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Thyroid hormone and folinic acid in young children with Down syndrome: the phase 3 ACTHYF trial.
Mircher, C, Sacco, S, Bouis, C, Gallard, J, Pichot, A, Le Galloudec, E, Cieuta, C, Marey, I, Greiner-Mahler, O, Dorison, N, et al
Genetics in medicine : official journal of the American College of Medical Genetics. 2020;(1):44-52
Abstract
PURPOSE To determine whether folinic acid (FA) and thyroxine, in combination or alone, benefit psychomotor development in young patients with Down syndrome (DS). METHODS The Assessment of Systematic Treatment With Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children (ACTHYF) was a single-center, randomized, double-blind, placebo-controlled phase 3 trial in DS infants aged 6-18 months. Patients were randomly assigned to one of four treatments: placebo, folinic acid (FA), L-thyroxine, or FA+L-thyroxine, administered for 12 months. Randomization was done by age and sex. The primary endpoint was adjusted change from baseline in Griffiths Mental Development Scale global development quotient (GDQ) after 12 months. RESULTS Of 175 patients randomized, 143 completed the study. The modified intention-to-treat (mITT) population included all randomized patients who did not prematurely discontinue due to elevated baseline thyroid stimulating hormone (TSH). Baseline characteristics in the mITT were well balanced between groups, with reliable developmental assessment outcomes. Adjusted mean change in GDQ in the mITT showed similar decreases in all groups (placebo: -5.10 [95% confidence interval (CI) -7.84 to -2.37]; FA: -4.69 [95% CI -7.73 to -1.64]; L-thyroxine: -3.89 [95% CI -6.94 to -0.83]; FA+L-thyroxine: -3.86 [95% CI -6.67 to -1.06]), with no significant difference for any active treatment group versus placebo. CONCLUSION This trial does not support the hypotheses that thyroxine and/or folinic acid improve development of young children with DS or are synergistic. This trial is registered with ClinicalTrials.gov number, NCT01576705.
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Association of Weight-Adjusted Caffeine and β-Blocker Use With Ophthalmology Fellow Performance During Simulated Vitreoretinal Microsurgery.
Roizenblatt, M, Dias Gomes Barrios Marin, V, Grupenmacher, AT, Muralha, F, Faber, J, Jiramongkolchai, K, Gehlbach, PL, Farah, ME, Belfort, R, Maia, M
JAMA ophthalmology. 2020;(8):819-825
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Abstract
IMPORTANCE Vitreoretinal surgery can be technically challenging and is limited by physiologic characteristics of the surgeon. Factors that improve accuracy and precision of the vitreoretinal surgeon are invaluable to surgical performance. OBJECTIVES To establish weight-adjusted cutoffs for caffeine and β-blocker (propranolol) intake and to determine their interactions in association with the performance of novice vitreoretinal microsurgeons. DESIGN, SETTINGS, AND PARTICIPANTS This single-blind cross-sectional study of 15 vitreoretinal surgeons who had less than 2 years of surgical experience was conducted from September 19, 2018, to September 25, 2019, at a dry-laboratory setting. Five simulations were performed daily for 2 days. On day 1, performance was assessed after sequential exposure to placebo, low-dose caffeine (2.5 mg/kg), high-dose caffeine (5.0 mg/kg), and high-dose propranolol (0.6 mg/kg). On day 2, performance was assessed after sequential exposure to placebo, low-dose propranolol (0.2 mg/kg), high-dose propranolol (0.6 mg/kg), and high-dose caffeine (5.0 mg/kg). INTERVENTIONS Surgical simulation tasks were repeated 30 minutes after masked ingestion of placebo, caffeine, or propranolol pills during the 2 days. MAIN OUTCOMES AND MEASURES An Eyesi surgical simulator was used to assess surgical performance, which included surgical score (range, 0 [worst] to 700 [best]), task completion time, intraocular trajectory, and tremor rate (range, 0 [worst] to 100 [best]). The nonparametric Friedman test followed by Dunn-Bonferroni post hoc test was applied for multiple comparisons. RESULTS Of 15 vitreoretinal surgeons, 9 (60%) were male, with a mean (SD) age of 29.6 (1.4) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 23.15 (2.9). Compared with low-dose propranolol, low-dose caffeine was associated with a worse total surgical score (557.0 vs 617.0; difference, -53.0; 95% CI, -99.3 to -6.7; P = .009), a lower antitremor maneuver score (55.0 vs 75.0; difference, -12.0; 95% CI, -21.2 to -2.8; P = .009), longer intraocular trajectory (2298.6 vs 2080.7 mm; difference, 179.3 mm; 95% CI, 1.2-357.3 mm; P = .048), and increased task completion time (14.9 minutes vs 12.7 minutes; difference, 2.3 minutes; 95% CI, 0.8-3.8 minutes; P = .048). Postcaffeine treatment with propranolol was associated with performance improvement; however, surgical performance remained inferior compared with low-dose propranolol alone for total surgical score (570.0 vs 617.0; difference, -51.0; 95% CI, -77.6 to -24.4; P = .01), tremor-specific score (50.0 vs 75.0; difference, -16.0; 95% CI, -31.8 to -0.2; P = .03), and intraocular trajectory (2265.9 mm vs 2080.7 mm; difference, 166.8 mm; 95% CI, 64.1-269.6 mm; P = .03). CONCLUSIONS AND RELEVANCE The findings suggest that performance of novice vitreoretinal surgeons was worse after receiving low-dose caffeine alone but improved after receiving low-dose propranolol alone. Their performance after receiving propranolol alone was better than after the combination of propranolol and caffeine. These results may be helpful for novice vitreoretinal surgeons to improve microsurgical performance.
