From the Cover: Ryanodine receptor fragmentation and sarcoplasmic reticulum Ca2+ leak after one session of high-intensity interval exercise

High-intensity interval training (HIIT) is a time-efficient way of improving physical performance in healthy subjects and in patients with common chronic diseases, but less so in elite endurance athletes. The mechanisms underlying the effectiveness of HIIT are uncertain. Here, recreationally active human subjects performed highly demanding HIIT consisting of 30-s bouts of all-out cycling with 4-min rest in between bouts (≤3 min total exercise time). Skeletal muscle biopsies taken 24 h after the HIIT exercise showed an extensive fragmentation of the sarcoplasmic reticulum (SR) Ca²⁺ release channel, the ryanodine receptor type 1 (RyR1). The HIIT exercise also caused a prolonged force depression and triggered major changes in the expression of genes related to endurance exercise. Subsequent experiments on elite endurance athletes performing the same HIIT exercise showed no RyR1 fragmentation or prolonged changes in the expression of endurance-related genes. Finally, mechanistic experiments performed on isolated mouse muscles exposed to HIIT-mimicking stimulation showed reactive oxygen/nitrogen species (ROS)-dependent RyR1 fragmentation, calpain activation, increased SR Ca²⁺ leak at rest, and depressed force production due to impaired SR Ca²⁺ release upon stimulation. In conclusion, HIIT exercise induces a ROS-dependent RyR1 fragmentation in muscles of recreationally active subjects, and the resulting changes in muscle fiber Ca²⁺-handling trigger muscular adaptations. However, the same HIIT exercise does not cause RyR1 fragmentation in muscles of elite endurance athletes, which may explain why HIIT is less effective in this group.It is increasingly clear that regular physical exercise plays a key role in the general well-being, disease prevention, and longevity of humans. Impaired muscle function manifesting as muscle weakness and premature fatigue development are major health problems associated with the normal aging process as well as with numerous common diseases (1). Physical exercise has a fundamental role in preventing and/or reversing these muscle problems, and training also improves the general health status in numerous diseases (2–4). On the other side of the spectrum, excessive muscle use can induce prolonged force depressions, which may set the limit on training tolerance and performance of top athletes (5, 6).Recent studies imply a key role of the sarcoplasmic reticulum (SR) Ca²⁺ release channel, the ryanodine receptor 1 (RyR1), in the reduced muscle strength observed in numerous physiological conditions, such as after strenuous endurance training (6), in situations with prolonged stress (7), and in normal aging (8, 9). Defective RyR1 function is also implied in several pathological states, including generalized inflammatory disorders (10), heart failure (11), and inherited conditions such as malignant hyperthermia (12) and Duchenne muscular dystrophy (13). In many of the above conditions, there is a link between the impaired RyR1 function and modifications induced by reactive oxygen/nitrogen species (ROS) (6, 8, 10, 12, 13). Conversely, altered RyR1 function may also be beneficial by increasing the cytosolic free [Ca²⁺] ([Ca²⁺]_i) at rest, which can stimulate mitochondrial biogenesis and thereby increase fatigue resistance (14–16). Intriguingly, effective antioxidant treatment hampers beneficial adaptations triggered by endurance training (17–19), and this effect might be due to antioxidants preventing ROS-induced modifications of RyR1 (20).A high-intensity interval training (HIIT) session typically consists of a series of brief bursts of vigorous physical exercise separated by periods of rest or low-intensity exercise. A major asset of HIIT is that beneficial adaptations can be obtained with much shorter exercise duration than with traditional endurance training (21–25). HIIT has been shown to effectively stimulate mitochondrial biogenesis in skeletal muscle and increase endurance in untrained and recreationally active healthy subjects (22, 26), whereas positive effects in elite endurance athletes are less clear (21, 27, 28). Moreover, HIIT improves health and physical performance in various pathological conditions, including cardiovascular disease, obesity, and type 2 diabetes (29, 30). Thus, short bouts of vigorous physical exercise trigger intracellular signaling of large enough magnitude and duration to induce extensive beneficial adaptations in skeletal muscle. The initial signaling that triggers these adaptations is not known.In this study, we tested the hypothesis that a single session of HIIT induces ROS-dependent RyR1 modifications. These modifications might cause prolonged force depression due to impaired SR Ca²⁺ release during contractions. Conversely, they may also initiate beneficial muscular adaptations due to increased SR Ca²⁺ leak at rest.     

Acute Toxicity by Water Containing Hexavalent or Trivalent Chromium in Native Brazilian Fish, Piaractus mesopotamicus: Anatomopathological Alterations and Mortality

This study evaluated the toxicity of hexavalent and trivalent compounds of chromium to the pacu, Piaractus mesopotamicus, in acute exposures of 96 h through mortality and histopathological responses. Hexavalent potassium dichromate was more toxic than trivalent compounds of chromium chloride, chromium oxide and chromium carbochelate. Sufficient mortalities occurred only with potassium dichromate to yield an LC₅₀ value at 124.2 mg L^?1. Hexavalent chromium caused reversible and irreversible lesions, which may affect organ functionality. Histopathological evaluation showed that trivalent chromium caused lesions of lower severity. Pacu subjected to different concentrations of chromium carbochelate showed no histopathological changes in the kidneys, liver, skin and gills, being similar to those of the control fish. Among the three sources of Cr³⁺, only chromium chloride at 200 mg L^?1 resulted in mortality, which reached 100 % within the first 18 h. These findings confirm that trivalent chromium, when administered within recommended levels, may be used safely in aquaculture.     

