Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Comparative metabolomics of muscle interstitium fluid in human trapezius myalgia: an in vivo microdialysis study.

PURPOSE: The mechanisms behind trapezius myalgia are unclear. Many hypotheses have been presented suggesting an altered metabolism in the muscle. Here, muscle microdialysate from healthy and myalgic muscle is analysed using metabolomics. Metabolomics analyse a vast number of metabolites, enabling a comprehensive explorative screening of the cellular processes in the muscle. METHODS: Microdialysate samples were obtained from the shoulder muscle of healthy and myalgic subjects that performed a work and stress test. Samples from the baseline period and from the recovery period were analysed using gas chromatography­mass spectrometry (GC­MS) together with multivariate analysis to detect differences in extracellular content of metabolites between groups. Systematic differences in metabolites between groups were identified using multivariate analysis and orthogonal partial least square discriminate analysis (OPLS-DA). A complementary Mann­Whitney U test of group difference in individual metabolites was also performed. RESULTS: A large number of metabolites were detected and identified in this screening study. At baseline, no systematic differences between groups were observed according to the OPLS-DA. However, two metabolites, l-leucine and pyroglutamic acid, were significantly more abundant in the myalgic muscle compared to the healthy muscle. In the recovery period, systematic difference in metabolites between the groups was observed according to the OPLS-DA. The groups differed in amino acids, fatty acids and carbohydrates. Myristic acid and putrescine were significantly more abundant and beta-d-glucopyranose was significantly less abundant in the myalgic muscle. CONCLUSION: This study provides important information regarding the metabolite content, thereby presenting new clues regarding the pathophysiology of the myalgic muscle.

Changes in interstitial noradrenaline, trapezius muscle activity and oxygen saturation during low-load work and recovery.

Both physical as well as mental demands result in an increased activity in the sympathetic nervous system (SNS) with changes in blood-pressure and heart-rate. Through local release of catecholamines, e.g. noradrenaline (NAd) SNS exerts various actions at the muscle level. The aims of this study were to investigate the effects of low-load repetitive work alone and in combination with mental demands on local muscle interstitial noradrenaline concentration [NAd](i), muscle activity and oxygenation, assessed with microdialysis, surface electromyography, and near-infrared spectroscopy, respectively. Healthy females (n = 15) were exposed to (1) 30 min repetitive work (RW) and (2) 30 min repetitive work with superimposed mental load (RWML) on two different occasions. Muscle [NAd](i) and muscle activity increased significantly in response to RW, but did not increase further during RWML. For RW, [NAd](i) was found to be inversely correlated to muscle activity. Oxygenation decreased significantly during work, independently of occasion. Our findings indicate that low-load work causes significantly increased trapezius muscle [NAd](i) in healthy females, and short periods of superimposed mental load do not add to this increase and further, that both muscle activity and oxygenation were unaffected by the superimposed mental load.

Characterization of a laboratory model of computer mouse use - applications for studying risk factors for musculoskeletal disorders.

In the present study, we assessed the wrist kinetics (range of motion, mean position, velocity and mean power frequency in radial/ulnar deviation, flexion/extension, and pronation/supination) associated with performing a mouse-operated computerized task involving painting rectangles on a computer screen. Furthermore, we evaluated the effects of the painting task on subjective perception of fatigue and wrist position sense. The results showed that the painting task required constrained wrist movements, and repetitive movements of about the same magnitude as those performed in mouse-operated design tasks. In addition, the painting task induced a perception of muscle fatigue in the upper extremity (Borg CR-scale: 3.5, p<0.001) and caused a reduction in the position sense accuracy of the wrist (error before: 4.6 degrees , error after: 5.6 degrees , p<0.05). This standardized painting task appears suitable for studying relevant risk factors, and therefore it offers a potential for investigating the pathophysiological mechanisms behind musculoskeletal disorders related to computer mouse use.

Transcapillary fluid responses to lower body negative pressure.

