The acute effect of trimetazidine on the high frequency fatigue in the isolated Rat diaphragm muscle

The objective of this study was to determine the acute effect of trimetazidine (TMZ) on the pre-fatigue, fatigue and post-fatigue contractile characteristics and tension-frequency relationships of isolated rat diaphragm muscle. Muscle strips were taken from the ventral-costal aspects of the diaphragm muscle of rats killed by decapitation. The muscle strips were suspended in organ baths containing Krebs solution, with a gas mixture of 95% O2 and 5% CO2 at 37 degrees C and pH 7.35-7.45. After determining the thermoregulation and optimum muscle length the muscles were subjected to direct supramaximal stimulation with 0.05 Hz frequency square pulses for periods of 0.5 msec to obtain control values. After adding 5 x 10(-6) and 5 x 10(-5) M trimetazidine solution to the respective bath media, the contractile parameters of the muscles were recorded. The contractile parameters were also recorded for both the trimetazidine and trimetazidine-free media after application of the high frequency fatigue protocols. Later, the tension-frequency relationship was determined by applying stimulating pulses of 10, 20, 50 and 100 Hz to the muscle strips. Whilst the twitch tension obtained from the 5 x 10(-6) and 5 x 10(-5) M trimetazidine media showed numerical increases compared to that of the controls, these were not statistically significant (p>0.05). The contraction time exhibited a dose dependent increase (p<0.001), whilst the contraction and relaxation rates did not differ significantly. The isometric contraction forces obtained with the different stimulating frequencies showed a significant increase in the tetanic contraction only at 100 Hz (p<0.05). A comparison of the pre- and post-fatigue twitch tensions in the trimetazidine media showed the post- fatigue twitch tensions to be significantly higher than those of the pre-fatigue contraction forces (p<0.05). In the 5 x 10(-6) and 5 x 10(-5) M trimetazidine media the increases in the post-fatigue contraction force were 22 and 30%, respectively. These results demonstrated that in isolated rat diaphragm muscle, TMZ significantly limited the mechanical performance decrease during fatigue. It is our opinion that trimetazidine contributed to the observed fatigue tolerance by eliminating the factors of fatigue, due to preservation of intracellular calcium homeostasis, provision of the ATP energy levels needed by ATPase dependent pumps and especially by keeping the intracellular pH within certain limits.     

Symptom control

Symptom control has become increasingly recognized as an important goal in patient care. In this article, advances in symptom assessment, and various definitions of symptom improvement are reviewed. Theoretical concepts underlying symptom control and clinically significant change are presented, as well as the role of symptom control as an endpoint in clinical trials. Symptom control is then surveyed in two broad categories for selected symptoms. The first area is therapy related symptoms, secondary to chemotherapy, radiation, hormonal therapy, and surgery. Symptoms reviewed include chemotherapy related mucositis, emesis, fatigue; hot flashes; and radiation related dermatitis, xerostomia, and mucositis. The second area is palliative oncologic approaches to disease-related symptoms. Results in palliative chemotherapy, palliative radiation therapy, cancer pain, and lack of appetite are summarized. Areas requiring further research are noted. Findings are presented in both a clinical and research context to help guide the reader with interpreting symptom control studies.     

Physiopathology and treatment of fatigue in multiple sclerosis

Fatigue is a common symptom of patients with multiple sclerosis (MS). It is reported by about one-third of patients, and for many fatigue is the most disabling symptom. Fatigue may be associated with motor disturbances and/or mood disorders, which makes it very difficult to determine whether the fatigue is an aspect of these features or a result per se of the disease. Although peripheral mechanisms have some role in the pathogenesis of fatigue, in MS there are clear indications that the more important role is played by “central” abnormalities. Neurophysiological studies have shown that fatigue does not depend on involvement of the pyramidal tracts and implicate impairment of volitional drive of the descending motor pathways as a physiopathological mechanism. Metabolic abnormalities of the frontal cortex and basal ganglia revealed by positronemission tomography and correlations between fatigue and magnetic resonance imaging lesion burden support this hypothesis. Some recent studies also suggest that pro-inflammatory cytokines contribute to the sense of tiredness. No specific treatments are available. Management strategies include medications, exercise, and behavioural therapy; in most cases a combined approach is appropritate. Received: 26 September 2000, Accepted: 28 September 2000     

Associations between infections and fatigue in a Dutch working population: results of the Maastricht Cohort Study on Fatigue at Work

The relationship between fatigue and common infections was further explored, as part of a 3 year prospective cohort study on Fatigue at Work. The current study is based on seven successive questionnaires, covering the first 2 years of follow-up. The overall response at baseline was 45% (n = 12,140). On T1 10,592 (87.2% compared to baseline response) employees returned the questionnaire. For T2, T3, T4, T5 and T6, 10,270 (84.6%), 9655 (79.5%), 8956 (73.8%), 8692 (71.6%) and 8070 (66.5%) employees respectively returned the questionnaire. Self-administered questionnaires were used to determine the level of fatigue with the Checklist Individual Strength (CIS) and the occurrence of common cold, flu-like illness and gastroenteritis. Regression analysis using generalized estimated equations (GEE) were used for data analysis. We found a cross-sectional relationship between fatigue and the infections flu-like illness and gastroenteritis, and a longitudinal relationship between an infection as a predictor of fatigue. For fatigue as a predictor of an infection, we found odds ratios (ORs) of 1.35 (confidence interval (CI) 1.28–1.42) for flu-like illness and 1.33 (CI: 1.25–1.42) for gastroenteritis. The highest incidence of infections was found among employees who reported high fatigue levels on two successive occasions. The increased incidence of infections, is regarded as a substantial effect of fatigue because it is associated with significant absenteeism from work and leads to discomfort.     

