Epidemiological profile of pain and non-steroid anti-inflammatory drug use in collegiate athletes in the United States.

BACKGROUND: Although athletic endeavours are associated with a high amount of physical stress and injury, the prevalence of pain is underreported in the sports medicine literature with only a few studies reporting pain on collegiate athletes or exploring sex difference of pain. Impact of pain on athlete availability, training and performance can be mitigated when key epidemiological information is used to inform adequate pain management strategies. This study aims to 1) provide an epidemiological profile of self-reported pain experienced by the National Collegiate Athletic Association (NCAA) athletes by sex during the first half of the 2019 season, 2) describe their self-reported non-steroidal anti-inflammatory drug (NSAID) use. METHODS: Online survey was completed by athletes at three NCAA institutions from 1 August to 30 September 2019. Descriptive statistics were used to describe player demographic data, self-reported pain and self-reported NSAID use. Pain incidence proportion were calculated. RESULTS: Two hundred thirty female athletes and 83 male athletes completed the survey. Self-reported pain incidence proportion for female athletes was 45.0 (95% CI 41.5-48.5) vs 34.9 (95% CI 29.4-40.4) for male athletes. Majority of the athletes did not report pain (55% female vs 62% male) during the first half of the 2019 season. Female athletes reported pain in their back (35%), knee (26%), and ankle/foot (23%) whilst male athletes reported pain in their knee (35%), back (28%), and shoulder (24%). Of all athletes, 28% female vs 20% male athletes reported currently taking NSAIDs. Of athletes that reported pain, 46% female vs 38% male athletes currently took NSAIDs. 70% female vs 61% male athletes self-purchased NSAIDs, and 40% female vs 55% male athletes consumed alcohol. CONCLUSIONS: Half of female athletes and one in three male athletes reported pain. Most commonly back, knee and foot/ankle pain and knee, back and shoulder pain was reported in female and male athletes respectively. One in four female athletes and one in five male athletes use NSAIDs for pain or prophylactic purpose. Majority self-purchase these medications indicating need for health literacy interventions to mitigate potential adverse effects.

Inflammation and oxidative stress are lower in physically fit and active adults.

The objective of this study was to determine if the inverse relationship between perceived physical fitness (pFIT) and exercise frequency (ExFreq) levels and chronic inflammation and oxidative stress exists after making statistical adjustments for confounders including body mass index (BMI), age, gender, and cigarette smoking. Study participants (60% female and 40% male; n = 998) varied widely in age (18-85 years) and BMI (16.7-52.7 kg/m(2)) completed an extensive medical/health and lifestyle questionnaire, and data were used to establish pFIT and ExFreq tertiles. Biomarkers included serum C-reactive protein (CRP), total blood leukocytes, five plasma cytokines [interleukin (IL)-6, IL-10, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP1), and granulocyte colony-stimulating factor (GCSF)], F2 -isoprostanes, ferric reducing ability of plasma (FRAP), and oxygen radical absorbance capacity (ORAC). A general linear model was used to examine relationships between pFIT and ExFreq with inflammation and oxidative stress while controlling for age, gender, BMI, and smoking. Benjamini-Hochberg method for false discovery rate correction was used for multiple testing corrections. Significant tests (P < 0.05) for trend were found for the effect of pFIT and ExFreq on CRP, white blood cell, IL-6, TNF-α, GCSF, and F2 -isoprostanes, but not MCP1, IL-10, FRAP, and ORAC, after adjustment for confounders. These data indicate that an inverse relationship exists among chronic inflammation, oxidative stress, and pFIT and ExFreq at the community level even after adjustment for important confounders.

Pharmacological manipulation of the dopaminergic system affects wheel-running activity in differentially active mice.

The genetic factors involved in the regulation of physical activity are not well understood. The dopamine system has been implicated in the control of voluntary locomotion and wheel running (WR) in mice and is thus a likely candidate as a genetic/biological system important to the regulation of physical activity. This study evaluated the effects of four different dopaminergic acting drugs on WR in differentially active inbred strains of mice. High active C57L/J (n=7, 3 controls, 4 experimental) and low active C3H/HeJ (n=8, 3 controls, 5 experimental) were analyzed for baseline wheel-running indices of distance (km/day), duration (mins/day), and speed (m/min) for 21 days. Experimental mice received increasing doses over four days of each of the following drugs: SKF 81297 (D1 agonist), SCH 23390 (D1 antagonist), GBR 12783 (DAT inhibitor), and AMPT (tyrosine hydroxylase inhibitor). Each drug dose response treatment was separated by three days of recovery (no drug injections). WR indices were monitored during drug treatments and during drug wash-out phases. SKF 81297 significantly reduced (p=0.0004) WR in the C57L/J mice, but did not affect WR in the C3H/HeJ mice. GBR 12783 significantly increased (p=0.0005) WR in C3H/HeJ mice, but did not affect WR in C57L/J mice. Only duration (not overall WR) was significantly reduced in C57L/J mice in response to SCH 23390 (p=0.003) and AMPT (p=0.043). SCH 23390 (p=0.44) and AMPT (p=0.98) did not significantly affect WR in C3H/HeJ mice. These results suggest that genetic differences in dopamine signaling may play a role in the WR response to dopaminergic-acting drugs in inbred strains of mice. The high activity in the C57L/J strain appears most responsive to D1-like receptor acting drugs, while in the C3H/HeJ strain, dopamine re-uptake appears to have an influence on activity level.

The variable plasma quercetin response to 12-week quercetin supplementation in humans.

