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Run-in periods in randomized trials: implications for the application of results in clinical practice.

Prerandomization run-in periods are being used to select or exclude patients in an increasing number of clinical trials, but the implications of run-in periods for interpreting the results of clinical trials and applying these results in clinical practice have not been systematically examined. We analyzed illustrative examples of reports of clinical trials in which run-in periods were used to exclude noncompliant subjects, placebo responders, or subjects who could not tolerate or did not respond to active drug. The Physicians' Health Study exemplifies the use of a prerandomization run-in period to exclude subjects who are nonadherent, while recent trials of tacrine for Alzheimer disease and carvedilol for congestive heart failure typify the use of run-in periods to exclude patients who do not tolerate or do not respond to the study drug. The reported results of these studies are valid. However, because the reported results apply to subgroups of patients who cannot be defined readily based on demographic or clinical characteristics, the applicability of the results in clinical practice is diluted. Compared with results that would have been observed without the run-in period, the reported results overestimate the benefits and underestimate the risks of treatment, underestimate the number needed to treat, and yield a smaller P value. The Cardiac Arrhythmia Suppression Trial exemplifies the use of an active-drug run-in period that enhances clinical applicability by selecting a group of study subjects who closely resembled patients undergoing active clinical management for this problem. Run-in periods can dilute or enhance the clinical applicability of the results of a clinical trial, depending on the patient group to whom the results will be applied. Reports of clinical trials using run-in periods should indicate how this aspect of their design affects the application of the results to clinical practice.

Clinical Protocols↗

Interactions between nocturnal feeding and wheel running patterns in the rat.

The purpose of this experiment was to investigate the relationship between daily patterns of wheel running activity and feeding behavior. Wheel running and bar pressing for food were continuously recorded from rats which had concurrent access to both wheels and food. In a second condition, wheel running and (non-reinforced) bar pressing were recorded during food deprivation. In a third condition, bar pressing for food was recorded while wheel running was prevented. During ad lib access to wheels and food, both behaviors occurred primarily during the dark phase of the light-dark cycle. However, the nocturnal distribution of these responses differed: the early dark hours were primarily devoted to running, while feeding occurred in small, frequent meals. Maximal food intake occurred during the late dark hours, when meals were larger and less frequent, and there was little running. During three days of complete food deprivation, both wheel running and meal initiation attempts (as indicated by nonreinforced bar pressing) maintained their normal daily patterns. However, during wheel deprivation, changes occurred in the temporal distribution of meals which equalized early and late dark food intake. These results show that the availability of an alternative activity, like wheel running, can be an important determinant of daily feeding patterns. However, the daily pattern of wheel running is not influenced by food availability. Different behaviors may show differential plasticity in the coordination of an overall daily behavioral program.

Animals↗

The effects of chlorimipramine and protriptyline on tube running activity in mice.

We have developed a new technique, tube running activity, to study the effects of drugs on a specific behaviour in mice. The time it takes for a mouse to run 100 cm in a narrow tube is measured. The effects on tube running activity of chlorimipramine, a relatively specific blocker of the amine pump in the 5-hydroxytryptaminergic neurons, and protriptyline, a relatively specific blocker of the amine pump in the noradrenergic neurons, were studied. During the first two hours after the administration of chlorimipramine 7.5 mg/kg IP there was a decreased run time as compared with controls. The run time could not be further decreased by increasing the dose of chlorimipramine, but the effect was prolonged. Protriptyline in the dose range of 3.75-30 mg/kg IP had no observable effect on the run time, but protriptyline 60 mg/kg IP decreased the run time in the same way as chlorimipramine 60 mg/kg IP did. The decreased run time after protriptyline 60 mg/kg IP is probably due to a blockade of the amine pump in the 5-hydroxytryptamine neurons at this high dose. Our results suggest that tube running activity more specifically measures functional effects of 5-hydroxytryptamine than functional effects of noradrenaline.

Animals↗

Relationship between free-running period and motor activity in blinded rats.

