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This work summarizes our knowledge of the physiological basis of fatigue and the effects of exercise and pharmacological interventions on fatigue. Fatigue may be defined as physical and/or mental weariness resulting from exertion, that is, an inability to continue exercise at the same intensity with a resultant deterioration in performance. The concept of deconditioning in patients is discussed as well as the implications for their rehabilitation and exercise. Because fatigue may result from a number of causes, including loss of muscle mass, deconditioning, nutritional deficiencies, oxygen delivery, and anemia, it should be treated comprehensively. Antifatigue therapy should be the standard of care for most chronic conditions associated with fatigue. [ABSTRACT FROM AUTHOR]

Purpose: Although data suggest that physical activity is associated with decreased insulin resistance, recommendations for exercise training are not specific for age or level of obesity. Therefore, we examined the influence of moderate-intensity (50% of VO2max) exercise training (MI) versus high-intensity (75% of VO2max) exercise training (HI) on insulin-stimulated glucose disposal (ISGD) in elderly individuals., Methods: Following medical examinations, 21 overweight (body mass index = 29 +/- 1 kg x m(-2)) elderly (74 +/- 1 yr) subjects were randomized to 1) HI, 2) MI, or a 3) nonexercising control group. Subjects enrolled in HI or MI completed a 12-wk exercise training regimen designed to expend 1000 kcal x wk. ISGD was assessed using a hyperinsulinemic, euglycemic clamp pre- and postintervention. ISGD was corrected for hepatic glucose production (glucose Ra) using a constant rate infusion of [6,6-H2]glucose and determined during the last 30 min of the clamp by subtracting glucose Ra from the exogenous glucose infusion rate. Nonoxidative glucose disposal was calculated using indirect calorimetry. Body composition testing was completed using dual energy x-ray absorptiometry., Results: ISGD increased by approximately 20% with HI (Delta of 1.4 +/- 0.5 mg x kg(-1) FFM.min(-1)). However, ISGD did not change (Delta of -0.4 +/- 0.1 mg x kg(-1) FFM.min(-1)) with MI and was not different (Delta of -0.2 +/- 0.1 mg x kg(-1) FFM.min(-1)) in the control group. Nonoxidative glucose disposal increased with HI (Delta of 1.4 +/- 0.5 mg x kg(-1) FFM.min(-1)), but there was no change in nonoxidative glucose disposal with MI or in the control group. No change in body weight or percentage of body fat was observed in any group., Conclusion: In weight-stable subjects, MI resulted in no change in ISGD, and the improvement in ISGD with HI was completely reliant on improvements in nonoxidative glucose disposal.

Purpose: Determine the independent and combined effects of progressive resistance muscle strength training (PRMST) and testosterone on strength, muscle mass, and function in hypogonadal elderly male recuperative care patients., Methods: Between 1999 and 2004, 71 subjects (mean age 78.2 +/- 6.4 yr, 86% white) were enrolled. After baseline one-repetition maximum (1RM) strength testing and then randomization to one of four treatment groups (low-resistance (20% of the 1RM) exercises and weekly injections of either 100 mg of testosterone enanthate or placebo or high-intensity PRMST (> or =80% 1RM) and weekly injections), each subject received training and injections for 12 wk., Results: Ten subjects withdrew from the study before its completion. Based on intent-to-treat analyses, strength improved in all groups, but was greater with high-intensity PRMST compared with low-resistance exercise (e.g., leg press, (mean +/- SE), 28 +/- 4 vs 13 +/- 4%, P = 0.009). Although testosterone led to significantly greater increases in midthigh cross-sectional muscle area compared with placebo (7.9 +/- 1.3 vs 2.4 +/- 1.4%, P = 0.005), it produced only a nonsignificant trend toward greater strength gains (e.g., leg press 25 +/- 4 vs 16 +/- 4%, P = 0.144). Change in aggregate functional performance score (the sum of 4 functional performance test scores) did not differ between the four intervention groups nor with high-intensity PRMST compared with low-resistance exercise (7 +/- 5 vs 15 +/- 5%, P = 0.263). There was not a significant interaction between exercise and testosterone for any outcome., Conclusion: High-intensity PRMST is as safe and well tolerated as a similarly structured low-resistance exercise regimen for very frail elderly patients, but produces greater muscle strength improvements. The addition of testosterone leads to greater muscle size and a trend toward greater strength but did not produce a synergistic interaction with exercise. Neither intervention had a significant effect on functional performance.

