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Diagnostics (Basel, Switzerland) May 2024Sudden unexpected deaths often remain unresolved despite forensic examination, posing challenges for pathologists. Molecular autopsy, through genetic testing, can reveal... (Review)
Review
Sudden unexpected deaths often remain unresolved despite forensic examination, posing challenges for pathologists. Molecular autopsy, through genetic testing, can reveal hidden causes undetectable by standard methods. This review assesses the role of molecular autopsy in clarifying SUD cases, examining its methodology, utility, and effectiveness in autopsy practice. This systematic review followed PRISMA guidelines and was registered with PROSPERO (registration number: CRD42024499832). Searches on PubMed, Scopus, and Web of Science identified English studies (2018-2023) on molecular autopsy in sudden death cases. Data from selected studies were recorded and filtered based on inclusion/exclusion criteria. Descriptive statistics analyzed the study scope, tissue usage, publication countries, and journals. A total of 1759 publications from the past 5 years were found, with 30 duplicates excluded. After detailed consideration, 1645 publications were also excluded, leaving 84 full-text articles for selection. Out of these, 37 full-text articles were chosen for analysis. Different study types were analyzed. Mutations were identified in 17 studies, totaling 47 mutations. Molecular investigations are essential when standard exams fall short in determining sudden death causes. Expertise in molecular biology is crucial due to diverse genetic conditions. Discrepancies in post-mortem protocols affect the validity of results, making standardization necessary. Multidisciplinary approaches and the analysis of different tissue types are vital.
PubMed: 38893676
DOI: 10.3390/diagnostics14111151 -
Diagnostics (Basel, Switzerland) May 2024Kounis Syndrome (KS) is a clinical entity triggered by allergic or hypersensitivity reactions capable of inducing acute coronary events. Several causes can induce KS,...
Kounis Syndrome (KS) is a clinical entity triggered by allergic or hypersensitivity reactions capable of inducing acute coronary events. Several causes can induce KS, including drugs and insect stings. Here, a rare case of post mortem assessment of fatal KS related to fluorescein retinal angiography has been reported. An 80-year-old man in follow-up for a retinal vein thrombosis underwent a retinal fluoroangiography. Approximately 30 min later, the patient complained of sweating and dizziness, and suddenly lost consciousness due to a cardiac arrest. Despite the immediate cardiopulmonary resuscitation, he died. The autopsy revealed foamy yellowish edema in the respiratory tract and coronary atherosclerosis with eccentric plaques partially obstructing the lumen. The routine histology highlighted lung emphysema and myocyte break-up with foci of contraction band necrosis at the myocardial tissue. Biochemistry showed increased serum tryptase, troponin, and p-BNP. Activated and degranulated (tryptase) mast cells were detected, using immunohistochemistry, in the larynx, lungs, spleen, and heart. Acute myocardial ischemia due to allergic coronary vasospasm related to fluorescein hypersensitivity has been assessed as cause of death. KS-related deaths are considered rare events, and the post mortem assessment of KS quite difficult. The integration of several investigations (gross and microscopic examination, biochemistry, immunohistochemistry) can provide useful findings to support the diagnosis, helping to reduce the unrecognized cases as much as possible.
PubMed: 38893621
DOI: 10.3390/diagnostics14111092 -
International Journal of Molecular... May 2024Pathogenic variants in the gene lead to a systemic disease with karyomegalic interstitial nephritis (KIN) at the forefront clinically. The phenotypic-genotypic features...
Pathogenic variants in the gene lead to a systemic disease with karyomegalic interstitial nephritis (KIN) at the forefront clinically. The phenotypic-genotypic features of a mutation-related disease involving five members of a Hungarian Caucasian family are presented. Each had adult-onset chronic kidney disease of unknown cause treated with renal replacement therapy and elevated liver enzymes. Short stature, emaciation, latte-colored skin, freckles, and a hawk-like nose in four patients, a limited intellect in two patients, and chronic restrictive lung disease in one patient completed the phenotype. Severe infections occurred in four patients. All five patients had ceased. Four patients underwent autopsy. KIN and extrarenal karyomegaly were observed histologically; the livers showed no specific abnormality. The genotyping using formalin-fixed tissue samples detected a hitherto undescribed homozygous mutation (c.1673_1674insT/p.Met558lfs*4; exon 5) in three of these patients and a heterozygous mutation in one patient. The reason for the heterozygosity is discussed. In addition, 56 family members consented to the screening for mutation from which 17 individuals proved to be heterozygous carriers; a blood chemistry evaluation of their kidney and liver function did not find any abnormality. The clinical presentation of FAN1-related disease was multifaceted, and not yet described manifestations were observed besides kidney and liver disease. Mutation in this gene should be suspected in adults with small kidneys of unknown cause, elevated liver enzymes, and recurrent infections, even without a family history.
