Skin Diseases in Elite Athletes.

An athlete's skin has to cope with various stressors that influence skin integrity. This study investigated the effect of intense sporting activity at a competitive level on skin health, independent of the type of sport. The prevalence of dermatoses in elite athletes who exercise 8 or more hours per week was compared to recreational athletes. By applying a questionnaire, we acquired data from n=492 recruited athletes and recreational athletes regarding the prevalence of dermatoses, the extent of physical activity, and sports discipline practiced. Compared to the reference group, elite athletes showed less inflammatory, traumatic, infectious, and sebaceous skin diseases and especially neurodermitis, pruritus, bullae, tinea pedis, acne, and herpes were less common. Women suffered from skin diseases more often than men. With advanced age, the incidence of dermatoses increased, but less so among elite athletes. The discipline practiced and the duration of training, especially when performed outdoors, strongly influenced the development of dermatoses. Even though the skin of athletes is exposed to higher stress levels and physical strain, we can state that intensive physical activity seems to act as a protecting factor against skin diseases and significantly promotes skin health.

Retrospective evaluation of the performance of the electrical impedance spectroscopy system Nevisense in detecting keratinocyte cancers.

BACKGROUND: Keratinocyte cancers, also referred to as non-melanoma skin cancers (NMSCs), are one of the most common malignant skin tumors. We performed a retrospective analysis of lesions from patients of a private dermatology practice to evaluate the use of electrical impedance spectroscopy (EIS) in detecting keratinocyte malignancies. The aim of the study is to assess the accuracy of the technique and to rate its use as supportive tool in NMSC diagnosis. MATERIAL AND METHODS: The period evaluated ranges from September 2015 to November 2019. In total, 1712 lesions from 951 patients were included. All lesions suspicious for malignancy were gauged with the Nevisense device. Excised lesions were sent in for histopathological classification, and the results were compared to the Nevisense score. RESULTS: A total of 767 lesions (44.8%) received a negative score (0-3) from the Nevisense system and 945 lesions (55.2%) a positive score (4-10). The combination of the dermatologist's visual assessment plus the technical determined Neviscore resulted in the excision of 52.5% of all 1712 suspicious lesions whereof 15% were found to be malignant. The sensitivity of Nevisense was 98.4% for NMSC detection. CONCLUSION: Electrical impedance spectroscopy was found to be a valuable adjunct support tool in clinical decisions for cases with suspicion for NMSC.

Sphingosine 1-Phosphate Produced by Sphingosine Kinase 2 Intrinsically Controls Platelet Aggregation In Vitro and In Vivo.

RATIONALE: Platelets are known to play a crucial role in hemostasis. Sphingosine kinases (Sphk) 1 and 2 catalyze the conversion of sphingosine to the bioactive metabolite sphingosine 1-phosphate (S1P). Although platelets are able to secrete S1P on activation, little is known about a potential intrinsic effect of S1P on platelet function. OBJECTIVE: To investigate the role of Sphk1- and Sphk2-derived S1P in the regulation of platelet function. METHODS AND RESULTS: We found a 100-fold reduction in intracellular S1P levels in platelets derived from Sphk2(-/-) mutants compared with Sphk1(-/-) or wild-type mice, as analyzed by mass spectrometry. Sphk2(-/-) platelets also failed to secrete S1P on stimulation. Blood from Sphk2-deficient mice showed decreased aggregation after protease-activated receptor 4-peptide and adenosine diphosphate stimulation in vitro, as assessed by whole blood impedance aggregometry. We revealed that S1P controls platelet aggregation via the sphingosine 1-phosphate receptor 1 through modulation of protease-activated receptor 4-peptide and adenosine diphosphate-induced platelet activation. Finally, we show by intravital microscopy that defective platelet aggregation in Sphk2-deficient mice translates into reduced arterial thrombus stability in vivo. CONCLUSIONS: We demonstrate that Sphk2 is the major Sphk isoform responsible for the generation of S1P in platelets and plays a pivotal intrinsic role in the control of platelet activation. Correspondingly, Sphk2-deficient mice are protected from arterial thrombosis after vascular injury, but have normal bleeding times. Targeting this pathway could therefore present a new therapeutic strategy to prevent thrombosis.

Critical role of platelet glycoprotein ibα in arterial remodeling.

