Novel ageing-biomarker discovery using data-intensive technologies.

Ageing is accompanied by many visible characteristics. Other biological and physiological markers are also well-described e.g. loss of circulating sex hormones and increased inflammatory cytokines. Biomarkers for healthy ageing studies are presently predicated on existing knowledge of ageing traits. The increasing availability of data-intensive methods enables deep-analysis of biological samples for novel biomarkers. We have adopted two discrete approaches in MARK-AGE Work Package 7 for biomarker discovery; (1) microarray analyses and/or proteomics in cell systems e.g. endothelial progenitor cells or T cell ageing including a stress model; and (2) investigation of cellular material and plasma directly from tightly-defined proband subsets of different ages using proteomic, transcriptomic and miR array. The first approach provided longitudinal insight into endothelial progenitor and T cell ageing. This review describes the strategy and use of hypothesis-free, data-intensive approaches to explore cellular proteins, miR, mRNA and plasma proteins as healthy ageing biomarkers, using ageing models and directly within samples from adults of different ages. It considers the challenges associated with integrating multiple models and pilot studies as rational biomarkers for a large cohort study. From this approach, a number of high-throughput methods were developed to evaluate novel, putative biomarkers of ageing in the MARK-AGE cohort.

Ankyrin is the major oxidised protein in erythrocyte membranes from end-stage renal disease patients on chronic haemodialysis and oxidation is decreased by dialysis and vitamin C supplementation.

Chronically haemodialysed end-stage renal disease patients are at high risk of morbidity arising from complications of dialysis, the underlying pathology that has led to renal disease and the complex pathology of chronic kidney disease. Anaemia is commonplace and its origins are multifactorial, involving reduced renal erythropoietin production, accumulation of uremic toxins and an increase in erythrocyte fragility. Oxidative damage is a common risk factor in renal disease and its co-morbidities and is known to cause erythrocyte fragility. Therefore, we have investigated the hypothesis that specific erythrocyte membrane proteins are more oxidised in end-stage renal disease patients and that vitamin C supplementation can ameliorate membrane protein oxidation. Eleven patients and 15 control subjects were recruited to the study. Patients were supplemented with 2 × 500 mg vitamin C per day for 4 weeks. Erythrocyte membrane proteins were prepared pre- and post-vitamin C supplementation for determination of protein oxidation. Total protein carbonyls were reduced by vitamin C supplementation but not by dialysis when investigated by enzyme linked immunosorbent assay. Using a western blot to detect oxidised proteins, one protein band, later identified as containing ankyrin, was found to be oxidised in patients but not controls and was reduced significantly by 60% in all patients after dialysis and by 20% after vitamin C treatment pre-dialysis. Ankyrin oxidation analysis may be useful in a stratified medicines approach as a possible marker to identify requirements for intervention in dialysis patients.

Monitoring changes in thioredoxin and over-oxidised peroxiredoxin in response to exercise in humans.

INTRODUCTION: Peroxiredoxin (PRDX) and thioredoxin (TRX) are antioxidant proteins that control cellular signalling and redox balance, although their response to exercise is unknown. This study aimed to assess key aspects of the PRDX-TRX redox cycle in response to three different modes of exercise. METHODS: Healthy males (n = 10, mean ± SD: 22 ± 3 yrs) undertook three exercise trials on separate days: two steady-state cycling trials at moderate (60% [Formula: see text]O2MAX; 27 min, MOD) and high (80% [Formula: see text]O2MAX; 20 min, HIGH) intensities, and a low-volume high-intensity interval training trial (10 × 1 min 90% [Formula: see text]O2MAX, LV-HIIT). Peripheral blood mononuclear cells were assessed for TRX-1 and over-oxidised PRDX (isoforms I-IV) protein expression before, during, and 30 min following exercise (post + 30). The activities of TRX reductase (TRX-R) and the nuclear factor kappa B (NF-κB) p65 subunit were also assessed. RESULTS: TRX-1 increased during exercise in all trials (MOD, + 84.5%; HIGH, + 64.1%; LV-HIIT, + 205.7%; p < 05), whereas over-oxidised PRDX increased during HIGH only (MOD, - 28.7%; HIGH, + 202.9%; LV-HIIT, - 22.7%; p < .05). TRX-R and NF-κB p65 activity increased during exercise in all trials, with the greatest response in TRX-R activity seen in HIGH (p < 0.05). DISCUSSION: All trials stimulated a transient increase in TRX-1 protein expression during exercise. Only HIGH induced a transient over-oxidation of PRDX, alongside the greatest change in TRX-R activity. Future studies are needed to clarify the significance of heightened peroxide exposure during continuous high-intensity exercise and the mechanisms of PRDX-regulatory control.