The effect of lower body negative pressure (LBNP) on transcapillary fluid balance is unknown. Therefore, our objective was to assess leg interstitial fluid pressures (IFP), leg circumference, plasma volume (PV), and net whole body transcapillary fluid transport (TFT) during and after supine LBNP and to evaluate the addition of oral saline ingestion on transcapillary exchange. Six healthy men 23-41 yr old underwent 4 h of 30 mmHg LBNP, followed by 50 min of supine recovery on two separate occasions, once with and once without ingestion of 1 liter of isotonic saline. IFP was measured continuously in subcutis as well as superficial and deep regions of the tibialis anterior muscle by slit catheters. TFT was calculated by subtracting urine production and calculated insensible fluid loss from changes in PV. During exposure to LBNP, IFP decreased in parallel with chamber pressure, foot venous pressure did not change, leg circumference increased by 3 +/- 0.35% (SE) (P < 0.05), and PV decreased by 14 +/- 2.3%. IFP returned to near control levels after LBNP. At the end of minute 50 of recovery, PV remained decreased (by 7.5 +/- 5.2%) and leg circumference remained elevated (by 1 +/- 0.37%). LBNP alone produced significant movement of fluid into the lower body but no net TFT (-7 +/- 12 ml/h). During LBNP with saline ingestion, 72 +/- 4% of the ingested fluid volume filtered out of the vascular space (TFT = 145 +/- 10 ml/h), and PV decreased by 6 +/- 3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct measurement of capillary blood pressure in the human lip.

In this study, we developed and tested a new procedure for measuring microcirculatory blood pressures above heart level in humans. Capillary and postcapillary venule blood pressures were measured directly in 13 human subjects by use of the servo-nulling micropressure technique adapted for micropuncture of lip capillaries. Pressure waveforms were recorded in 40 separate capillary vessels and 14 separate postcapillary venules over periods ranging from 5 to 64 s. Localization and determination of capillary and postcapillary vessels were ascertained anatomically before pressure measurements. Capillary pressure was 33.2 +/- 1.5 (SE) mmHg in lips of subjects seated upright. Repeated micropunctures of the same vessel gave an average coefficient of variation of 0.072. Postcapillary venule pressure was 18.9 +/- 1.6 mmHg. This procedure produces a direct and reproducible means of measuring microvascular blood pressures in a vascular bed above heart level in humans.

Transcapillary fluid shifts in tissues of the head and neck during and after simulated microgravity.

To understand the mechanism, magnitude, and time course of facial puffiness that occurs in microgravity, seven male subjects were tilted 6 degrees head-down for 8 h, and all four Starling transcapillary pressures were directly measured before, during, and after tilt. Head-down tilt (HDT) caused facial edema and a significant elevation of microvascular pressures measured in the lower lip: capillary pressures increased from 27.7 +/- 1.5 mmHg (mean +/- SE) pre-HDT to 33.9 +/- 1.7 mmHg by the end of tilt. Subcutaneous and intramuscular interstitial fluid pressures in the neck also increased as a result of HDT, whereas interstitial fluid colloid osmotic pressures remained unchanged. Plasma colloid osmotic pressure dropped significantly by 4 h of HDT (21.5 +/- 1.5 mmHg pre-HDT to 18.2 +/- 1.9 mmHg), suggesting a transition from fluid filtration to absorption in capillary beds between the heart and feet during HDT. After 4 h of seated recovery from HDT, microvascular pressures in the lip (capillary and venule pressures) remained significantly elevated by 5-8 mmHg above baseline values. During HDT, urine output was 126.5 ml/h compared with 46.7 ml/h during the control baseline period. These results suggest that facial edema resulting from HDT is caused primarily by elevated capillary pressures and decreased plasma colloid osmotic pressures. The negativity of interstitial fluid pressures above heart level also has implications for maintenance of tissue fluid balance in upright posture.

Intramuscular pressure and electromyography as indexes of force during isokinetic exercise.

A direct method for measuring force production of specific muscles during dynamic exercise is presently unavailable. Previous studies indicate that both intramuscular pressure (IMP) and electromyography (EMG) correlate linearly with muscle contraction force during isometric exercise. The objective of this study was to compare IMP and EMG as linear assessors of muscle contraction force during dynamic exercise. IMP and surface EMG activity were recorded during concentric and eccentric isokinetic plantarflexion and dorsiflexion of the ankle joint from the tibialis anterior (TA) and soleus (SOL) muscles of nine male volunteers (28-54 yr). Ankle torque was measured using a dynamometer, and IMP was measured via catheterization. IMP exhibited better linear correlation than EMG with ankle joint torque during concentric contractions of the SOL (IMP R2 = 0.97, EMG R2 = 0.81) and the TA (IMP R2 = 0.97, EMG R2 = 0.90), as well as during eccentric contractions (SOL: IMP R2 = 0.91, EMG R2 = 0.51; TA: IMP R2 = 0.94, EMG R2 = 0.73). IMP provides a better index of muscle contraction force than EMG during concentric and eccentric exercise through the entire range of torque. IMP reflects intrinsic mechanical properties of individual muscles, such as length-tension relationships, which EMG is unable to assess.

