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Nature Communications Jun 2024Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples,...
Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries offer more nuanced and accurate insights into the regulatory mechanisms of RNA editing in the human brain.
Topics: Humans; RNA Editing; Adenosine; Adenosine Deaminase; Brain; Inosine; RNA-Binding Proteins; Autopsy; Prefrontal Cortex; Postmortem Changes; Male
PubMed: 38926387
DOI: 10.1038/s41467-024-49268-z -
International Journal of Legal Medicine Jun 2024Forensic pathologists need to have comprehensive knowledge of a large variety of causes of sudden natural death. We describe a case of sudden and unexpected death in...
Forensic pathologists need to have comprehensive knowledge of a large variety of causes of sudden natural death. We describe a case of sudden and unexpected death in woman in her sixties due to rupture of a large paraesophageal hematoma. The post-mortem examination and differential diagnosis are discussed. The combined findings of whole-body post-mortem CT imaging (PMCT), targeted PMCT angiography, autopsy, and histology are most in keeping with 'esophageal apoplexy'; a rare cause of hemorrhage in the esophageal wall. A review of the literature indicates that most cases of esophageal apoplexy are self-limiting and that fatal complications are exceedingly rare. Our case demonstrates that esophageal apoplexy can present as sudden unexpected death.
PubMed: 38926244
DOI: 10.1007/s00414-024-03280-6 -
Alzheimer's & Dementia : the Journal of... Jun 2024The established cerebrospinal fluid (CSF) phosphorylated tau181 (p-tau181) may not reliably reflect concomitant Alzheimer's disease (AD) and primary age-related...
INTRODUCTION
The established cerebrospinal fluid (CSF) phosphorylated tau181 (p-tau181) may not reliably reflect concomitant Alzheimer's disease (AD) and primary age-related tauopathy (PART) found in Creutzfeldt-Jakob disease (CJD) at autopsy.
METHODS
We investigated CSF N-terminal p-tau181, p-tau217, and p-tau231 with in-house Simoa assays in definite CJD (n = 29), AD dementia (n = 75), mild cognitive impairment (MCI) due to AD (n = 65), and subjective cognitive decline (SCD, n = 28). Post-mortem examination performed in patients with CJD 1.3 (0.3-14.3) months after CSF collection revealed no co-pathology in 10, concomitant AD in 8, PART in 8, and other co-pathologies in 3 patients.
RESULTS
N-terminal p-tau was increased in CJD versus SCD (p < 0.0001) and correlated with total tau (t-tau) in the presence of AD and PART co-pathology (rho = 0.758-0.952, p ≤ 001). Concentrations in CJD were indistinguishable from AD dementia, with the largest fold-change in p-tau217 (11.6), followed by p-tau231 and p-tau181 (3.2-4.5).
DISCUSSION
Variable fold-changes and correlation with t-tau suggest that p-tau closely associates with neurodegeneration and concomitant AD in CJD.
HIGHLIGHTS
N-terminal phosphorylated tau (p-tau) biomarkers are increased in Creutzfeldt-Jakob disease (CJD) with and without concomitant AD. P-tau217, p-tau231, and p-tau181 correlate with total tau (t-tau) and increase in the presence of amyloid beta (Aβ) co-pathology. N-terminal p-tau181 and p-tau231 in Aβ-negative CJD show variation among PRNP genotypes. Compared to mid-region-targeting p-tau181, cerebrospinal fluid (CSF) N-terminal p-tau has greater potential to reflect post-mortem neuropathology in the CJD brain.
PubMed: 38924651
DOI: 10.1002/alz.13907 -
Molecular Genetics & Genomic Medicine Jun 2024Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle, systolic dysfunction, and normal or reduced thickness of the left ventricular wall. It...
BACKGROUND
Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle, systolic dysfunction, and normal or reduced thickness of the left ventricular wall. It is a leading cause of heart failure and cardiac death at a young age. Cases with neonatal onset DCM were correlated with severe clinical presentation and poor prognosis. A monogenic molecular etiology accounts for nearly half of cases.
FAMILY DESCRIPTION
Here, we report a family with three deceased offspring at the age of 1 year old. The autopsy of the first deceased infant revealed a DCM. The second infant presented a DCM phenotype with a severely reduced Left Ventricular Ejection Fraction (LVEF) of 10%. Similarly, the third infant showed a severe DCM phenotype with LVEF of 30% as well, in addition to eccentric mitral insufficiency.
RESULTS
Exome sequencing was performed for the trio (the second deceased infant and her parents). Data analysis following the autosomal dominant and recessive patterns of inheritance was carried out along with a mitochondrial pathways-based analysis. We identified a homozygous frameshift variant in the TNNI3 gene (c.204delG; p.(Arg69AlafsTer8)). This variant has been recently reported in the ClinVar database in association with cardiac phenotypes as pathogenic or likely pathogenic and classified as pathogenic according to ACMG.