The antioxidant enzyme peroxiredoxin-2 is depleted in lymphocytes seven days after ultra-endurance exercise.

PURPOSE: Peroxiredoxin-2 (PRDX-2) is an antioxidant and chaperone-like protein critical for cell function. This study examined whether the levels of lymphocyte PRDX-2 are altered over 1 month following ultra-endurance exercise. METHODS: Nine middle-aged men undertook a single-stage, multi-day 233 km (145 mile) ultra-endurance running race. Blood was collected immediately before (Pre), upon completion/retirement (Post), and following the race at Day 1, Day 7 and Day 28. Lymphocyte lysates were examined for PRDX-2 by reducing and non-reducing SDS-PAGE with western blotting. In a sub-group of men who completed the race (n = 4), PRDX-2 oligomeric state (indicative of redox status) was investigated. RESULTS: Ultra-endurance exercise caused significant changes in lymphocyte PRDX-2 (F(4,32) 3.409, p = 0.020, η(2) = 0.299): 7 days after the race, PRDX-2 levels in lymphocytes had fallen to 30% of pre-race values (p = 0.013) and returned to near-normal levels at Day 28. Non-reducing gels demonstrated that dimeric PRDX-2 (intracellular reduced PRDX-2 monomers) was increased in three of four race completers immediately post-race, indicative of an 'antioxidant response'. Moreover, monomeric PRDX-2 was also increased immediately post-race in two of four race-completing subjects, indicative of oxidative damage, which was not detectable by Day 7. CONCLUSIONS: Lymphocyte PRDX-2 was decreased below normal levels 7 days after ultra-endurance exercise. Excessive accumulation of reactive oxygen species induced by ultra-endurance exercise may underlie depletion of lymphocyte PRDX-2 by triggering its turnover after oxidation. Low levels of lymphocyte PRDX-2 could influence cell function and might, in part, explain reports of dysregulated immunity following ultra-endurance exercise.

Multisensory perception and action in 3-ball cascade juggling.

Multisensory perception and action in 3-ball cascade juggling was investigated in intermediate-skilled performers by manipulating vision (full or lower field restricted) or ball weight (equal or different). There were main effects for both independent variables but no interactions. Manipulation of ball weight had a more pervasive effect on performance outcome, as well as central tendency and dispersion of kinematic measures of the juggling action. A common finding to both manipulations was that balls were tossed to higher zeniths, thus increasing parabola height and flight time. For intermediate-skilled jugglers, proprioception-haptics available when the balls were in the hands and vision of the balls and hands around the moment of ball toss and catch both make a contribution to the juggling action.

The relative timing between eye and hand in rapid sequential pointing is affected by time pressure, but not by advance knowledge.

