SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.

4

Objectives The aim of this study was to assess the effectiveness of sonography for diagnosing sialolithiasis in comparison with the existing reference standard of direct identification of a stone. Methods A total of 659 glands with signs of obstructive sialadenopathy were evaluated retrospectively. Sonographic examinations of the large head salivary glands had been performed initially in all cases. Direct depiction of a stone during sialoendoscopy or transoral ductal surgery or observation of stone fragmentation with discharge of concrements after extracorporeal shock wave lithotripsy, was regarded as definitive evidence and as the reference standard for the presence of sialolithiasis. The sonographic results were compared with those for direct identification of stones. Results The sensitivity of sonography was 94.7%, with specificity of 97.4%, a positive predictive value of 99.4%, and a negative predictive value of 79.6%. Stones that were not diagnosed correctly on sonography were most often located in the distal area of the duct. Conclusions These results show that sialolithiasis can be diagnosed by sonography with a high degree of certainty. Sonography thus appears to be highly appropriate as the examination method of choice.

Extracellular chromatin, for example in the form of neutrophil extracellular traps (NETs), is an important element that propels the pathological progression of a plethora of diseases. DNA drives the interferon system, serves as autoantigen, and forms the extracellular scaffold for proteins of the innate immune system. An insufficient clearance of extruded chromatin after the release of DNA from the nucleus into the extracellular milieu can perform a secret task of moonlighting in immune-inflammatory and occlusive disorders. Here, we discuss (I) the cellular events involved in the extracellular release of chromatin and NET formation, (II) the devastating consequence of a dysregulated NET formation, and (III) the imbalance between NET formation and clearance. We include the role of NET formation in the occlusion of vessels and ducts, in lung disease, in autoimmune diseases, in chronic oral disorders, in cancer, in the formation of adhesions, and in traumatic spinal cord injury. To develop effective therapies, it is of utmost importance to target pathways that cause decondensation of chromatin during exaggerated NET formation and aggregation. Alternatively, therapies that support the clearance of extracellular chromatin are conceivable.

4. Laryngoscope, 127:2038-2044, 2017.

Salivary gland stones, or sialoliths, are the most common cause of the obstruction of salivary glands. The mechanism behind the formation of sialoliths has been elusive. Symptomatic sialolithiasis has a prevalence of 0.45% in the general population, is characterized by recurrent painful periprandial swelling of the affected gland, and often results in sialadenitis with the need for surgical intervention. Here, we show by the use of immunohistochemistry, immunofluorescence, computed tomography (CT) scans and reconstructions, special dye techniques, bacterial genotyping, and enzyme activity analyses that neutrophil extracellular traps (NETs) initiate the formation and growth of sialoliths in humans. The deposition of neutrophil granulocyte extracellular DNA around small crystals results in the dense aggregation of the latter, and the subsequent mineralization creates alternating layers of dense mineral, which are predominantly calcium salt deposits and DNA. The further agglomeration and appositional growth of these structures promotes the development of macroscopic sialoliths that finally occlude the efferent ducts of the salivary glands, causing clinical symptoms and salivary gland dysfunction. These findings provide an entirely novel insight into the mechanism of sialolithogenesis, in which an immune system-mediated response essentially participates in the physicochemical process of concrement formation and growth.

Background: Since the discovery of autonomous leptin production in salivary glands, very few studies have reported on the physiological or pathological meaning of this particular cytokine in saliva. The aim of this study was to investigate the expression of leptin and its receptors Ob-Ra and Ob-Rb in parotid salivary gland tumors, with particular regard to a potential use of leptin as a tumor marker. Methods: Parotid tissue samples from healthy individuals (n = 31) and tumor patients (n = 97, including tissue samples from pleomorphic adenomas, adenolymphomas, basal cell adenomas, and diverse carcinomas) were analyzed by use of ApoTome-technique microscopy, immunohistochemistry, immunofluorescence, immunoblotting, and quantitative real-time PCR. Salivary and plasma leptin concentrations were measured by using ELISA. Ultrasound was used to determine tumor size before surgery. Results: In all salivary gland tumors leptin was expressed in much higher amounts than in healthy parotid tissues. The cytokine was not imported from the blood but actively produced by the tumors. Immunoblotting results indicated that leptin was present as oligomers in salivary glands. Furthermore, the examined tumors overexpressed the receptor isoforms Ob-Ra and Ob-Rb. Measured leptin concentrations in mixed saliva samples were significantly increased in patients with parotid tumors [mean (SD) 673 (484) pg/mL in pleomorphic adenomas, 679 (465) pg/mL in adenolymphomas, and 880 (618) pg/mL in carcinomas] vs controls [125 (36) pg/mL] (P < 0.001). Conclusions: This is the first study to show that the analysis of salivary leptin in mixed saliva samples may allow preoperative differentiation between tumor patients and healthy individuals.

Objectives/Hypothesis To assess long‐term results after the treatment of parotid pleomorphic adenomas (PPAs) using different surgical techniques and focusing on recurrence rates and the risk of adverse effects. Study Design Retrospective analysis. Methods Retrospective analysis of 182 patients treated exclusively for PPAs at a tertiary referral center between 2000 and 2004. Thorough follow‐up examinations over a mean period of 13 years were possible in 53.8% (n = 98/182). Tumors were categorized according to the European Salivary Gland Society (ESGS) system to improve the comparison of outcomes. After different surgical resection strategies, recurrence rates, postoperative facial nerve paresis (FNP), and incidence of Frey's syndrome were assessed. The follow‐up period included clinical examinations and imaging of every patient in the treating department. Results Of 182 patients, extracapsular dissection (ED) was performed in 29.7%, and other surgical modalities (OSMs), including facial nerve dissection, in 70.3%. After the long‐term follow‐up, 98% of all the patients (n = 96/98) were recurrence free. When recurrence rates were compared, no significant differences were noted (P < .331). ED resulted in significantly lower FNP rates compared to OSMs (P < .001). FNP rates significantly increased with size and location of the tumors according to ESGS categories (temporary and permanent FNP, P = .04). Surgical invasiveness corresponded to a significant increase in the incidence of Frey's syndrome (P < .001). Conclusions ED was associated with the lowest complication rates, but not with a higher risk of recurrence, when compared with OSM in the long‐term course. As ED can be performed in the majority of PPAs, it can be regarded as the treatment of choice whenever possible. Level of Evidence 4 Laryngoscope, 131:E445–E451, 2021