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Living with severe orthostatic hypotension.
Jordan J, Diedrich A, Grassi G, Tank J
(2016) J Hypertens 34: 1942-4
MeSH Terms: Blood Pressure, Humans, Hypotension, Orthostatic, Posture
Added October 14, 2016
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4 MeSH Terms
Synaptic roles for phosphomannomutase type 2 in a new Drosophila congenital disorder of glycosylation disease model.
Parkinson WM, Dookwah M, Dear ML, Gatto CL, Aoki K, Tiemeyer M, Broadie K
(2016) Dis Model Mech 9: 513-27
MeSH Terms: Animals, Congenital Disorders of Glycosylation, Disease Models, Animal, Down-Regulation, Drosophila, Drosophila Proteins, Extracellular Matrix, Glycoproteins, Glycosylation, Longevity, Movement, Neuromuscular Junction, Oligosaccharides, Phosphotransferases (Phosphomutases), Polysaccharides, Posture, Presynaptic Terminals, Signal Transduction, Synapses, Synaptic Transmission
Show Abstract · Added March 29, 2017
Congenital disorders of glycosylation (CDGs) constitute a rapidly growing family of human diseases resulting from heritable mutations in genes driving the production and modification of glycoproteins. The resulting symptomatic hypoglycosylation causes multisystemic defects that include severe neurological impairments, revealing a particularly critical requirement for tightly regulated glycosylation in the nervous system. The most common CDG, CDG-Ia (PMM2-CDG), arises from phosphomannomutase type 2 (PMM2) mutations. Here, we report the generation and characterization of the first Drosophila CDG-Ia model. CRISPR-generated pmm2-null Drosophila mutants display severely disrupted glycosylation and early lethality, whereas RNAi-targeted knockdown of neuronal PMM2 results in a strong shift in the abundance of pauci-mannose glycan, progressive incoordination and later lethality, closely paralleling human CDG-Ia symptoms of shortened lifespan, movement impairments and defective neural development. Analyses of the well-characterized Drosophila neuromuscular junction (NMJ) reveal synaptic glycosylation loss accompanied by defects in both structural architecture and functional neurotransmission. NMJ synaptogenesis is driven by intercellular signals that traverse an extracellular synaptomatrix and are co-regulated by glycosylation and matrix metalloproteinases (MMPs). Specifically, trans-synaptic signaling by the Wnt protein Wingless (Wg) depends on the heparan sulfate proteoglycan (HSPG) co-receptor Dally-like protein (Dlp), which is regulated by synaptic MMP activity. Loss of synaptic MMP2, Wg ligand, Dlp co-receptor and downstream trans-synaptic signaling occurs with PMM2 knockdown. Taken together, this Drosophila CDG disease model provides a new avenue for the dissection of cellular and molecular mechanisms underlying neurological impairments and is a means by which to discover and test novel therapeutic treatment strategies.
© 2016. Published by The Company of Biologists Ltd.
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20 MeSH Terms
Relative contributions of visual and auditory spatial representations to tactile localization.