The present study examined the effect of timing constraints and advance knowledge on eye-hand coordination strategy in a sequential pointing task. Participants were required to point at two successively appearing targets on a screen while the inter-stimulus interval (ISI) and the trial order were manipulated, such that timing constraints were high (ISI = 300 ms) or low (ISI = 450 ms) and advance knowledge of the target location was present (fixed order) or absent (random order). Analysis of eye and finger onset and completion times per segment of the sequence indicated that oculo-manual behaviour was in general characterized by eye movements preceding the finger, as well as 'gaze anchoring' (i.e. eye fixation of the first target until completion of the finger movement towards that target). Advance knowledge of future target locations lead to shorter latency times of eye and hand, and smaller eye-hand lead times, which in combination resulted in shorter total movement times. There was, however, no effect of advance knowledge on the duration of gaze anchoring. In contrast, gaze anchoring did change as a function of the interval between successive stimuli and was shorter with a 300 ms ISI versus 450 ms ISI. Further correlation analysis provided some indication that shorter residual latency is associated with shorter pointing duration, without affecting accuracy. These results are consistent with a neural mechanism governing the coupling of eye and arm movements, which has been suggested to reside in the superior colliculus. The temporal coordination resulting from this coupling is a function of the time pressure on the visuo-manual system resulting from the appearance of external stimuli.

Interception of moving objects while walking in children with spastic hemiparetic cerebral palsy.

PURPOSE: The purpose of the study was to examine the coordination of reaching and walking behaviour when children with Spastic Hemiparetic Cerebral Palsy (SHCP) intercept an approaching and hence externally-timed object. METHOD: Using either the impaired or non-impaired arm, children intercepted a ball approaching from a fixed distance with one of three velocities. Each participant's initial starting position was scaled to their maximum walking velocity determined prior to testing; for the medium ball velocity, participants would arrive at the point of interception at the correct time if they walked with their maximum velocity. RESULTS: Children with SHCP adapted their reaching and walking behaviour to the different ball approach velocities. These adaptations were exhibited when using the impaired and non-impaired arm, and resulted in similar outcome performance irrespective of which arm was used. Still, children with SHCP found it necessary to increase trunk movement to compensate for the decreased elbow excursion and a decreased peak velocity of the impaired arm. CONCLUSION: Children with SHCP exhibited specific adaptations to their altered movement capabilities when performing a behaviourally-realistic task. The provision of an external timing constraint appeared to facilitate both reaching and walking movements and hence could represent a useful technique in rehabilitation.

External timing constraints facilitate performance of everyday interceptive actions in children with Spastic Hemiparetic Cerebral Palsy.

We examined how children with Spastic Hemiparetic Cerebral Palsy (SHCP) perform interceptive actions they experience in daily life. Children were required to walk towards and intercept a stationary ball or a moving ball, with either their impaired or non-impaired arm. In the stationary ball condition the child was free to determine the speed of their response (internal timing), whereas in the moving ball condition there was a restricted time available (external timing). It was found that the reach movements of the non-impaired arm were different to the impaired arm, and were characterized by some of the typical movement limitations imposed by SHCP. However, there was no evidence of increased contribution from trunk motion or a lengthening of reach movement time or deceleration time. Instead, there was a coordinated change with the walking kinematics, whereby the children spent proportionately more time slowing down as they approached the point of interception when reaching with the impaired arm. There were also several differences in the response when intercepting a moving ball compared to a stationary ball. When the timing constraints were imposed externally (moving ball) rather than internally (stationary ball), children reached with a reduced movement time and deceleration time, and an increased peak wrist velocity and elbow excursion. These adaptations to behaviour were necessary to deal with the restricted time available to make the interception in the moving ball condition compared to when the ball was stationary, and reveal how children with SHCP coordinate walking and reaching when performing natural interceptive actions.

Effects of attentional strategies and anxiety constraints on perceptual-motor organisation of rhythmical arm movements.