Molecular prognostic indicators in HPV-positive oropharyngeal cancer: an updated review

Infection with HPV virus and exposure to extrinsic carcinogens are the main causative factors for oropharyngeal squamous cell carcinoma (OPSCC). While HPV-related OPSCC typically shows a better prognosis and may be a candidate for de-intensification therapy, there is a subset of HPV-related cancers that show aggressive phenotype with frequent metastatic spread. The identification and refinement of molecular markers can better serve for prediction of prognosis and thus improve treatment decisions and outcome. We conducted a systematic review according to the PRISMA guidelines of all relevant studies addressing novel biomarkers in publications prior to July 2021. We identified studies that evaluated the association between molecular markers and prognosis in HPV-positive OPSCC. Full-text publications were entirely reviewed, classified, and selected if a clear predictive/prognostic value was seen in patients with HPV-positive OPSCC. Furthermore, a functional analysis of the target genes was conducted to understand biological processes and molecular pathways impacting on HPV-positive OPSCC outcomes. The systematic review yielded a total of 14 studies that matched the inclusion and exclusion criteria. Differential expression was identified for 31 different biomarkers. The first common pattern identified was the association of HPV-related circulating antibodies to activated immune function. Second, gene–gene interaction analysis further identified interacting gene networks tightly implicated in hypoxia tumor metabolism including the Warburg effect. Survival in HPV-positive OPSCC can be predicted by distinct selective biomarkers mainly indicative of immune host response and oxidative metabolism. Among these markers, some were identified to be unsuitable for HPV-positive de-escalation trials aimed at improving patients’ quality of life.

     

Association between mucosal surface pattern under near focus technology and Helicobacter pylori infection

BACKGROUND Many studies evaluated magnification endoscopy(ME) to correlate changes on the gastric mucosal surface with Helicobacter pylori(H. pylori) infection. However, few studies validated these concepts with high-definition endoscopy without ME.AIM To access the association between mucosal surface pattern under near focus technology and H. pylori infection status in a western population.METHODS Cross-sectional study including all patients referred to routine upper endoscopy. Endoscopic exams were performed using standard high definition(S-HD) followed by near focus(NF-HD) examination. Presence of erythema, erosion, atrophy, and nodularity were recorded during S-HD, and surface mucosal pattern was classified using NF-HD in the gastric body. Biopsies were taken for rapid urease test and histology.RESULTS One hundred and eighty-seven patients were analyzed from August to November 2019. Of those, 47(25.1%) were H. pylori+, and 42(22.5%) had a previous H. pylori treatment. In the examination with S-HD, erythema had the best sensitivity for H. pylori detection(80.9%). Exudate(99.3%), nodularity(97.1%), and atrophy(95.7%) demonstrated better specificity values, but with low sensitivity(6.4%-19.1%). On the other hand, the absence of erythema was strongly associated with H. pylori-(negative predictive value = 92%). With NF-HD, 56.2% of patients presented type 1 pattern(regular arrangement of collecting venules, RAC), and only 5.7% of RAC+ patients were H. pylori+. The loss of RAC presented 87.2% sensitivity for H. pylori detection, 70.7% specificity, 50% positive predictive value, and 94.3% negative predictive value, indicating that loss of RAC was suboptimal to confirm H. pylori infection, but when RAC was seen, H. pylori infection was unlikely.CONCLUSION The presence of RAC at the NF-HD exam and the absence of erythema at S-HD were highly predictive of H. pylori negative status. On the other hand, the loss of RAC had a suboptimal correlation with the presence of H. pylori.     

The expanding role of lymphoscintigraphy in the management of cutaneous melanoma. First Place Winner: Conrad Jobst award

Accepted therapy for intermediate-thickness melanomas is wide local excision and regional lymphadenectomy for nodes known to be in the lymph drainage basin. Lymphoscintigraphy has been shown to be of great help in predicting the drainage pattern of truncal, shoulder, proximal extremity, and head and neck melanomas. Lymphoscintigraphy using Technetium-99 antimony sulfur colloid was performed on 17 patients with cutaneous melanomas at H. Lee Moffitt Cancer Center at the University of South Florida. Of 13 patients with primary truncal and shoulder lesions, drainage patterns were discordant 54 per cent of the time and resulted in dissection of nodal groups different than would otherwise have been planned. This resulted in several lymph nodes positive for metastatic disease removed from operative sites not expected to show metastatic spread by clinical experience alone. The discordant rate for head and neck drainage was also high with 2 of 3 forehead studies showing drainage to both anterior and posterior cervical chains when only anterior chain drainage was expected, while only one of these drained to the preauricular nodes. Again, this led to elective lymph-node dissections of nodal basins not anticipated on clinical grounds alone. After a mean follow-up of 2 years, in which 60 to 75 per cent of all recurrences from melanoma are expected to occur, there has been no lymph-node metastasis development in basins that were not predicted by the scan. It is clear from our data that well-known historical patterns of lymph drainage in addition to the clinical impression of experienced surgeons cannot reliably predict the lymphatic drainage of many truncal, shoulder, and head and neck melanomas.(ABSTRACT TRUNCATED AT 250 WORDS)