Description:
Rationale: Following prolonged endurance events such as marathons, elevated levels of cardiospecific biomarkers are commonly reported. Although transiently raised levels are generally not considered to indicate clinical myocardial damage, comprehension of this phenomenon remains incomplete. The popularity of high-intensity interval training highlights a paucity of research measuring cardiac biomarker response to this type of exercise. This a posteriori case report discusses the elevation of cardiac troponins (cTn) associated with short interval, high-intensity exercise. Patient concerns: In this case report, an apparently healthy 29-year-old recreationally active female presented clinically raised cardiac troponin I (cTnI) levels (>0.04 ng/mL), after performing high-intensity cycle ergometer sprints. As creatine kinase (CK) is expressed by multiple organs (e.g., skeletal muscle, brain, and myocardium), cTnI assays were performed to determine any changes in total serum CK levels not originating from skeletal muscle damage. Diagnosis: A posteriori the individual's daily energy expenditure indicated chronically low-energy availability. Psychometric testing suggested that the individual scored positive for disordered eating, highly for fatigue levels, and low in mental health components. Outcomes: The current case report provides novel evidence of elevated cTnI occurring as a result of performing short duration, high intensity, cycle ergometer exercise in an individual with self-reported chronically depleted energy balance. A schematic to identify potentially “at risk” individuals is presented. Lessons: Considering this as a case report, results cannot be generalized; however, the main findings suggest that individuals who habitually restrict their calorie intake below their bodies’ daily energy requirements, may have elevated biomarkers of exercise induced myocardial stress from performing high-intensity exercise.
Description:
Rationale: Following prolonged endurance events such as marathons, elevated levels of cardiospecific biomarkers are commonly reported. Although transiently raised levels are generally not considered to indicate clinical myocardial damage, comprehension of this phenomenon remains incomplete. The popularity of high-intensity interval training highlights a paucity of research measuring cardiac biomarker response to this type of exercise. This a posteriori case report discusses the elevation of cardiac troponins (cTn) associated with short interval, high-intensity exercise. Patient concerns: In this case report, an apparently healthy 29-year-old recreationally active female presented clinically raised cardiac troponin I (cTnI) levels (>0.04 ng/mL), after performing high-intensity cycle ergometer sprints. As creatine kinase (CK) is expressed by multiple organs (e.g., skeletal muscle, brain, and myocardium), cTnI assays were performed to determine any changes in total serum CK levels not originating from skeletal muscle damage. Diagnosis: A posteriori the individual's daily energy expenditure indicated chronically low-energy availability. Psychometric testing suggested that the individual scored positive for disordered eating, highly for fatigue levels, and low in mental health components. Outcomes: The current case report provides novel evidence of elevated cTnI occurring as a result of performing short duration, high intensity, cycle ergometer exercise in an individual with self-reported chronically depleted energy balance. A schematic to identify potentially “at risk” individuals is presented. Lessons: Considering this as a case report, results cannot be generalized; however, the main findings suggest that individuals who habitually restrict their calorie intake below their bodies’ daily energy requirements, may have elevated biomarkers of exercise induced myocardial stress from performing high-intensity exercise.
Description:
BACKGROUND: It is unclear whether the hypertriglyceridemic waist phenotype (HTWP) can be used to identify those at most risk of cardiometabolic disorders. OBJECTIVES: The utility of the HTWP as a useful predictor of cardiometabolic risk in youth stratified by body mass index was assessed. METHODS: Three hundred and eighty-seven children (12-17.5 years) were used within this cross-sectional study. Participants were classified as normal weight or overweight/obese according to the International Obesity Task Force criteria. The HTWP phenotype was defined as having a waist circumference >/=90th percentile for age and gender with concomitant triglyceride concentrations >/=1.24 mmol L(-1) . Cardiometabolic risk profiles were compared using MANCOVA. RESULTS: Normal weight participants with the HTWP had significantly higher levels of C-reactive protein 2.6 +/- 0.4 vs. 1.6 +/- 0.3 mg L(-1) (P < 0.05) and cardiometabolic risk scores (1.3 +/- 0.3 vs. -0.7 +/- 0.2 and 2.1 +/- 0.4 vs. -0.5 +/- 0.2; both P < 0.05) compared with those of a normal weight without the HTWP. Overweight/obese participants with the HTWP had significantly higher C-reactive protein levels (3.5 +/- 0.6 vs. 2.6 +/- 0.5; P < 0.05) as well as both cardiometabolic risk scores (1.6 +/- 0.6 vs. 0.9 +/- 0.2 and 2.2 +/- 0.6 vs. 0.8 +/- 0.2; both P < 0.001) when compared with overweight/obese participants without the HTWP. CONCLUSIONS: The HTWP may serve as a simple and clinically useful approach to identify youth at increased cardiometabolic risk.
