Diplopia as the First Sign of Gastric Carcinoma

Orbital metastasis may be the initial manifestation of a malignancy of unknown origin. The primary locations of orbital metastasis are usually the lung, prostate, gastrointestinal tract, skin, kidney, eye, or thyroid gland. Metastasis of gastric carcinoma to an extraocular eye muscle is extremely rare. A solitary thickening in an extraocular eye muscle with no inflammatory features is suspect for a tumor. Symptoms such as diplopia, proptosis, ptosis, vision loss, or pain may be associated with an orbital malignancy. Our patient, a 67-year-old man known with radically resected prostate cancer, presented with complaints of vertigo with a tendency to fall, headache, and diplopia when looking to the right. As a coincidental finding, swelling of the rectus lateralis muscle of the left eye was observed on imaging. Extensive additional investigations showed that a gastric carcinoma with intraorbital and leptomeningeal metastasis was the cause. In conclusion, a solitary thickened extraocular eye muscle should be recognized in time and examined further

Increase in venous thromboembolism in SARS-CoV-2 infected lung tissue:proteome analysis of lung parenchyma, isolated endothelium, and thrombi

Aims: COVID-19 pneumonia is characterized by an increased rate of deep venous thrombosis and pulmonary embolism. To better understand the pathophysiology behind thrombosis in COVID-19, we performed proteomics analysis on SARS-CoV-2 infected lung tissue. Methods: Liquid chromatography mass spectrometry was performed on SARS-CoV-2 infected postmortem lung tissue samples. Five protein profiling analyses were performed: whole slide lung parenchyma analysis, followed by analysis of isolated thrombi and endothelium, both stratified by disease (COVID-19 versus influenza) and thrombus morphology (embolism versus in situ). Influenza autopsy cases with pulmonary thrombi were used as controls. Results: Compared to influenza controls, both analyses of COVID-19 whole-tissue and isolated endothelium showed upregulation of proteins and pathways related to liver metabolism including urea cycle activation, with arginase being among the top upregulated proteins in COVID-19 lung tissue. Analysis of isolated COVID-19 thrombi showed significant downregulation of pathways related to platelet activation compared to influenza thrombi. Analysis of isolated thrombi based on histomorphology shows that in situ thrombi have significant upregulation of coronavirus pathogenesis proteins. Conclusions: The decrease in platelet activation pathways in severe COVID-19 thrombi suggests a relative increase in venous thromboembolism, as thrombi from venous origin tend to contain fewer platelets than arterial thrombi. Based on histomorphology, in situ thrombi show upregulation of various proteins related to SARS-CoV-2 pathogenesis compared to thromboemboli, which may indicate increased in situ pulmonary thrombosis in COVID-19. Therefore, this study supports the increase of venous thromboembolism without undercutting the involvement of in situ thrombosis in severe COVID-19.</p

COVID-19 in the Netherlands:lessons from a nationwide query of dutch autopsy, histology, and cytology pathological reports

Since the onset of the COVID-19 pandemic, autopsies have played a valuable role in understanding the pathophysiology of COVID-19. In this study, we have analyzed COVID-19-related pathology reports from autopsies, histology, and cytology on a nationwide level. Pathology reports from all 43 pathology laboratories in the Netherlands stating “COVID,” “Corona,” and/or “SARS” were queried from the Dutch Nationwide Pathology Database (Palga). Consecutive reports of the included patients were also retrieved. Out of 5065 entries, a total of 1833 eligible COVID-19-related pathology reports between January 2020 and June 2021 were included in this collection of reports. Lung histopathology reports reflected differences in the severity of abnormalities (acute diffuse alveolar damage, alveolar histiocytes, and thrombi during the first three pandemic waves (Wuhan variant) versus the fourth wave (alpha variant)). Autopsy reports from 2020 state significantly shorter disease duration and younger age of death compared to autopsy reports from 2021. All reports together reflected a more granular pathology with comorbidities such as chronic histiocytic intervillositis, perniosis, and thrombi found in a variety of organs (lungs, kidneys, and small and large intestines). This nationwide overview of pathology reports provides data related to deaths as well as comorbidities in a clinical setting of COVID-19. Certain findings reported in SARS-CoV-infected lungs and placentas were also reported in post-COVID-19 tissue of the same kind. Consecutive reports after the earliest reports with COVID-19 allowed for follow-up reports. These follow-up reports can help with post-viral studies regarding long-term effects of COVID-19 as well as identifying the effects of different SARS-CoV-2 variants.</p

