The role of oxidative, inflammatory and neuroendocrinological systems during exercise stress in athletes

University of Technology, Sydney. Faculty of Nursing, Midwifery and Health.Introduction: Exercise induces a stress reaction that initiates adaptive processes, which can be modified by intensive physical training and / or exogenous antioxidant supplementation. However, the optimal exercise training strategy and corresponding level of antioxidant support for positive adaptation remains unclear. Therefore, the overall aim of this thesis was to investigate the interactions between exercise-induced changes within the oxidative, inflammatory and neuroendocrinological systems and antioxidant supplementation on athletic performance during intensive physical training. Three separate studies were undertaken and reported in four manuscripts. Study 1: In Study 1, well-trained athletes (n = 23) completed a 4 day food record during a period of intensified physical training. Collectively, the participants consumed a sufficient dietary intake of antioxidants (vitamin A, C and E) according to the Australian recommendations. Study 2: Study 2 used a crossover experimental design to examine the effect of intensive physical training on oxidative damage, inflammation, hormonal disturbances and performance capacity. Participants (n = 7) completed a high-intensity intermittent running protocol following both a reduced (LOW) and intensive (HIGH) 4 day physical training period. The results demonstrated that HIGH physical training led to an increased amount of muscle damage, decreases in sprint velocity (P < 0.001) and a reduction in total distance covered (P < 0.05) during the high-intensity intermittent running protocol. HIGH physical training also induced a greater increase in oxidative damage (xanthine oxidase) markers 2 h post-exercise (paper 1). Neuroendocrinological measures (growth and thyroid hormones) were not altered by training-induced fatigue (paper 2). These findings suggest that 4 day HIGH training can impair high-intensity running performance and exacerbate oxidative damage. Study 3: Study 3 used a double blind randomised placebo-controlled crossover design to investigate the effect of 9 d oral N-acetylcysteine (NAC) supplementation (1200 mg/day) in eight well-trained triathletes. Changes in performance (cycle ergometer race simulation) and pre- to post-exercise biochemistry measures were taken to determine the ergogenic effect of NAC and associated reaction within the oxidative and inflammatory systems. It was demonstrated that oral NAC supplementation enhanced repeat sprint cycling performance via an improved redox balance and promoted adaptive processes in well-trained triathletes undergoing intensive physical training. NAC supplementation was also effective at blunting the inflammatory response to exercise. Conclusion: Collectively, this thesis provides novel information regarding the dose-response relationship between training-induced fatigue, antioxidant supplementation and athletic performance

Intermittent hypoxic resistance training: Does it provide added benefit?

Methods to enhance the adaptive responses to resistance training are of great interest to clinical and athletic populations alike. Altering the muscular environment by restricting oxygen availability during resistance exercise has been shown to induce favorable physiological adaptations. An acute hypoxic stimulus during exercise essentially increases reliance on anaerobic pathways, augmenting metabolic stress responses, and subsequent hypertrophic processes (Scott et al., 2014). Hypoxic strategies during resistance exercise were originally investigated using blood flow restriction (BFR) methods (Takarada et al., 2000), whereby a cuff is applied proximally to a limb to partially limit arterial inflow while occluding venous outflow from the working muscles. Another method that has been investigated more recently is performing resistance exercise in systemic hypoxia, by means of participants breathing a hypoxic air mixture. The addition of systemic hypoxia to resistance training has previously resulted in significantly enhanced hypertrophic and strength responses to both low-load (20% 1-repetition maximum; 1RM) (Manimmanakorn et al., 2013a,b) and moderate-load (70% 1RM) (Nishimura et al., 2010) resistance training. While research into intermittent hypoxic resistance training (IHRT) is in its infancy, some studies have reported conflicting results, which is likely due to differing research methodologies. In a recent review, it has been suggested that many of the potential mechanisms underpinning muscle adaptations to BFR training and IHRT are linked to the muscular oxygenation status and degree of metabolic stress associated with exercise (Scott et al., 2014). The purpose of this paper is to briefly summarize the adaptive responses that have been reported following both low- and moderate-load IHRT and to highlight key areas of concern for IHRT methodology, including the level of hypoxia used and the degree of metabolic stress imposed during exercise

Temperate Performance Benefits after Heat, but Not Combined Heat and Hypoxic Training