The information transmitted by ensembles of primary spindle afferents is diminished when ketamine is used as a pre-anaesthetic.

The effect of pre-anaesthetic ketamine on ensemble coding of different stimuli consisting of muscle stretches of various amplitudes was studied for ensembles of simultaneously recorded primary muscle spindle afferents (MSAs). The experiments were conducted on 8 alpha-chloralose anaesthetised cats. Three of the cats received a pre-anaesthetic dose of ketamine (25 mg/kg) injected subcutaneously (ketamine group), while the remaining five animals did not (non-ketamine group). Data for ensemble coding were collected both before and after cutting the ventral root. A method based on principal component analysis and algorithms was used to quantify stimulus discrimination and an ANOVA tested differences between groups as well as differences due to ventral root cutting. When the fusimotor supply was intact, a general trend of an increase in the ability to discriminate stimuli with increasing ensemble size was observed for both groups, however, this trend was significantly greater for the non-ketamine group as compared to the ketamine group. When the ventral root was cut, the discrimination pattern for the non-ketamine group decreased significantly (as compared to before ventral root cutting), however, no change occurred for the ketamine group. Consequently, no difference in discrimination pattern was detected between groups after ventral root cutting. The reduction in information transmitted by ensembles of primary MSAs when ketamine is used as a pre-anaesthetic may suggest that ketamine elicits an adverse affect on the fusimotor system.

A new "transducer-tipped" fiber optic catheter for measuring intramuscular pressures.

Laboratory and clinical tests were used to determine the efficacy of a new fiber optic "transducer-tipped" catheter for measuring intramuscular pressures. When pressures ranging from 0 to 250 mm Hg were applied by a mercury manometer, the fiber optic system accurately recorded the pressures. In addition, the fiber optic system showed long-term stability by accurately recording the manometer pressure over a 3 day period. The Slit system showed a higher magnitude of hydrostatic pressure artifacts with catheter tip movement as compared to the fiber optic system. The two catheters showed no difference when measuring pressures in pig muscle at rest or when being compressed throughout a range of 0 to 250 mm Hg. In human volunteers, both catheters measured essentially equal pressures at rest, during venous stasis, and during a combination of venous stasis and compression. For long-term assessment, the Slit system required as many as three saline flushes, whereas the fiber optic system measured pressures continuously without manipulation. We conclude that the fiber optic system is as accurate as the Slit catheter for measuring tissue fluid pressures at rest. In addition, the fiber optic system offers distinct advantages over conventional fluid-filled systems for measuring intramuscular pressures due to a lack of hydrostatic pressure artifacts caused by limb position and to the lack of flushing for long-term measurements.

Intraarticular pressure during continuous passive motion of the human knee.

Intraarticular pressure (IAP) was continuously monitored during continuous passive motion (CPM) of five normal and 11 abnormal human knees using a new fiberoptic, transducer-tipped Camino catheter. IAP varied in a consistent hysteresis pattern in the normal knees, with subatmospheric pressures recorded at intermediate angles of joint flexion. A similar pattern was recorded in the abnormal knees without cruciate ligament pathology, whereas considerable variability was noted in the knees with cruciate ligament abnormality. IAP was lower in the extension to flexion than in the flexion to extension portion of the CPM cycle, providing evidence of intraarticular fluid flow during portions of the CPM cycle. IAP changes were consistent with "physiologic compartmentation" within the knee at extremes of joint position. Capsular viscoelastic changes and/or synovial fluid volume changes were observed during CPM. The therapeutic mechanism of continuous passive motion may be related to cyclic variation of the intraarticular pressure.

Long-term measurement of muscle function in the dog hindlimb using a new apparatus.

