Smell dysfunction: a biomarker for COVID‐19 Moein, Shima T.; Hashemian, Seyed MohammadReza; Mansourafshar, Babak ...
International forum of allergy & rhinology,
August 2020, Letnik:
10, Številka:
8
Journal Article
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Background
Severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2), the virus that causes coronavirus disease 2019 (COVID‐19), is responsible for the largest pandemic since the 1918 influenza A ...virus subtype H1N1 influenza outbreak. The symptoms presently recognized by the World Health Organization are cough, fever, tiredness, and difficulty breathing. Patient‐reported smell and taste loss has been associated with COVID‐19 infection, yet no empirical olfactory testing on a cohort of COVID‐19 patients has been performed.
Methods
The University of Pennsylvania Smell Identification Test (UPSIT), a well‐validated 40‐odorant test, was administered to 60 confirmed COVID‐19 inpatients and 60 age‐ and sex‐matched controls to assess the magnitude and frequency of their olfactory dysfunction. A mixed effects analysis of variance determined whether meaningful differences in test scores existed between the 2 groups and if the test scores were differentially influenced by sex.
Results
Fifty‐nine (98%) of the 60 patients exhibited some smell dysfunction (mean 95% CI UPSIT score: 20.98 19.47, 22.48; controls: 34.10 33.31, 34.88; p < 0.0001). Thirty‐five of the 60 patients (58%) were either anosmic (15/60; 25%) or severely microsmic (20/60; 33%); 16 exhibited moderate microsmia (16/60; 27%), 8 mild microsmia (8/60; 13%), and 1 normosmia (1/60; 2%). Deficits were evident for all 40 UPSIT odorants. No meaningful relationships between the test scores and sex, disease severity, or comorbidities were found.
Conclusion
Quantitative smell testing demonstrates that decreased smell function, but not always anosmia, is a major marker for SARS‐CoV‐2 infection and suggests the possibility that smell testing may help, in some cases, to identify COVID‐19 patients in need of early treatment or quarantine.
The compositions of grain boundaries (GBs) and other interfaces surrounding Nd2Fe14B grains in commercial Nd–Fe–B sintered magnets have been investigated by laser-assisted three-dimensional atom ...probe to understand the mechanism of the coercivity enhancement by post-sinter annealing. While only a slight segregation of Nd and Pr to the GBs was confirmed in the as-sintered sample, a thin Nd-rich amorphous phase layer was observed along the GBs with Cu segregation to the interfaces in the annealed sample. The segregation of Cu to NdOx/Nd2Fe14B interfaces was also found, suggesting that the Nd2Fe14B grains are enveloped by a Cu-enriched layer after the annealing. The concentration of Fe+Co in the thin GB layer was found to be as high as 65at.%, and a model amorphous film processed by sputtering with the same composition as the thin GB layer was found to be ferromagnetic. Ferromagnetic behavior of the thin GB layer suggested that Nd2Fe14B grains are magnetically coupled. The coercivity mechanism of the sintered magnets is discussed based on these new findings.
With ageing extracellular material is deposited in Bruch's membrane, as drusen. Lipofuscin is deposited in retinal pigment epithelial cells. Both of these changes are associated with age related ...macular degeneration, a disease now believed to involve chronic inflammation at the retinal-choroidal interface. We hypothesise that these molecules may act as danger signals, causing the production of inflammatory chemokines and cytokines by the retinal pigment epithelium, via activation of pattern recognition receptors.
ARPE-19 cells were stimulated in vitro with the following reported components of drusen: amyloid-ß (1-42), Carboxyethylpyrrole (CEP) modified proteins (CEP-HSA), Nε-(Carboxymethyl)lysine (CML) modified proteins and aggregated vitronectin. The cells were also stimulated with the major fluorophore of lipofuscin: N-retinylidene-N-retinylethanolamine (A2E). Inflammatory chemokine and cytokine production was assessed using Multiplex assays and ELISA. The mechanistic evaluation of the NLRP3 inflammasome pathway was assessed in a stepwise fashion.
Of all the molecules tested only A2E induced inflammatory chemokine and cytokine production. 25 µM A2E induced the production of significantly increased levels of the chemokines IL-8, MCP-1, MCG and MIP-1α, the cytokines IL-1ß, IL-2, IL-6, and TNF-α, and the protein VEGF-A. The release of IL-1ß was studied further, and was determined to be due to NLRP3 inflammasome activation. The pathway of activation involved endocytosis of A2E, and the three inflammasome components NLRP3, ASC and activated caspase-1. Immunohistochemical staining of ABCA4 knockout mice, which show progressive accumulation of A2E levels with age, showed increased amounts of IL-1ß proximal to the retinal pigment epithelium.
