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Functional evaluation of muscle oxidative metabolism in metabolic myophaties. A cross-talk between exercise physiology and clinical medicine
Full text linkMetabolic myopathies are a heterogeneous group of diseases characterized by genetically determined defects which impair skeletal muscle energy production and/or function. These diseases include errors of glycogen metabolism, lipid metabolism, and mitochondrial respiratory chain. The most common clinical features are muscle weakness, pain, easy fatigability, cramping and, sometimes myoglobinuria due to muscle fiber necrosis. Exercise intolerance is another hallmark of clinical features of metabolic myopathies. As a result, patients note undue fatigue and dyspnea during low levels of exertion, including moderate activities of daily living. Symptoms are usually first experienced in childhood or early adulthood, however, late-onset is well recognized. The diagnostic process of these diseases usually begins with a careful medical history, a physical and neurological examination to assess reflexes, strength and the distribution of weakness. Creatine kinase is an extremely useful laboratory test for the evaluation of patients with a suspected myopathy and electromyography may be used to rule out a number of other neuromuscular disorders that cause similar patterns of weakness. As for exercise testing, the six minute walking test and the forearm ischaemic lactate test have traditionally been employed to screen for suspected disorders of glycogen metabolism; however, they have been superseded by improved biochemical and genetic techniques. Confirmation of the diagnosis usually requires muscle biopsy and/or molecular genetic testing.
Functional evaluation of oxidative metabolism during exercise provides information regarding the physiological responses required by the cardiovascular and respiratory systems to meet the metabolic demands of the skeletal muscle. Moreover, the study of the physiological adjustments to
exercise in patients is of extreme interest also from a “basic science” point of view, allowing to investigate aspects related to the regulation and integration of physiological and bioenergetic responses. Although exercise testing is widely utilized by cardiology, pulmonary, and sports medicine clinicians as a means to assess heart failure, respiratory disease, or athletic capacity, only few neurologists utilize a comprehensive assessment of oxidative metabolism to clarify the etiology of exercise intolerance and unexplained dyspnea among patients with metabolic myopathies. In previous studies our group applied on mitochondrial myopathies (MM) and McArdle’s disease (McA) patients two non−invasive methods of functional evaluation specifically aimed at oxidative metabolism at the skeletal muscle level. The variables of functional evaluation that we investigated were: A) Skeletal muscle oxygenation indices during exercise, obtained by near−infrared spectroscopy (NIRS) and taken as estimates of the capacity of O2 extraction; B) Kinetics of adjustment of pulmonary O2 uptake (V’O2 kinetics) during the transition from rest to exercise. We demonstrated that these methods allow to identify and quantify, in MM and in McA, the metabolic impairment. Moreover, these studies represent a typical example of “translational medicine”, in which methods and tools developed over the years in the exercise physiology laboratory are taken to the bed of the patient. In this thesis will be reported data of four studies in which the above−mentioned tools of functional
evaluation of muscle oxidative metabolism were utilized, with specific purposes, on patients with metabolic myopathies. In the first study we evaluated, during a 24-month follow-up, cardiovascular and metabolic responses to exercise of a 50-yr-old patient with glycogen storage disease type II (Pompe disease)undergoing enzyme replacement therapy (ERT). At the same constant-workload submaximal exercise, rate of perceived exertion, pulmonary ventilation, and heart rate were lower during ERT versus pre-treatment, suggesting an increased exercise tolerance. Peak oxygen uptake increased by approximately 35% after 1 month of treatment and did not significantly change thereafter. Also, peak cardiac output significantly increased during ERT, whereas peak skeletal muscle fractional O2 extraction was unchanged compared with pre-treatment. Thus, this case report suggest that ERT may increase peak exercise capacity and exercise tolerance