Topics: Humans; Male; Female; Hungary; Mutation; Adult; Phenotype; Pedigree; Middle Aged; Exodeoxyribonucleases; Multifunctional Enzymes; Endodeoxyribonucleases; Genotype; Renal Insufficiency, Chronic
PubMed: 38892095
DOI: 10.3390/ijms25115907 -
International Journal of Molecular... May 2024Plaque erosion (PE), a distinct etiology of acute coronary syndromes (ACSs), is often overshadowed by plaque ruptures (PRs). Concerning its epidemiology, PE has garnered... (Review)
Review
Plaque erosion (PE), a distinct etiology of acute coronary syndromes (ACSs), is often overshadowed by plaque ruptures (PRs). Concerning its epidemiology, PE has garnered increasing recognition, with recent studies revealing its prevalence to be approximately 40% among ACS patients, challenging earlier assumptions based on autopsy data. Notably, PE exhibits distinct epidemiological features, preferentially affecting younger demographics, particularly women, and often manifesting as a non-ST-segment elevation myocardial infarction. There are seasonal variations, with PE events being less common in winter, potentially linked to physiological changes and cholesterol solidification, while peaking in summer, warranting further investigation. Moving to molecular mechanisms, PE presents a unique profile characterized by a lesser degree of inflammation compared to PR, with endothelial shear stress emerging as a plausible molecular mechanism. Neutrophil activation, toll-like receptor-2 pathways, and hyaluronidase 2 expression are among the factors implicated in PE pathophysiology, underscoring its multifactorial nature. Advancements in intravascular imaging diagnostics, particularly optical coherence tomography and near-infrared spectroscopy coupled with intravascular ultrasound, offer unprecedented insights into plaque composition and morphology. Artificial intelligence algorithms show promise in enhancing diagnostic accuracy and streamlining image interpretation, augmenting clinician decision-making. Therapeutically, the management of PE evolves, with studies exploring less invasive approaches such as antithrombotic therapy without stenting, particularly in cases identified early through intravascular imaging. Additionally, the potential role of drug-coated balloons in reducing thrombus burden and minimizing future major adverse cardiovascular events warrants further investigation. Looking ahead, the integration of advanced imaging modalities, biomarkers, and artificial intelligence promises to revolutionize the diagnosis and treatment of coronary PE, ushering in a new era of personalized and precise cardiovascular care.
Topics: Humans; Plaque, Atherosclerotic; Tomography, Optical Coherence; Coronary Artery Disease; Acute Coronary Syndrome
PubMed: 38891972
DOI: 10.3390/ijms25115786 -
International Journal of Molecular... May 2024While considerable attention has been devoted to respiratory manifestations, such as pneumonia and acute respiratory distress syndrome (ARDS), emerging evidence...
While considerable attention has been devoted to respiratory manifestations, such as pneumonia and acute respiratory distress syndrome (ARDS), emerging evidence underlines the significance of extrapulmonary involvement. In this study, we examined 15 hospitalized patients who succumbed to severe complications following SARS-CoV-2 infection. These patients were admitted to the Sibiu County Clinical Emergency Hospital in Sibiu, Romania, between March and October 2021. All patients were ethnic Romanians. Conducted within a COVID-19-restricted environment and adhering to national safety protocols, autopsies provided a comprehensive understanding of the disease's multisystemic impact. Detailed macroscopic evaluations and histopathological analyses of myocardial, renal, hepatic, splenic, and gastrointestinal tissues were performed. Additionally, reverse transcription-quantitative polymerase chain reaction (rt-qPCR) assays and immunohistochemical staining were employed to detect the viral genome and nucleocapsid within the tissues. Myocardial lesions, including ischemic microstructural changes and inflammatory infiltrates, were prevalent, indicative of COVID-19's cardiac implications, while renal pathology revealed the chronic alterations, acute tubular necrosis, and inflammatory infiltrates most evident. Hepatic examination identified hepatocellular necroinflammatory changes and hepatocytic cytopathy, highlighting the hepatic involvement of SARS-CoV-2 infection. Splenic parenchymal disorganization was prominent, indicating systemic immune dysregulation. Furthermore, gastrointestinal examinations unveiled nonspecific changes. Molecular analyses detected viral genes in various organs, with immunohistochemical assays confirming viral presence predominantly in macrophages and fibroblasts. These findings highlighted the systemic nature of SARS-CoV-2 infection, emphasizing the need for comprehensive clinical management strategies and targeted therapeutic approaches beyond respiratory systems.
