Loss of Aβ-nerve endings associated with the Merkel cell-neurite complex in the lesional oral mucosa epithelium of lichen planus and hyperkeratosis

The Merkel cell-neurite complex initiates the perception of touch and mediates Ap slowly adapting type I responses. Lichen planus is a chronic inflammatory autoimmune disease with T-cell-mediated inflammation, whereas hyperkeratosis is characterized with or without epithelial dysplasia in the oral mucosa. To determine the effects of lichen planus and hyperkeratosis on the Merkel cell-neurite complex, healthy oral mucosal epithelium and lesional oral mucosal epithelium of lichen planus and hyperkeratosis patients were stained by immunohistochemistry （the avidin-biotin-peroxidase complex and double immunofluorescence methods）using pan cytokeratin, cytokeratin 20 （K20, a Merkel cell marker）, and neurofilament 200 （NF200, a myelinated Aβ- and Aδ-nerve fibre marker） antibodies. N F200-immunoreactive （ir） nerve fibres in healthy tissues and in the lesional oral mucosa epithelium of lichen planus and hyperkeratosis were counted and statistically analysed. In the healthy oral mucosa, K20-positive Merkel cells with and without close association to the intraepithelial NF200-ir nerve fibres were detected. In the lesional oral mucosa of lichen planus and hyperkeratosis patients, extremely rare NF200-ir nerve fibres were detected only in the lamina propria. Compared with healthy tissues, lichen planus and hyperkeratosis tissues had significantly decreased numbers of NF200-ir nerve fibres in the oral mucosal epithelium. Lichen planus and hyperkeratosis were associated with the absence of Aβ-nerve endings in the oral mucosal epithelium. Thus, we conclude that mechanosensation mediated by the Merkel cell-neurite complex in the oral mucosal epithelium is impaired in lichen planus and hvperkeratosis.

Evaluation of tetrahydrobiopterin(BH4)as a potential therapeutic agent to treat erectile dysfunction

Aim： Nitric oxide （NO）-mediated smooth muscle relaxation causes penile erections. The endothelial NO synthase （eNOS） coenzyme tetrahydrobiopterin （BH4） converts eNOS-mediated catalytic activity from oxygen radical to NO production, improving endothelial function and vascular smooth muscle relaxation. Methods： Using quantitative immunohistochemistry, 8-isoprostane and nitrotyrosine concentrations were compared in cavernosal tissue from 17 potent and 7 impotent men, and the effect of single oral doses of BH4 on penile rigidity and tumescence was investigated. The pharmacodynamic effect of single oral doses of BH4 on penile rigidity and tumescence was investigated in a randomized, placebo-controlled, double-blind cross-over fashion in 18 patients with erectile dysfunction （ED） while receiving visual sexual stimulation. Results： 8-isoprostane content in endothelium and smooth muscle was signifi- cantly higher in impotent patient samples; the level of nitrotyrosine was unchanged in ED patients. Relative to placebo, a single dose of 200 mg BH4 led to a mean increase in duration of 〉 60% penile rigidity （33.5 rain [95% confidence interval （CI）： 13.1-49.3] at base and 29.4 rain [95% CI： 8.9-42,2] at tip）. A 500-mg dose increased the relative duration of 〉 60% penile rigidity by 36. I rain （95% CI： 16.3-51.8） at the base and 33.7 rain （95% CI： 11.4-43.9） at the tip. Treatments were well tolerated. Conclusion： BH4 treatment is suggested to switch eNOS catalytic activity from super-oxide to NO formation, leading to a reduced formation of free radical reaction product 8-isoprostane without alteration of nitrotyrosine. The observed results make BH4 a suitable candidate as an ED treatment through reconstitution of altered catalytic activity of the eNOS. （Asian JAndro12006 Mar; 8： 159-167）

Does endurance training improve red blood cell aging and hemorheology in moderate-trained healthy individuals?