The objective of this study was to develop an apparatus for reliable, reproducible, and minimally invasive measurements of long-term, myoneural function. Twenty conditioned dogs were anesthetized and placed supine with one hindlimb secured in a boot apparatus. The hindpaw was attached to a force transducer that was connected to a recorder for continuous monitoring of torque. Muscles within the anterolateral compartment were stimulated by percutaneous electrodes over the peroneal nerve near the fibular head. This elicited isometric dorsiflexion of the hindpaw. Twitch and tetanic torques correlated positively with dog weight whereas other skeletal-muscle function parameters (time to peak tension, one-half relaxation time, and endurance) were independent of dog weight. Muscle function results were consistent with an overall compartmental composition of 30% Type I and 70% Type II fibers. Repetitive testing of twitch and tetanic torques in the dog legs yielded coefficients of variance of 3-4% (intraday) and 7% (interday). Thus, about one-half of the interday variability may be accounted for by diet, exercise, and other physiological conditions that change daily. The apparatus was also used to detect myoneural degeneration following tourniquet ischemia. The results indicate that this procedure for evaluating muscle function yields reliable and quantitative results noninvasively, and thus allows long-term testing of muscle function in normal and diseased hindlimbs of dogs.

Oxygenation, EMG and position sense during computer mouse work. Impact of active versus passive pauses.

We investigated the effects of active versus passive pauses implemented during computer mouse work on muscle oxygenation and EMG of the forearm extensor carpi radialis muscle, and on wrist position sense. Fifteen healthy female subjects (age: 19-24 years) performed a 60-min mouse-operated computer task, divided into three 20 min periods, on two occasions separated by 3-6 days. On one occasion a passive pause (subjects resting) was implemented at the end of each 20-min period, and on another occasion an active pause (subjects performed a number of high intensity extensions of the forearm) was implemented. Also at the end of each 20-min period, test contractions were conducted and subjective ratings of fatigue and stress were obtained. Another parameter of interest was total haemoglobin calculated as the summation of oxy-and deoxy-haemoglobin, since it reflects blood volume changes. The most interesting findings were an overall increasing trend in total haemoglobin throughout the mouse work (P<0.001), and that this trend was greater for the active pause as compared to the passive pause (P<0.01). These data were accompanied by an overall increase in oxygen saturation (P<0.001), with a tendency, albeit not significant, toward a higher increase for the active pause (P=0.13). EMG amplitude and median frequency tended to decrease (P=0.08 and 0.05, respectively) during the mouse work but was not different between pause types. Borg ratings of forearm fatigue showed an overall increase during the activity (P<0.001), but the perceptions of stress did not change. Position sense did not change due to the mouse work for either pause type. While increasing trends were found for both pause types, the present study lends support to the hypothesis of an enhancement in oxygenation and blood volume for computer mouse work implemented with active pauses. However, a presumption of an association between this enhancement and attenuated fatigue during the mouse work was not supported.

Effects of 30 versus 60 min of low-load work on intramuscular lactate, pyruvate, glutamate, prostaglandin E(2) and oxygenation in the trapezius muscle of healthy females.

The aim of this study was to investigate the effects of duration of low-load repetitive work on intramuscular lactate, pyruvate, glutamate and prostaglandin E(2) (PGE(2)), and oxygen saturation in the trapezius muscle. Twenty healthy females were studied during baseline rest, during low-load repetitive work for either 30 (REP 30) or 60 min (REP 60) and 60 min recovery. Intramuscular microdialysate (IMMD) samples were obtained, and local muscle tissue oxygenation (%StO(2)) assessed with near-infrared spectroscopy (NIRS). Subjects rated their perceived exertion (Borg CR-10 scale) and capillary blood was sampled for lactate analysis. The results showed a significant increase in IMMD lactate in response to both REP 30 and REP 60 (P < 0.05 and P < 0.01, respectively) and glutamate (P < 0.0001), but no progressive increase with increasing work duration. Both IMMD pyruvate and lactate tended to be significantly increased during the recovery period. No corresponding increase in blood lactate was found. Local muscle %StO(2) did not change significantly in response to work and was not correlated to the IMMD lactate concentration. The ratings of perceived exertion increased in response to work, and remained increased after recovery for REP 60. In conclusion, the results of this study show significantly increased IMMD lactate and, glutamate concentrations in the trapezius muscle of healthy females in response to low-load work, but no progressive increase with increased work duration. Further, they do not indicate that the increased IMMD lactate concentration was caused by a locally decreased or insufficient muscle tissue oxygenation.

Effects of time pressure and precision demands during computer mouse work on muscle oxygenation and position sense.