CONCLUSION
Genetic counseling was provided for the family and a prenatal diagnosis of choronic villus was proposed in the absence of pre-implantation genetic diagnosis possibilities. Our study expands the case series of early-onset DCM patients with a protein-truncating variant in the TNNI3 gene by reporting three affected infant siblings.
Topics: Humans; Cardiomyopathy, Dilated; Frameshift Mutation; Female; Homozygote; Pedigree; Consanguinity; Male; Infant; Phenotype; Troponin I
PubMed: 38924380
DOI: 10.1002/mgg3.2486 -
Journal of Forensic Sciences Jun 2024Gallstones are common in the general population and are often asymptomatic, but they can also cause complications such as cholecystitis and pancreatitis. In rare...
Gallstones are common in the general population and are often asymptomatic, but they can also cause complications such as cholecystitis and pancreatitis. In rare instances, they can lead to the formation of a cholecystoduodenal fistula and gallstone ileus. Gastric dilatation and distension following gallstone ileus are extremely uncommon and have rarely been reported in the literature. We report a fatal case of massive gastropathy as a result of Bouveret syndrome secondary to gallstone obstruction.
PubMed: 38922918
DOI: 10.1111/1556-4029.15573 -
Drug Testing and Analysis Jun 2024Atrazine is a triazine organochloride herbicide, frequently used in different agricultural activities. Rare acute intoxication with atrazine is reported in production...
Atrazine is a triazine organochloride herbicide, frequently used in different agricultural activities. Rare acute intoxication with atrazine is reported in production animals, and its metabolism in mammals is unknown. We report a spontaneous case of atrazine acute intoxication in 16.1% animals of a 168-beef heifer herd exposed to the herbicide at a farm located in Buenos Aires province, Argentina. Affected heifers showed different neurological signs and died suddenly, similar to the previous natural atrazine intoxication report. During autopsy, no gross lesions were observed. Different body fluids and tissues samples were collected during postmortem examination. No relevant histopathological findings were observed. High levels of atrazine and its metabolites were detected in different fluids and tissues by ultra-liquid chromatography high performance coupled to triple quadrupole mass spectrometry. These findings suggest ruminal or hepatic metabolization of atrazine in the exposed cattle. This is the first report of quantification and distribution of atrazine and its metabolites in intoxicated mammals providing relevant information for diagnostic purposes.
PubMed: 38922760
DOI: 10.1002/dta.3754 -
Cells Jun 2024Multiple sclerosis (MS) is a clinically heterogeneous disease underpinned by inflammatory, demyelinating and neurodegenerative processes, the extent of which varies...
BACKGROUND
Multiple sclerosis (MS) is a clinically heterogeneous disease underpinned by inflammatory, demyelinating and neurodegenerative processes, the extent of which varies between individuals and over the course of the disease. Recognising the clinicopathological features that most strongly associate with disease outcomes will inform future efforts at patient phenotyping.
AIMS
We used a digital pathology workflow, involving high-resolution image acquisition of immunostained slides and opensource software for quantification, to investigate the relationship between clinical and neuropathological features in an autopsy cohort of progressive MS.
METHODS
Sequential sections of frontal, cingulate and occipital cortex, thalamus, brain stem (pons) and cerebellum including dentate nucleus (n = 35 progressive MS, females = 28, males = 7; age died = 53.5 years; range 38-98 years) were immunostained for myelin (anti-MOG), neurons (anti-HuC/D) and microglia/macrophages (anti-HLA). The extent of demyelination, neurodegeneration, the presence of active and/or chronic active lesions and quantification of brain and leptomeningeal inflammation was captured by digital pathology.
RESULTS
Digital analysis of tissue sections revealed the variable extent of pathology that characterises progressive MS. Microglia/macrophage activation, if found at a higher level in a single block, was typically elevated across all sampled blocks. Compartmentalised (perivascular/leptomeningeal) inflammation was associated with age-related measures of disease severity and an earlier death.
CONCLUSION
Digital pathology identified prognostically important clinicopathological correlations in MS. This methodology can be used to prioritise the principal pathological processes that need to be captured by future MS biomarkers.
Topics: Humans; Middle Aged; Female; Male; Multiple Sclerosis; Aged; Adult; Biomarkers; Aged, 80 and over; Inflammation; Brain; Microglia; Macrophages
PubMed: 38920650
DOI: 10.3390/cells13121020 -
Archive of Clinical Cases 2024Mediastinal tumors are exceedingly rare during fetal development, presenting significant diagnostic challenges and potentially leading to severe outcomes such as...