Description:
OBJECTIVES: To evaluate the ability of BMI, WC, and WHtR to identify increased cardiometabolic risk in pre-adolescents. METHODS: This is a cross-sectional study involving 192 children (10.92 +/- 0.58 years, 56% female) from the United Kingdom between 2010 and 2013. Receiver operating characteristic curves determined the discriminatory ability of BMI, WC and WHtR to identify individuals with increased cardiometabolic risk (increased clustered triglycerides, HDL-cholesterol, systolic blood pressure, cardiorespiratory fitness, and glucose). RESULTS: A WHtR >/= 0.5 increased the odds by 5.2 (95% confidence interval 2.6 - 10.3) of having increased cardiometabolic risk. Similar associations were observed for BMI and WC. Both BMI-z and WHtR were fair predictors of increased cardiometabolic risk, although BMI-z demonstrated the best trade-off between sensitivity and specificity, 76.1% and 63.6%, compared with 68.1% and 65.5% for WHtR. Cross-validation analysis revealed that BMI-z and WHtR correctly classified 84% of individuals (kappa score = 0.671, 95% CI 0.55, 0.79). The sensitivity of the cut-points suggests that 89.3% of individuals were correctly classified as being at risk with only 10.7% misdiagnosed whereas the specificity of the cut-points indicated that 77.8% of individuals were correctly identified as being healthy with 22.2% of individuals incorrectly diagnosed as being at risk. CONCLUSIONS: Findings suggest that WHtR provides similar cardiometabolic risk estimates to age and sex adjusted BMI.
Long-term aerobic exercise improves vascular function into old age : A systematic review, meta-analysis and meta regression of observational and interventional studies
Description:
There is an emerging body of literature relating to the effectiveness of frequent aerobic exercise as a prophylactic for age-associated dysfunction of large arteries, yet systematic evaluation and precise estimate of this effect is unknown. We conducted a systematic review and meta-analysis of controlled studies examining flow mediated dilatation (FMD) of athletic older persons and otherwise healthy sedentary counterparts to (i) compare FMD as a determinant of endothelial function between athletes and sedentary individuals and, (ii) summarize the effect of exercise training on FMD in studies of sedentary aging persons. Studies were identified from systematic search of major electronic databases from inception to January 2018. Study quality was assessed before conducting a random effects meta-analysis to calculate a pooled ES (mean difference) with 95% CI's. Thirteen studies [4 interventional (n = 125); 10 cross-sectional [including one study from the interventional analysis; (n = 485)] with age ranges from 62 to 75 years underwent quantitative pooling of data. The majority of study participants were male. Older athletes had more favorable FMD compared with sedentary controls (2.1%; CI: 1.4, 2.8%; P < 0.001). There was no significant improvement in the vascular function of sedentary cohorts following a period of exercise training (0.7%; CI: −0.675, 2.09%; P = 0.316). However, there was a significant increase in baseline diameter from pre to post intervention (0.1 mm; CI: 0.07, 0.13 mm; P < 0.001). In addition, there was no significant difference in endothelial independent vasodilation between the trained and sedentary older adults (1.57%; CI: −0.13, 3.27%; P = 0.07), or from pre to post exercise intervention (1.48%; CI: −1.34, 4.3%; P = 0.3). In conclusion, long-term aerobic exercise appears to attenuate the decline in endothelial vascular function, a benefit which is maintained during chronological aging. However, currently there is not enough evidence to suggest that exercise interventions improve vascular function in previously sedentary healthy older adults.