The present study investigated the effects of time pressure and precision demands during computer mouse work on muscle oxygenation and position sense in the upper extremity. Twenty-four healthy subjects (12 males and 12 females) performed a 45-min standardized mouse-operated computer task on two occasions. The task consisted of painting rectangles that were presented on the screen. On one occasion, time pressure and precision demands were imposed (more demanding task, MDT), whereas, on the other occasion, no such restraints were added (less demanding task, LDT). The order of the two task versions was randomized. Tissue oxygen saturation in the trapezius and extensor carpi radialis muscles was recorded throughout, and the position-matching ability of the wrist was measured before and after the tasks. In addition, measurements of autonomic nervous system reactivity and subjective ratings of tenseness and physical fatigue were obtained. Performance was measured in terms of the number of rectangles that were painted during the task. During MDT, oxygen saturation in extensor carpi radialis decreased (P < 0.05) compared to LDT. These data were paralleled by increased electrodermal activity (P < 0.05), skin blood flow (P < 0.05), ratings of tenseness and fatigue (P < 0.01), and increased performance (P < 0.01) during MDT. Females exhibited lower oxygen saturation than males, during rest as well as during the computer tasks (P < 0.01). Wrist repositioning error increased following LDT as compared to MDT (P < 0.05). In conclusion, computer mouse work under time pressure and precision demands caused a decrease in forearm muscle oxygenation, but did not affect wrist position sense accuracy. We attribute our changes in oxygenation more to increased oxygen consumption as a result of enhanced performance, than to vasoconstriction.

Intramuscular pressure, torque and swelling for the exercise-induced sore vastus lateralis muscle.

This study investigated changes in intramuscular fluid pressure (IMP), torque and swelling related to delayed onset muscle soreness (DOMS) of the vastus lateralis muscle. IMP was measured via catheterization in the unstretched (0 degree, full extension) and stretched (90 degrees of knee flexion) muscle at rest; then IMP and knee extension torque were determined during maximal contractions pre and 2 d after (post) repetitive eccentric activity in one leg for eight male subjects. DOMS of the vastus lateralis muscle was associated with a significant elevation in IMP at rest as indicated by pre (0 degree: 5.4 mmHg, 90 degrees: 80 mmHg) and post (0 degree: 8.4 mmHg, 90 degrees: 13.2 mmHg) comparisons (P = 0.02). Soreness symptoms were aggravated when the muscle was stretched and this was accompanied by a significantly higher post IMP at 90 degrees vs. 0 degree (P = 0.01). During maximal contractions, peak torque declined by 15% relative to pre and peak IMP declined by 26%; DOMS symptoms, however, were most severe during this manoeuvre. Biopsies from the sore vastus lateralis muscle revealed significantly larger fibre areas for all fibre types as compared with contralateral controls (P < 0.01); however, no differences were detected for extracellular volume percent comparisons. This study shows that DOMS of the vastus lateralis muscle is associated with extensive intracellular swelling and with elevated IMP. In line with previous studies, fibre swelling may be a common subsequence to repetitive eccentric activity; the ability of IMP measurements to detect this swelling at rest and during various manoeuvres for other muscles may depend on compartmental compliance.

Intramuscular pressures during exercise: an evaluation of a fiber optic transducer-tipped catheter system.

The efficacy of a modified fibre optic transducer-tipped catheter system for measuring intramuscular pressures during exercise was determined. A microcapillary infusion technique using a catheter was employed as the standard of comparison due to its established dynamic properties. Pressures were measured in the tibialis anterior muscle of six healthy adults at rest before exercise, during isometric and concentric exercise, and at rest after exercise. The fibre optic system measured contraction pressures equal to the microcapillary infusion technique during all phases of the exercise protocols but recorded a lower relaxation pressure during isometric exercise and a lower rest pressure following 20 min of concentric exercise. Negative relaxation pressures were recorded by the fibre optic system for two subjects during continuous concentric exercise. It is hypothesized that a piston effect, due to the sliding of muscle fibres at the catheter tip following a contraction, rendered falsely low pressures during relaxation and that this artefact was reflected in the subsequent rest pressure following exercise. The larger volume (157 mm3) and area (3.49 mm2) of the fibre optic catheter in the muscle made it more prone to this effect than the conventional catheter (39 mm3 and 0.87 mm2, respectively). The fibre optic system may be preferred when recording the muscle contraction pressures during complex limb movements but should not be used when assessing the relaxation pressures or the pressure at rest following exercise.