Increase in venous thromboembolism in SARS-CoV-2 infected lung tissue:proteome analysis of lung parenchyma, isolated endothelium, and thrombi

Aims: COVID-19 pneumonia is characterized by an increased rate of deep venous thrombosis and pulmonary embolism. To better understand the pathophysiology behind thrombosis in COVID-19, we performed proteomics analysis on SARS-CoV-2 infected lung tissue. Methods: Liquid chromatography mass spectrometry was performed on SARS-CoV-2 infected postmortem lung tissue samples. Five protein profiling analyses were performed: whole slide lung parenchyma analysis, followed by analysis of isolated thrombi and endothelium, both stratified by disease (COVID-19 versus influenza) and thrombus morphology (embolism versus in situ). Influenza autopsy cases with pulmonary thrombi were used as controls. Results: Compared to influenza controls, both analyses of COVID-19 whole-tissue and isolated endothelium showed upregulation of proteins and pathways related to liver metabolism including urea cycle activation, with arginase being among the top upregulated proteins in COVID-19 lung tissue. Analysis of isolated COVID-19 thrombi showed significant downregulation of pathways related to platelet activation compared to influenza thrombi. Analysis of isolated thrombi based on histomorphology shows that in situ thrombi have significant upregulation of coronavirus pathogenesis proteins. Conclusions: The decrease in platelet activation pathways in severe COVID-19 thrombi suggests a relative increase in venous thromboembolism, as thrombi from venous origin tend to contain fewer platelets than arterial thrombi. Based on histomorphology, in situ thrombi show upregulation of various proteins related to SARS-CoV-2 pathogenesis compared to thromboemboli, which may indicate increased in situ pulmonary thrombosis in COVID-19. Therefore, this study supports the increase of venous thromboembolism without undercutting the involvement of in situ thrombosis in severe COVID-19.</p

Neuroinflammation is increased in the parietal cortex of atypical Alzheimer's disease

BACKGROUND: While most patients with Alzheimer's disease (AD) present with memory complaints, 30% of patients with early disease onset present with non-amnestic symptoms. This atypical presentation is thought to be caused by a different spreading of neurofibrillary tangles (NFT) than originally proposed by Braak and Braak. Recent studies suggest a prominent role for neuroinflammation in the spreading of tau pathology. METHODS: We aimed to explore whether an atypical spreading of pathology in AD is associated with an atypical distribution of neuroinflammation. Typical and atypical AD cases were selected based on both NFT distribution and amnestic or non-amnestic clinical presentation. Immunohistochemistry was performed on the temporal pole and superior parietal lobe of 10 typical and 9 atypical AD cases. The presence of amyloid-beta (N-terminal; IC16), pTau (AT8), reactive astrocytes (GFAP), microglia (Iba1, CD68, and HLA-DP/DQ/DR), and complement factors (C1q, C3d, C4b, and C5b-9) was quantified by image analysis. Differences in lobar distribution patterns of immunoreactivity were statistically assessed using a linear mixed model. RESULTS: We found a temporal dominant distribution for amyloid-beta, GFAP, and Iba1 in both typical and atypical AD. Distribution of pTau, CD68, HLA-DP/DQ/DR, C3d, and C4b differed between AD variants. Typical AD cases showed a temporal dominant distribution of these markers, whereas atypical AD cases showed a parietal dominant distribution. Interestingly, when quantifying for the number of amyloid-beta plaques instead of stained surface area, atypical AD cases differed in distribution pattern from typical AD cases. Remarkably, plaque morphology and localization of neuroinflammation within the plaques was different between the two phenotypes. CONCLUSIONS: Our data show a different localization of neuroinflammatory markers and amyloid-beta plaques between AD phenotypes. In addition, these markers reflect the atypical distribution of tau pathology in atypical AD, suggesting that neuroinflammation might be a crucial link between amyloid-beta deposits, tau pathology, and clinical symptoms