Description:
There is an emerging body of literature relating to the effectiveness of frequent aerobic exercise as a prophylactic for age-associated dysfunction of large arteries, yet systematic evaluation and precise estimate of this effect is unknown. We conducted a systematic review and meta-analysis of controlled studies examining flow mediated dilatation (FMD) of athletic older persons and otherwise healthy sedentary counterparts to (i) compare FMD as a determinant of endothelial function between athletes and sedentary individuals and, (ii) summarize the effect of exercise training on FMD in studies of sedentary aging persons. Studies were identified from systematic search of major electronic databases from inception to January 2018. Study quality was assessed before conducting a random effects meta-analysis to calculate a pooled ES (mean difference) with 95% CI's. Thirteen studies [4 interventional (n = 125); 10 cross-sectional [including one study from the interventional analysis; (n = 485)] with age ranges from 62 to 75 years underwent quantitative pooling of data. The majority of study participants were male. Older athletes had more favorable FMD compared with sedentary controls (2.1%; CI: 1.4, 2.8%; P < 0.001). There was no significant improvement in the vascular function of sedentary cohorts following a period of exercise training (0.7%; CI: −0.675, 2.09%; P = 0.316). However, there was a significant increase in baseline diameter from pre to post intervention (0.1 mm; CI: 0.07, 0.13 mm; P < 0.001). In addition, there was no significant difference in endothelial independent vasodilation between the trained and sedentary older adults (1.57%; CI: −0.13, 3.27%; P = 0.07), or from pre to post exercise intervention (1.48%; CI: −1.34, 4.3%; P = 0.3). In conclusion, long-term aerobic exercise appears to attenuate the decline in endothelial vascular function, a benefit which is maintained during chronological aging. However, currently there is not enough evidence to suggest that exercise interventions improve vascular function in previously sedentary healthy older adults.
Description:
BACKGROUND: Previous research has shown that the performance of skeletal muscle declines with advancing age. Coordination of the transverse abdominis (TrA), a deep postural muscle, has been shown to be reduced in persons with low back pain. No previous research has studied the effect of age on the activation on this muscle. OBJECTIVE: To assess the effect of age on TrA activation in response to rapid arm abduction. DESIGN: Cross-sectional cohort study. SETTING: University exercise physiology laboratory. PARTICIPANTS: A total of 18 adult men (aged 27 +/- 7.0 years) for the younger group and 11 older adults (5 men and 6 women, aged 59.6 +/- 4.0 years) were recruited for this study. METHOD: Participants were positioned on a treatment table and performed a series of rapid arm abduction movements with their right arm while the activation of the TrA muscle was recorded using ultrasound imaging. Onset of arm abduction was measured using surface electromyography and synchronized with the ultrasound through the ultrasound unit's electrocardiogram channel. The mean time difference between the 2 events was calculated during post-hoc analysis. MAIN OUTCOME MEASUREMENTS: A Mann-Whitney test was performed to test for differences in the onset performance of the TrA muscle between the 2 groups. RESULTS: Results showed that the older group was significantly slower than the younger group in engaging their TrA in response to the rapid arm abduction (P = .036). A separate analysis of the older group data showed that no significant differences existed between the male and female participants that could potentially have acted as a confounding factor for the main finding (P = .126). CONCLUSIONS: This study shows that older adults were slower than younger adults in activating their TrA muscle in response to rapid arm abduction. This delay has the potential to lead to increased occasions when the low back is unprotected, increasing the likelihood of injury or low back pain.
Description:
Both cycle ergometry and treadmill exercise are commonly employed to examine the cardiopulmonary system under conditions of precisely controlled metabolic stress. Although both forms of exercise are effective in elucidating a maximal stress response, it is unclear whether breathing strategies or ventilator efficiency differences exist between exercise modes. The present study examines breathing strategies, ventilatory efficiency and ventilatory capacity during both incremental cycling and treadmill exercise to volitional exhaustion. Subjects (n = 9) underwent standard spirometric assessment followed by maximal cardiopulmonary exercise testing utilising cycle ergometry and treadmill exercise using a randomised cross-over design. Respiratory gases and volumes were recorded continuously using an online gas analysis system. Cycling exercise utilised a greater portion of ventilatory capacity and higher tidal volume at comparable levels of ventilation. In addition, there was an increased mean inspiratory flow rate at all levels of ventilation during cycle exercise, in the absence of any difference in inspiratory timing. Exercising V(E)/VCO(2)slope and the lowest V(E)/VCO(2)value, was lower during cycling exercise than during the treadmill protocol indicating greater ventilatory efficiency. The present study identifies differing breathing strategies employed during cycling and treadmill exercise in young, trained individuals. Exercise mode should be accounted for when assessing breathing patterns and/or ventilatory efficiency during incremental exercise.