at submaximal workloads in patients with glycogen storage disease type II after 1 month of therapy, without no further changes occurring up to 24 months. In the second study, we followed the same approach of the case study previously mentioned and we evaluated the effects of 12-month of ERT on physiological variables related to exercise tolerance of four patients with Pompe disease. Patients performed an incremental exercise on a cycle ergometer, up to voluntary exhaustion, before and after 12 months of ERT. Peak workload and oxygen uptake values significantly increased after ERT whereas the observed increases of both peak cardiac output and the NIRS-determined peak skeletal muscle fractional O2 extraction were not statistically significant. These findings suggest that in glycogen storage disease type II patients enzyme replacement therapy is associated with a mild improvement of exercise tolerance. Since exercise training could improve exercise tolerance, motor function and muscle strength, counteracting the general deconditioning typical of chronic diseases, in the future may be interesting to evaluate if exercise training could be helpful in increasing ERT clinical efficacy, improving patients' muscle function and ameliorating their quality of life. A new study based upon a collaboration between neurologists and exercise physiologists has now started and it should give the opportunity to better investigate crucial issues related to patients’ follow-up and treatment. In the third study we evaluated in McArdle’s (McA) patients whether a first bout of exercise determines a sudden decrease in heart rate (HR) and an improved exercise tolerance (the so-called “second-wind” phenomenon) during a second bout, separated by the first by a few minutes of recovery. A second-wind phenomenon (marked decrease in heart rate and in the rating of perceived exertion) was indeed observed in McA patients during the second of two consecutive 6-min constant-work rate submaximal exercises. The second wind was associated with changes of physiological variables, suggesting an enhanced skeletal muscle oxidative metabolism: enhanced O2 extraction; signs of better matching between intramuscular O2 delivery and O2 utilization; disappearance of the “slow component” of pulmonary VO2 kinetics. The second wind was not described in McA patients after a longer (18-min) recovery period or in patients affected by a mitochondrial myopathy who have similar exercise intolerance. Besides being of interest from a basic science point of view (elucidating the mechanisms responsible for the second wind in McA patients), results of the present study are of interest also from a clinical point of view, since they
identify a method (a warm up moderate-intensity exercise, carried out a few minutes before performing a task) capable of significantly increasing exercise tolerance in these patients. Finally, still unpublished data of another study are presented in this thesis, demonstrating the utility of non−invasive functional evaluation methods utilized by physiologists in the follow−up of patients as well as in the evaluation of the effects of therapies and/or rehabilitation intervention (i.e. exercise training). Since at present the therapeutic interventions available for metabolic myopathies patients are very limited and evidence from the literature suggests that moderate−intensity aerobic
exercise training represents a safe intervention, the variables of functional evaluation determined by the above−mentioned tools were utilized to evaluate, in MM and McA patients, the effects of a program of moderate−intensity aerobic exercise training carried out by the patients at their home. Peak O2 uptake, variable evaluating maximal aerobic power, and peak skeletal muscle (vastus lateralis) fractional O2 extraction, as estimated by near-infrared spectroscopy (NIRS), increased significantly with training both in MM and in McA. Thus, training induced an increase of exercise tolerance at least in part due to a reduction of the impaired fractional O2 extraction by skeletal muscles. Moreover, training significantly speeded the V’O2 kinetics, even though only in the patients who had presented, before training, markedly slow V’O2 kinetics (i.e. sign of the most pronounced metabolic impairment). Surprisingly, the improvements in exercise tolerance obtained by the training program did not determine an increase in the habitual level of physical activity evaluated a couple of months after the termination of the training program.