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Effects of 90 Days of Resveratrol Supplementation on Cognitive Function in Elders: A Pilot Study.
Anton, SD, Ebner, N, Dzierzewski, JM, Zlatar, ZZ, Gurka, MJ, Dotson, VM, Kirton, J, Mankowski, RT, Marsiske, M, Manini, TM
Journal of alternative and complementary medicine (New York, N.Y.). 2018;(7):725-732
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Abstract
OBJECTIVE The purpose of this trial was to study the effects of chronic resveratrol use on cognitive function in humans. DESIGN The authors conducted a double-blind, Phase IIa randomized, placebo-controlled trial to obtain preliminary estimates of the effects of resveratrol supplementation on cognitive function over a 90-day period in older adults. LOCATION University of Florida in Gainesville, FL. SUBJECTS Sedentary, overweight older adults (N = 32; age range: 65-93 years, M age = 73.34 years, SD age = 7.02 years). INTERVENTION Participants were randomized to one of three treatment groups (placebo, 300 mg/day resveratrol, 1000 mg/day resveratrol) for 90 days. OUTCOME MEASURES Cognitive function was assessed before and after treatment using a well-characterized test battery: Trail Making, Digits Forward and Backward, Erikson-Flanker, Controlled Oral Word Association, Hopkins Verbal Learning Test-Revised, and Task Switching. RESULTS Psychomotor speed improved on the Trail Making Test part A in participants taking 1000 mg/day of resveratrol compared with participants in both the 300 mg/day condition and the placebo condition (p = 0.02). CONCLUSION This pilot study suggests that 90 days of resveratrol supplementation at a dose of 1000/mg per day selectively improves psychomotor speed but does not significantly affect other domains of cognitive function in older adults. These findings provide modest support to further study the effects of resveratrol on cognitive function in older adults.
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Intraduodenal levodopa-carbidopa intestinal gel infusion improves both motor performance and quality of life in advanced Parkinson's disease.
Chang, FC, Kwan, V, van der Poorten, D, Mahant, N, Wolfe, N, Ha, AD, Griffith, JM, Tsui, D, Kim, SD, Fung, VS
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2016;:41-5
Abstract
We report the efficacy and adverse effect profile of intraduodenal levodopa-carbidopa intestinal gel (LCIG) infusion from patients treated in a single Australian movement disorder centre. We conducted an open-label, 12 month prospective study of treatment with LCIG in patients with advanced Parkinson's disease in a single tertiary referral hospital unit specialising in movement disorders. Patients with levodopa-responsive, advanced Parkinson's disease with motor fluctuations despite optimal pharmacological treatment were enrolled and underwent a 16 hour daily infusion of LCIG for 12 months. Fifteen participants completed the trial. The mean (± standard deviation) improvement in Unified Parkinson's Disease Rating Scale part III was 37 ± 11%, mean daily "off" period reduced from 6.3 ± 2 to 1.9 ± 2 hours, total daily "on" time increased from 10.2 ± 3 to 13.7 ± 2 hours, "on" period without dyskinesia increased from 4.5 ± 3 to 7.5 ± 5 hours, and 39-item Parkinson's Disease Questionnaire Summary Index score improved by 32.5 ± 35%. The most common adverse event was reversible peripheral neuropathy secondary to vitamin B12 ± B6 deficiency (40%), local tube problems (40%), and impulse control disorder (ICD) (27%). No patient had stoma bleeding or peritonitis. All patients with ICD had a past psychiatric diagnosis of depression with or without anxiety and a higher daily levodopa intake at 6 and 12 months of LCIG infusion. Intraduodenal LCIG improves motor performance, quality of life and daily "on" period. Prior to and during duodenal LCIG infusion, clinicians should monitor for peripheral neuropathy and vitamin B12 and B6 deficiency, as supplementation can reverse peripheral neuropathy. This trial is registered at Clinicaltrials.gov as CT00335153.