Noel JP, Wallace M
(2016) Neuropsychologia 82: 84-90
MeSH Terms: Acoustic Stimulation, Adult, Female, Humans, Judgment, Male, Photic Stimulation, Physical Stimulation, Posture, Spatial Processing, Touch Perception, Young Adult
Show Abstract · Added February 15, 2016
Spatial localization of touch is critically dependent upon coordinate transformation between different reference frames, which must ultimately allow for alignment between somatotopic and external representations of space. Although prior work has shown an important role for cues such as body posture in influencing the spatial localization of touch, the relative contributions of the different sensory systems to this process are unknown. In the current study, we had participants perform a tactile temporal order judgment (TOJ) under different body postures and conditions of sensory deprivation. Specifically, participants performed non-speeded judgments about the order of two tactile stimuli presented in rapid succession on their ankles during conditions in which their legs were either uncrossed or crossed (and thus bringing somatotopic and external reference frames into conflict). These judgments were made in the absence of 1) visual, 2) auditory, or 3) combined audio-visual spatial information by blindfolding and/or placing participants in an anechoic chamber. As expected, results revealed that tactile temporal acuity was poorer under crossed than uncrossed leg postures. Intriguingly, results also revealed that auditory and audio-visual deprivation exacerbated the difference in tactile temporal acuity between uncrossed to crossed leg postures, an effect not seen for visual-only deprivation. Furthermore, the effects under combined audio-visual deprivation were greater than those seen for auditory deprivation. Collectively, these results indicate that mechanisms governing the alignment between somatotopic and external reference frames extend beyond those imposed by body posture to include spatial features conveyed by the auditory and visual modalities - with a heavier weighting of auditory than visual spatial information. Thus, sensory modalities conveying exteroceptive spatial information contribute to judgments regarding the localization of touch.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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12 MeSH Terms
Dysfunctional vestibular system causes a blood pressure drop in astronauts returning from space.
Hallgren E, Migeotte PF, Kornilova L, Delière Q, Fransen E, Glukhikh D, Moore ST, Clément G, Diedrich A, MacDougall H, Wuyts FL
(2015) Sci Rep 5: 17627
MeSH Terms: Adult, Astronauts, Blood Pressure, Cardiovascular System, Humans, Male, Middle Aged, Posture, Space Flight, Vestibule, Labyrinth, Vision, Ocular
Show Abstract · Added October 14, 2016
It is a challenge for the human body to maintain stable blood pressure while standing. The body's failure to do so can lead to dizziness or even fainting. For decades it has been postulated that the vestibular organ can prevent a drop in pressure during a position change--supposedly mediated by reflexes to the cardiovascular system. We show--for the first time--a significant correlation between decreased functionality of the vestibular otolith system and a decrease in the mean arterial pressure when a person stands up. Until now, no experiments on Earth could selectively suppress both otolith systems; astronauts returning from space are a unique group of subjects in this regard. Their otolith systems are being temporarily disturbed and at the same time they often suffer from blood pressure instability. In our study, we observed the functioning of both the otolith and the cardiovascular system of the astronauts before and after spaceflight. Our finding indicates that an intact otolith system plays an important role in preventing blood pressure instability during orthostatic challenges. Our finding not only has important implications for human space exploration; they may also improve the treatment of unstable blood pressure here on Earth.
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11 MeSH Terms
Manual therapy and exercise to improve outcomes in patients with muscle tension dysphonia: a case series.
Tomlinson CA, Archer KR
(2015) Phys Ther 95: 117-28
MeSH Terms: Adult, Aged, 80 and over, Dysphonia, Ergonomics, Exercise Therapy, Feasibility Studies, Humans, Laryngeal Muscles, Middle Aged, Movement, Muscle Tonus, Musculoskeletal Manipulations, Neck Muscles, Pain Measurement, Posture, Range of Motion, Articular, Stress, Psychological
Show Abstract · Added February 19, 2015
BACKGROUND AND PURPOSE - Muscle tension dysphonia (MTD), a common voice disorder that is not commonly referred for physical therapy intervention, is characterized by excessive muscle recruitment, resulting in incorrect vibratory patterns of vocal folds and an alteration in voice production. This case series was conducted to determine whether physical therapy including manual therapy, exercise, and stress management education would be beneficial to this population by reducing excess muscle tension.
CASE DESCRIPTION - Nine patients with MTD completed a minimum of 9 sessions of the intervention. Patient-reported outcomes of pain, function, and quality of life were assessed at baseline and the conclusion of treatment. The outcome measures were the numeric rating scale (NRS), Patient-Specific Functional Scale (PSFS), and Voice Handicap Index (VHI). Cervical and jaw range of motion also were assessed at baseline and postintervention using standard goniometric measurements.
