The relationship between fatigue impact and walking capacity and perceived ability in patients with multiple sclerosis (MS) is inconclusive in the existing literature. A better understanding might ...guide new treatment avenues for fatigue and/or walking capacity in patients with MS.
To investigate the relationship between the subjective impact of fatigue and objective walking capacity as well as subjective walking ability in MS patients.
A cross-sectional multicenter study design was applied. Ambulatory MS patients (n = 189, age: 47.6 ± 10.5 years; gender: 115/74 women/men; Expanded Disability Status Scale (EDSS): 4.1 ± 1.8 range: 0–6.5) were tested at 11 sites. Objective tests of walking capacity included short walking tests (Timed 25-Foot Walk (T25FW), 10-Metre Walk Test (10mWT) at usual and fastest speed and the timed up and go (TUG)), and long walking tests (2- and 6-Minute Walk Tests (MWT). Subjective walking ability was tested applying the Multiple Sclerosis Walking Scale-12 (MSWS-12). Fatigue impact was measured by the self-reported modified fatigue impact scale (MFIS) consisting of a total score (MFIStotal) and three subscales (MFISphysical, MFIScognitive and MFISpsychosocial). Uni- and multivariate regression analysis were performed to evaluate the relation between walking and fatigue impact.
MFIStotal was negatively related with long (6MWT, r = −0.14, p = 0.05) and short composite (TUG, r = −0.22, p = 0.003) walking measures. MFISphysical showed a significant albeit weak relationship to walking speed in all walking capacity tests (r = −0.22 to −0.33, p < .0001), which persisted in the multivariate linear regression analysis. Subjective walking ability (MSWS-12) was related to MFIStotal (r = 0.49, p < 0.0001), as well as to all other subscales of MFIS (r = 0.24–0.63, p < 0.001), showing stronger relationships than objective measures of walking.
The physical impact of fatigue is weakly related to objective walking capacity, while general, physical, cognitive and psychosocial fatigue impact are weakly to moderately related to subjective walking ability, when analysed in a large heterogeneous sample of MS patients.
•Despite being equally prevalent symptoms in MS the relation between gait impairments and fatigue is unclear.•General fatigue impact is not related to most walking outcomes in MS.•The physical impact of fatigue is weak to moderately related to both objective and subjective walking capacity in MS.
Background: Many persons with multiple sclerosis (PwMS) report increased fatigue in the afternoon and evening compared with the morning. It is commonly accepted that physical capacity also decreases ...as time of day progresses, potentially influencing the outcomes of testing.
Objective: The objective of this article was to determine whether self-reported fatigue level and walking capacity are influenced by time of day in PwMS.
Methods: A total of 102 PwMS from 8 centers in 5 countries, with a diverse level of ambulatory dysfunction (Expanded Disability Status Scale EDSS <6.5), participated. Patients performed walking capacity tests and reported fatigue level at three different time points (morning, noon, afternoon) during 1 day. Walking capacity was measured with the 6-Minute Walk Test (6MWT) and the 10-m walk test performed at usual and fastest speed. Self-reported fatigue was measured by the Rochester Fatigue Diary (RFD). Subgroups with mild (EDSS 1.5–4.0, n = 53) and moderate (EDSS 4.5–6.5, n = 49) ambulatory dysfunction were formed, as changes during the day were hypothesized to depend on disability status.
Results: Subgroups had different degree of ambulatory dysfunction (p < 0.001) but reported similar fatigue levels. Although RFD scores were affected by time of day with significant differences between morning and noon/afternoon (p < 0.0001), no changes in walking capacity were found in any subgroup. Additional analyses on subgroups distinguished by diurnal change in self-reported fatigue failed to reveal analogous changes in walking capacity.
Conclusions: Testing of walking capacity is unaffected by time of day, despite changes in subjective fatigue.
Abstract Background Different walking capacity test formats are applied, but their impact on the gait pattern in persons with MS (pwMS) has not yet been investigated according to baseline velocity ...performance. Objective To assess, in pwMS with different ambulation dysfunction, the impact of speed instructions and previous walking tests (2 and 6 min walking test; 2MWT and 6MWT) on spatiotemporal gait parameters. Methods 27 participants, divided in three groups based on usual gait speed (Most Limited Community Walkers; MLCW<0.82 m/s, CW>1.14 m/s, LCW show intermediate values), completed the 2MWT and 6MWT. Before and after each test, they walked on the GAITRite walkway system at both usual and fastest speed. Spatio-temporal gait parameters were measured and analyzed with ANOVA. Results All gait parameters in the MLCW were significantly different from other groups. In contrast to the MLCW, the LCW and CW subgroups showed greater velocity in the fastest compared to usual speed condition, associated with a significant increase in cadence and step length. After the 6MWT, small changes in cadence at usual speed and step time at fastest speed were observed in the MLCW subgroup only. No impact of the 2MWT on gait parameters was found in any group. Conclusions The ability to accelerate was dependent on the severity of ambulatory dysfunction. Prolonged walking during the 6MWT has, in contrast to the 2MWT, some impact on gait parameters in the most disabled group only.
To examine the aerobic intensity level and pacing pattern during the 6-min walk test (6MWT) in persons with multiple sclerosis, taking into account time of day, fatigue, disability level and multiple ...sclerosis subtype.
Cross-sectional study.
Eighty multiple sclerosis patients (Expanded Disability Status Scale, EDSS ≤ 6.5).
Participants performed the 6MWT at 3 different time-points (morning, noon, afternoon) during 1 day. Heart rate and pacing strategy (distance covered every minute) were registered. A sub-group analysis determined the effects of fatigue, disability level and multiple sclerosis subtype.