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Performance on the Iowa Gambling Task is related to magnitude of weight loss and salivary cortisol in a diet-induced weight loss intervention in overweight women.
Witbracht, MG, Laugero, KD, Van Loan, MD, Adams, SH, Keim, NL
Physiology & behavior. 2012;(2):291-7
Abstract
The overall objective of this study was to examine the relationship between executive function, specifically decision-making, and weight loss. We used the Iowa Gambling Task (IGT) to characterize decision-making and compared performance on this task to weight loss in obese women (n=29) participating in a 12-week controlled, calorie-reduced intervention. We hypothesized that a greater amount of weight loss over the course of the intervention would be associated with better performance on the IGT, assessed at the end of the intervention. The intervention led to significant weight loss of 5.8±3.1 kg (p<0.05) and fat loss of 5.1±3.0 kg (p<0.05). Body weight and fat mass losses over the 12-week intervention varied widely, ranging from -12.5 kg to 0.0 kg for body weight and -10.4 kg to +0.8 kg for fat mass. A greater amount of body weight loss was correlated (r=0.425; p<0.01) with a higher total score on the IGT. Similarly, the reduction in body fat mass was also correlated with the IGT score (r=0.408; p<0.05). We examined other physiological (salivary cortisol), metabolic (resting energy expenditure), and behavioral (food intake; dietary restraint) factors that might be related to differences in the magnitude of weight loss. Of these variables, ad libitum consumption of energy, fat and protein during a buffet meal was inversely related to weight loss (r=-0.428; p<0.05; r=-0.375; p<0.05 and r=-0.472; p=0.01, respectively). The present study is the first to report an association between diet-induced weight loss and performance on the IGT, and this association was specific to the loss of body fat. Our results suggest that differences in weight loss may be linked to executive function that involves decision-making about events that have emotionally or socially salient ramifications. These findings underscore the need to further investigate higher cognitive and neuroendocrine pathways that may influence or be altered by the process of dieting and weight loss.
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Drug treatment and familiar music aids an attention shift from vision to somatosensation in Parkinson's disease on the reach-to-eat task.
Sacrey, LA, Travis, SG, Whishaw, IQ
Behavioural brain research. 2011;(2):391-8
Abstract
Sensory control of the natural skilled movement of reaching for a food target to eat (reach-to-eat) is closely coupled to the successive phases of the movement. Control subjects visually fixate the target from hand movement onset to the point that the digits contact the food, at which point they look away. This relationship between sensory attention and limb movement suggests that whereas limb advance is under visual control, grasping, limb withdrawal, and releasing the food to the mouth is guided by somatosensation. The pattern of sensory control is altered in Parkinson's disease (PD). PD subjects may visually fixate the target for longer durations prior to movement initiation, during the grasp, and during the initial portion of hand withdrawal suggesting that vision compensates for a somatosensory impairment. Because both medication and listening to favorite musical pieces have been reported to normalize some movements in subjects with PD, the present study compared the effect of medication and listening to preferred musical pieces on sensory attention shifts from vision to somatosensation during the reach-to-eat movement. Biometric measures of eye movement and the movement of the reaching limb were collected from PD subjects and aged-matched control subjects in four conditions in their own homes: off medication, off medication with music, on medication, and on medication with music. Unmedicated PD subjects were slower to visually disengage the target after grasping it. Their disengage latency was shortened by both music and medication. Medication and music did not improve other aspects of reaching, including reaching duration and the ratings of the movement elements of limb advance, grasping, and limb withdrawal. The results are discussed in relation to the idea that one way in which medication and music may aid movement in PD by normalizing somatosensory control of forelimb movement thus reducing compensatory visual monitoring.
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Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype.
Ramaekers, JG, Conen, S, de Kam, PJ, Braat, S, Peeters, P, Theunissen, EL, Ivgy-May, N
Psychopharmacology. 2011;(2):321-32
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INTRODUCTION Esmirtazapine is evaluated as a novel drug for treatment of insomnia. PURPOSE The present study was designed to assess residual effects of single and repeated doses of esmirtazapine 1.5 and 4.5 mg on actual driving in 32 healthy volunteers in a double-blind, placebo-controlled study. Treatment with single doses of zopiclone 7.5 mg was included as active control. METHODS Treatments were administered in the evening. Driving performance was assessed in the morning, 11 h after drug intake, in a standardized on-the-road highway driving test. The primary study parameter was standard deviation of lateral position (SDLP), a measure of "weaving". All subjects were subjected to CYP2D6 phenotyping in order to distinguish poor metabolizers from extensive metabolizers of esmirtazapine. RESULTS Overall, esmirtazapine 1.5 mg did not produce any clinically relevant change in SDLP after single and repeated dosing. Driving impairment, i.e., a rise in SDLP, did occur after a single-dose administration of esmirtazapine 4.5 mg but was resolved after repeated doses. Acute driving impairment was more pronounced after both doses of esmirtazapine in a select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected. CONCLUSION It is concluded that single and repeated doses of 1.5 mg esmirtazapine are generally not associated with residual impairment. Single-dose administration of 4.5 mg esmirtazapine was associated with residual impairment that generally resolved after repeated administration. Exploratory analysis in a small group of poor CYP 2D6 metabolizers suggested that these subjects are more sensitive to the impairing effects of esmirtazapine on car driving.