Topics: Humans; SARS-CoV-2; COVID-19; Male; Female; Middle Aged; Genome, Viral; Aged; Kidney; Liver; Adult; Spleen; Romania; Nucleocapsid; Myocardium; Autopsy; Aged, 80 and over; Coronavirus Nucleocapsid Proteins
PubMed: 38891942
DOI: 10.3390/ijms25115755 -
International Journal of Molecular... May 2024Suicide is a major public health priority, and its molecular mechanisms appear to be related to glial abnormalities and specific transcriptional changes. This study... (Review)
Review
Suicide is a major public health priority, and its molecular mechanisms appear to be related to glial abnormalities and specific transcriptional changes. This study aimed to identify and synthesize evidence of the relationship between glial dysfunction and suicidal behavior to understand the neurobiology of suicide. As of 26 January 2024, 46 articles that met the inclusion criteria were identified by searching PubMed and ISI Web of Science. Most postmortem studies, including 30 brain regions, have determined no density or number of total Nissl-glial cell changes in suicidal patients with major psychiatric disorders. There were 17 astrocytic, 14 microglial, and 9 oligodendroglial studies using specific markers of each glial cell and further on their specific gene expression. Those studies suggest that astrocytic and oligodendroglial cells lost but activated microglia in suicides with affective disorder, bipolar disorders, major depression disorders, or schizophrenia in comparison with non-suicided patients and non-psychiatric controls. Although the data from previous studies remain complex and cannot fully explain the effects of glial cell dysfunction related to suicidal behaviors, they provide risk directions potentially leading to suicide prevention.
Topics: Humans; Neuroglia; Suicide; Brain; Biomarkers; Autopsy; Suicidal Ideation; Bipolar Disorder
PubMed: 38891940
DOI: 10.3390/ijms25115750 -
Annals of Emergency Medicine Jun 2024Acute aortic syndrome is a life-threatening emergency condition. Previous systematic reviews of D-dimer diagnostic accuracy for acute aortic syndrome have been...
STUDY OBJECTIVE
Acute aortic syndrome is a life-threatening emergency condition. Previous systematic reviews of D-dimer diagnostic accuracy for acute aortic syndrome have been contradictory and based on limited data, but recently published studies offer potential for a more definitive overview. We aimed to perform a systematic review and meta-analysis to determine the diagnostic accuracy of D-dimer for diagnosing acute aortic syndrome.
METHODS
We searched MEDLINE, EMBASE, and the Cochrane Library from inception to February 2024. Additionally, the reference lists of included studies and other systematic reviews were thoroughly searched. All diagnostic cohort studies (prospective or retrospective) that assessed the use of D-dimer for diagnosing acute aortic syndrome compared with a reference standard test (eg, computed tomographic angiography (CTA), ECG-gated CTA, echocardiography, magnetic resonance angiography, operation, or autopsy) were included. Two independent reviewers completed study selection, data extractions and quality assessment using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Data were synthesized using a bivariate meta-analysis model.
RESULTS
Of 2017 potentially relevant citations, 25 cohort studies met the inclusion criteria, and 18 reporting the 500 ng/mL threshold were included in the primary meta-analysis. Risk of bias domains were mostly unclear due to limited study reporting. The summary sensitivity was 96.5% (95% credible interval [CrI] 94.8% to 98%) and summary specificity was 56.2% (95% CrI, 48.3% to 63.9%). Study specificity varied markedly from 33% to 86%, indicating substantial heterogeneity. Sensitivity analysis including the 7 studies reporting other thresholds showed summary sensitivity of 95.7% (95% CrI, 93.2% to 97.5%) and summary specificity of 57.5% (95% CrI, 50.1% to 64.6%).