Animal studies indicate that beta(2)-adrenergic receptor agonists enhance transport of levodopa across the blood-brain barrier. Preliminary studies showed improved response to levodopa in patients with Parkinson disease (PD) who were given albuterol as adjunctive therapy. Beta(2)-adrenergic agonists may offer additional benefits to PD patients via their skeletal muscle anabolic effects, particularly those who experience decreased muscle strength and weight loss. Nondemented, fluctuating PD patients receiving levodopa but not experiencing severe dyskinesias underwent the following tests at baseline and 14 weeks after treatment with albuterol sulfate (4 mg four times a day, orally): Unified Parkinson's Disease Rating Scale motor, tapping, and stand-walk-sit tests every 30 minutes between 8 am and 5 pm; body composition analyses using whole-body plethysmography and computed tomography of the thigh; muscle strength tests; and the Parkinson's Disease Questionnaire (PDQ-39). Results were analyzed using paired t-tests (2 tailed), repeated-measures analysis of variance, and the Wilcoxon signed-rank test. Seven of 8 enrolled patients completed the study; 1 patient withdrew because of headache and anxiety. The area under the curve for all-day UPDRS motor scores improved by 9.8 +/- 9.1% (mean +/- standard deviation; P < 0.05) and tapping improved by 7.6 +/- 8.1% (P < 0.05). The effect was more pronounced when only the response to the first levodopa dose (area under the curve, 8-11 am) was analyzed: 13.0 +/- 9.8% and 9.8 +/- 9.6% respectively. Thigh muscle cross-sectional area increased significantly as measured by computed tomography (5.3 +/- 3.2%, P < 0.01), as did fat-free mass by whole-body plethysmography combined with total-body water determination (9.5 +/- 2.9%, P < 0.05). There was no significant improvement in the stand-walk-sit test, muscle strength tests, other UPDRS sections, daily OFF time, or PDQ-39. Four patients were rated as having a mild global improvement (+1 point) on a -3 to +3-point scale, and 3 of them chose to continue albuterol beyond the termination of the study. The mean heart rate increased from 78.3 +/- 9.3 beats/minute to 85.6 +/- 8.7 beats/minute (P < 0.05). No laboratory abnormalities or electrocardiographic changes were induced by albuterol in any subject. This open-label pilot study suggests that albuterol increases muscle mass and improves the therapeutic response to levodopa in patients with fluctuating PD. A double-blind, placebo-controlled study is needed to confirm the effects and safety profile of beta(2)-agonists in PD.

Background: Early information processing deficits are consistently reported for patients with schizophrenia on smooth pursuit tracking tasks. A growing number of studies have applied a transient (magnocellular) or sustained (parvocellular) explanation to account for deficient processing of briefly presented visual stimuli, moving stimuli, and particularly, stimuli requiring smooth tracking eye movements in patients with schizophrenia., Objective: Although the preponderance of findings offer support for transient (where is it?) as opposed to sustained (what is it?) deficit, a need remains for specific depiction of the deficit. This was accomplished by applying a unique analytic method to a smooth pursuit tracking task., Methods: Fourteen patients with schizophrenia and fifteen normal control subjects were tested on smooth pursuit tracking performance at five different "within-wave" dot velocity frequencies that ranged from .3 to 1.1 hz. Performance data was extracted from each of the five frequencies and then separated into 12 discrete components that corresponded to light velocity (i.e., 12 bins)., Results: A repeated measures multivariate analysis of covariance indicated that the performance of patients with schizophrenia was significantly poorer than that of their normal counterparts for three separate analyses of the time in smooth pursuit, F(11,594) = 8.99; p <0.00001, percentage of time in smooth pursuit, F(11,594) = 3.06; p <0.0005, and time in saccade eye movement, F(11,594) = 3.11; p <0.0004. A regression analysis revealed that the medication dosage was not significantly associated with performance on any of the critical measures, although trends were observed., Conclusions: The findings provide support for an early information processing deficit in patients with schizophrenia. In addition, the results support the current neurophysiologic model for abnormal smooth pursuit tracking in patients with schizophrenia, specifically implicating a transient channel deficiency.