Description:
Lifelong exercise is associated with regulation of skeletal mass and function, reductions in frailty, and successful aging. Yet, the influence of exercise on myostatin and myostatin‐interacting factors is relatively under examined in older males. Therefore, we investigated whether serum total myostatin, free myostatin, follistatin, and growth and differentiation factor 11 (GDF11) were altered following high‐intensity interval training (HIIT) in a group of 13 lifelong sedentary (SED; 64 [6] years) and 11 lifelong exercising (LEX; 62 [6] years) older males. SED follistatin was moderately greater than LEX pre‐HIIT (Cohen's d = 0.66), and was largely greater post‐HIIT (Cohen's d = 1.22). The HIIT‐induced increase in follistatin was large in SED (Cohen's d = 0.82) and absent in LEX (Cohen's d = 0.03). GDF11 was higher in LEX pre‐HIIT (Cohen's d = 0.49) and post‐HIIT (Cohen's d = 0.63) compared to SED. HIIT resulted in no change to GDF11 in LEX or SED (Cohen's d = 0.00–0.03). Peak power output and GDF11 were correlated (r = 0.603), independent of grouping. Differences in GDF11 with lifelong exercise training, paired with the correlation between GDF11 and peak power output, suggested that GDF11 may be a relevant myostatin‐interacting peptide to successful aging in humans, and strategies to maintain this need to be further explored.
Description:
The purpose of this study was to investigate the effects of resistance training and long-term anabolic androgenic steroids (AASs) administration on respiratory function. Subject groups consisted of AAS users (n = 9) who were still using AAS at time of testing (SU); AAS users (n = 6) who had been abstinent for > 3 months (SA), bodybuilding controls (n = 8) (BC), and (n = 8) sedentary male controls (SC). FEV(1), FVC, and PEF were measured. The results found that all subjects were within normal range, and there were no differences between groups. Maximum inspiratory pressure (MIP), and grip strength were both significantly greater in SU (P < 0.05) compared with SC; no significant difference was found between the other groups. Their MIP and grip strength was significantly correlated (r = 0.57; P < 0.05). The data from this study suggest that the combination of resistance training and AAS administration produce a significant increase in MIP in a cohort of long-term AAS users.
Description:
Health pregnant women are encouraged to partake in exercise, which is increasingly being shown to to be beneficial for both the mother and child (Davies et al., 2003; Dempsey et al., 2005). While exercise training during pregnancy is common practice among a subgroup of physically active women, pregnancy and postpartum studies reveal there is generally a high risk for inactivity among pregnant womwn, with signficant reductions in previously established levels of activity (Albright and Maddock, 2006; Downs and Hausenbals, 2004; Zhang and Savitz, 1996
Age related vascular endothelial function following lifelong sedentariness: positive impact of cardiovascular conditioning without further improvement following low frequency high intensity interval training
Description:
Aging is associated with diffuse impairments in vascular endothelial function and traditional aerobic exercise is known to ameliorate these changes. High intensity interval training (HIIT) is effective at improving vascular function in aging men with existing disease, but its effectiveness remains to be demonstrated in otherwise healthy sedentary aging. However, the frequency of commonly used HIIT protocols may be poorly tolerated in older cohorts. Therefore, the present study investigated the effectiveness of lower frequency HIIT (LfHIIT) on vascular function in a cohort of lifelong sedentary (SED; n = 22, age 62.7 +/- 5.2 years) men compared with a positive control group of lifelong exercisers (LEX; n = 17, age 61.1 +/- 5.4 years). The study consisted of three assessment phases; enrolment to the study (Phase A), following 6 weeks of conditioning exercise in SED (Phase B) and following 6 weeks of low frequency HIIT in both SED and LEX (LfHIIT; Phase C). Conditioning exercise improved FMD in SED (3.4 +/- 1.5% to 4.9 +/- 1.1%; P < 0.01) such that the difference between groups on enrolment (3.4 +/- 1.5% vs. 5.3 +/- 1.4%; P < 0.01) was abrogated. This was maintained but not further improved following LfHIIT in SED whilst FMD remained unaffected by LfHIIT in LEX. In conclusion, LfHIIT is effective at maintaining improvements in vascular function achieved during conditioning exercise in SED. LfHIIT is a well-tolerated and effective exercise mode for reducing cardiovascular risk and maintaining but does not improve vascular function beyond that achieved by conditioning exercise in aging men, irrespective of fitness level.