CONCLUSION
D-dimer concentration has high sensitivity (96.5%) and moderate specificity (56.2%) for acute aortic syndrome, with some uncertainty around estimates due to risk of bias and heterogeneity. Previous meta-analysis reporting higher specificity may be explained by inclusion of case-control studies that may overestimate accuracy.
PubMed: 38888529
DOI: 10.1016/j.annemergmed.2024.05.001 -
Alzheimer's Research & Therapy Jun 2024Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a...
BACKGROUND
Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer's disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine's neuroprotective effects, potentially compromising the neuronal integrity of LC's cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness.
METHODS
A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample.
RESULTS
Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP.
CONCLUSIONS
Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.
Topics: Humans; Locus Coeruleus; Female; Alzheimer Disease; Male; Aged; Magnetic Resonance Imaging; tau Proteins; Aged, 80 and over; Cohort Studies; Amyloid beta-Peptides; Positron-Emission Tomography; Cerebral Cortex; Carbolines; Thiazoles; Aniline Compounds; Brain Cortical Thickness
PubMed: 38886798
DOI: 10.1186/s13195-024-01500-0 -
Heliyon Jun 2024The molecular pathology of lung injury in patients with Corona Virus Disease 2019 (COVID-19) remain unclear. In this study, we performed a proteomic study of lung...
The molecular pathology of lung injury in patients with Corona Virus Disease 2019 (COVID-19) remain unclear. In this study, we performed a proteomic study of lung tissues from seven patients with COVID-19, and eight without. Lung parenchymal tissues with COVID-19 were obtained from autopsy samples, while control samples were obtained from paracancerous tissues. Proteins were extracted using phenol extraction. A tandem mass tag-based quantitative proteomic approach combined with bioinformatic analysis was used to detect proteomic changes in the SARS-CoV-2-infected lung tissues. A total of 6,602, and 6,549 proteins were identified in replicates 1 and 2, respectively. Of these, 307, and 278, respectively, were identified as differentially expressed proteins (DEPs). In total, 216 DEPs were identified in this study. These proteins were enriched in 189 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The downregulated proteins are mainly involved in focal adhesion (n = 5), and the PI3K-Akt signaling pathway (n = 4). The upregulated proteins were related to neutrophil extracellular trap (NET) formation (n = 16), and the phagosome pathway (n = 11). The upregulated proteins in these two pathways interact with one another. Further immunohistochemistry verified NET enrichment in the tissues with COVID-19 compared to the controls. Our results systematically outlined the proteomic profiles of the lung's response to SARS-CoV-2 infection and indicated that NET formation was hyper-activated. These results will hopefully provide new evidence for understanding the mechanism behind fatal COVID-19.
PubMed: 38882332
DOI: 10.1016/j.heliyon.2024.e31878 -
Cureus Jun 2024Background Inborn errors of metabolism (IEM) are collectively rare but potentially preventable causes of sudden unexpected death (SUD) in infancy or childhood, and...
Background Inborn errors of metabolism (IEM) are collectively rare but potentially preventable causes of sudden unexpected death (SUD) in infancy or childhood, and metabolic autopsy serves as the final tool for establishing the diagnosis. We conducted a retrospective review of the metabolic and molecular autopsy on SUD and characterized the biochemical and genetic findings. Methodology A retrospective review of postmortem metabolic investigations (dried blood spot acylcarnitines and amino acid analysis, urine metabolic profiling where available, and next-generation sequencing on a panel of 75 IEM genes) performed for infants and children who presented with SUD between October 2016 and December 2021 with inconclusive autopsy findings or autopsy features suspicious of underlying IEM in our locality was conducted. Clinical and autopsy findings were reviewed for each case. Results A total of 43 infants and children aged between zero days to 10 years at the time of death were referred to the authors' laboratories throughout the study period. One positive case of multiple acyl-CoA dehydrogenase deficiency was diagnosed. Postmortem reference intervals for dried blood spot amino acids and acylcarnitines profile were established based on the results from the remaining patients. Conclusions Our study confirmed the importance of metabolic autopsy and the advantages of incorporating biochemical and genetic testing in this setting.
PubMed: 38882225
DOI: 10.7759/cureus.62347