steatohepatitis.

Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) affect 29 million people in the European Union. Patients with ASH and NASH may exhibit cognitive impairment, reducing their quality of life. Steatohepatitis induces cerebral alterations. It is not known if histological analysis could allow distinguishing ASH, NASH, and/or cirrhosis neuropathology and other entities. The aim of this work was to analyze a set of histopathological features characterizing the brain lesions due to ASH, NASH, and cirrhosis. We performed a histological study using hematoxylin and eosin staining and immunohistochemical techniques in cerebellum of 31 subjects who died with healthy liver (n = 6), NASH (n = 14), ASH (n = 3), nonalcoholic cirrhosis (n = 4), and alcoholic cirrhosis (n = 4). We analyzed in cerebellum, as an early marker for brain injury: 1) vascular damage; 2) cerebellar atrophy and neurodegeneration in Purkinje layer; and 3) microglia and astrocytes activation in white matter and molecular layer. Patients with steatohepatitis have increased number of microtrombi in cerebellar parenchyma, neuronal loss in Purkinje layer and microglial and astrocyte activation in white matter and molecular layer. These alterations are stronger in patients with ASH than in those with NASH. These results provide a set of histopathological features in brain that may allow differentiation of steatohepatitis from other conditions.

The Cerebellum of Patients with Steatohepatitis Shows Lymphocyte Infiltration, Microglial Activation and Loss of Purkinje and Granular Neurons.

Peripheral inflammation contributes to minimal hepatic encephalopathy in chronic liver diseases, which could be mediated by neuroinflammation. Neuroinflammation in cerebellum of patients with chronic liver diseases has not been studied in detail. Our aim was to analyze in cerebellum of patients with different grades of liver disease, from mild steatohepatitis to cirrhosis and hepatic encephalopathy: (a) neuronal density in Purkinje and granular layers; (b) microglial activation; (c) astrocyte activation; (d) peripheral lymphocytes infiltration; (e) subtypes of lymphocytes infiltrated. Steatohepatitis was classified as SH1, SH2 and SH3. Patients with SH1 show Th17 and Tfh lymphocytes infiltration in the meninges, microglia activation in the molecular layer and loss of 16 ± 4% of Purkinje and 19 ± 2% of granular neurons. White matter remains unaffected. With the progression of liver disease to worse stages (SH2, SH3, cirrhosis) activation of microglia and astrocytes extends to white matter, Bergman glia is damaged in the molecular layer and there is a further loss of Purkinje neurons. The results reported show that neuroinflammation in cerebellum occurs at early stages of liver disease, even before reaching cirrhosis. Neuroinflammation occurs earlier in the molecular layer than in white matter, and is associated with infiltration of peripheral Th17 and Tfh lymphocytes.

Rosette-forming glioneuronal tumor of the fourth ventricle. Two cases report and literature review. / Tumor glioneuronal formador de rosetas del IV ventrículo. Presentación de 2casos y revisión de la literatura.

Rosette-forming glioneuronal tumor of the fourth ventricle is a primary central nervous system tumor introduced in the group of glioneuronal tumors in the WHO classification of 2007. Initially it was described around the fourth ventricle, but recently have been published cases in different locations. We present 2cases of this rare tumor, both surgically treated. The first in a 41 year old man with typical symptoms of posterior fossa injury. The second in an 18 year old woman, with incidental finding of posterior fossa injury that was also surgically treated. We present pre- and post-surgical magnetic resonance images, histological pictures of this tumor and we make a review of the literature.

El grosor y una expresión de miARN alterada en la grasa epicárdica se asocian con enfermedad coronaria en víctimas de muerte súbita / Thickness and an altered miRNA expression in the epicardial adipose tissue is associated with coronary heart disease in sudden death victims