The free-running rhythms of motor activity in blinded rats were measured by two different devices, an Automex or a running wheel. The period of free-running rhythm measured by a running wheel was likely to be shorter than that measured by an Automex, indicating that subtle environmental difference, such as whether a cage is equipped with a wheel or not, can affect the free-running period. In addition, we found a negative correlation not only between the free-running period measured by a running wheel and that measured by an Automex, but between the free-running period and the number of wheel revolutions per day. This is the first evidence that motor activity, other than the external factors such as light intensity and temperature, may be related to change in the free-running period.

Animals↗

The effects of chronic treadmill and wheel running on behavior in rats.

In order to better understand the behavioral adaptations induced by physical activity, this set of experiments assessed the effects of two modes of running exercise on a battery of behavioral tests. The effects of 8 weeks of forced treadmill running and voluntary wheel running on behavior measures in the elevated plus maze, open field, social interaction and conditioned freezing paradigms were investigated. Eight weeks of treadmill running did not alter behavior in any test paradigm. Rats given unrestricted access to running wheels (WR) had a lower percent open arm time (6.0+/-2.3%) compared to locked wheel controls (LC) (20.7+/-5.7%) in the elevated plus maze. WR also showed decreased entries into center (0.2+/-0.2) and crossed fewer lines (61.0+/-14.9) in the open field compared to control groups. Both WR and LC groups showed increased social interaction; however, these differences are attributed to housing conditions. The effects of 4 weeks of wheel running on elevated plus maze and open field behavior were also investigated to address the possibility of a temporal effect of exercise on behavior. Four weeks of wheel running produced behavioral changes in the open field similar to those found at 8 weeks, but not in the elevated plus maze suggesting a temporal effect of wheel running on plus maze behavior. The behavioral adaptations found after 4 and 8 weeks of wheel running were not due solely to enriched environment and appear to be indicative of enhanced defensive behavior.

Animals↗

Entrainment and phase shifting of circadian rhythms in mice by forced treadmill running.

Daily schedules of spontaneous, drug-, or novelty-induced running can entrain circadian rhythms in rodents. Forced running, by contrast, has been reported to have weak or no effects, although a thorough comparative study in a single species is lacking. To fill this gap, drinking or activity rhythms were monitored in C57 mice subjected to daily, 3-h bouts of forced treadmill running or to 3-h daily access to home cage running wheels. Entrainment to treadmill running was observed in 17/27 mice, and to restricted wheel access in 11/20 mice. Entrainment was affected by availability of a home cage wheel (e.g., 14/16 mice with no wheel entrained to treadmill running). Phase angle of entrainment was related to prior circadian period (tau), and tau following entrainment exhibited aftereffects. No mice entrained to a 3-h daily schedule of water access, suggesting that entrainment to scheduled running was not related to water or associated food intake. Phase shifts in response to single 3-h bouts of treadmill running or wheel access were small and not reliably induced. The entrainment paradigm is thus recommended for further study of behavioral effects on the mouse circadian system; forced running, in particular, offers several methodological advantages. The results do not support prior suggestions that forced and voluntary activity differ in value as nonphotic zeitgebers.

Animals↗

Voluntary wheel running modulates glutamate receptor subunit gene expression and stress hormone release in Lewis rats.

Lewis rats that are known to be addiction-prone, develop compulsive running if they have access to running wheels. The present experiments were aimed 1) to evaluate the activation of stress systems following chronic and acute voluntary wheel running in Lewis rats by measurement of hormone release and gene expression of neuropeptides related to hypothalamic-pituitary-adrenocortical (HPA) axis activity and 2) to test the hypothesis that wheel running as a combined model of addictive behavior and stress exposure is associated with modulation of ionotropic glutamate receptor subunits in the ventral tegmental area. Voluntary running for three weeks but not for one night resulted in a rise in plasma corticosterone and adrenocorticotropic hormone (ACTH) levels (p<0.05) compared to those in control rats. Principal component analysis revealed the relation between POMC gene expression in the intermediate pituitary and running rate. Acute exposure of animals to voluntary wheel running induced a significant decrease in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor GluR1 subunit mRNA levels (p<0.01), while repeated voluntary physical activity increased levels of GluR1 mRNA in the ventral tegmentum (p<0.05). Neither acute nor chronic wheel running influenced N-methyl-D-aspartate (NMDA) receptor subunit NR1 mRNA levels in the ventral tegmental area. Thus, the present study revealed changes in AMPA receptor subunit gene expression in a reward-related brain structure as well as an activation of HPA axis in response to compulsive wheel running in Lewis rats. It may be suggested that hormones of HPA axis and glutamate receptors belong to the factors that substantiate higher vulnerability to addictive behavior.

