ACE2 and TAS2R38 receptor expression in pediatric and adult patients in the nasal and oral cavity.

Objective: To investigate differences in angiotensin-converting-enzyme-2 (ACE2) and bitter taste receptor (TAS2R38) expression between patient age groups and comorbidities to characterize the pathophysiology of coronavirus 19(COVID-19) pandemic. ACE2 is the receptor implicated to facilitate SARS-CoV-2 infections and levels of expression may correlate to the severity of COVID-19 infection. TAS2R38 has many non-gustatory roles in disease, with some evidence of severe COVID-19 disease in certain receptor phenotypes. Methods: We conducted a prospective cohort study and collected nasal and lingual tissue from healthy pediatric (n = 22) and adult (n = 25) patients undergoing general anesthesia for elective procedures. RNA isolation and qPCR were performed with primers targeting ACE2 and TAS2R38. Results: A total of 25 adult (52% male; 44% obese) and 22 pediatric (50% male; 36% obese) patients were enrolled, pediatric tissue had 43% more nasal ACE2 RNA expression than adults with a median fold change of 0.69 (IQR 0.37, 0.98) in adults and 0.99 (IQR 0.74, 1.43) in children (p < .05). There were no differences between the age groups in ACE2 expression of lingual tissue (p = .14) or TAS2R38 expression collected from either nasal (p = 049) or lingual tissue (p = .49). Stratifying for obesity yielded similar differences between nasal ACE2 expression between adults and children with median fold change of 0.56 (IQR 0.32, 0.87) in adults and 1.0 (IQR 0.82, 1.52) in children (p < .05). Conclusions: ACE2 receptor expression is higher in nasal tissue collected from children compared to adults, suggesting COVID-19 infectivity is more complicated than ACE2 and TAS2R38 mRNA expression. Level of Evidence: NA.

The speech perception gap in cochlear implant patients.

OBJECTIVE: To determine how commonly word recognition scores obtained using insert microphones (PB max) overestimate word recognition scores obtained through appropriately fit hearing aids (A-WRS). METHODS: Aided speech recognition tests may not be performed during routine hearing aid fittings; however, they are regularly performed for cochlear implant (CI) candidacy evaluation. Therefore, audiologic data from CI recipients were queried in a retrospective cohort study at a tertiary care center. PB max and A-WRS were obtained. The Speech Perception (SP) gap, defined as PB max minus A-WRS, was calculated for each patient and a high SP gap was defined as ≥20%. RESULTS: Analyzing 78 patients with complete data, 30 patients had PB max ≥20%. Of these, 18 (60%) had a high SP gap. Eighteen of the 78 patients had PB max ≥40%, and of these patients, 15 (83%) had a high SP gap. DISCUSSION/CONCLUSION: A Speech Perception Gap of ≥20% may exist in a sizable percentage of patients with hearing loss. Our pilot study suggests that over 80% of these patients could have Class D hearing (speech recognition <50%) using conventional hearing aids and may be better served using alternate rehabilitation strategies such as middle ear or cochlear implants. Therefore, aided speech testing should be performed as part of a verified hearing aid fit in all patients, especially those with PB Max ranging from 40% to 70%.

A Systematic Review of the Association between Cigarette Smoke Exposure and Chronic Rhinosinusitis.

Objectives Cigarette smoking and passive smoke exposure have been associated with chronic rhinosinusitis (CRS). Our goal in this systematic review was to (1) determine if there was a strong correlative effect in large population studies between cigarette smoke exposure and the prevalence of CRS, (2) investigate pathogenic mechanisms of cigarette smoke in the upper airway, and (3) determine if a history of cigarette smoking affects the medical and surgical outcomes of CRS. Data Sources MEDLINE, Embase, Cochrane CENTRAL, Web of Science SCI and CPCI-S, and websites. Methods A comprehensive literature review and quantitative meta-analysis of studies based on the PRISMA protocol and examining the relationship between cigarette smoke exposure and CRS was performed. A search strategy was developed using various terms such as sinusitis, rhinitis, rhinosinusitis, and smoking. The articles were categorized by (1) epidemiology, (2) pathophysiology, and (3) outcomes. Data regarding study design, population/setting, methods, and bias were collected. Results The initial search generated 2621 titles/abstracts with 309 articles undergoing secondary review and 112 articles for final review. We determined that there is a strong correlation between active and passive cigarette smoke with the prevalence of CRS. Cigarette smoke challenge to sinonasal epithelia results in the release of inflammatory mediators and altered ciliary beat frequency. Pediatric patients exposed to secondhand smoke appear to have particularly poor outcomes. Conclusion There is clear evidence that cigarette smoke is related to CRS, but longitudinal and mechanistic studies are required to determine a causative effect. This information is critical for greater understanding of CRS health outcomes.

Clots Are Potent Triggers of Inflammatory Cell Gene Expression: Indications for Timely Fibrinolysis.