Background: Despite advances in the pharmacologic treatment of schizophrenia, the neurophysiologic mechanism(s) of disordered attention in schizophrenia remain elusive., Objective: The goal of the present study was to assess specific components of attention, including disengagement, movement, re-engagement, and the inhibitory processes involved their control., Methods: Thirteen chronic schizophrenics from the inpatient and outpatient units of the Veterans Administration Medical Center (New Orleans, LA) and thirteen normal control subjects were administered a saccadic eye movements task. Saccade latency was measured in the presence of contra-lateral distracter stimuli that preceded the target onset (Distracter-before), followed the target onset (Distracter - after) or in the absence of a distracter (No-distracter). In order to assess the interactive process of fixation disengagement and target selection, fixation was either offset before the target (Gap) or it remained on in the presence of the target (Overlap)., Results: Repeated measures analysis of variance revealed that saccadic latency in patients with schizophrenia is prolonged to a greater extent than in normal control subjects in the presence of distracter stimuli. Patients with schizophrenia are also characterized by a greater percentage of error saccades directed to the distracter, and require a longer latency to "issue" corrective saccades following error saccades., Conclusions: The findings suggest that patients with schizophrenia are required to invoke volitional control under distracter conditions, whereas normal control subjects require minimal volitional control. The results are interpreted in terms of the inhibitory mechanisms that regulate attention.

Objective: Early information processing deficits are consistently reported for patients with schizophrenia. A growing number of studies have applied a transient (magnocellular) or sustained (parvocellular) explanation to account for deficient processing of briefly presented visual stimuli, moving stimuli, and stimuli requiring eye movements in patients with schizophrenia. This reasoning is based on research that makes the distinction between a magnocellular channel, which primarily responds to low spatial frequency and moving or rapidly presented visual information, and a parvocellular channel, which is primarily responsive to high spatial frequency and detailed information., Background: Although the preponderance of findings offer support for transient ("where is it") as opposed to sustained ("what is it") deficit in patients with schizophrenia, there remains a need for more specific depiction of the deficit., Method: The present study evaluated normal control subjects and patients with schizophrenia recruited from in-patient and out-patient settings. A Motion Defined Letter task was used, owing to its sensitivity to transient (magnocellular) activation., Results: Twenty-three patients with schizophrenia and sixteen normal control subjects were tested on eight dot velocity levels, ranging from 88 arc min/sec to 0.69 arc min/sec. A repeated measures analysis of variance indicated that the performance of patients with schizophrenia was significantly poorer than that of their normal counterparts on the three fastest dot velocity conditions (88 arc min/sec, p < 0.0001, 44 arc min/sec, p < 0.00001, and 22 arc min/sec, p < 0.00003), but performance did not differ on the five slower dot velocity conditions. A regression analysis revealed that the dosage of medication was positively associated with performance on three middle range dot velocity conditions (11 arc min/sec F (1,22) = 6.99; p < 0.025; 5.5 arc min/sec, F (2,20) = 0.379; p = 0.05, and 2.25 arc min/sec F (2,20) = 7.37; p < 0.005)., Conclusions: The findings afford support for an early information processing deficit in schizophrenics. These data also support the neurophysiologic model that explains the poor performance of patients with schizophrenia as it relates to a transient channel deficiency.

Unlabelled: The capacity of older men and women to adapt to increased levels of physical activity is preserved, even in the most elderly. Aerobic exercise results in improvements in functional capacity and reduced risk of developing Type II diabetes in the elderly. High-intensity resistance training (above 60% of the one repetition maximum) has been demonstrated to cause large increases in strength in the elderly. In addition, resistance training result in significant increases in muscle size in elderly men and women. Resistance training has also been shown to significantly increase energy requirements and insulin action of the elderly., Purpose: We have recently demonstrated that resistance training has a positive effect on multiple risk factors for osteoporotic fracture in previously sedentary postmenopausal women., Methods: Because the sedentary lifestyle of a long-term care facility may exacerbate losses of muscle function, we have applied this same training program to frail, institutionalized elderly men and women., Results: In a population of 100 nursing home residents, a randomly assigned high-intensity strength-training program resulted in significant gains in strength and functional status. In addition, spontaneous activity, measured by activity monitors, increased significantly in those participating in the exercise program whereas there was no change in the sedentary control group. Before the strength training intervention, the relationship of whole body potassium and leg strength was seen to be relatively weak (r2 = 0.29, P < 0.001), indicating that in the very old, muscle mass is an important but not the only determining factor of functional status., Conclusions: Thus, exercise may minimize or reverse the syndrome of physical frailty, which is so prevalent among the most elderly. Because of their low functional status and high incidence of chronic disease, there is no segment of the population that can benefit more from exercise than the elderly.