© Copyright 2017 by the American College of Sports Medicine. Purpose Independent heat and hypoxic exposure can enhance temperate endurance performance in trained athletes, although their combined effects remain unknown. This study examined whether the addition of heat interval training during "live high, train low" (LHTL) hypoxic exposure would result in enhanced performance and physiological adaptations as compared with heat or temperate training. Methods Twenty-six well-trained runners completed 3 wk of interval training assigned to one of three conditions: 1) LHTL hypoxic exposure plus heat training (H + H; 3000 m for 13 h·d -1, train at 33°C, 60% relative humidity [RH]), 2) heat training with no hypoxic exposure (HOT, live at <600 m and train at 33°C, 60% RH), or 3) temperate training with no hypoxic exposure (CONT; live at <600 m and train at 14°C, 55% RH). Performance 3-km time-trials (3-km TT), running economy, hemoglobin mass, and plasma volume were assessed using magnitude-based inferences statistical approach before (Baseline), after (Post), and 3 wk (3wkP) after exposure. Results Compared with Baseline, 3-km TT performance was likely increased in HOT at 3wkP (-3.3% ± 1.3%; mean ± 90% confidence interval), with no performance improvement in either H + H or CONT. Hemoglobin mass increased by 3.8% ± 1.8% at Post in H + H only. Plasma volume in HOT was possibly elevated above H + H and CONT at Post but not at 3wkP. Correlations between changes in 3-km TT performance and physiological adaptations were unclear. Conclusion Incorporating heat-based training into a 3-wk training block can improve temperate performance at 3 wk after exposure, with athlete psychology, physiology, and environmental dose all important considerations. Despite hematological adaptations, the addition of LHTL to heat interval training has no greater 3-km TT performance benefit than temperate training alone

Exploring multilocus associations of inflammation genes and colorectal cancer risk using hapConstructor

<p>Abstract</p> <p>Background</p> <p>In candidate-gene association studies of single nucleotide polymorphisms (SNPs), multilocus analyses are frequently of high dimensionality when considering haplotypes or haplotype pairs (diplotypes) and differing modes of expression. Often, while candidate genes are selected based on their biological involvement in a given pathway, little is known about the functionality of SNPs to guide association studies. Investigators face the challenge of exploring multiple SNP models to elucidate which variants, independently or in combination, might be associated with a disease of interest. A data mining module, hapConstructor (freely-available in Genie software) performs systematic construction and association testing of multilocus genotype data in a Monte Carlo framework. Our objective was to assess its utility to guide statistical analyses of haplotypes within a candidate region (or combined genotypes across candidate genes) beyond that offered by a standard logistic regression approach.</p> <p>Methods</p> <p>We applied the hapConstructor method to a multilocus investigation of candidate genes involved in pro-inflammatory cytokine IL6 production, <it>IKBKB</it>, <it>IL6</it>, and <it>NFKB1 </it>(16 SNPs total) hypothesized to operate together to alter colorectal cancer risk. Data come from two U.S. multicenter studies, one of colon cancer (1,556 cases and 1,956 matched controls) and one of rectal cancer (754 cases and 959 matched controls).</p> <p>Results</p> <p>HapConstrcutor enabled us to identify important associations that were further analyzed in logistic regression models to simultaneously adjust for confounders. The most significant finding (nominal <it>P </it>= 0.0004; false discovery rate <it>q </it>= 0.037) was a combined genotype association across <it>IKBKB </it>SNP rs5029748 (1 or 2 variant alleles), <it>IL6 </it>rs1800797 (1 or 2 variant alleles), and <it>NFKB1 </it>rs4648110 (2 variant alleles) which conferred an ~80% decreased risk of colon cancer.</p> <p>Conclusions</p> <p>Strengths of hapConstructor were: systematic identification of multiple loci within and across genes important in CRC risk; false discovery rate assessment; and efficient guidance of subsequent logistic regression analyses.</p

Detection of genotoxic and non-genotoxic renal carcinogens in vitro in NRK-52E cells using a transcriptomics approach. (2012).

There is a need to develop quick, cheap, sensitive and specific methods to detect the carcinogenic potential of chemicals. Currently there is no in vitro model system for reliable detection of non-genotoxic carcinogens (NGTX) and current tests for detection of genotoxic carcinogens (GTX) can have low specificity. A transcriptomics approach holds promise and a few studies have utilised this technique. However, the majority of these studies have examined liver carcinogens with little work on renal carcinogens which may act via renal-specific NGTX mechanisms. In this study the normal rat renal cell line (NRK-52E) was exposed to sub-toxic concentrations of selected rat renal carcinogens and non-carcinogens (NC) for 6 h, 24 h and 72 h. Renal carcinogens were classified based on their presumed mode of action into GTX and NGTX classes. A whole-genome transcriptomics approach was used to determined genes and pathways as potential signatures for GTX, NGTX and those common to both carcinogenic events in vitro. For some of the GTX compounds an S9 drug metabolising system was included to aid pro-carcinogen activation. Only three genes were commonly deregulated after carcinogen (GTX + NGTX) exposure, one Mdm2 with a detection rate of 67%, and p21 and Cd55 with a detection rate of 56%. However, examination of enriched pathways showed that 3 out of 4 NGTX carcinogens and 4 out of 5 GTX carcinogens were related to known pathways involved in carcinogenesis giving a detection rate of 78%. In contrast, none of the NC chemicals induced any of the above genes or well-established carcinogenic pathways. Additionally, five genes (Lingo1, Hmox1, Ssu72, Lyrm and Usp9x) were commonly altered with 3 out of 4 NGTX carcinogens but not with NC or GTX carcinogens. However, there was no clear separation of GTX and NGTX carcinogens using pathway analysis with several pathways being common to both classes. The findings presented here indicate that the NRK-52E cell line has the potential to detect carcinogenic chemicals, although a much larger number of chemicals need to be used to confirm these findings