Adrenocorticotropic Hormone↗

[The shuttle run test is not valid for the detection of asthma in school physical education programs].

OBJECTIVE: Certain sporting activities may trigger asthma exacerbations of varying intensity in children. Such exacerbations may lead to limitations in and rejection of such activities. During school hours, teachers are in a good position to observe these phenomena. The aim of the present study was to evaluate the shuttle run, a test of physical fitness used in school physical education programs, as a way of detecting asthma. PATIENTS AND METHODS: We carried out a cross-sectional observational study of school children between the ages of 6 and 12 years using the asthma symptom questionnaire of the International Study of Asthma and Allergies in Childhood (ISAAC), a shuttle run test, and a free running test at maximum effort in order to study bronchial hyperresponsiveness. The principal measure of bronchial hyperresponsiveness used in both physical fitness tests was peak expiratory flow rate as measured with a peak flow meter. In comparing the results of the shuttle run test with those of the free running test and the ISAAC questionnaire we used the chi(2) test to measure association and the Cohen kappa coefficient to measure agreement. RESULTS: We distributed the ISAAC questionnaire (n=919) to 460 (50.1%) boys and 459 (49.9%) girls between the ages of 6 and 12 years. All the tests were completed by 826 children. The level of agreement between the shuttle run test and free running test was positive but low for decreases in peak expiratory flow rate compared to baseline of 15% (chi(2)=5.6; P< .05; kappa=0.093; SE, 0.042) and of 20% (chi(2)=4.5; P< .05; kappa=0.08; SE, 0.046). For 10% decreases association was not significant and agreement was low (kappa=0.05; SE, 0.04). There was no agreement between the ISAAC questionnaire and the shuttle run test (kappa=0.095; SE, 0.63). CONCLUSIONS: The shuttle run test using peak expiratory flow rate as the principal measure of bronchial hyperresponsiveness is not valid for the detection of asthma in schoolchildren.

Asthma↗

Oxygen intake in track and treadmill running with observations on the effect of air resistance.

1. The relation of V(O2) and speed was measured on seven athletes running on a cinder track and an all-weather track. The results were compared with similar observations on four athletes running on a treadmill.2. In treadmill running the relation was linear and the zero intercept coincided with resting V(O2).3. In track running the relation was curvilinear, but was adequately represented by a linear regression over a range of speeds extending from 8.0 km/hr (2.2 m/sec) to 21.5 km/hr (6.0 m/sec). The slope of this line was substantially steeper than the regression line slope for treadmill running.4. The influence of air resistance in running was estimated from measurements of V(O2) on a subject running on a treadmill at constant speed against wind of varying velocity.5. The extra O(2) intake (DeltaV(O2)) associated with wind increased as the square of wind velocity. If wind velocity and running velocity are equal, as in running on a track in calm air, DeltaV(O2) will increase as the cube of velocity.6. It was estimated that the energy cost of overcoming air resistance in track running is about 8% of total energy cost at 21.5 km/hr (5000 m races) and 16% for sprinting 100 m in 10.0 sec.

Adult↗

Base composition of mononucleotide runs affects DNA polymerase slippage and removal of frameshift intermediates by mismatch repair in Saccharomyces cerevisiae.