Objective:To examine the impact of a 6-week endurance training on red blood cell(RBC)aging and deformability of healthy participants to detect possible improved hemorheological and performance-related adaptations.Methods:A total of 31 participants(17 females and 14 males)performed a 6-week moderate training protocol(three 1-h running sessions per week at 70%of maximal heart rate).Blood was sampled before and after the training.RBCs from each participant were fractioned according to density and age into 4 RBC subfractions.Subfractions were examined for changes of RBC properties,including aging distribution,RBC deformability,RBC microparticles,and phosphatidylserine concentrations.RBC and plasma nitrite levels were measured as indicators of nitric oxide metabolism.Results:Aerobic performance,peak oxygen consumption,ventilatory thresholds,velocity at the aerobic-anaerobic threshold,and lactate at exhaustion improved after training.The relative amount of both young RBCs and old RBCs increased,and the amount of the main RBC fraction decreased.Phosphatidylserine externalization and RBC-derived microparticles decreased.Overall deformability expressed as shear stress required to achieve half-maximum deformation to theoretical maximal elongation index at infinite shear stress improved in unfractioned RBCs(p<0.001).Nitrite decreased in total(p=0.001),young(p<0.001),main(p<0.001),and old(p=0.020)aged RBCs and in plasma(p=0.002),but not in very old RBCs.Conclusion:These results indicate that non-endurance-trained healthy participants benefit from a regular moderate running training program because performance-related parameters improve and a younger RBC population with improved RBC properties is induced,which might support oxygen supply in the microcirculation.

Exercise precision medicine for type 2 diabetes:Targeted benefit or risk?

Concurrent exercise and metformin administration may reduce the acute and chronic effects of exercise on glucose metabolism in the patients with type 2 diabetes(T2D).However,several studies suggest that combing metformin and exercise treatment may have neither additive effect nor even cause adverse effects in T2D patients.This case report aimed to highlight the challenges associated with prescribing exercise to type 2 diabetes patients undergoing metformin treatment.A 67-years old woman was followed-up for five months,including assessment of the acute and chronic glucose and lactate metabolism induced by concomitant exercise and metformin.The findings were four-fold:1)During a high-intensity interval training bout,blood glucose systematically decreased,while blood lactate concentrations fluctuated randomly;2)Basal blood lactate levels were well above 2 mmol/L on days with medication only;3)Combined exercise and metformin administration induced additive effects on the normalization of glucose and 4)high levels of physical activity had a positive impact on the continuous glucose fluctuations,while decreased levels of physical activity induced a large fluctuation of glucose due to home confinement of an infectious disease caused by the SARS-CoV-2 virus.Our findings showed that when combined with exercise and metformin treatment for T2D patients,exercise may contribute to improving glycemic control while metformin may elevate lactate levels in the long term.The observed results underline the need to prescribe exercise and monitor lactate levels for reducing possible risks associated with metformin treatment and reinforce the importance of tailoring exercise therapy.

Advanced Exercise Prescription for Cancer Patients and its Application in Germany

The scientific interest of exercise medicine for the treatment of cancer is ever expanding.Recently published and updated guidelines for exercise training in cancer patients by the American College of Sports Medicine(ACSM),the Clinical Oncol-ogy Society of Australia(COSA)or the Exercise and Sports Science Australia(ESSA)are leading the way towards an indi-vidualized approach for exercise prescription.These guidelines provide physicians and therapists with a comprehensive and detailed overview about the beneficial effects of exercise training and,more so,summarize the evidence on potential dose-response mechanisms,including pathways of exercise-induced stimuli to counteract tumour microenvironmental pathologies.However,the most optimal types and doses of exercise training across the cancer disease and treatment continuum are yet to be determined.Therefore,the purpose of this narrative review was to illustrate the current implications but also limitations of exercise training during the different stages of cancer therapy,as well as to discuss necessary future directions.As a second purpose,special attention will be given to the current role of exercise in the treatment of cancer in Germany.