BACKGROUND/OBJECTIVES: Quercetin supplementation results in a variable plasma quercetin response in humans. The purpose of this study was to determine whether this variance is related to gender, age, body mass index (BMI), and other demographic and lifestyle factors. SUBJECTS/METHODS: Subjects (N=1002, ages 18-85 years, 60% female and 40% male) were recruited from the community and randomized to one of three groups, with supplements administered using double-blinded procedures: Q-500 (500 mg/day), Q-1000 (1000 mg/day), or placebo. Subjects ingested two soft chew supplements twice daily during the 12-week study. Fasting blood samples were obtained pre- and post-study, analyzed for plasma quercetin, and then compared between and within groups by gender, age group (<40, 40-59, and >or=60 years), BMI (<25, 25-29.9, and >or=30 kg/m(2)), self-reported physical fitness level, and diet intake (food group servings). RESULTS: Quercetin supplementation over 12 weeks caused a significant increase in overnight-fasted plasma quercetin, with a net increase of 332+/-21.0 and 516+/-30.8 microg/l for Q-500 and Q-1000 compared with 53.6+/-6.4 microg/l for placebo (interaction effect, P<0.001). The increase in plasma quercetin was highly variable within each quercetin supplementation group, but was unrelated to age, gender, BMI, fitness levels, or diet intake. CONCLUSIONS: In summary, quercetin supplementation in doses of 500 and 1000 mg/day caused large but highly variable increases in plasma quercetin that were unrelated to demographic or lifestyle factors.

A camptothecin-resistant DNA topoisomerase I mutant exhibits altered sensitivities to other DNA topoisomerase poisons.

The cytotoxic plant alkaloid camptothecin promotes DNA topoisomerase I-linked nicks in DNA by stabilizing a covalently bound enzyme-DNA complex. In the yeast Saccharomyces cerevisiae, substitution of Arg and Ala for the amino acid residues immediately N-terminal to the active site tyrosine in the yeast and human DNA topoisomerase I mutants, top1 vac, results in camptothecin resistance. To examine the mechanism of drug resistance, we assessed the sensitivity of these enzymes to several classes of DNA topoisomerase poisons. Yeast cells expressing the camptothecin-resistant top1 vac mutants were resistant to all of the camptothecin derivatives cytotoxic to wild-type TOP1-expressing cells. This correlated with a significant reduction in drug-induced DNA cleavage in vitro. However, the yeast and human mutant enzymes differed in their responses to the minor groove binding ligand netropsin and to saintopin, a DNA intercalator that targets both DNA topoisomerase I and II. The yeast mutant enzyme demonstrated enhanced sensitivity to the action of saintopin but was resistant to the inhibitory effects of netropsin. In contrast, the human Top1 vac enzyme was resistant to saintopin and indistinguishable from the wild-type enzyme in its response to the netropsin. These results are discussed in terms of enzyme function and the different modes of action of these DNA topoisomerase poisons.

Yeast Saccharomyces cerevisiae as a model system to study the cytotoxic activity of the antitumor drug camptothecin.

Eukaryotic DNA topoisomerase I catalyzes the relaxation of positively and negatively supercoiled DNA and plays a critical role in processes involving DNA, such as DNA replication, transcription and recombination. The enzyme is encoded by the TOP1 gene and is highly conserved in its amino acid sequence and sensitivity to the anti-neoplatic agent camptothecin. This plant alkaloid specifically targets DNA topoisomerase I by reversibly stabilizing the covalent enzyme-DNA intermediate. Presumably, it is the interaction of these drug-stabilized adducts with other cellular components, such as replication forks, that actually produces the DNA lesions leading to cell death. A conservation of the mechanism(s) of camptothecin-induced cell killing is also implicit in studies of the yeast Saccharomyces cerevisiae, where the camptothecin sensitivity of delta TOP1 yeast cells can be restored by plasmids expressing either yeast or human TOP1 sequences. This genetically tractable system is currently being exploited to describe the specific molecular interactions required for the cytotoxic action of camptothecin. The results of mutational analyses of yeast and human DNA topoisomerase I are presented, as well as a genetic screen designed to identify genes, other than TOP1, that are required for the cytotoxic activity of camptothecin.

Mechanisms of camptothecin resistance in yeast DNA topoisomerase I mutants.

The anti-cancer drug camptothecin targets eukaryotic DNA topoisomerase I by trapping the covalent complex formed between the catalytically active enzyme and DNA. Saccharomyces cerevisiae cells expressing yeast DNA topoisomerase I mutant top1 vac (I725R, N726A) or top1N726L, in which the amino acid residues N terminus to the active site tyrosine Tyr-727 were changed as indicated, were found to be camptothecin-resistant even though the mutant proteins expressed in Escherichia coli were previously shown to be active. Assays of enzyme-catalyzed relaxation of supercoiled DNA in vitro and in vivo in yeast showed that the camptothecin resistance of these mutants arises by entirely different mechanisms. Top1N726L-catalyzed DNA relaxation was not detected in yeast. The Top1 vac protein was catalytically active; however, camptothecin was inefficient in trapping the covalent intermediate formed between the Top1 vac enzyme and DNA. Yeast cells expressing human mutant htop1 vac, with similar substitutions near the active site tyrosine Tyr-723, were also camptothecin-resistant. Surprisingly, in the absence of camptothecin, yeast rad52 mutants defective in the repair of double-stranded DNA breaks were nonviable when top1N726L or top1 vac was overexpressed but viable when htop1 vac was overexpressed. These results suggest differences between yeast and human enzyme function in vivo.