Exercise training and DNA methylation in humans

The response to exercise training (trainability) has been shown to have a strong heritable component. There is growing evidence suggesting that traits such as trainability do not only depend on the genetic code, but also on epigenetic signals. Epigenetic signals play an important role in the modulation of gene expression, through mechanisms such as DNA methylation and histone modifications. There is an emerging evidence to show that physical activity influences DNA methylation in humans. The present review aims to summarize current knowledge on the link between DNA methylation and physical activity in humans. We have critically reviewed the literature and only papers focused on physical activity and its influence on DNA methylation status were included; a total of 25 papers were selected. We concluded that both acute and chronic exercises significantly impact DNA methylation, in a highly tissue‐ and gene‐specific manner. This review also provides insights into the molecular mechanisms of exercise‐induced DNA methylation changes, and recommendations for future research.     

Short-term vestibulo-ocular reflex adaptation in humans

We investigated the effect of short-term vestibulo-ocular reflex (VOR) adaptation in normal human subjects on the dynamic properties of the velocity-to-position ocular motor integrator that holds positions of gaze. Subjects sat in a sinusoidally rotating chair surrounded by an optokinetic nystagmus drum. The movement of the visual surround (drum) was manipulated relative to the chair to produce an increase (× 1.7 viewing), decrease (× 0.5, × 0 viewing), or reversal (× (-2.5) viewing) of VOR gain. Before and after 1 h of training, VOR gain and gaze-holding after eccentric saccades in darkness were measured. Depending on the training paradigm, eccentric saccades could be followed by centrifugal drift (after × 0.5 viewing), implying an unstable integrator, or by centripetal drift [after × 1.7 or × (-2.5) viewing], implying a leaky integrator. The changes in the neural integrator appear to be context specific, so that when the VOR was tested in non-training head orientations, both the adaptive change in VOR gain and the changes in the neural integrator were much smaller. The changes in VOR gain were on the order of 10% and the induced drift velocities were several degrees per secend at 20 deg eccentric positions in the orbit. We propose that (1) the changes in the dynamic properties of the neural integrator reflect an attempt to modify the phase (timing) relationships of the VOR and (2) the relative directions of retinal slip and eye velocity during head rotation determine whether the integrator becomes unstable (and introduces more phase lag) or leaky (and introduces less phase lag).Visiting scientist from: 1 INSERM-U94. 16, avenue du Doyen Lépine, F-69500 Bron, France     

Functional anatomy of saccadic adaptation in humans

Positron emission tomography (PET) was used to investigate the neurophysiological substrate of human saccadic adaptation. Subjects made saccadic eye movements toward a visual target that was displaced during the course of the initial saccade, a time when visual perception is suppressed. In one condition, displacement was random from trial to trial, precluding any systematic modification of the initial saccade amplitude. In the second condition, the direction and magnitude of displacement were consistent, causing adaptative modification of the initial saccade amplitude. PET difference images reflecting metabolic changes attributable to the process of saccadic adaptation showed selective activation of the medioposterior cerebellar cortex. This localization is consistent with neurophysiological findings in monkeys and brain-lesioned humans.     