Overall, the results of the studies reported in this thesis demonstrate that, within a translational approach, a combination of traditional and more innovative functional evaluation methods can effectively detect the functional improvements of patients with metabolic myopathies following pharmacological and/or exercise interventions, yielding insights also on the mechanisms of the improvements at the pathophysiological level. Thus, functional evaluation of oxidative metabolism by non−invasive methods could be usefully employed in the diagnostic process of metabolic myopathies, in the follow−up of patients, and in the evaluation of the effects of therapies and/or rehabilitation interventions. Moreover, the analysis of the physiological and bioenergetics adaptations to exercise in patients with metabolic myopathies represents an interesting model to investigate and elucidate, in vivo, the regulation of basic physiological processes
NIRS-Based Muscle Oxygenation Is Not Suitable to Compute Convective and Diffusive Components of O2 Transport at V̇O2max: Response to Manferdelli, Barstow, and Millet
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Reliability of Mental Workload Index Assessed by EEG with Different Electrode Configurations and Signal Pre-Processing Pipelines
No full textBackground and Objective: Mental workload (MWL) is a relevant construct involved in all cognitively demanding activities, and its assessment is an important goal in many research fields. This paper aims at evaluating the reproducibility and sensitivity of MWL assessment from EEG signals considering the effects of different electrode configurations and pre-processing pipelines (PPPs). Methods: Thirteen young healthy adults were enrolled and were asked to perform 45 min of Simon’s task to elicit a cognitive demand. EEG data were collected using a 32-channel system with different electrode configurations (fronto-parietal; Fz and Pz; Cz) and analyzed using different PPPs, from the simplest bandpass filtering to the combination of filtering, Artifact Subspace Reconstruction (ASR) and Independent Component Analysis (ICA). The reproducibility of MWL indexes estimation and the sensitivity of their changes were assessed using Intraclass Correlation Coefficient and statistical analysis. Results: MWL assessed with different PPPs showed reliability ranging from good to very good in most of the electrode configurations (average consistency > 0.87 and average absolute agreement > 0.92). Larger fronto-parietal electrode configurations, albeit being more affected by the choice of PPPs, provide better sensitivity in the detection of MWL changes if compared to a single-electrode configuration (18 vs. 10 statistically significant differences detected, respectively). Conclusions: The most complex PPPs have been proven to ensure good reliability (>0.90) and sensitivity in all experimental conditions. In conclusion, we propose to use at least a two-electrode configuration (Fz and Pz) and complex PPPs including at least the ICA algorithm (even better including ASR) to mitigate artifacts and obtain reliable and sensitive MWL assessment during cognitive tasks
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Home-based aerobic exercise training improves skeletal muscle oxidative metabolism in patients with metabolic myopathies
No full textAerobic training can be effective in patients with mitochondrial myopathies (MM) and McArdle's disease (McA). The aim of the study was to use noninvasive functional evaluation methods, specifically aimed at skeletal muscle oxidative metabolism, to evaluate the effects of an aerobic exercise training (cycle ergometer, 12 wk, 4 days/wk, 65-70% of maximal heart rate) in 6 MM and 7 McA. Oxygen uptake and skeletal muscle vastus lateralis fractional O2 extraction by near-infrared spectroscopy were assessed during incremental and low-intensity constant work rate (CWR) exercises before (BEFORE) and at the end (AFTER) of training. Peak O2 uptake increased significantly with training both in MM [14.7 1.2 vs. 17.6 1.4 mlkg1min1 (mean SD)] and in McA (18.5 1.8 mlkg1min1 vs. 21.6 1.9). Peak skeletal muscle fractional O2 extraction increased with training both in MM (22.0 6.7 vs. 32.6 5.9%) and in McA (18.5 6.2 vs. 37.2 7.2%). During low-intensity CWR in both MM and McA: V ? O2 kinetics became faster in AFTER, but only in the patients with slow V ? O2 kinetics in BEFORE; the transient overshoot in fractional O2 extraction kinetics disappeared. The level of habitual physical activity was not higher 3 mo after training (FOLLOW-UP vs. PRE). In MM and McA patients a homebased aerobic training program significantly attenuated the impairment of skeletal muscle oxidative metabolism and improved variables associated with exercise tolerance. Our findings indicate that in MM and McA patients near-infrared spectroscopy and V ? O2 kinetics can effectively detect the functional improvements obtained by training
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