Effects of anxiety on perceptual-motor organisation of rhythmical forearm movements were examined using an interrupted time series design with staggered baselines. Participants were exposed to repeated baseline sessions interrupted with two anxiety-inducing sessions. Results showed that under moderate levels of anxiety, determined from CSAI-2 and heart rate data, phase relations between oscillating forearms became more stable in in-phase (0 degrees ) and anti-phase (180 degrees ) modes, although these patterns were not maintained in baseline sessions following the anxiety manipulation. Data were consistent with participants employing a strategy of allocating greater attentional effort in stabilizing preferred co-ordination patterns under anxiety-inducing conditions. Results suggest that anxiety can temporarily act as a source of behavioural information, leading to the re-parameterisation of participants' intrinsic dynamics.

Local stability in coordinated rhythmic movements: fluctuations and relaxation times.

An experiment was conducted to examine the stability of the anti-phase and in-phase modes of coordination by means of both fluctuations and relaxation times. Participants (n=6) performed a rhythmic bimanual forearm coordination task that required them to oscillate their forearms in-phase and anti-phase while grasping two manipulanda at fixed frequencies ranging from 0.6 to 1.8 Hz. Relaxation times were measured as the time taken to return to a stable mode following the application of a transient mechanical torque. It was found that relaxation times were not different statistically across participants, frequencies, and coordinative modes. However, fluctuations, as indicated by the mean S.D. of relative phase across individual frequency plateaus, were significantly greater in the anti-phase than in the in-phase mode of coordination, p<0.05. Whilst providing new empirical support for the notion that relaxation times should be of the same order of magnitude at frequencies outside transition regions, the findings suggest that the level of stochastic noise in the anti-phase mode is greater than that of the in-phase mode. Implications are made for the future assessment of local pattern stability.

Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure.

PURPOSE: Because the bioavailability of oral furosemide is erratic and often incomplete, we tested the hypothesis that patients with heart failure who were treated with torsemide, a predictably absorbed diuretic, would have more favorable clinical outcomes than would those treated with furosemide. PATIENTS AND METHODS: We conducted an open-label trial of 234 patients with chronic heart failure (mean [+/- SD] age, 64 +/- 11 years) from an urban public health care system. Patients received oral torsemide (n = 113) or furosemide (n = 121) for 1 year. The primary endpoint was readmission to the hospital for heart failure. Secondary endpoints included readmission for all cardiovascular causes and for all causes, numbers of hospital days, and health-related quality of life. RESULTS: Compared with furosemide-treated patients, torsemide-treated patients were less likely to need readmission for heart failure (39 [32%] vs. 19 [17%], P <0.01) or for all cardiovascular causes (71 [59%] vs. 50 [44%], P = 0.03). There was no difference in the rate of admissions for all causes (92 [76%] vs. 80 [71%], P = 0.36). Patients treated with torsemide had significantly fewer hospital days for heart failure (106 vs. 296 days, P = 0.02). Improvements in dyspnea and fatigue scores from baseline were greater among patients treated with torsemide, but the differences were statistically significant only for fatigue scores at months 2, 8, and 12. CONCLUSIONS: Compared with furosemide-treated patients, torsemide-treated patients were less likely to be readmitted for heart failure and for all cardiovascular causes, and were less fatigued. If our results are confirmed by blinded trials, torsemide may be the preferred loop diuretic for patients with chronic heart failure.

Specificity of task constraints and effects of visual demonstrations and verbal instructions in directing learners' search during skill acquisition.

In the present study, the efficacy of visual demonstrations and verbal instructions as instructional constraints on the acquisition of movement coordination was investigated. Fifteen participants performed an aiming task on 100 acquisition and 20 retention trials, under 1 of 3 conditions: a modeling group (MG), a verbally directed group (VDG), and a control group (CG). The MG observed a model intermittently throughout acquisition, whereas the VDG was verbally instructed to use the model's movement pattern. Participants in the CG received neither form of instruction. Kinematic analysis revealed that compared with verbal instructions or no instructions, visual demonstrations significantly improved participants' approximation of the model's coordination pattern. No differences were found in movement outcomes. Coordination data supported the visual perception perspective on observational learning, whereas outcome data suggested that the modeling effect is mainly a function of task constraints, that is, the novelty of a movement pattern.