Mediastinal tumors are exceedingly rare during fetal development, presenting significant diagnostic challenges and potentially leading to severe outcomes such as stillbirth or metastatic disease if not promptly identified and managed. Pleuropulmonary blastomas are primitive mesenchymal tumors often linked to mutations in the DICER1 gene, indicating a hereditary pattern associated with other common adult neoplasms with dominant inheritance. This report describes a case involving a 20-year-old Caucasian woman whose pregnancy was complicated by a stillbirth in the second trimester. Initial suspicions of a mediastinal tumor arose from blood tests and ultrasound examinations during pregnancy surveillance. However, the definitive diagnosis of a type II pleuropulmonary blastoma was established through a pathological examination at autopsy. This case underscores the complexities of diagnosing fetal mediastinal tumors and contributes to the sparse literature on neonatal pleuropulmonary blastomas. Our comprehensive review of the differential diagnoses and literature emphasizes the unique characteristics of pleuropulmonary blastoma and its similarities to other soft tissue sarcomas, enhancing understanding of their clinical and genetic profiles.
PubMed: 38919847
DOI: 10.22551/2024.43.1102.10286 -
Cureus May 2024Atypical aortic origin of coronary artery (AAOCA) is a rare heart condition that has been identified in only a few autopsy cases and in some patients who have undergone...
Atypical aortic origin of coronary artery (AAOCA) is a rare heart condition that has been identified in only a few autopsy cases and in some patients who have undergone angiographic evaluation. AAOCA is known to be closely linked with aortic valve malformations, with the most common type being the bicuspid aortic valve (BAV). A 77-year-old male with a medical history of hypertension and diabetes presented with dyspnea and orthopnea for three days. During the eventual cardiac catheterization, it was noted that the left coronary artery had an anomalous origin from the right side, coursing between the aorta and pulmonary artery. Contrast-enhanced computerized tomography (CECT) also showed a type 2 BAV and a left main coronary artery arising lower at the level of the pulmonary trunk. The dyspnea in this patient was attributed to diastolic dysfunction, and surgical correction of the coronaries was not done. The patient was managed on an outpatient basis for heart failure. In this case, the patient had an anomalous origin of the left coronary artery and type 2 BAV, which posed significant cardiovascular complications. It is unclear if the presence of the concomitant type 2 BAV led to the origin of the anomalous left coronary artery being at a lower level through its effect on the developmental mechanics. This lower origin may have resulted in lower compressive forces on the coronary artery as the inter-arterial pressures would be lower closer to the heart and farther from the lungs. Our case report aims to highlight this complex presentation where the BAV likely provides a benefit in AAOCA cases.
PubMed: 38919205
DOI: 10.7759/cureus.61136 -
The American Journal of Tropical... Jun 2024We examined the self-rated competence of Ugandan healthcare workers (HCWs) in obtaining informed consent for autopsies, considering the challenges of low autopsy...
We examined the self-rated competence of Ugandan healthcare workers (HCWs) in obtaining informed consent for autopsies, considering the challenges of low autopsy acceptance rates globally. In September and October 2023, we conducted a nationwide cross-sectional study of HCWs, who provided informed consent to participate and completed an online, self-administered questionnaire. Participants' self-rated competence in obtaining informed consent for autopsy was assessed through Likert scale questions. Knowledge and practices were also assessed. All scores were converted to percentages, with scores ≥80% indicating higher competence. We enrolled 216 HCWs (including 145 [67.1%] doctors), with a mean age of 31.6 ± 7.2 years. Overall, 55.6% (n = 120) had ever assisted in obtaining consent for autopsy, 43.6% (n = 100) had ever obtained consent for autopsy themselves, and 13.4% (n = 29) had ever attended training on obtaining consent for autopsy. The mean competency score was 59.8 ± 17.0% (perfect score, 100%), with 29 (13.4%) participants demonstrating high competence. Healthcare workers with adequate knowledge had higher competence scores (odds ratio [OR]: 15.0, 95% CI: 6.17-36.58, P <0.001). Compared with nurses/midwives, doctors had 73% lower odds of having a high competence score (adjusted OR: 0.27, 95% CI: 0.08-0.94, P = 0.040). Fewer than one in five Ugandan HCWs demonstrated high self-rated competence or possessed adequate knowledge regarding informed consent for autopsies, and only a few had received specialized training on how to obtain consent for an autopsy. Therefore, there is a pressing need for enhanced training and increased awareness among Ugandan HCWs in obtaining informed consent for autopsies.
PubMed: 38917811
DOI: 10.4269/ajtmh.23-0854