The postreplicative mismatch repair (MMR) system is important for removing mutational intermediates that are generated during DNA replication, especially those that arise as a result of DNA polymerase slippage in simple repeats. Here, we use a forward mutation assay to systematically examine the accumulation of frameshift mutations within mononucleotide runs of variable composition in wild-type and MMR-defective yeast strains. These studies demonstrate that (i) DNA polymerase slippage occurs more often in 10-cytosine/10-guanine (10C/10G) runs than in 10-adenine/10-thymine (10A/10T) runs, (ii) the MMR system removes frameshift intermediates in 10A/10T runs more efficiently than in 10C/10G runs, (iii) the MMR system removes -1 frameshift intermediates more efficiently than +1 intermediates in all 10-nucleotide runs, and (iv) the repair specificities of the Msh2p-Msh3p and Msh2p-Msh6p mismatch recognition complexes with respect to 1-nucleotide insertion/deletion loops vary dramatically as a function of run composition. These observations are relevant to issues of genome stability, with both the rates and types of mutations that accumulate in mononucleotide runs being influenced by the primary sequence of the run as well as by the status of the MMR system.

Base Composition↗

Spontaneous running activity in male rats: effect of age.

Alterations in the intensity and pattern of spontaneous running activity as rats increase in age from 7 wk to 1 yr was studied in male rats placed in exercise wheel cages. Daily running records were obtained on 27 rats for periods up to 12 mo, and 24-h activity recordings were made of selected runners to study the variation in activity during the day. The data indicate that for rats running over 2,940 revolutions (or 2 miles/day), the maximum intensity of running attained can be divided into a group of high achievers (approximately 8 miles/day) and moderate achievers (averaging 4.5 miles/day). For both groups, spontaneous running activity reached maximal rates after 4-5 wk. This maximal rate was sustained for 7-8 wk, then fell to levels approximately 60% of maximum for 4-5 mo, and then fell again to levels approximately 25% of maximum from 8 to 12 mo of age. The hourly pattern of running activity during the day was defined in rats of increasing age, who averaged 13,280, 6,662, 3,874, and 1,755 rev/day, corresponding to 9.0, 4.5, 2.6, and 1.2 miles/day, respectively. The overall patterns at each level indicated that the major running period occurred between 6:00 P.M. and 6:00 A.M., the greater activity of younger rats was paralleled by faster speeds and longer duration at each hour of the day, and the peak running activity for each group generally occurred between 7:00 and 9:00 P.M. In summary, there is a progressive loss in speed and duration of spontaneous running activity as male rats increase in age, with intensity of exercise falling below 2 miles/day after 7-8 mo of age.

Aging↗

Spectrum of aerobic endurance running performance in eleven inbred strains of rats.

The goal of this study was to identify inbred rat strains that could serve as useful models for exploration of the genetic basis of aerobic endurance performance. Six rats of each gender from 11 different inbred strains were tested for 1) maximal running capacity on a treadmill and 2) isolated cardiac performance. Running performance was estimated from 1) duration of the run, 2) distance run, and 3) vertical work performed. Cardiac output, during constant preload and afterload, was taken as a measure of cardiac performance from an isolated working heart preparation. The COP rats were the lowest performers and the DA rats were the best performers by all estimates of running performance. Across the 11 strains, the distance run correlated positively with isolated cardiac performance (r = 0.87). Estimates of performance were as follows (COP vs. DA strain, respectively): duration of run, 19.9 +/- 1.8 vs. 41.5 +/- 2. 2 min; distance run, 298 +/- 30 vs. 840 +/- 64 m; vertical work, 15 +/- 1.7 vs. 40 +/- 4.4 kg/m. These approximately 2.5-fold differences in running performance between the COP and DA suggest that these strains could serve as models for evaluation of the genetic basis of variance in aerobic performance.

Aerobiosis↗

Loss of desmin leads to impaired voluntary wheel running and treadmill exercise performance.

We examined voluntary wheel running and forced treadmill running exercise performance of wild-type mice and mice null for the desmin gene. When given access to a cage wheel, desmin null mice spent less time running and ran less far than wild-type mice. Wild-type mice showed a significant training effect with prolonged voluntary wheel running, as evidenced by an increase in mean running speed across the 3-wk exercise period, whereas desmin null mice did not. Desmin null mice also performed less well in acute treadmill stress and endurance tests compared with wild-type mice. We also evaluated serum creatine kinase (CK) activity in wild-type and desmin null mice in response to running. Voluntary running did not result in elevated CK activity in either wild-type or desmin null mice, whereas downhill treadmill running caused significant increases in serum CK activity in both wild-type and desmin null mice. However, the increase in serum CK was significantly less in desmin null mice than in wild-type mice. These results suggest that the lack of desmin adversely affects the ability of mice to engage in both chronic and acute bouts of endurance running exercise but that this decrement in performance is not associated with an increase in serum CK activity.