Increase of Mast Cells in COVID-19 Pneumonia may Contribute to Pulmonary Fibrosis and Thrombosis

AIMS: Lung tissue from COVID-19 patients shares similar histomorphological features with chronic lung allograft disease, suggesting activation of autoimmune related pathways in COVID-19 as well. To better understand the underlying spectrum of pathophysiology in COVID-19 pneumonia, we analyzed mRNA expression of autoimmune-related genes in post-mortem lung tissue from COVID-19 patients. METHODS AND RESULTS: Formalin-fixated, paraffin-embedded lung tissue samples of 18 COVID-19 patients and 8 influenza patients were used for targeted gene expression profiling using NanoString technology. Multiplex immunofluorescence for tryptase and chymase was applied for validation. Genes related to mast cells were significantly increased in COVID-19. This finding was strengthened by multiplex immunofluorescence showing a significant increase of tryptase- and chymase positive cells in COVID-19 as well. Furthermore, RAGE (receptor for advanced glycation end-products) and PPBP (pro-platelet basic protein) were upregulated in COVID-19 compared to influenza. Genes associated with type I interferon signaling showed a significant correlation to detected SARS-CoV2 pathway-related genes. The comparison of lung tissue samples from both groups based on the presence of histomorphological features indicative of ARDS did not result in finding any specific gene or pathways. CONCLUSION: Two separate means of measuring show significant increase of mast cells in SARS-CoV-2 infected lung tissue compared to influenza. Additionally, several genes involved in fibrosis and thrombosis, among which are RAGE and PPBP, are upregulated in COVID-19. As mast cells are able to induce thrombosis and fibrosis, they may play an important role in the pathogenesis of COVID-19

CYP19A1 mediates severe SARS-CoV-2 disease outcome in males

Stanelle-Bertram S, Beck S, Mounogou NK, et al. CYP19A1 mediates severe SARS-CoV-2 disease outcome in males. Cell Reports Medicine . 2023: 101152.Male sex represents one of the major risk factors for severe COVID-19 outcome. However, underlying mechanisms that mediate sex-dependent disease outcome are as yet unknown. Here, we identify the CYP19A1 gene encoding for the testosterone-to-estradiol metabolizing enzyme CYP19A1 (also known as aromatase) as a host factor that contributes to worsened disease outcome in SARS-CoV-2-infected males. We analyzed exome sequencing data obtained from a human COVID-19 cohort (n= 2,866) using a machine-learning approach and identify a CYP19A1-activity-increasing mutation to be associated with the development of severe disease in men but not women. We further analyzed human autopsy-derived lungs (n= 86) and detect increased pulmonary CYP19A1 expression at the time point of death in men compared with women. In the golden hamster model, we show that SARS-CoV-2 infection causes increased CYP19A1 expression in the lung that is associated with dysregulated plasma sex hormone levels and reduced long-term pulmonary function in males but not females. Treatment of SARS-CoV-2-infected hamsters with a clinically approved CYP19A1 inhibitor (letrozole) improves impaired lung function and supports recovery of imbalanced sex hormones specifically in males. Our study identifies CYP19A1 as a contributor to sex-specific SARS-CoV-2 disease outcome in males. Furthermore, inhibition of CYP19A1 by the clinically approved drug letrozole may furnish a new therapeutic strategy for individualized patient management and treatment. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved