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Mutations at specific hotspots in non-coding regions of ADGRG6, PLEKHS1, WDR74, TBC1D12 and LEPROTL1 frequently occur in bladder cancer (BC). These mutations could function as biomarkers for the non-invasive detection of BC but this remains largely unexplored. Massively-parallel sequencing of non-coding hotspots was applied to 884 urine cell pellet DNAs: 591 from haematuria clinic patients (165 BCs, 426 non-BCs) and 293 from non-muscle invasive BC surveillance patients (29 with recurrence). Urine samples from 142 non-BC haematuria clinic patients were used to optimise variant calling. Non-coding mutations are readily detectable in the urine of BC patients and undetectable, or present at much lower frequencies, in the absence of BC. The mutations can be used to detect incident BC with 66% sensitivity (95% CI 58–75) at 92% specificity (95% CI 88–95) and recurrent disease with 55% sensitivity (95% CI 36–74) at 85% specificity (95% CI 80–89%) using a 2% variant allele frequency threshold. In the NMIBC surveillance setting, the detection of non-coding mutations in urine in the absence of clinically detectable disease was associated with an increased relative risk of future recurrence (RR = 4.62 (95% CI 3.75–5.48)). As urinary biomarkers, non-coding hotspot mutations behave similarly to driver mutations in BC-associated genes and could be included in biomarker panels for BC detection. [ABSTRACT FROM AUTHOR]

Purpose: Inter-individual variability in bone mineral density (BMD) exists within and between endurance runners and non-athletes, probably in part due to differing genetic profiles. Certainty is lacking, however, regarding which genetic variants may contribute to BMD in endurance runners and if specific genotypes are sensitive to environmental factors, such as mechanical loading via training. Method: Ten single-nucleotide polymorphisms (SNPs) were identified from previous genome-wide and/or candidate gene association studies that have a functional effect on bone physiology. The aims of this study were to investigate (1) associations between genotype at those 10 SNPs and bone phenotypes in high-level endurance runners, and (2) interactions between genotype and athlete status on bone phenotypes. Results: Female runners with P2RX7 rs3751143 AA genotype had 4% higher total-body BMD and 5% higher leg BMD than AC + CC genotypes. Male runners with WNT16 rs3801387 AA genotype had 14% lower lumbar spine BMD than AA genotype non-athletes, whilst AG + GG genotype runners also had 5% higher leg BMD than AG + GG genotype non-athletes. Conclusion: We report novel associations between P2RX7 rs3751143 genotype and BMD in female runners, whilst differences in BMD between male runners and non-athletes with the same WNT16 rs3801387 genotype existed, highlighting a potential genetic interaction with factors common in endurance runners, such as high levels of mechanical loading. These findings contribute to our knowledge of the genetic associations with BMD and improve our understanding of why some runners have lower BMD than others. [ABSTRACT FROM AUTHOR]

Purpose: Physical activity, particularly mechanical loading that results in high-peak force and is multi-directional in nature, increases bone mineral density (BMD). In athletes such as endurance runners, this association is more complex due to other factors such as low energy availability and menstrual dysfunction. Moreover, many studies of athletes have used small sample sizes and/or athletes of varying abilities, making it difficult to compare BMD phenotypes between studies. Method: The primary aim of this study was to compare dual-energy X-ray absorptiometry (DXA) derived bone phenotypes of high-level endurance runners (58 women and 45 men) to non-athletes (60 women and 52 men). Our secondary aim was to examine the influence of menstrual irregularities and sporting activity completed during childhood on these bone phenotypes. Results: Female runners had higher leg (4%) but not total body or lumbar spine BMD than female non-athletes. Male runners had lower lumbar spine (9%) but similar total and leg BMD compared to male non-athletes, suggesting that high levels of site-specific mechanical loading was advantageous for BMD in females only and a potential presence of reduced energy availability in males. Menstrual status in females and the number of sports completed in childhood in males and females had no influence on bone phenotypes within the runners. Conclusion: Given the large variability in BMD in runners and non-athletes, other factors such as variation in genetic make-up alongside mechanical loading probably influence BMD across the adult lifespan. [ABSTRACT FROM AUTHOR]