A2E has the ability to stimulate inflammatory chemokine and cytokine production by RPE cells. The pattern recognition receptor NLRP3 is involved in this process. This provides further evidence for the link between A2E, inflammation, and the pathogenesis of AMD. It also supports the recent discovery of NLRP3 inflammasome activation in AMD.
This study provides normative data useful for interpreting scores from the Pocket Smell Test
®
(PST
®
), a brief "scratch & sniff" neuropsychological olfactory screening test comprised of 8 items ...from the 40-item University of Pennsylvania Smell Identification Test (UPSIT
®
). We combined 3,485 PST
®
scores from the 2013 to 2014 National Health and Nutrition Survey (NHANES) of persons 40 years of age and older with equivalent PST
®
items extracted from an UPSIT
®
database of 3,900 persons ranging in age from 5 to 99 years. Decade-related age- and gender-adjusted percentile normative data were established across the entire age spectrum. Cut-points for defining clinically useful categories of anosmia, probable microsmia, and normosmia were determined using receiver operating characteristic (ROC) curve analyses. An age-related decline in test scores was evident for both sexes after the age of 40 years, with women outperforming men. Based on the ROC analyses, subjects scoring 3 or less (AUC = 0.81) defines anosmia. Regardless of sex, a score of 7 or 8 on the N-PST
®
signifies normal function (AUC of 0.71). Probable microsmia is classified as scores extending from 3 to 6. These data provide an accurate means for interpreting PST
®
scores within a number of clinical and applied settings.
Vascular endothelial growth factor-A (VEGF-A) has recently been recognized as an important neuroprotectant in the central nervous system. Given its position as an anti-angiogenic target in the ...treatment of human diseases, understanding the extent of VEGF's role in neural cell survival is paramount. Here, we used a model of ischemia-reperfusion injury and found that VEGF-A exposure resulted in a dose-dependent reduction in retinal neuron apoptosis. Although mechanistic studies suggested that VEGF-A-induced volumetric blood flow to the retina may be partially responsible for the neuroprotection, ex vivo retinal culture demonstrated a direct neuroprotective effect for VEGF-A. VEGF receptor-2 (VEGFR2) expression was detected in several neuronal cell layers of the retina, and functional analyses showed that VEGFR2 was involved in retinal neuroprotection. VEGF-A was also shown to be involved in the adaptive response to retinal ischemia. Ischemic preconditioning 24 hours before ischemia-reperfusion injury increased VEGF-A levels and substantially decreased the number of apoptotic retinal cells. The protective effect of ischemic preconditioning was reversed after VEGF-A inhibition. Finally, chronic inhibition of VEGF-A function in normal adult animals led to a significant loss of retinal ganglion cells yet had no observable effect on several vascular parameters. These findings have implications for both neural pathologies and ocular vascular diseases, such as diabetic retinopathy and age-related macular degeneration.
Background
Considerable evidence suggests that smell dysfunction is common in coronavirus disease‐2019 (COVID‐19). Unfortunately, extant data on prevalence and reversibility over time are highly ...variable, coming mainly from self‐report surveys prone to multiple biases. Thus, validated psychophysical olfactory testing is sorely needed to establish such parameters.
Methods
One hundred severe acute respiratory syndrome‒coronavirus‐2 (SARS‐CoV‐2)‐positive patients were administered the 40‐item University of Pennsylvania Smell Identification Test (UPSIT) in the hospital near the end of the acute phase of the disease. Eighty‐two were retested 1 or 4 weeks later at home. The data were analyzed using analysis of variance and mixed‐effect regression models.
Results
Initial UPSIT scores were indicative of severe microsmia, with 96% exhibiting measurable dysfunction; 18% were anosmic. The scores improved upon retest (initial test: mean, 21.97; 95% confidence interval CI, 20.84‐23.09; retest: mean, 31.13; 95% CI, 30.16‐32.10; p < 0.0001); no patient remained anosmic. After 5 weeks from COVID‐19 symptom onset, the test scores of 63% of the retested patients were normal. However, the mean UPSIT score at that time continued to remain below that of age‐ and sex‐matched healthy controls (p < 0.001). Such scores were related to time since symptom onset, sex, and age.
Conclusion
Smell loss was extremely common in the acute phase of a cohort of 100 COVID‐19 patients when objectively measured. About one third of cases continued to exhibit dysfunction 6 to 8 weeks after symptom onset. These findings have direct implications for the use of olfactory testing in identifying SARS‐CoV‐2 carriers and for counseling such individuals with regard to their smell dysfunction and its reversibility.
