RESUMEN
Thermal safety guidelines with upper thresholds aim to protect athletes' health, yet evidence-based sport-specific thresholds remain unestablished. Experimenting with athletes in severely hot conditions raises ethical concerns, so we used a thermo-physiological model to validate the thresholds of guidelines for outdoor sports. First, the reproducibility of the joint system thermoregulation model (JOS-3) of core temperature has been validated for 18 sports experiments (n = 213) and 11 general exercise experiments (n = 121) using the Bland - Altman analysis. Then, core temperatures were predicted using the JOS-3 in conditions corresponding to the upper thresholds, and if the 90th-99.7th percentile core temperature value (corresponding to 0.3%-10% of the participants) exceeded 40°C, the thresholds were judged as potentially hazardous. Finally, we proposed revisions for sports with potentially hazardous thresholds. As a result, the JOS-3 could simulate core temperature increases in most experiments (27/29) for six sports and general exercises with an accuracy of 0.5°C. The current upper thresholds for marathons, triathlons, and football are potentially hazardous. Suggested revisions, based on specified percentiles, include: Football: revise from wet bulb globe temperature (WBGT) 32°C to 29-31°C or not revise. Marathon: revise from WBGT 28°C to 24-27°C. Triathlon: revise from WBGT 32.2°C to 23-26°C. If conducting sports events under the revised upper thresholds proves difficult, taking measures for a possible high incidence of heat illness becomes crucial, such as placing additional medical resources, assisting heat acclimatization and cooling strategies for participants, and rule changes such as shorter match times and increased breaks.
RESUMEN
Nicotinamide adenine dinucleotide (NAD+) plays a pivotal role in various physiological processes within mammalian cells, including energy metabolism, redox homeostasis, and genetic regulation. In the majority of mammalian cellular contexts, NAD+ biosynthesis primarily relies on vitamin B3, including nicotinamide (NAM) and nicotinic acid (NA). The concept of NAD+ augmentation therapy has recently emerged as a promising strategy to mitigate aging-associated phenomena, termed rejuvenation. Despite the involvement of diverse enzymatic cascades in NAD+ biosynthesis, certain cellular environments exhibit deficiencies in specific enzymes, suggesting cell type-dependent variability in optimal NAD+ precursor selection. However, the optimization of NAD+ precursors for topical formulations has received scant attention thus far. In the present investigation, we sought to delineate the most efficacious precursor for augmenting NAD+ levels in human skin keratinocytes. Remarkably, NA supplementation led to a significant 1.3-fold elevation in intracellular NAD+ levels, even in the presence of nicotinamide phosphoribosyltransferase inhibition by FK866. Additionally, NA mononucleotide demonstrated a 1.5-fold increase (but not significant) in NAD+ levels following 100 µM application. Conversely, NAM and its derivatives failed to elicit a NAD+ response in keratinocytes. Notably, NA supplementation elicited up-regulation of mitochondrial superoxide dismutase (SOD2) and sirtuin 3 (SIRT3), indicative of its beneficial impact on mitochondrial function. Furthermore, NA mitigated rotenone-induced mitochondrial reactive oxygen species (ROS) accumulation. Collectively, these findings advocate for the potential utility of NA in topical applications aimed at skin rejuvenation.
RESUMEN
With cancer diagnosis occurring at older ages, the use of immune checkpoint inhibitors (ICIs) has extended to older adults. However, the safety of immune-related adverse events (irAEs) in this population remains unclear and relies on data extrapolated from younger adults. This multicenter retrospective study aimed to examine irAE prevalence and tolerability in older adults. We included 436 patients with non-small lung cancer undergoing ICI therapy and dichotomized them into two age groups (< or ≥75 years). Incidence of any irAE grade, grade ≥3 irAEs, and steroid usage after irAE occurrence was similar between younger (n = 332) and older groups (n = 104). While the younger patients with irAEs showed prolonged overall survival in the 12-month landmark Kaplan-Meier analysis (Hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.38-0.89, p = 0.013), the older cohort did not (HR 0.80, 95% CI 0.36-1.78, p = 0.588). Although no differences were observed with ICI continuation or re-challenge after irAE onset, the elderly cohort had double the irAE cases that required a transition to best supportive care (BSC) (11.3% vs. 22.4%, p = 0.026). In conclusion, although irAE prevalence remains consistent regardless of age, the increased conversion to BSC post-irAE onset in older adults suggests diminished tolerability and the potential absence of favorable prognosis associated with irAEs in this population.
RESUMEN
Spinal cord injury (SCI) induces devastating permanent deficits. Recently, cell transplantation therapy has become a notable treatment for SCI. Although stem cells from human exfoliated deciduous teeth (SHED) are an attractive therapy, their precise mechanism of action remains to be elucidated. In this study, we explored one of the neuroprotective mechanisms of SHED treatment at the subacute stage after SCI. We used a rat clip compression SCI model. The animals were randomly divided into three groups: SCI, SCI + phosphate-buffered saline (PBS), and SCI + SHED. The SHED or PBS intramedullary injection was administered immediately after SCI. After SCI, we explored the effects of SHED on motor function, as assessed by the Basso-Beattie-Bresnahan score and the inclined plane method, the signal transduction pathway, especially the Janus kinase (JAK) and the signal transducer and activator of transcription 3 (STAT3) pathway, the apoptotic pathway, and the expression of neurocan, one of the chondroitin sulfate proteoglycans. SHED treatment significantly improved functional recovery from Day 14 relative to the controls. Western blot analysis showed that SHED significantly reduced the expression of glial fibrillary acidic protein (GFAP) and phosphorylated STAT3 (p-STAT3) at Tyr705 on Day 10 but not on Day 5. However, SHED had no effect on the expression levels of Iba-1 on Days 5 or 10. Immunohistochemistry revealed that p-STAT3 at Tyr705 was mainly expressed in GFAP-positive astrocytes on Day 10 after SCI, and its expression was reduced by administration of SHED. Moreover, SHED treatment significantly induced expression of cleaved caspase 3 in GFAP-positive astrocytes only in the epicenter lesions on Day 10 after SCI but not on Day 5. The expression of neurocan was also significantly reduced by SHED injection on Day 10 after SCI. Our results show that SHED plays an important role in reducing astrogliosis and glial scar formation between Days 5 and 10 after SCI, possibly via apoptosis of astrocytes, ultimately resulting in improvement in neurological functions thereafter. Our data revealed one of the neuroprotective mechanisms of SHED at the subacute stage after SCI, which improved functional recovery after SCI, a serious condition.