Coffee consumption and prostate cancer risk: further evidence for inverse relationship

<p>Abstract</p> <p>Background</p> <p>Higher consumption of coffee intake has recently been linked with reduced risk of aggressive prostate cancer (PC) incidence, although meta-analysis of other studies that examine the association between coffee consumption and overall PC risk remains inconclusive. Only one recent study investigated the association between coffee intake and grade-specific incidence of PC, further evidence is required to understand the aetiology of aggressive PCs. Therefore, we conducted a prospective study to examine the relationship between coffee intake and overall as well as grade-specific PC risk.</p> <p>Methods</p> <p>We conducted a prospective cohort study of 6017 men who were enrolled in the Collaborative cohort study in the UK between 1970 and 1973 and followed up to 31st December 2007. Cox Proportional Hazards Models were used to evaluate the association between coffee consumption and overall, as well as Gleason grade-specific, PC incidence.</p> <p>Results</p> <p>Higher coffee consumption was inversely associated with risk of high grade but not with overall risk of PC. Men consuming 3 or more cups of coffee per day experienced 55% lower risk of high Gleason grade disease compared with non-coffee drinkers in analysis adjusted for age and social class (HR 0.45, 95% CI 0.23-0.90, p value for trend 0.01). This association changed a little after additional adjustment for Body Mass Index, smoking, cholesterol level, systolic blood pressure, tea intake and alcohol consumption.</p> <p>Conclusion</p> <p>Coffee consumption reduces the risk of aggressive PC but not the overall risk.</p

Recombination dynamics of a human Y-chromosomal palindrome:rapid GC-biased gene conversion, multi-kilobase conversion tracts, and rare inversions

The male-specific region of the human Y chromosome (MSY) includes eight large inverted repeats (palindromes) in which arm-to-arm similarity exceeds 99.9%, due to gene conversion activity. Here, we studied one of these palindromes, P6, in order to illuminate the dynamics of the gene conversion process. We genotyped ten paralogous sequence variants (PSVs) within the arms of P6 in 378 Y chromosomes whose evolutionary relationships within the SNP-defined Y phylogeny are known. This allowed the identification of 146 historical gene conversion events involving individual PSVs, occurring at a rate of 2.9-8.4×10(-4) events per generation. A consideration of the nature of nucleotide change and the ancestral state of each PSV showed that the conversion process was significantly biased towards the fixation of G or C nucleotides (GC-biased), and also towards the ancestral state. Determination of haplotypes by long-PCR allowed likely co-conversion of PSVs to be identified, and suggested that conversion tract lengths are large, with a mean of 2068 bp, and a maximum in excess of 9 kb. Despite the frequent formation of recombination intermediates implied by the rapid observed gene conversion activity, resolution via crossover is rare: only three inversions within P6 were detected in the sample. An analysis of chimpanzee and gorilla P6 orthologs showed that the ancestral state bias has existed in all three species, and comparison of human and chimpanzee sequences with the gorilla outgroup confirmed that GC bias of the conversion process has apparently been active in both the human and chimpanzee lineages

Search for New Physics in e mu X Data at D0 Using Sleuth: A Quasi-Model-Independent Search Strategy for New Physics

We present a quasi-model-independent search for the physics responsible for electroweak symmetry breaking. We define final states to be studied, and construct a rule that identifies a set of relevant variables for any particular final state. A new algorithm ("Sleuth") searches for regions of excess in those variables and quantifies the significance of any detected excess. After demonstrating the sensitivity of the method, we apply it to the semi-inclusive channel e mu X collected in 108 pb^-1 of ppbar collisions at sqrt(s) = 1.8 TeV at the D0 experiment during 1992-1996 at the Fermilab Tevatron. We find no evidence of new high p_T physics in this sample.Comment: 23 pages, 12 figures. Submitted to Physical Review

Ratio of the Isolated Photon Cross Sections at \sqrt{s} = 630 and 1800 GeV

The inclusive cross section for production of isolated photons has been measured in \pbarp collisions at $\sqrt{s} = 630$ GeV with the \D0 detector at the Fermilab Tevatron Collider. The photons span a transverse energy ($E_T$) range from 7-49 GeV and have pseudorapidity $|\eta| < 2.5$. This measurement is combined with to previous \D0 result at $\sqrt{s} = 1800$ GeV to form a ratio of the cross sections. Comparison of next-to-leading order QCD with the measured cross section at 630 GeV and ratio of cross sections show satisfactory agreement in most of the $E_T$ range.Comment: 7 pages. Published in Phys. Rev. Lett. 87, 251805, (2001