Is there a relationship between muscle fatigue resistance and cardiovascular responses to isometric exercise in mild chronic heart failure?

BACKGROUND: Exercise intolerance in chronic heart failure (CHF) may be due to altered fatigue resistance and muscle afferent input to the cardiovascular system from dysfunctional skeletal muscle. AIM: To determine whether calf muscle fatigue resistance was associated with the magnitude of a muscle afferent driven cardiovascular response to isometric exercise. METHODS AND RESULTS: Cardiovascular responses were recorded in eight stable CHF patients (ejection fraction 20-40%) and nine healthy, age-matched controls during voluntary and electrically evoked isometric plantar flexion and post-exercise circulatory occlusion. The force developed by the plantar flexors during a 2-min submaximal electrically evoked fatigue test was measured. There was no relationship between ischaemic muscle fatigue and cardiovascular changes during and after voluntary contraction in either group nor evoked contraction in the CHF group. In the control group, the change in diastolic blood pressure (DBP) at the end of evoked contraction was related to the severity of fatigue at 90 s and 120 s (FI=0.01DeltaDBP+0.3, r=0.81, P<0.05 and FI=0.02DeltaDBP+0.8, r=0.84, P<0.01, respectively). CONCLUSION: Muscle fatigue resistance did not relate to the magnitude of the cardiovascular stress generated by isometric exercise of the same muscle in these patients.     

Small-cell lung cancer patients are just ‘a little bit’ tired: response shift and self-presentation in the measurement of fatigue

Background Response shift has gained increasing attention in the measurement of health-related quality of life (QoL) as it may explain counter-intuitive findings as a result of adaptation to deteriorating health. Objective To search for response shift type explanations to account for counter-intuitive findings in QoL measurement. Methods Qualitative investigation of the response behaviour of small-cell lung cancer (SCLC) patients (n = 23) in the measurement of fatigue with The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) question ‘were you tired’. Interviews were conducted at four points during 1st line chemotherapy: at the start of chemotherapy, 4 weeks later, at the end of chemotherapy, and 6 weeks later. Patients were asked to ‘think aloud’ when filling in the questionnaire. Results Fifteen patients showed discrepancies between their answer to the EORTC question ‘were you tired’ and their level of fatigue spontaneously reported during the interview. These patients chose the response options ‘not at all’ or ‘a little’ and explained their answers in various ways. In patients with and without discrepancies, we found indications of recalibration response shift (e.g. using a different comparison standard over time) and of change in perspective (e.g. change towards a more optimistic perspective). Patients in the discrepancy group reported spontaneously how they dealt with diagnosis and treatment, i.e. by adopting protective and assertive behaviour and by fighting the stigma. They distanced themselves from the image of the stereotypical cancer patient and presented themselves as not suffering and accepting fatigue as consequence of treatment. Conclusion In addition to response shift, this study suggests that ‘self-presentation’ might be an important mechanism affecting QoL measurement, particularly during phases when a new equilibrium needs to be found.     

Progress in understanding fatigue associated with breast cancer treatment

Fatigue is one of the most common and distressing symptoms reported by cancer patients. This article reviews research that has examined the extent to which breast cancer patients experience fatigue during and following completion of chemotherapy and radiotherapy. The article also addresses methodological issues in the study of fatigue as well as the current status of efforts to prevent or relieve fatigue associated with breast cancer treatment.     

Comparison of the fatigue characteristics of centrifuged and uncentrifuged Simplex P bone cement

Fatigue test specimens of Simplex P bone cement (Howmedica Inc., Rutherford, NJ) prepared according to the manufacturer's instructions and specimens of Simplex P prepared by centrifuging the cement immediately after mixing were subjected to fully reversed tension-compression fatigue tests at initial strain levels ranging from 0.01 to 0.001. S:N curves for both cement preparations were generated and compared on the basis of regression analysis, Weibull analysis, and Student's t tests. Centrifuged Simplex P was able to withstand significantly more fatigue cycles than uncentrifuged Simplex P at all strain levels tested. Importantly, at the more physiologic strain levels of 2,000 and 1,000 microstrain, the centrifuged cement demonstrated superior fatigue life. Specifically, at the 1,000-microstrain level eight of the 11 uncentrifuged specimens fractured before undergoing 10 million cycles. Of those that failed, the average number of cycles to failure was 1.8 million with a range of 560,000 to 4 million cycles. In contrast, all 11 centrifuged specimens tested at 1,000 microstrain remained intact at 10 million cycles.     

A fatigue questionnaire (QFES) for child athletes: a four-year follow-up study in young skiers]

BACKGROUND: The use of a fatigue monitoring questionnaire is an increasingly widespread practice in sports medicine. OBJECTIVE: To evaluate variations in the QFES fatigue questionnaire score according to periods of rest, training or competition. METHODS: Sixty-six skiers (either alpine or cross-country skiers, aged between 11 and 14 years and training for between 12 and 18 hours per week) filled out a total of 400 fatigue questionnaires over a four-year follow-up period. RESULTS: Our analysis of the QFES fatigue scores showed that only a small proportion of the skiers (5.25%, on average) exceeded the fatigue alert threshold at some point during the longitudinal follow-up; periods of competition correspond to rising fatigue scores, in comparison with the beginning of season and girls always have higher scores than boys (25.32+/-0.90 versus 20.46+/-0.91, respectively; p<0.0002). In contrast, there was no correlation between fatigue levels and the type of skiing discipline practiced. CONCLUSION: Our main results show that the QFES fatigue questionnaire is a sensitive tool for tracking down particular periods of fatigue (competition, intense training). Even though the mechanism of fatigue is still not fully understood (highlighting the complexity of this syndrome), the systematic use of a fatigue questionnaire when monitoring children performing competitive sport and high volumes of training confirms the possible preventive role of this type of tool.