Multi-segment coordination: fatigue effects.

PURPOSE: The aim of this study was to investigate the segmental coordination of vertical jumps under fatigue. METHODS: Twelve subjects performed maximal countermovement jumps with and without fatigue, which was imposed by maximal continuous jumps in place until their maximal jump height corresponded to 70% of the nonfatigued condition. Video, ground reaction forces, and electromyographic signals were recorded to analyze the segmental coordination of countermovement jumps before (CMJ1) and after (CMJ2) fatigue. The magnitude of joint extension initiation, peak joint angular velocity, and peak net power around the ankle, knee, and hip joints and their respective times were determined. RESULTS: CMJ2 was characterized by a longer contact time, which was accompanied with an earlier movement initiation and several differences (P < 0.05) in the variables used to describe coordination. When the movement duration was normalized with respect to the contact phase duration, the differences between CMJ1 and CMJ2 were not sustained. A consistent pattern was indicated, in which the segmental coordination did not differ between jump conditions. When the magnitude of the muscle activation was set aside, a remarkably consistent muscle activation time was noticed between conditions. CONCLUSIONS: It was indicated that countermovement jumps were performed with a consistent well-timed motion of the segments. A "common drive," which acts without the knowledge of the muscle properties, was suggested as mediating and controlling the muscle activation timing between agonist-antagonist muscle pairs.

Effects of manipulating relative and absolute motion information during observational learning of an aiming task.

In the visual perception perspective of observational learning, the manipulation of relative and absolute motion information in visual demonstrations optimally directs learners' search towards appropriate task solutions. We assessed the effect of emphasizing transformational information and removal of structural information using point-light kinematic displays in approximating the model's relative motion patterns. Participants viewed computer-simulated point-light demonstrations or normal video demonstrations before and intermittently throughout 100 acquisition trials with knowledge of results on an underarm modified-dart aiming task. On the next day, all participants performed 20 retention trials without demonstrations. The kinematics of spatial and temporal coordination and control variables were examined relative to the model's action, as well as performance scores. The results indicated that approximation of the model's spatial and temporal coordination and control patterns was achieved after observation of either type of demonstrations. No differences were found in movement outcomes. In a second experiment, the effects of manipulating absolute motion information by slow-motion demonstrations were examined relative to real-time demonstrations. Real-time demonstrations led to a closer approximation to the model's spatial and temporal coordination patterns and better outcome scores, contradicting predictions that slow-motion displays convey intact relative motion information. We speculate that the effect of visual demonstration speed on action perception and reproduction is a function of task constraints--that is, novelty or familiarity of relative motion of demonstrated activities.

Reliability and validity of the compliance belief scales among patients with heart failure.

BACKGROUND: Lack of medication and dietary compliance leads to troublesome symptoms and hospitalization in patients with heart failure. Compliance behaviors are influenced by beliefs about the behavior. OBJECTIVE: The purpose of this study was to evaluate the reliability and validity of the Beliefs about Medication Compliance Scale (BMCS) and the Beliefs about Dietary Compliance Scale (BDCS) among patients with heart failure. THEORETICAL FRAMEWORK: This study's theoretical framework is the Health Belief Model. METHODS: A convenience sample of 234 patients with heart failure completed the BMCS and the BDCS. Patients completed the scales at baseline by face-to-face interviews and at 8 and 52 weeks after baseline by telephone interview. RESULTS: Construct validity of the scales was supported by confirmatory factor analysis. Both the BMCS and the BDCS had benefits and barriers scales with clear factor loadings. The internal consistency reliability estimates of the scales ranged from.63 to.88, with the BMCS having some estimates lower than.70. The test-retest reliability estimates ranged from.07 to.57. The intraclass correlation coefficient estimates were higher between the 8-week and 52-week scores for all scales. Possible reasons for the varying estimates are discussed. CONCLUSIONS: The BMCS and the BDCS have documented reliability and validity. Future work should be directed at evaluating the responsiveness of the scales to changing patient conditions and testing interventions to improve medication and dietary compliance through changing beliefs.