OUTCOMES - Eight of the patients had no pain after treatment. All 9 of the patients demonstrated an improvement in PSFS score, with 7 patients exceeding a clinically meaningful improvement at the conclusion of the intervention. Three of the patients also had a clinically meaningful change in VHI scores. All 9 of the patients demonstrated improvement in cervical flexion and lateral flexion and jaw opening, whereas 8 patients improved in cervical extension and rotation postintervention.
DISCUSSION - The findings suggest that physical therapists can feasibly implement an intervention to improve outcomes in patients with MTD. However, a randomized clinical trial is needed to confirm the results of this case series and the efficacy of the intervention. A clinical implication is the expansion of physical therapy to include referrals from voice centers for the treatment of MTD.
© 2015 American Physical Therapy Association.
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17 MeSH Terms
Understanding the placebo effect in clinical trials for postural tachycardia syndrome.
Nwazue VC, Arnold AC, Raj V, Black BK, Biaggioni I, Paranjape SY, Orozco C, Dupont WD, Robertson D, Raj SR
(2014) Clin Exp Pharmacol Physiol 41: 325-30
MeSH Terms: Adult, Analysis of Variance, Blood Pressure, Cardiovascular Physiological Phenomena, Circadian Rhythm, Cross-Over Studies, Female, Heart Rate, Humans, Male, Placebo Effect, Placebos, Postural Orthostatic Tachycardia Syndrome, Posture, Prospective Studies, Time Factors
Show Abstract · Added March 21, 2014
Postural tachycardia syndrome (POTS) is characterized by excessive increases in heart rate (HR) upon standing. Previous studies have shown that standing HR decreases over time in POTS patients given placebo. We hypothesized that this reduction is due to cardiovascular physiological alteration, as opposed to psychological benefit from perceived therapy. To prospectively test this hypothesis, we examined the effects of an open-label 'no treatment' intervention (NoRx) compared with a patient-blinded placebo on standing HR in POTS patients. Twenty-one POTS patients participated in a randomized cross-over trial with oral placebo versus NoRx administered at 0900 h. Seated blood pressure (BP) and HR were measured at baseline and every hour for 4 h. Similarly, BP and HR were measured while patients stood for 10 min at these time points. Standing HR decreased significantly over time with both NoRx (112±13 and 103±16 b.p.m. at baseline and 4 h, respectively) and placebo (112±14 and 102±16 b.p.m. at baseline and 4 h, respectively; Ptime<0.001), but this effect was not different between interventions (Pdrug=0.771). Postural tachycardia syndrome patients have exaggerated orthostatic tachycardia in the morning that decreases over time with either placebo or NoRx interventions, suggesting this phenomenon is due to cardiovascular physiological variation. These data highlight the need for a placebo arm in haemodynamic clinical trials in POTS and may have important implications for the diagnosis of these patients.
© 2014 Wiley Publishing Asia Pty Ltd.
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16 MeSH Terms
Diagnosing postural tachycardia syndrome: comparison of tilt testing compared with standing haemodynamics.