The main determinant of muscle carnosine (M-Carn) content is undoubtedly species, with, for example, aerobically trained female vegetarian athletes [with circa 13 mmol/kg dry muscle (dm)] having just 1/10th of that found in trained thoroughbred horses. Muscle fibre type is another key determinant, as type II fibres have a higher M-Carn or muscle histidine containing dipeptide (M-HCD) content than type I fibres. In vegetarians, M-Carn is limited by hepatic synthesis of β-alanine, whereas in omnivores this is augmented by the hydrolysis of dietary supplied HCD's resulting in muscle levels two or more times higher. β-alanine supplementation will increase M-Carn. The same increase in M-Carn occurs with administration of an equal molar quantity of carnosine as an alternative source of β-alanine. Following the cessation of supplementation, M-Carn returns to pre-supplementation levels, with an estimated t of 5-9 weeks. Higher than normal M-Carn contents have been noted in some chronically weight-trained subjects, but it is unclear if this is due to the training per se, or secondary to changes in muscle fibre composition, an increase in β-alanine intake or even anabolic steroid use. There is no measureable loss of M-Carn with acute exercise, although exercise-induced muscle damage may result in raised plasma concentrations in equines. Animal studies indicate effects of gender and age, but human studies lack sufficient control of the effects of diet and changes in muscle fibre composition. [ABSTRACT FROM AUTHOR]

Due to the well-defined role of β-alanine as a substrate of carnosine (a major contributor to H buffering during high-intensity exercise), β-alanine is fast becoming a popular ergogenic aid to sports performance. There have been several recent qualitative review articles published on the topic, and here we present a preliminary quantitative review of the literature through a meta-analysis. A comprehensive search of the literature was employed to identify all studies suitable for inclusion in the analysis; strict exclusion criteria were also applied. Fifteen published manuscripts were included in the analysis, which reported the results of 57 measures within 23 exercise tests, using 18 supplementation regimes and a total of 360 participants [174, β-alanine supplementation group (BA) and 186, placebo supplementation group (Pla)]. BA improved ( P = 0.002) the outcome of exercise measures to a greater extent than Pla [median effect size (IQR): BA 0.374 (0.140-0.747), Pla 0.108 (−0.019 to 0.487)]. Some of that effect might be explained by the improvement ( P = 0.013) in exercise capacity with BA compared to Pla; no improvement was seen for exercise performance ( P = 0.204). In line with the purported mechanisms for an ergogenic effect of β-alanine supplementation, exercise lasting 60-240 s was improved ( P = 0.001) in BA compared to Pla, as was exercise of >240 s ( P = 0.046). In contrast, there was no benefit of β-alanine on exercise lasting <60 s ( P = 0.312). The median effect of β-alanine supplementation is a 2.85% (−0.37 to 10.49%) improvement in the outcome of an exercise measure, when a median total of 179 g of β-alanine is supplemented. [ABSTRACT FROM AUTHOR]

Objective:This study examined the acute effects of ingesting a widely used commercial formula containing extracts of bitter orange, green tea and guarana (Gx) on the metabolic rate and substrate utilisation in overweight, adult males at rest (study 1) and during treadmill walking (study 2).Subjects:Two different groups of 10 sedentary males with more than 20% body fat participated in studies 1 and 2.Design:In each study, subjects participated in two experimental trials during which they were given two 500 mg capsules containing either Gx or a placebo (P) in a counterbalanced double-blind manner. Doses of the main active ingredients were 6 mg of synephrine, 150 mg caffeine and 150 mg catechin polyphenols.Measurements:In study 1, subjects completed 7 h supine rest with baseline measures taken during the first hour, with expired gases, blood pressure, heart rate and venous blood being collected every 30 min for the remaining 6 h following ingestion of Gx or P. In study 2, subjects exercised for 60 min at 60% heart rate reserve following ingestion of Gx or P 1 h previously. Venous blood samples were collected twice at rest and at 5, 10, 15, 20, 30, 40, 50 and 60 min, with expired gas measurements taken at 4, 9, 14, 19, 29, 39, 49 and 59 min. In both studies, venous blood was analysed for NEFA, glycerol, glucose and lactate concentrations, while expired gases were used to calculate ATP production from carbohydrate and NEFA, as well as the total substrate utilised.Results and conclusion:The results did not show any significant effect of Gx ingestion on total ATP utilisation during 6 h rest or during 60 min treadmill walking. Changes were observed in the relative contributions of CHO and NEFA oxidation to ATP production in both studies, such that there was an increase in ATP production from CHO and a decrease from NEFA. The increase in CHO oxidation was shown to be as high as 30% at rest.International Journal of Obesity (2006) 30, 764–773. doi:10.1038/sj.ijo.0803209; published online 17 January 2006 [ABSTRACT FROM AUTHOR]