Introducción y objetivos: El aumento de la grasa epicárdica (GE) es un nuevo factor de riesgo de enfermedad coronaria (EC). El estudio se propone profundizar en el papel de la GE como marcador de EC centrándose en su espesor, el perfil de expresión de los microARN (miARN) y los factores que podrían influir en ello. Métodos: Se recogieron prospectivamente 155 autopsias de víctimas de muerte súbita cardiaca por EC y 84 de controles con muerte súbita no debida a EC. En un subgrupo se analizaron el espesor de la GE y su patrón de expresión de miARN. Resultados: El grosor de GE estaba incrementado y brindaba buena precisión para discriminar a los pacientes (entre otras mediciones, área bajo la curva de la puntuación de GE, 0,718; p < 0,001). La GE de los pacientes presentó 14 miARN suprarregulados y 14 infrarregulados, y se validaron por reacción en cadena de la polimerasa en tiempo real miR-34a-3p, -34a-5p, -124-3p, -125a-5p, 628-5p, -1303 y -4286. Las proporciones de miR-34a-3p y -34a-5p en la GE de los pacientes fueron mayores que en los controles (con progresión entre la GE de coronarias sin estenosis, con estenosis estables y con placas complicadas) y solo se correlacionaron con la edad en los controles. La discreta correlación del miR-34a-5p en el hígado y la GE de los pacientes (r = 0,295; p = 0,020) aumentó llamativamente al considerar exclusivamente la GE de placas complicadas (r = 0,799; p = 0,017). Se observaron correlaciones similares con la proteína C reactiva ultrasensible y el miR-34a-5p en las muestras de GE e hígado. Conclusiones: El patrón de expresión de miARN en la GE de la EC típicamente muestra un aumento de miR-34a-3p y -34a-5p que es independiente de la edad, el grosor de la GE, las mediciones antropométricas y la presencia de lesiones coronarias subyacentes

Introduction and objectives: An increased epicardial adipose tissue (EAT) thickness has become a new risk factor for coronary heart disease (CHD). We aimed to study the role of EAT dysfunction as a CHD marker by focusing on its thickness and microRNA (miRNA) expression profile, and the potential factors possibly influencing them. Methods: One hundred and fifty-five CHD sudden cardiac death victims and 84 non-CHD-sudden death controls were prospectively enrolled at autopsy. A representative subset underwent EAT thickness measurements and EAT miRNA expression profiling. Results: Epicardial adipose tissue thickness was increased and allowed an accurate diagnosis of patient status (among other measurements, EAT score area under the curve 0.718, P < .001). Epicardial adipose tissue from patients showed 14 up- and 14 down-regulated miRNAs and miR-34a-3p, -34a-5p, -124-3p, -125a-5p, 628-5p, -1303 and -4286 were validated by quantitative real-time polymerase chain reaction. Patients exhibited higher EAT levels of miR-34a-3p and -34a-5p than controls (with a positive trend considering EAT from coronaries without stenosis, with stable stenosis and complicated plaques) and correlated with age only in controls. The mild positive correlation between liver and EAT miR-34a-5p levels in patients (r = 0.295, P = .020) dramatically increased in EAT from complicated plaques (r = 0.799, P = .017). Similar correlations were observed for high-sensitivity-C-reactive protein levels and miR-34a-5p levels both in EAT and liver extracts. Conclusions: Increased age-independent levels of miR-34a-3p and -34a-5p characterize the EAT miRNA expression profile of CHD regardless of EAT thickness, anthropometric parameters, and the presence of underlying atherosclerotic plaques

Tumor glioneuronal formador de rosetas del IV ventrículo. Presentación de 2casos y revisión de la literatura / Rosette-forming glioneuronal tumor of the fourth ventricle. Two cases report and literature review

El tumor glioneuronal formador de rosetas del IV ventrículo es un tumor primario del sistema nervioso central introducido en el grupo de tumores glioneuronales en la clasificación de la OMS de 2007. Inicialmente se describió alrededor del IV ventrículo, pero recientemente se han publicados casos en distintas localizaciones. Presentamos 2casos de este raro tumor, ambos tratados quirúrgicamente. El primero en un varón de 41 años de edad, con síntomas típicos de lesión de fosa posterior; el segundo, en una mujer de 18 años de edad, con hallazgo incidental de lesión en fosa posterior que también fue tratada quirúrgicamente. Presentamos imágenes de resonancia magnética pre- y posquirúrgicas, aportamos imágenes histológicas de este tumor y realizamos una revisión de la literatura