Animals↗

Free-running rhythms of pineal circadian output.

Circadian rhythms are self-sustaining oscillations that free-run in constant conditions with a period close to 24 h. Overt circadian rhythms have been studied mostly using onset phase as the marker for the underlying pacemaker. Using in vivo online pineal microdialysis, the authors have performed detailed analysis of free-running profiles of rat pineal secretory products, including N-acetylserotonin (NAS) and melatonin that have precisely defined onsets and offsets. When rats entrained in LD 12:12 were released into constant darkness (DD), both onset and offset phases of melatonin and NAS free-run. However, while onsets free-run with a period closer to a day (FRP(on) = 24-24.17 h) at the beginning, offset phases free-run with significantly larger FRPs (free-running periods) (FRP(off) = 24.24-24.42 h). This asymmetric free-running of onset and offset of NAS and melatonin in DD resulted in a 60- to 120-min increase of secretion duration of both NAS and melatonin. The rate of expansion of melatonin duration was 10 to 15 min per circadian cycle. The expansion of melatonin secretion duration ended for some within 4 days, while others were still expanding by the end of 10th day in DD. These results revealed that upon release into DD, the pacemaker's oscillation is initially driven by 2 forces, free running and decompression, before reaching a stable state of free running, and suggest that the circadian pacemaker may be an elastic structure that can decompress and compress under varying photic conditions. They also illustrate the importance of using both onset and offset of a given rhythm as phase markers, as compression/decompression, and transient disparity between FRP(on) and FRP(off) may be a common phenomenon of the circadian pacemaker.

Animals↗

Behavioral assessment of intermittent wheel running and individual housing in mice in the laboratory.

Physical cage enrichment--exercise devices for rodents in the laboratory--often includes running wheels. This study compared responses of mice in enriched physical and social conditions and in standard social conditions to wheel running, individual housing, and open-field test. The study divided into 6 groups, 48 female BALB/c mice group housed in enriched and standard conditions. On alternate days, the study exposed 2 groups to individual running wheel cages. It intermittently separated from their cage mates and housed individually 2 groups with no running wheels; 2 control groups remained in enriched or standard condition cages. There were no significant differences between enriched and standard group housed mice in alternate days' wheel running. Over time, enriched, group housed mice ran less. Both groups responded similarly to individual housing. In open-field test, mice exposed to individual housing without running wheel moved more and faster than wheel running and home cage control mice. They have lower body weights than group housed and wheel running mice. Intermittent withdrawal of individual housing affects the animals more than other commodities. Wheel running normalizes some effects of intermittent separation from the enriched, social home cage.