OBJECTIVE: Arteriogenesis is strongly dependent on the recruitment of leukocytes, especially monocytes, into the perivascular space of growing collateral vessels. On the basis of previous findings that platelets are central players in inflammatory processes and mediate the recruitment of leukocytes, the aim of this study was to assess the role of platelets in a model of arterial remodeling. APPROACH AND RESULTS: C57Bl6 wild-type mice, IL4-R/Iba mice lacking the extracellular domain of the glycoprotein Ibα (GPIbα) receptor, and mice treated with antibodies to block GPIbα or deplete circulating platelets were studied in peripheral arteriogenesis. Using a novel model of intravital 2-photon and epifluorescence imaging, we visualized and quantified the interaction of platelets with leukocytes and the vascular endothelium in vivo. We found that transient platelet adhesion to the endothelium of collateral vessels was a major event during arteriogenesis and depended on GPIbα. Furthermore, leukocyte recruitment was obviously affected in animals with defective platelet GPIbα function. In IL4-R/Iba mice, transient and firm leukocyte adhesion to the endothelium of collateral vessels, as well as leukocyte accumulation in the perivascular space, were significantly reduced. Furthermore, we detected platelet-leukocyte aggregates within the circulation, which were significantly reduced in IL4-R/Iba animals. Finally, platelet depletion and loss of GPIbα function resulted in poor reperfusion recovery as determined by laser Doppler imaging. CONCLUSIONS: Thus, GPIbα-mediated interactions between platelets and endothelial cells, as well as leukocytes, support innate immune cell recruitment and promote arteriogenesis-establishing platelets as critical players in this process.

Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases.

Blood neutrophils provide the first line of defense against pathogens but have also been implicated in thrombotic processes. This dual function of neutrophils could reflect an evolutionarily conserved association between blood coagulation and antimicrobial defense, although the molecular determinants and in vivo significance of this association remain unclear. Here we show that major microbicidal effectors of neutrophils, the serine proteases neutrophil elastase and cathepsin G, together with externalized nucleosomes, promote coagulation and intravascular thrombus growth in vivo. The serine proteases and extracellular nucleosomes enhance tissue factor- and factor XII-dependent coagulation in a process involving local proteolysis of the coagulation suppressor tissue factor pathway inhibitor. During systemic infection, activation of coagulation fosters compartmentalization of bacteria in liver microvessels and reduces bacterial invasion into tissue. In the absence of a pathogen challenge, neutrophil-derived serine proteases and nucleosomes can contribute to large-vessel thrombosis, the main trigger of myocardial infarction and stroke. The ability of coagulation to suppress pathogen dissemination indicates that microvessel thrombosis represents a physiological tool of host defense.

Platelets contribute to postnatal occlusion of the ductus arteriosus.

The ductus arteriosus (DA) is a fetal shunt vessel between the pulmonary artery and the aorta that closes promptly after birth. Failure of postnatal DA closure is a major cause of morbidity and mortality particularly in preterm neonates. The events leading to DA closure are incompletely understood. Here we show that platelets have an essential role in DA closure. Using intravital microscopy of neonatal mice, we observed that platelets are recruited to the luminal aspect of the DA during closure. DA closure is impaired in neonates with malfunctioning platelet adhesion or aggregation or with defective platelet biogenesis. Defective DA closure resulted in a left-to-right shunt with increased pulmonary perfusion, pulmonary vascular remodeling and right ventricular hypertrophy. Our findings indicate that platelets are crucial for DA closure by promoting thrombotic sealing of the constricted DA and by supporting luminal remodeling. A retrospective clinical study revealed that thrombocytopenia is an independent predictor for failure of DA closure in preterm human newborns, indicating that platelets are likely to contribute to DA closure in humans.

Protein disulfide isomerase as a trigger for tissue factor-dependent fibrin generation.

Recent evidence suggests that protein disulfide isomerase (PDI) represents an injury response signal that can activate tissue factor (TF), a major initiator protein of blood coagulation. PDI was found to be specifically exposed at the site of vessel injury, originating both from disrupted vessel-wall cells and adhering platelets. The exposed PDI promotes TF-dependent fibrin deposition in different mouse models of thrombosis. In particular, PDI can mediate stimulation of circulating (intravascular) TF present on microparticles. It has been proposed that PDI activates TF by changing the disulfide status of the membrane-proximal Cys186-Cys209 pair of TF. Indeed, PDI was shown to cleave mixed disulfide bonds of TF with glutathione. This might enable the formation of an intrachain disulfide bond which is associated with an increased procoagulant efficiency of TF. The PDI-induced activation of TF could represent the primary step of the entire coagulation process.

Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation.

Upon vascular injury, locally controlled haemostasis prevents life-threatening blood loss and ensures wound healing. Intracellular material derived from damaged cells at these sites will become exposed to blood components and could contribute to blood coagulation and pathological thrombus formation. So far, the functional and mechanistic consequences of this concept are not understood. Here, we present in vivo and in vitro evidence that different forms of eukaryotic and prokaryotic RNA serve as promoters of blood coagulation. Extracellular RNA was found to augment (auto-)activation of proteases of the contact phase pathway of blood coagulation such as factors XII and XI, both exhibiting strong RNA binding. Moreover, administration of exogenous RNA provoked a significant procoagulant response in rabbits. In mice that underwent an arterial thrombosis model, extracellular RNA was found associated with fibrin-rich thrombi, and pretreatment with RNase (but not DNase) significantly delayed occlusive thrombus formation. Thus, extracellular RNA derived from damaged or necrotic cells particularly under pathological conditions or severe tissue damage represents the long sought natural "foreign surface" and provides a procoagulant cofactor template for the factors XII/XI-induced contact activation/amplification of blood coagulation. Extracellular RNA thereby reveals a yet unrecognized target for antithrombotic intervention, using RNase or related therapeutic strategies.