Rosette-forming glioneuronal tumor of the fourth ventricle is a primary central nervous system tumor introduced in the group of glioneuronal tumors in the WHO classification of 2007. Initially it was described around the fourth ventricle, but recently have been published cases in different locations. We present 2cases of this rare tumor, both surgically treated. The first in a 41 year old man with typical symptoms of posterior fossa injury. The second in an 18 year old woman, with incidental finding of posterior fossa injury that was also surgically treated. We present pre- and post-surgical magnetic resonance images, histological pictures of this tumor and we make a review of the literature

Xantogranuloma de silla turca / Sellar xanthogranuloma

Se trata de una paciente de 16 años con antecedentes de pubertad precoz idiopática con imagen hipofisaria normal. Diez años después y en relación con el agravamiento de los episodios de cefalea de Horton, se realizó una nueva resonancia magnética craneal, en la que se objetivó una lesión sospechosa de sangrado intrahipofisario. Fue tratada con corticoides, que mejoraron la cefalea pero ocasionaron una complicación grave, la psicosis por esteroides. La decisión de tratamiento quirúrgico y el estudio anatomopatológico de la lesión llevaron al diagnóstico diferencial entre craneofaringioma y xantogranuloma de silla turca. La evolución de la lesión (ausente 10 años antes), la indemnidad de la funcionalidad hormonal y visual, la resección total (muy difícil cuando se trata de craneofaringiomas) y la ausencia de recidiva hacen que el diagnóstico de xantogranuloma de silla turca sea prácticamente seguro Objetivo: Conocer el proceso de adaptación a la diabetes mellitus tipo 1 (DM1) y analizar su correspondencia con las etapas del proceso de duelo descritas por Kübler-Ross. Sujetos y método: Estudio etnográfico mediante entrevistas en profundidad a 20 pacientes, 10 familiares y 12 profesionales (6 médicos y 6 enfermeras). Para el análisis se siguió el esquema de análisis de datos cualitativos de Miles y Huberman. Resultados: El paciente diagnosticado de DM1 y su familia afrontan la pérdida del estilo de vida y los objetos reales o imaginarios de su vida pasada. Enfermos y familiares experimentan reacciones emocionales que, en algún caso, pueden asemejarse a las etapas de duelo descritas por Kübler-Ross en una enfermedad terminal (negación, rebeldía, negociación, depresión y aceptación), pero hay diferencias que dependen de factores personales y psicosociales. Los profesionales tienden a relacionar la mala adherencia con la negación de la enfermedad, pero algunos pacientes se sienten amenazados por las exigencias de tratamiento y control y por sus consecuencias en su calidad de vida, y conscientemente optan por no seguir las recomendaciones. Es más realista hablar de adaptación a la enfermedad que de aceptación, puesto que los procesos de pérdida son constantes y el enfermo debe reconstruir nuevas identidades según su estado. El proceso de duelo afecta también a la familia y puede ser diferente que el del enfermo en tiempo, intensidad y valoración de los problemas. Conclusiones: La adaptación es un proceso complejo en el que intervienen muchas variables. Se observan diferencias en los mecanismos que utiliza cada sujeto en particular. Los profesionales sanitarios y, particularmente la enfermera, deben considerar las múltiples dimensiones psicosociales de la enfermedad crónica (AU)

We report the case of a 16-year-old girl with a history of idiopathic precocious puberty and normal results on pituitary imaging scan. Ten years later, a new cranial magnetic resonance imaging scan was performed due to worsening of episodes resembling Horton's headache and a lesion suggestive of pituitary bleeding was detected. The headaches diminished with glucocorticoid administration but a severe complication, steroid psychosis, occurred. Surgical treatment and pathological study of the lesion led to the differential diagnosis between craniopharyngyoma and xanthogranuloma of the sella turcica. The clinical progression of the tumor (not visualized 10 years previously), together with preservation of pituitary and visual function both before and after surgery, gross total removal of the tumor (difficult to achieve with craniopharyngioma) and the absence of recurrence provide strong support for the diagnosis of xanthogranuloma of the sella turcica (AU)