The relative aerobic intensity was constant throughout the day (67 ± 10% of estimated maximal heart rate). In all sub-groups heart rate increased and distance walked declined after the first minute (p < 0.001). The mild EDSS sub-group showed a slightly larger increase throughout the 6MWT in heart rate development, while no differences were seen in sub-groups of fatigue and multiple sclerosis subtype. In most sub-groups walking speed was fastest in the first minute and constant during the final 4 minutes.
In patients with multiple sclerosis aerobic intensity is moderate during the 6MWT and unaffected by time of day. Disability may have some influence on aerobic intensity, but not on pacing strategy during the 6MWT, whereas neither fatigue nor multiple sclerosis subtype has any effect.
The current diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders are being challenged by the heterogeneity and the symptom overlap of psychiatric disorders. Therefore, a ...framework toward a more etiology-based classification has been initiated by the US National Institute of Mental Health, the research domain criteria project. The basic neurobiology of human psychiatric disorders is often studied in rodent models. However, the differences in outcome measurements hamper the translation of knowledge. Here, we aimed to present a translational panic model by using the same stimulus and by quantitatively comparing the same outcome measurements in rodents, healthy human subjects and panic disorder patients within one large project. We measured the behavioral-emotional and bodily response to CO2 exposure in all three samples, allowing for a reliable cross-species comparison. We show that CO2 exposure causes a robust fear response in terms of behavior in mice and panic symptom ratings in healthy volunteers and panic disorder patients. To improve comparability, we next assessed the respiratory and cardiovascular response to CO2, demonstrating corresponding respiratory and cardiovascular effects across both species. This project bridges the gap between basic and human research to improve the translation of knowledge between these disciplines. This will allow significant progress in unraveling the etiological basis of panic disorder and will be highly beneficial for refining the diagnostic categories as well as treatment strategies.
Until recently, genetic research into panic disorder (PD) has had only limited success. Inspired by rodent research, demonstrating that the acid-sensing ion channel 1a (ASIC1a) is critically involved ...in the behavioral fear response to carbon dioxide (CO2) exposure, variants in the human homologue gene amiloride-sensitive cation channel 2 (ACCN2) were shown to be associated with PD. However, the relationship between changes in brain pH and ACCN2, as done in rodents by CO2 exposure, has not been investigated yet in humans. Here, we examined this link between the ACCN2 gene and the response to CO2 exposure in two studies: in healthy volunteers as well as PD patients and using both behavioral and physiological outcome measures. More specifically, 107 healthy volunteers and 183 PD patients underwent a 35% CO2 inhalation. Negative affect was assessed using visual analogue scales and the panic symptom list (PSL), and, in healthy volunteers, cardiovascular measurements. The single nucleotide polymorphism rs10875995 was significantly associated with a higher emotional response in PD patients and with an increase in systolic as well as diastolic blood pressure in healthy subjects. In all measurements, subjects homozygous for the T-allele showed a heightened reactivity to CO2. Furthermore, a trend towards an rs685012 genotype effect on the emotional response was found in PD patients. We provide the first evidence that genetic variants in the ACCN2 are associated with differential sensitivity to CO2 in PD patients as well as healthy volunteers, further supporting ACCN2 as a promising candidate for future research to improve current treatment options.
Practical silicon stacking requires pre-tested dies, but contact probing of TSV interconnects requires much higher density, lower probing forces, and lower cost per pin than conventional probe cards ...have achieved. This paper examines a cost-effective, lithographic-based MEMS probe card technology that is suitable for probing 40μm pitch arrays, and scalable to finer pitches. Initial mechanical and electrical results are presented, demonstrating the feasibility of probing large arrays at 1 gram-force per tip with very low pad damage, so as not to impair downstream bonding or other processing steps.
This study demonstrates the stereoselective metabolism of the optical isomers of omeprazole in human liver microsomes. The intrinsic clearance (CL(int)) of the formation of the hydroxy metabolite ...from S-omeprazole was 10-fold lower than that from R-omeprazole. However, the CL(int) value for the sulfone and 5-O-desmethyl metabolites from S-omeprazole was higher than that from R-omeprazole. The sum of the CL(int) of the formation of all three metabolites was 14.6 and 42.5 microl/min/mg protein for S- and R-omeprazole, respectively. This indicates that S-omeprazole is cleared more slowly than R-omeprazole in vivo. The stereoselective metabolism of the optical isomers is mediated primarily by cytochrome P450 (CYP) 2C19, as indicated by studies using cDNA-expressed enzymes. This is the result of a considerably higher CL(int) of the 5-hydroxy metabolite formation for R- than for S-omeprazole. For S-omeprazole, CYP2C19 is more important for 5-O-desmethyl formation than for 5-hydroxylation. Predictions of the CL(int) using data from cDNA-expressed enzymes suggest that CYP2C19 is responsible for 40 and 87% of the total CL(int) of S- and R-omeprazole, respectively, in human liver microsomes. According to experiments using cDNA-expressed enzymes, the sulfoxidation of both optical isomers is metabolized by a single isoform, CYP3A4. The CL(int) of the sulfone formation by CYP3A4 is 10-fold higher for S-omeprazole than for R-omeprazole, which may contribute to their stereoselective disposition. The results of this study show that both CYP2C19 and CYP3A4 exhibit a stereoselective metabolism of omeprazole. CYP2C19 favors 5-hydroxylation of the pyridine group of R-omeprazole, whereas the same enzyme mainly 5-O-demethylates S-omeprazole in the benzimidazole group. Sulfoxidation mediated by CYP3A4 highly favors the S-form.
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