Social support and health-related quality of life in chronic heart failure patients.

OBJECTIVES: Objectives of this study were to: (1) describe perceived social support during a baseline hospitalization and 12 months later among heart failure patients; (2) examine differences in social support as a function of gender and age (less than 65 and 65 years or older); and (3) examine social support as a predictor of health-related quality of life. BACKGROUND: Social support is a predictor of well-being and mortality, but little is known about support patterns among heart failure patients and how they influence quality of life. METHODS: The sample included 227 hospitalized patients with heart failure who completed the Social Support Survey and the Chronic Heart Failure Questionnaire at baseline; 147 patients completed these questionnaires again 12 months after baseline. RESULTS: Mean baseline and 12-month total support scores were 56 and 53, respectively, with a score of 76 indicating the most positive perceptions of support. The ANOVA indicated significant interactions of gender by age for total (F = 5.04; p = 0.03) and emotional/informational support (F = 4.87; p = 0.03) and for positive social interactions (F = 4.43; p = 0.04), with men under age 65 perceiving less support than men aged 65 and older and women in either age group. Baseline support did not predict 12-month health-related quality of life, but changes in social support significantly predicted changes in health-related quality of life (R2 = 0.14). CONCLUSIONS: Overall, perceptions of support were moderate to high, but there was wide variation in perceptions over time. Men under age 65 reported less support than other groups of patients. Importantly, changes in social support were significant predictors of changes in health-related quality of life.

Mechanical perturbation of the wrist during one-handed catching.

In the present study, the co-ordination of grasp and transport components of one-handed catching was examined following mechanical perturbations applied to the wrist. Six skilled catchers (mean age = 27.5 years) performed 64 trials in which tennis balls were projected at approximately 8 ms-1. The trial blocks consisted of 10 non-perturbed trials (NPTs) (baseline), and a block of 54 trials of which 20 trials were perturbed. The perturbation was in the form of a resistive force (12 N) applied via a piece of cord attached to a mechanical brake. In baseline trials participants reached maximal wrist velocity closer to the time of hand-ball contact (237 ms +/- 68) than in the perturbed (309 ms +/- 61) condition. Furthermore the wrist velocity profile of five out of six participants exhibited a double peak immediately after a perturbation. However, aperture variables such as the relative moment of final hand closure (approximately 70% of overall movement time) were not typically affected. The stability of grasp and transport coupling for one-handed catching was shown to vary from trial to trial. Skilled performers exploited redundant degrees of freedom in the motor system when faced with a sudden, unexpected change in task constraints.

Self-care strategies for symptom management in patients with chronic heart failure.

BACKGROUND: The troublesome symptoms experienced by patients with chronic heart failure are associated with diminished quality of life, frequent hospitalizations, and mortality. OBJECTIVES: To describe the symptoms experienced by patients with heart failure, to detail the self-care strategies used by these patients in managing their symptoms, and to categorize the self-care strategies. METHODS: Six focus groups were used with 23 patients who had heart failure, along with six focus groups with 18 family members of the patients. Data analysis was performed by transcription of audiotape recordings of the group sessions and review of field notes. RESULTS: The patients reported a large number of troublesome symptoms, many consistent with past empirical findings, but some not reported in previous studies. Self-care strategies to manage the symptoms clustered into 11 categories. CONCLUSIONS: Results from this study provided direction for future studies to (a) identify the prevalence, severity, and etiologies of the commonly reported symptoms, particularly cognitive impairment, loss of balance, and depression; (b) evaluate the emotions reported by women with heart failure; and (c) test the strategies as part of an intervention program to improve symptom management in patients with heart failure.