Branching morphogenesis in the mammalian lung and Drosophila trachea relies on the precise localization of secreted modulators of epithelial growth to select branch sites and direct branch ...elongation, but the intercellular signals that control blood vessel branching have not been previously identified. We found that VEGF(120/120) mouse embryos, engineered to express solely an isoform of VEGF-A that lacks heparin-binding, and therefore extracellular matrix interaction domains, exhibited a specific decrease in capillary branch formation. This defect was not caused by isoform-specific differences in stimulating endothelial cell proliferation or by impaired isoform-specific signaling through the Nrp1 receptor. Rather, changes in the extracellular localization of VEGF-A in heparin-binding mutant embryos resulted in an altered distribution of endothelial cells within the growing vasculature. Instead of being recruited into additional branches, nascent endothelial cells were preferentially integrated within existing vessels to increase lumen caliber. The disruption of the normal VEGF-A concentration gradient also impaired the directed extension of endothelial cell filopodia, suggesting that heparin-binding VEGF-A isoforms normally provide spatially restricted stimulatory cues that polarize and thereby guide sprouting endothelial cells to initiate vascular branch formation. Consistent with this idea, we found opposing defects in embryos harboring only a heparin-binding isoform of VEGF-A, including excess endothelial filopodia and abnormally thin vessel branches in ectopic sites. We conclude that differential VEGF-A isoform localization in the extracellular space provides a control point for regulating vascular branching pattern.
The vascular endothelium operates in a highly polarized environment, but to date there has been little exploration of apicobasal polarization of its signaling. We show that VEGF-A, histamine, IGFBP3, ...and LPA trigger unequal endothelial responses when acting from the circulation or the parenchymal side at blood-neural barriers. For VEGF-A, highly polarized receptor distribution contributed to distinct signaling patterns: VEGFR2, which was found to be predominantly abluminal, mediated increased permeability via p38; in contrast, luminal VEGFR1 led to Akt activation and facilitated cytoprotection. Importantly, such differential apicobasal signaling and VEGFR distribution were found in the microvasculature of brain and retina but not lung, indicating that endothelial cells at blood-neural barriers possess specialized signaling compartments that assign different functions depending on whether an agonist is tissue or blood borne.
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•At blood-neural barriers, only abluminal (tissue-side) VEGF-A induces permeability•Most VEGFR1 is localized on the luminal face of neural microvascular endothelium•Most VEGFR2 is localized on the abluminal face of neural microvascular endothelium•Luminal VEGFR1 stimulates Akt; abluminal VEGFR2 induces permeability via p38
Hudson et al. show that the microvascular endothelium of blood-neural barriers uses functional polarity of signaling to compartmentalize responses to vasoactive stimuli. VEGFR2, predominantly expressed on the abluminal face of the endothelium, mediates p38 and vascular permeability. Luminally polarized VEGFR1 activates Akt but does not contribute to permeability.
Hydrogen is chemically flexible revealing three aspects; protium (H
0
), proton (H
+
), and hydride (H
-
), which are active toward hydrogenation reactions. While the reactivity of protium is ...characterized by the potential energy at a catalyst surface, electron transfer is of importance as an additional degree of freedom in the reactions with proton and hydride. A promising strategy is to make full use of these active hydrogen species for hydrogenation of stable molecules and achieve chemical transformation of these molecules, which we call “Hydrogenomics”. By reviewing recent studies on the hydrogenation of hydrocarbon, carbon dioxide, dinitrogen, and so on using these active hydrogen species on model metal surfaces, nanoscale electrocatalysts, and multimetallic polyhydride clusters, we discuss the fundamental concepts behind the reactions and possible control of the efficient and selective hydrogenation reactions.
Graphic Abstract
Vascular endothelial growth factor A (VEGF-A) is a validated therapeutic target in several angiogenic- and vascular permeability–related pathological conditions, including certain cancers and ...potentially blinding diseases, such as age-related macular degeneration and diabetic retinopathy. We and others have shown that VEGF-A also plays an important role in neuronal development and neuroprotection, including in the neural retina. Antagonism of VEGF-A function might therefore present a risk to neuronal survival as a significant adverse effect. Herein, we demonstrate that VEGF-A acts directly on retinal ganglion cells (RGCs) to promote survival. VEGF receptor-2 signaling via the phosphoinositide-3-kinase/Akt pathway was required for the survival response in isolated RGCs. These results were confirmed in animal models of staurosporine-induced RGC death and experimental hypertensive glaucoma. Importantly, we observed that VEGF-A blockade significantly exacerbated neuronal cell death in the hypertensive glaucoma model. Our findings highlight the need to better define the risks associated with use of VEGF-A antagonists in the ocular setting.