Plash WB, Diedrich A, Biaggioni I, Garland EM, Paranjape SY, Black BK, Dupont WD, Raj SR
(2013) Clin Sci (Lond) 124: 109-14
MeSH Terms: Adult, Female, Heart Rate, Humans, Male, Middle Aged, Postural Orthostatic Tachycardia Syndrome, Posture, ROC Curve, Retrospective Studies, Sensitivity and Specificity, Tennessee, Tilt-Table Test, Time Factors
Show Abstract · Added March 7, 2014
POTS (postural tachycardia syndrome) is characterized by an increased heart rate (ΔHR) of ≥30 bpm (beats/min) with symptoms related to upright posture. Active stand (STAND) and passive head-up tilt (TILT) produce different physiological responses. We hypothesized these different responses would affect the ability of individuals to achieve the POTS HR increase criterion. Patients with POTS (n=15) and healthy controls (n=15) underwent 30 min of tilt and stand testing. ΔHR values were analysed at 5 min intervals. ROC (receiver operating characteristic) analysis was performed to determine optimal cut point values of ΔHR for both tilt and stand. Tilt produced larger ΔHR than stand for all 5 min intervals from 5 min (38±3 bpm compared with 33±3 bpm; P=0.03) to 30 min (51±3 bpm compared with 38±3 bpm; P<0.001). Sn (sensitivity) of the 30 bpm criterion was similar for all tests (TILT10=93%, STAND10=87%, TILT30=100%, and STAND30=93%). Sp (specificity) of the 30 bpm criterion was less at both 10 and 30 min for tilt (TILT10=40%, TILT30=20%) than stand (STAND10=67%, STAND30=53%). The optimal ΔHR to discriminate POTS at 10 min were 38 bpm (TILT) and 29 bpm (STAND), and at 30 min were 47 bpm (TILT) and 34 bpm (STAND). Orthostatic tachycardia was greater for tilt (with lower Sp for POTS diagnosis) than stand at 10 and 30 min. The 30 bpm ΔHR criterion is not suitable for 30 min tilt. Diagnosis of POTS should consider orthostatic intolerance criteria and not be based solely on orthostatic tachycardia regardless of test used.
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14 MeSH Terms
Distal sudomotor findings in postural tachycardia syndrome.
Peltier AC, Garland E, Raj SR, Sato K, Black B, Song Y, Wang L, Biaggioni I, Diedrich A, Robertson D
(2010) Clin Auton Res 20: 93-9
MeSH Terms: Adult, Autonomic Nervous System, Axons, Female, Heart Rate, Humans, Middle Aged, Motor Activity, Postural Orthostatic Tachycardia Syndrome, Posture
Show Abstract · Added December 10, 2013
OBJECTIVES - Postural tachycardia syndrome (POTS) is a heterogeneous disorder characterized by excessive orthostatic tachycardia in the absence of orthostatic hypotension and by sympathetic nervous system activation. Postganglionic sudomotor deficits have been used to define a neurogenic postural tachycardia POTS subtype. Norepinephrine levels above 600 pg/ml have also been used to delineate patients with a hyperadrenergic state. This study aims to determine the relationship of sudomotor abnormalities to other aspects of dysautonomia in POTS.
METHODS - Autonomic function was quantified in thirty women through tests of cardiovagal, adrenergic, and sudomotor function including quantitative sudomotor axon reflex testing (QSART) and spectral indices. Differences between patients with and without sudomotor dysfunction as defined by QSART and between patients with and without hyperadrenergic POTS were assessed with Mann-Whitney U test and Mantel-Haenszel Chi-Square test using a p value of 0.01 for significance. Spearman correlation coefficients were used to test raw sweat volume correlations with other variables.
RESULTS - Of 30 women (ages 20-58), 17 patients (56%) had an abnormal QSART which was typically patchy and involved the lower extremity, while 13 patients had normal QSART results. Other autonomic tests, catecholamines or spectral indices did not correlate with QSART results. No differences in autonomic tests or spectral indices were observed between hyperadrenergic and non-hyperadrenergic POTS.
INTERPRETATION - Our findings confirm that a large subset of POTS patients have sudomotor abnormalities which are typically patchy in distribution but do not correlate with other tests of autonomic function. Further studies are needed to determine the best method of endophenotyping patients with POTS.
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3 Members
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10 MeSH Terms
The hemodynamic and neurohumoral phenotype of postural tachycardia syndrome.
Garland EM, Raj SR, Black BK, Harris PA, Robertson D
(2007) Neurology 69: 790-8
MeSH Terms: Adolescent, Adult, Aldosterone, Autonomic Nervous System Diseases, Biomarkers, Blood Pressure, Catecholamines, Cerebrovascular Circulation, Cohort Studies, Female, Heart Rate, Humans, Male, Middle Aged, Neurosecretory Systems, Phenotype, Posture, Prospective Studies, Renin, Sympathetic Nervous System, Syncope, Tachycardia, Water-Electrolyte Balance
Show Abstract · Added December 10, 2013
BACKGROUND - Previous studies of patients with postural tachycardia syndrome (POTS) have been hampered by relatively small cohorts, failure to control medications and diet, and inconsistent testing procedures.