Saccadic latency of schizophrenics (N = 15) and normal controls (N = 11) was measured to the left and right visual fields with three fixation conditions that differentially affect saccade latency. Fixation was offset either 1) prior to the target (gap condition), 2) simultaneous with the target onset (control condition), or 3) after target onset (overlap condition). Saccade latencies are typically reduced in the gap condition, which is attributed to the fixation offset acting to facilitate attentional disengagement or as a preparatory warning signal. Repeated measures Analysis of Variance (ANOVA) revealed that whereas the saccadic latencies of schizophrenics and normal controls do not differ for right visual field targets, the schizophrenics' latencies were prolonged to left visual field targets. This difference was most pronounced in the overlap condition, where normal controls produced faster saccades to the left visual field targets, whereas schizophrenics showed the opposite asymmetry. Because the overlap condition provides no early warning of the upcoming target, the lateralized finding suggests a deficit in the right hemisphere mechanisms responsible for sustained attention.

Adaptations in resistance training are focused on the development and maintenance of the neuromuscular unit needed for force production [97, 136]. The effects of training, when using this system, affect many other physiological systems of the body (e.g., the connective tissue, cardiovascular, and endocrine systems) [16, 18, 37, 77, 83]. Training programs are highly specific to the types of adaptation that occur. Activation of specific patterns of motor units in training dictate what tissue and how other physiological systems will be affected by the exercise training. The time course of the development of the neuromuscular system appears to be dominated in the early phase by neural factors with associated changes in the types of contractile proteins. In the later adaptation phase, muscle protein increases, and the contractile unit begins to contribute the most to the changes in performance capabilities. A host of other factors can affect the adaptations, such as functional capabilities of the individual, age, nutritional status, and behavioral factors (e.g., sleep and health habits). Optimal adaptation appears to be related to the use of specific resistance training programs to meet individual training objectives.

There is an approximate 30% decline in muscle strength and a 40% reduction in muscle area between the second and seventh decades of life. Thus, the loss of muscle mass with aging appears to be the major factor in the age-related loss of muscle strength. The loss of muscle mass is partially due to a significant decline in the numbers of both Type I and Type II muscle fibers plus a decrease in the size of the muscle cells, with the Type II fibers showing a preferential atrophy. There appears to be no loss of glycolytic capacity in senescent skeletal muscle whereas muscle oxidative enzyme activity and muscle capillarization decrease by about 25%. Vigorous endurance exercise training in older people, where the stimulus is progressively increased, elicits a proliferation of muscle capillaries, an increase in oxidative enzyme activity, and a significant improvement in VO2max. Likewise, progressive resistive training in older individuals results in muscle hypertrophy and increased strength, if the training stimulus is of a sufficient intensity and duration. Since older individuals adapt to resistive and endurance exercise training in a similar fashion to young people, the decline in the muscle's metabolic and force-producing capacity can no longer be considered as an inevitable consequence of the aging process. Rather, the adaptations in aging skeletal muscle to exercise training may prevent sarcopenia, enhance the ease of carrying out the activities of daily living, and exert a beneficial effect on such age-associated diseases as Type II diabetes, coronary artery disease, hypertension, osteoporosis, and obesity.