Description:
Aging is associated with diffuse impairments in vascular endothelial function and traditional aerobic exercise is known to ameliorate these changes. High intensity interval training (HIIT) is effective at improving vascular function in aging men with existing disease, but its effectiveness remains to be demonstrated in otherwise healthy sedentary aging. However, the frequency of commonly used HIIT protocols may be poorly tolerated in older cohorts. Therefore, the present study investigated the effectiveness of lower frequency HIIT (LfHIIT) on vascular function in a cohort of lifelong sedentary (SED; n = 22, age 62.7 +/- 5.2 years) men compared with a positive control group of lifelong exercisers (LEX; n = 17, age 61.1 +/- 5.4 years). The study consisted of three assessment phases; enrolment to the study (Phase A), following 6 weeks of conditioning exercise in SED (Phase B) and following 6 weeks of low frequency HIIT in both SED and LEX (LfHIIT; Phase C). Conditioning exercise improved FMD in SED (3.4 +/- 1.5% to 4.9 +/- 1.1%; P < 0.01) such that the difference between groups on enrolment (3.4 +/- 1.5% vs. 5.3 +/- 1.4%; P < 0.01) was abrogated. This was maintained but not further improved following LfHIIT in SED whilst FMD remained unaffected by LfHIIT in LEX. In conclusion, LfHIIT is effective at maintaining improvements in vascular function achieved during conditioning exercise in SED. LfHIIT is a well-tolerated and effective exercise mode for reducing cardiovascular risk and maintaining but does not improve vascular function beyond that achieved by conditioning exercise in aging men, irrespective of fitness level.
High intensity interval training (HIIT) improves resting blood pressure, metabolic (MET) capacity and heart rate reserve without compromising resting myocardial function in sedentary aging men
Description:
Background This study examined a programme of pre-conditioning exercise with subsequent high intensity interval training (HIIT) on blood pressure, echocardiography, cardiac strain mechanics and maximal metabolic (MET) capacity in sedentary (SED) aging men compared with age matched masters athletes (LEX). Methods Using a STROBE compliant observational design, 39 aging male participants (SED; n = 22, aged 62.7 ± 5.2 yrs) (LEX; n = 17, aged = 61.1 ± 5.4 yrs) were recruited to a study that necessitated three distinct assessment phases; enrolment (Phase A), following pre-conditioning exercise in SED (Phase B), then following 6 weeks of HIIT performed once every five days by both groups before reassessment (Phase C). Hemodynamic, echocardiographic and cardiac strain mechanics were obtained at rest and maximal cardiorespiratory and chronotropic responses were obtained at each measurement phase. Results The training intervention improved systolic, mean arterial blood pressure, rate pressure product and heart rate reserve (each P < 0.05) in SED and increased MET capacity in both SED and LEX (P < 0.01) which was amplified by HIIT. Echocardiography and cardiac strain measures were unremarkable apart from trivial increase to intra-ventricular septum diastole (IVSd) (P < 0.05) and decrease to left ventricular internal dimension diastole (LVId) (P < 0.05) in LEX following HIIT. Conclusions A programme of preconditioning exercise with HIIT induces clinically relevant improvements in blood pressure, rate pressure product and encourages recovery of heart rate reserve in SED, while improving maximal MET capacity in both SED and LEX without inducing any pathological cardiovascular remodeling. These data add to the emerging repute of HIIT as a safe and promising exercise prescription to improve cardiovascular function and metabolic capacity in sedentary aging.