METHODS - The Vanderbilt Autonomic Dysfunction Center Database provided results of posture studies performed in 165 patients and 66 normal controls after dietary and medication restrictions. All posture studies were performed after an overnight fast and > or =30 minutes of supine rest.
RESULTS - In both the supine and standing positions, heart rate (HR) and plasma concentrations of norepinephrine (NE), epinephrine, and dopamine were higher in patients with POTS compared with the healthy controls. Supine diastolic blood pressure (BP) was also elevated in POTS, whereas supine plasma l-3,4-dihydroxyphenyalanine was reduced. In an analysis of patient subgroups with either an upright plasma NE > or = 3.54 nM (high NE) or an upright plasma NE < 3.54 nM (normal NE), HR and BP were greater in the patient subgroup with high NE. In addition to these significant differences in hemodynamic and catechol measurements, we demonstrated that supine and standing plasma aldosterone and the aldosterone/renin ratio were decreased in patients with POTS. Plasma renin activity (PRA) tended to be higher in patients, and standing HR for those in the highest PRA quartile was significantly greater than for those in the lowest PRA quartile.
CONCLUSIONS - Our results from larger cohorts of patients and controls than previously studied confirm published findings and contribute additional evidence of sympathetic activation in postural tachycardia syndrome (POTS). Abnormalities in the renin-angiotensin-aldosterone system may also contribute to the POTS phenotype.
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23 MeSH Terms
Norepinephrine transporter blockade with atomoxetine induces hypertension in patients with impaired autonomic function.
Shibao C, Raj SR, Gamboa A, Diedrich A, Choi L, Black BK, Robertson D, Biaggioni I
(2007) Hypertension 50: 47-53
MeSH Terms: Adrenergic Uptake Inhibitors, Aged, Atomoxetine Hydrochloride, Autonomic Nervous System Diseases, Blood Pressure, Cardiovascular System, Cross-Over Studies, Dose-Response Relationship, Drug, Female, Humans, Hypertension, Male, Middle Aged, Neurotransmitter Agents, Norepinephrine Plasma Membrane Transport Proteins, Posture, Propylamines, Systole
Show Abstract · Added December 10, 2013
Atomoxetine, a selective norepinephrine transporter blocker, could increase blood pressure by elevating norepinephrine concentration in peripheral sympathetic neurons. This effect may be masked in healthy subjects by central sympatholytic mechanisms. To test this hypothesis we studied the pressor effect of 18 mg of atomoxetine (pediatric dose) in 21 patients with damage of the central (10 subjects) and peripheral (11 subjects) autonomic nervous system. Atomoxetine was administered in a randomized, crossover, placebo-controlled fashion, and blood pressure and heart rate were measured at baseline and for 60 minutes after drug intake. Atomoxetine acutely increased seated and standing systolic blood pressure in patients with central autonomic failure by 54+/-26 (mean+/-standard deviation; P=0.004) and 45+/-23 mm Hg (P=0.016), respectively, as compared with placebo. At the end of the observation period the mean seated systolic blood pressure in the atomoxetine group was in the hypertensive range (149+/-26, range 113 to 209 mm Hg). However, in patients with peripheral autonomic failure, atomoxetine did not elicit a pressor response; seated and standing systolic blood pressure increased by 4+/-18 mm Hg (P=0.695) and 0.6+/-8 mm Hg (P=0.546) with atomoxetine as compared with placebo. In conclusion, atomoxetine induces a dramatic increase in blood pressure in patients with central autonomic failure even at very low doses. These findings suggest that a functional central sympatholytic pathway is essential to avoid hypertension in patients treated with this drug. Caution should be exercised when this medication is used in patients with milder form of autonomic impairment.
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18 MeSH Terms