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The planning of a sequence of saccades in pro- and antisaccade tasks: influence of visual integration time and concurrent motor processing.
Lavergne, L, Vergilino-Perez, D, Collins, T, Orriols, E, Doré-Mazars, K
Brain research. 2008;:82-95
Abstract
Previous studies have shown that a saccade is coded in a specific reference frame according to its goal: to aim for a new object or to explore an object which has already been fixated. In a two saccade sequence, the second saccade aiming for a new object is programmed in a retinocentric reference frame in which the spatial location of the second object is stored in spatial memory before the first saccade and updated after its execution. The second saccade exploring the same object is coded in an oculocentric reference frame in which object size is directly transformed into a fixed motor vector, encoded in motor memory before the first saccade and simply applied after its execution. The integration of parafoveal visual information appears to be crucial in the selection of the appropriate reference frame. The two experiments presented here investigate how and when the saccadic system integrates visual information to plan a sequence of saccades. In separate blocks, subjects were asked to execute a sequence of prosaccades directed toward a single object or two short objects, or to execute a sequence of antisaccades in the opposite direction of the stimuli. The latency of the initial saccade was modulated by using the Gap-200, Gap-0 and Overlap-600 ms paradigms. The results show that the time available for segmenting the visual stimulation into discrete objects and application of a specific reference frame according to this segmentation is critical for saccadic planning.
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Neural training for quick strength gains in the elderly: strength as a learned skill.
Knight, CA, Marmon, AR
Journal of strength and conditioning research. 2008;(6):1869-75
Abstract
A sample of 20 older adults (76 +/- 6 years) participated in a two-session training intervention with the goal of eliciting rapid and functionally meaningful strength gains in the ankle plantarflexors. Tests were conducted on a Monday-Wednesday-Friday schedule with two training sessions after tests one and two. During each test, subjects performed five maximal explosive force production contractions (MVCs) from which maximal voluntary torque (MVT) and peak rates of torque development (RTDs) were obtained. To augment the quick strength gains typically observed in response to serial strength measurements, these MVCs were supplemented with exercises consisting of high-velocity, low-force movements at the ankle joint. These exercises were chosen to elicit high rates of neural stimulation without high resistance. Maximal voluntary torque increased by 15% from 53.9 +/- 36 to 62.2 +/- 36.2 N x m (p = 0.02). There was a parallel trend toward increases in RTD based on RTD measures computed over various timescales (0.11 < p < 0.21). The nonsignificant increase in RTD was from 223.9 +/- 153.6 to 248.4 +/- 147.8 N x m x s(-1). This preliminary study has determined that rapid strength gains of functional magnitude are possible in the plantarflexors of the elderly. Subsequent work is necessary to test the translation of such gains to function in the frail elderly and to determine the specific contributions of the selected low-resistance exercises to overall gains.
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Effects of pharmacologically induced changes in NMDA receptor activity on human timing and sensorimotor performance.
Rammsayer, TH
Brain research. 2006;:407-16
Abstract
Unlike processing of time intervals in the range of seconds or more, processing of brief durations in the subsecond range appears to be beyond cognitive control and based on subcortical mechanisms located in the basal ganglia. The present study was designed to evaluate the effects of NMDA receptor activity on temporal processing in the second and subsecond range. In a double-blind crossover design, either 30 mg of the noncompetitive NMDA receptor antagonist memantine or placebo was administered to 32 healthy male volunteers. While memantine induced a marked impairment in temporal processing of intervals in the range of seconds, temporal processing of intervals in the range of milliseconds was not affected. Furthermore, no effect of memantine on speed of information processing could be observed. Speed of motor response execution, however, was significantly enhanced by memantine compared to placebo. The overall pattern of results provides converging evidence for the notion that temporal processing of longer intervals involves higher order working memory functions such as working memory capacity. The absence of an effect on temporal processing of very brief intervals in combination with the beneficial effect on movement time suggests that NMDA receptor activity in the basal ganglia is not directly related to the timing of intervals in the subsecond range.