OBJECTIVE: Blood vessel wall damage often results in the formation of a fibrin clot that traps inflammatory cells, including monocytes. The effect of clot formation and subsequent lysis on the expression of monocyte-derived genes involved in the development and progression of ischemic stroke and other vascular diseases, however, is unknown. Determine whether clot formation and lysis regulates the expression of human monocyte-derived genes that modulate vascular diseases. APPROACH AND RESULTS: We performed next-generation RNA sequencing on monocytes extracted from whole blood clots and using a purified plasma clot system. Numerous mRNAs were differentially expressed by monocytes embedded in clots compared with unclotted controls, and IL-8 (interleukin 8) and MCP-1 (monocyte chemoattractant protein-1) were among the upregulated transcripts in both models. Clotted plasma also increased expression of IL-8 and MCP-1, which far exceeded responses observed in lipopolysaccharide-stimulated monocytes. Upregulation of IL-8 and MCP-1 occurred in a thrombin-independent but fibrin-dependent manner. Fibrinolysis initiated shortly after plasma clot formation (ie, 1-2 hours) reduced the synthesis of IL-8 and MCP-1, whereas delayed fibrinolysis was far less effective. Consistent with these in vitro models, monocytes embedded in unresolved thrombi from patients undergoing thrombectomy stained positively for IL-8 and MCP-1. CONCLUSIONS: These findings demonstrate that clots are potent inducers of monocyte gene expression and that timely fibrinolysis attenuates inflammatory responses, specifically IL-8 and MCP-1. Dampening of inflammatory gene expression by timely clot lysis may contribute to the clinically proven efficacy of fibrinolytic drug treatment within hours of stroke onset.

Bacteria differentially induce degradation of Bcl-xL, a survival protein, by human platelets.

Bacteria can enter the bloodstream in response to infectious insults. Bacteremia elicits several immune and clinical complications, including thrombocytopenia. A primary cause of thrombocytopenia is shortened survival of platelets. We demonstrate that pathogenic bacteria induce apoptotic events in platelets that include calpain-mediated degradation of Bcl-x(L), an essential regulator of platelet survival. Specifically, bloodstream bacterial isolates from patients with sepsis induce lateral condensation of actin, impair mitochondrial membrane potential, and degrade Bcl-x(L) protein in platelets. Bcl-x(L) protein degradation is enhanced when platelets are exposed to pathogenic Escherichia coli that produce the pore-forming toxin α-hemolysin, a response that is markedly attenuated when the gene is deleted from E coli. We also found that nonpathogenic E coli gain degrading activity when they are forced to express α-hemolysin. Like α-hemolysin, purified α-toxin readily degrades Bcl-x(L) protein in platelets, as do clinical Staphylococcus aureus isolates that produce α-toxin. Inhibition of calpain activity, but not the proteasome, rescues Bcl-x(L) protein degradation in platelets coincubated with pathogenic E coli including α-hemolysin producing strains. This is the first evidence that pathogenic bacteria can trigger activation of the platelet intrinsic apoptosis program and our results suggest a new mechanism by which bacterial pathogens might cause thrombocytopenia in patients with bloodstream infections.

Staphylococcus aureus α-toxin triggers the synthesis of B-cell lymphoma 3 by human platelets.

The frequency and severity of bacteremic infections has increased over the last decade and bacterial endovascular infections (i.e., sepsis or endocarditis) are associated with high morbidity and mortality. Bacteria or secreted bacterial products modulate platelet function and, as a result, affect platelet accumulation at sites of vascular infection and inflammation. However, whether bacterial products regulate synthetic events in platelets is not known. In the present study, we determined if prolonged contact with staphylococcal α-toxin signals platelets to synthesize B-cell lymphoma (Bcl-3), a protein that regulates clot retraction in murine and human platelets. We show that α-toxin induced α(IIb)ß(3)-dependent aggregation (EC(50) 2.98 µg/mL ± 0.64 µg/mL) and, over time, significantly altered platelet morphology and stimulated de novo accumulation of Bcl-3 protein in platelets. Adherence to collagen or fibrinogen also increased the expression of Bcl-3 protein by platelets. α-toxin altered Bcl-3 protein expression patterns in platelets adherent to collagen, but not fibrinogen. Pretreatment of platelets with inhibitors of protein synthesis or the mammalian Target of Rapamycin (mTOR) decreased Bcl-3 protein expression in α-toxin stimulated platelets. In conclusion, Staphylococcusaureus-derived α-toxin, a pore forming exotoxin, exerts immediate (i.e., aggregation) and prolonged (i.e., protein synthesis) responses in platelets, which may contribute to increased thrombotic events associated with gram-positive sepsis or endocarditis.

Platelet-leukocyte interactions link inflammatory and thromboembolic events in ischemic stroke.

Stroke is a common and often fatal event, and, in survivors, it is accompanied by a high risk of recurrence. Ischemic stroke is associated with abnormal platelet activity and thrombus formation. In addition to their roles in the development of acute thrombi, platelets serve as a bridge for leukocytes within the vasculature. Myeloid leukocytes are critical mediators of atherosclerosis and atherothrombosis. Interactions between platelets and leukocytes foster an inflammatory and thrombotic milieu that influences lesion progression, facilitates plaque rupture, and triggers thrombus formation and embolization. Accordingly, antiplatelet agents, including aspirin, dipyridamole, and clopidogrel, are recommended therapies for most patients with a history of stroke. In addition to mitigating thrombosis, antiplatelet drugs have direct and indirect effects on inflammation, which may translate to enhanced clinical efficacy.