Animal Welfare↗

Energy absorption during running by leg muscles in a cockroach

Biologists have traditionally focused on a muscle's ability to generate power. By determining muscle length, strain and activation pattern in the cockroach Blaberus discoidalis, we discovered leg extensor muscles that operate as active dampers that only absorb energy during running. Data from running animals were compared with measurements of force and power production of isolated muscles studied over a range of stimulus conditions and muscle length changes.We studied the trochanter-femoral extensor muscles 137 and 179, homologous leg muscles of the mesothoracic and metathoracic legs, respectively. Because each of these muscles is innervated by a single excitatory motor axon, the activation pattern of the muscle could be defined precisely. Work loop studies using sinusoidal strains at 8 Hz showed these trochanter-femoral extensor muscles to be quite capable actuators, able to generate a maximum of 19-25 W kg-1 (at 25 degreesC). The optimal conditions for power output were four stimuli per cycle (interstimulus interval 11 ms), a strain of approximately 4 %, and a stimulation phase such that the onset of the stimulus burst came approximately half-way through the lengthening phase of the cycle. High-speed video analysis indicated that the actual muscle strain during running was 12 % in the mesothoracic muscles and 16 % in the metathoracic ones. Myographic recordings during running showed on average 3-4 muscle action potentials per cycle, with the timing of the action potentials such that the burst usually began shortly after the onset of shortening. Imposing upon the muscle in vitro the strain, stimulus number and stimulus phase characteristic of running generated work loops in which energy was absorbed (-25 W kg-1) rather than produced. Simulations exploring a wide parameter space revealed that the dominant parameter that determines function during running is the magnitude of strain. Strains required for the maximum power output by the trochanter-femoral extensor muscles simply do not occur during constant, average-speed running. Joint angle ranges of the coxa-trochanter-femur joint during running were 3-4 times greater than the changes necessary to produce maximum power output. None of the simulated patterns of stimulation or phase resulted in power production when strain magnitude was greater than 5 %. The trochanter-femoral extensor muscles 137/179 of a cockroach running at its preferred speed of 20 cm s-1 do not operate under conditions which maximize either power output or efficiency. In vitro measurements, however, demonstrate that these muscles absorb energy, probably to provide control of leg flexion and to aid in its reversal.

Journal Article↗

Preventive effects of running exercise on bones in heavy ion particle irradiated rats.

We examined the effects of running exercise on preventing decreases in bone mineral and tissue volume after heavy ion particle irradiation in rats. Male Wistar rats experienced whole-body irradiation by heavy ion particle beam (C-290 MeV) at doses of 0.5, 1.0, and 5.0 Gy and were divided into voluntary running groups and control groups. Rats in the running groups ran on the treadmill 15 m/min, 90 min/day for 35 days after exposure. At the end of the experiment, a tibia was obtained from each rat for measurement of bone mineral density (BMD) and cross-sectional area, strength strain index, and bone histomorphometric analysis. The weights of muscles and concentration of serum calcium were measured. Total BMD and trabecular BMD in the metaphysis and cortical BMD of the diaphysis of tibia in the running groups increased. Bone volume and trabecular thickness increased while trabecular separation decreased in the running groups compared to those in the control groups at respective doses. However, the osteoid surface and eroded surface varied in the running groups compared to those of the respective corresponding groups. The dynamic parameters such as mineralizing surface, mineral apposition rate, and bone formation rate in the running groups were varied, probably due to the differences in radiation-induced sensitivities of bones following radiation exposure. The overall results suggest that running exercise might have a beneficial effect on preventing bone mineral loss and changes in bone structure induced by space radiation, but it is necessary to examine the optimal conditions of running exercise response to doses.

Animals↗

Differential perceived exertion measured using a new visual analogue scale during pedaling and running.

The purpose of this study was to evaluate the differential perceived exertion measured using a new set of Visual Analogue Scales (VAS) during pedaling and running. The subjects were eleven healthy males. They performed an incremental maximal test and then three 4-min stages of exercise, for both pedaling and running. During the tests, VO2, V(CO2), V(E), f, and HR were monitored continuously. Bla and perceptual variables including VAS consisting of four scales (VAS 1-VAS 4) and Borg's RPE were measured at the end of each stage. Although the VO2 (%VO2max)) and HR for both pedaling and running were not significantly different, Bla in pedaling was significantly higher than that in running. A significant interaction (mode, stage) was also obtained. The VAS 1 of pedaling was significantly higher than that of running. A significant interaction in VAS 1 (mode, stage) was obtained. The VAS 2 of pedaling was significantly higher than that of running. The subjects indicated that local pain became stronger than central pain in pedaling, but they were almost equal in running. In both pedaling and running, leg pain became stronger than arm pain (VAS 3). VAS 4 showed that during running, breathing difficulty and heart pain were almost equal in perceived intensity. However, during pedaling, breathing difficulty became greater than heart pain. Thus, a new four-part visual analogue scale was found to be useful for monitoring exercise intensity. In addition, the new VAS gave us more information in relation to the differential perceived exertion reflected in the different physiological responses obtained by different exercise modes.

Adult↗