Plasma creatine kinase (CK) activity has often been used as a marker of exercise-induced skeletal muscle damage. While the pattern of muscle damage following eccentric exercise has been established in young adults, there is little data available on eccentric exercise-induced muscle damage in older individuals. The purpose of this study was to compare ultrastructural changes in skeletal muscle following high intensity eccentric exercise of young and older men and to determine whether CK activity is a reliable predictor of muscle damage. Five young (20-30 yr) and five older untrained men (59-63 yr) performed three 15-min bouts of eccentric exercise at 90, 80, and 70% of maximal concentric power output. There was a prolonged increase in CK up to 10 d following exercise that was not significantly different between groups. Light and electron microscopic examination of needle biopsies obtained from the vastus lateralis showed evidence of focal damage in greater than 90% of the post-exercise fibers examined in the older subjects, compared with values ranging from 5 to 50% reported previously in young subjects. Quantitative analysis using light microscopy showed greater damage in the older subjects than reported previously in young subjects. These data suggest that older adults experience greater muscle damage following eccentric exercise than young subjects, which may be due in part to the smaller muscle mass and lower VO2max seen in older men. In addition, there was no relationship between CK activity and the corresponding amount of muscle damage observed in each subject, suggesting that CK activity may be a poor predictor of exercise-induced muscle damage.

Exercise-induced skeletal muscle damage results in a remarkable number of localized and systemic changes, including release of intracellular proteins, delayed onset muscle soreness, the acute-phase response, and an increase in skeletal muscle protein turnover. These exercise-induced adaptations appear to be integral to the repair of the damaged muscle and may be essential for hypertrophy. Chronic exercise produces adaptations in skeletal muscle, resulting in increased capacity of oxidative metabolism; the repair of damaged muscle resulting in hypertrophy may be an important mechanism for protection against further exercise-induced damage. Although the release of CK from skeletal muscle following damage is a commonly observed phenomenon, circulating CK activity is not a quantitative and, in some cases, even a qualitative indicator of skeletal muscle damage. Eccentric exercise-induced skeletal muscle damage offers an opportunity to investigate the signals and modulators of the repair of muscle damage, a process that may be central to the adaptations in muscle as a result of chronic activity.

Aging is associated with increased body fat, decreased muscle mass, lower maximal O2 uptake, and lower energy intake. It has been asserted that these changes are caused in part by decreased activity. In order to determine the effects of aging in men who are habitually active, 6 young men (26.8 +/- 1.2 yr) and 6 middle-aged men (52.0 +/- 1.9 yr) who had been running, cycling, and/or rowing for at least 2 yr were studied in a metabolic ward. The men consumed a diet to maintain constant body weight while keeping to their usual exercise schedule and intensity. Both groups had a similar body mass index and muscle mass, but the middle-aged men had a 77% greater fat mass (P = 0.028). Daily energy requirement was 17% lower in the middle-aged men (P = 0.029) although basal metabolic rate was similar in both groups. Aerobic capacity was 15% lower in the middle-aged men per unit body weight (P = 0.048) but not per unit of lean body mass. The young men exercised for an average 12.3 hr.wk-1 and the middle-aged men for 7.5 hr.wk-1 (P = 0.018). For both young and middle-aged men, weekly hours of exercise were negatively correlated with fat mass, and positively correlated with daily energy requirements and maximal O2 uptake. These findings show that in both young and middle-aged men who habitually exercise aerobically at 65 to 80% maximal O2 uptake, the time spent training was associated with body composition, energy requirements, and aerobic capacity.

Traditional approaches to interrater reliability presuppose that reliability is diminished only by undifferentiated random measurement errors. Generalizability theory offers a more comprehensive and appropriate framework for viewing problems associated with assessments derived from multiple raters. A study involving the use of the Functional Limitation Scale (FLS) by three physicians to assess patient status at five points in time illustrates this new approach. Data were analyzed in a multi-way factorial ANOVA design with the levels of raters (3), occasions (5), and patients (15). Examination of the variance components and associated generalizability coefficients revealed that the raters along or in interaction with other factors contributed little variance, while the greatest proportion of variance was attributable to the difference measurement occasions and the patients or these factors in interaction. The FLS was found to be capable of differentiating between patients and the effect of time on patient status, regardless of the physician rater(s). This study illustrates how one multi-faceted design can answer questions that formerly required several separate data sets.

A method for increasing the size of a percutaneous needle biopsy specimen of skeletal muscle is described. Suction (700 TORR) is applied to the inner bore of the biopsy needle after the needle has been inserted into the subject's muscle. The suction pulls the surrounding muscle tissue into the needle, thus insuring the taking of a larger piece (X = 78.5 mg). In most cases, this technique will eliminate the need for repeated biopsies because of inadequate muscle sample size and enhance the validity of subsequent analysis procedures.