Description:
Background This study examined a programme of pre-conditioning exercise with subsequent high intensity interval training (HIIT) on blood pressure, echocardiography, cardiac strain mechanics and maximal metabolic (MET) capacity in sedentary (SED) aging men compared with age matched masters athletes (LEX). Methods Using a STROBE compliant observational design, 39 aging male participants (SED; n = 22, aged 62.7 ± 5.2 yrs) (LEX; n = 17, aged = 61.1 ± 5.4 yrs) were recruited to a study that necessitated three distinct assessment phases; enrolment (Phase A), following pre-conditioning exercise in SED (Phase B), then following 6 weeks of HIIT performed once every five days by both groups before reassessment (Phase C). Hemodynamic, echocardiographic and cardiac strain mechanics were obtained at rest and maximal cardiorespiratory and chronotropic responses were obtained at each measurement phase. Results The training intervention improved systolic, mean arterial blood pressure, rate pressure product and heart rate reserve (each P < 0.05) in SED and increased MET capacity in both SED and LEX (P < 0.01) which was amplified by HIIT. Echocardiography and cardiac strain measures were unremarkable apart from trivial increase to intra-ventricular septum diastole (IVSd) (P < 0.05) and decrease to left ventricular internal dimension diastole (LVId) (P < 0.05) in LEX following HIIT. Conclusions A programme of preconditioning exercise with HIIT induces clinically relevant improvements in blood pressure, rate pressure product and encourages recovery of heart rate reserve in SED, while improving maximal MET capacity in both SED and LEX without inducing any pathological cardiovascular remodeling. These data add to the emerging repute of HIIT as a safe and promising exercise prescription to improve cardiovascular function and metabolic capacity in sedentary aging.
Description:
The list of doping agents is enormous, and for the majority, any beneficial sporting effect is contentious. WADA and UK Anti-Doping have difficulty detecting the peptide hormones, Growth Hormone (GH), insulin and Erythropoietin (Epo), because they require blood analysis. Only in the last two years has an athlete been convicted of taking GH, which is still being used as a doping agent because the window for detection is so brief. This positive test was not contested, which suggests that science may be winning the war on drugs. Athletes appear to have ceased taking insulin, because of its life-threatening acute effects, and in recent years no adverse analytical findings have been reported for this drug. “Older” doping agents, which are known to enhance performance in sport, include testosterone and their derivatives, anabolic steroids. The pharmaceutical industry continues to manufacture new medicines, pushing back the boundaries in combating wasting disease states and the ageing process, but is inadvertently producing the latest generation of doping agents. This will challenge anti-doping scientists. WADA’s banned list also includes insulin-like growth factor-1, fibroblast growth factors, hepatocyte growth factor, mechano growth factors, platelet-derived growth factor, vascular-endothelial growth factor which may promote muscle, tendon or ligament development, vascularisation, energy utilisation, regenerative capacity and fibre type. Athletes will use whatever they believe works, but can only use what is available. Internet companies offer these anabolic products that but their veracity cannot be proven. There are questions that need to be answered? Are these products available to athletes, do they enhance performance, are athletes really taking them and are they so difficult to detect. The internet has made them available to anyone with a credit card and it appears that if they are cycled correctly, unless an athlete is caught in possession of them, the opportunity of proving a case of doping is almost impossible.
Description:
The list of doping agents is enormous, and for the majority, any beneficial sporting effect is contentious. WADA and UK Anti-Doping have difficulty detecting the peptide hormones, Growth Hormone (GH), insulin and Erythropoietin (Epo), because they require blood analysis. Only in the last two years has an athlete been convicted of taking GH, which is still being used as a doping agent because the window for detection is so brief. This positive test was not contested, which suggests that science may be winning the war on drugs. Athletes appear to have ceased taking insulin, because of its life-threatening acute effects, and in recent years no adverse analytical findings have been reported for this drug. “Older” doping agents, which are known to enhance performance in sport, include testosterone and their derivatives, anabolic steroids. The pharmaceutical industry continues to manufacture new medicines, pushing back the boundaries in combating wasting disease states and the ageing process, but is inadvertently producing the latest generation of doping agents. This will challenge anti-doping scientists. WADA’s banned list also includes insulin-like growth factor-1, fibroblast growth factors, hepatocyte growth factor, mechano growth factors, platelet-derived growth factor, vascular-endothelial growth factor which may promote muscle, tendon or ligament development, vascularisation, energy utilisation, regenerative capacity and fibre type. Athletes will use whatever they believe works, but can only use what is available. Internet companies offer these anabolic products that but their veracity cannot be proven. There are questions that need to be answered? Are these products available to athletes, do they enhance performance, are athletes really taking them and are they so difficult to detect. The internet has made them available to anyone with a credit card and it appears that if they are cycled correctly, unless an athlete is caught in possession of them, the opportunity of proving a case of doping is almost impossible.