Gene expression drives local adaptation in humans

The molecular basis of adaptation—and, in particular, the relative roles of protein-coding versus gene expression changes—has long been the subject of speculation and debate. Recently, the genotyping of diverse human populations has led to the identification of many putative “local adaptations” that differ between populations. Here I show that these local adaptations are over 10-fold more likely to affect gene expression than amino acid sequence. In addition, a novel framework for identifying polygenic local adaptations detects recent positive selection on the expression levels of genes involved in UV radiation response, immune cell proliferation, and diabetes-related pathways. These results provide the first examples of polygenic gene expression adaptation in humans, as well as the first genome-scale support for the hypothesis that changes in gene expression have driven human adaptation.The molecular mechanisms of adaptive mutations have long been a topic of great interest (King and Wilson 1975). In particular, the relative roles of protein-coding versus cis-regulatory changes have been much debated (King and Wilson 1975; Hoekstra and Coyne 2007; Prud''homme et al. 2007; Stern and Orgogozo 2008). However, no systematic comparisons between the two classes have been reported for humans; previously reported evidence supporting either mechanism has been either indirect, theoretical, or anecdotal (King and Wilson 1975; Hoekstra and Coyne 2007; Prud''homme et al. 2007; Stern and Orgogozo 2008). Many genome-wide scans for positive selection in humans have been conducted (Akey 2009; Pickrell et al. 2009; Torgerson et al. 2009; Hancock et al. 2011), but none have compared the prevalence of these two classes of human adaptations.Adaptations that have arisen in recent human evolution are likely to be present only in a subset of human populations. For example, the sickle-cell mutation in beta hemoglobin, which confers resistance to malaria, is present at high frequency only in populations where malaria is endemic (Kwiatkowski 2005). Likewise, alleles causing lactase persistence—the continued expression of the lactase enzyme beyond childhood, allowing lactose to be metabolized—are at high frequency primarily in populations that have historically practiced dairy farming (Harris and Meyer 2006). These represent “local adaptations,” since they are specific to the local environments of a subset of human populations.Recently, many other candidate local adaptations have been detected as correlations between population-specific allele frequencies and factors reflecting the climates or geographies of those populations (e.g., temperature, latitude, etc.) (Hancock et al. 2011). These associations are present even after controlling for genome-wide covariation due to population structure, and are enriched for nonsynonymous variants, suggesting the action of natural selection and not simply neutral drift (Hancock et al. 2011). Although the allele frequencies of these putatively adaptive variants typically differ only slightly between populations, presumably affecting phenotypes in a highly polygenic manner, collectively they may account for a significant fraction of recent human adaptation (Hancock et al. 2010, 2011; Pritchard et al. 2010).To what extent human polygenic adaptations may act via changes in gene expression levels has not been investigated. Despite many examples of polygenic gene expression adaptations in model organisms (Fraser et al. 2010, 2011, 2012; Fraser 2011), the handful of known human gene expression adaptations all involve changes at only single genes, such as lactase (Harris and Meyer 2006). Therefore I sought to address two questions: (1) How important is gene expression in recent human adaptation, relative to changes in protein sequences? and (2) What specific functional classes have been targets of gene expression adaptations?     

Misperception of adaptation and remodeling in vascular pathology

A prerequisite of scientific communications is that words should not be misrepresented. Currently, the frequent misuse of adaptation and remodeling derives from faulty analysis and misrepresentation of the pathology of coronary atherosclerotic lesions. This misperception of vascular pathology has misled the uncritical and unwary, and propagates fallacious data and concepts. Unless the misusage ceases, the terms will continue to be meaningless merely furthering promulgation of unscientific data and concepts that effectively obstructs scientific progress.     

Muscle enzyme adaptation to training and tapering-off in spinal-cord-injured humans

The activity of muscle metabolic enzymes depends on the amount and type of physical training. We examined muscle enzyme adaptation to prolonged training followed by a period of lowered activity in spinal-cord-injured individuals (SCI). Ten SCI [mean age 35 (SEM 2) years , mean body mass 78 (SEM 4) kg, mean time post-injury 12 (SEM 2) years and range of lesion C5–T4] were given 12 months of functional electrical stimulation of an upright cycling motion for 30 min a day, three times a week, followed by 6 months of training once a week. Activities of glycolytic (hexokinase HK, lactate dehydrogenase LDH) and oxidative (citrate synthase CS, 3-hydroxyacyl-CoA dehydrogenase HAD) enzymes were determined in biopsies of the vastus lateralis muscle taken at 0, 3, 6, 12, and 18 months of training. The degree of sympathoadrenergic activity was evaluated from arterial concentrations of catecholamines in response to acute exercise. Training three times a week induced increases (P<0.05) in HK (150%), LDH (40%), CS (100%), and HAD (70%) activities that reached a plateau after 3 months. Peak oxygen uptake and power output during exercise by electrical stimulation rose continuously over the first 12 months. After reducing the amount of training by two-thirds, HK, LDH and CS activities remained elevated above basal levels (P<0.05), whereas HAD, power output and maximal oxygen uptake returned to pretraining levels (P>0.05). It is concluded that most improvements in glycolytic and mitochondrial oxidative enzyme activities induced by long-term training can be maintained in spinal-cord-injured individuals despite a marked reduction in training frequency unrelated to performance or to the degree of sympathoadrenergic impairment. Electronic Publication     

Exercise hyperaemia: magnitude and aspects on regulation in humans

The primary function of the cardiovascular system is to supply oxygen to tissues and organs in the body. When muscles contract the aerobic demands are met by an increase in oxygen delivery both at the systemic and the regional levels, a match that is very close and holds at submaximal exercise and when small muscle group contract also at vigorous intensities. The level of muscle perfusion reached is 250 ml min⁻¹ (100 g)⁻¹ in muscle of sedentary subjects and in endurance-trained athletes 400 ml min⁻¹ (100 g)⁻¹ has been reported. These levels of peak exercise hyperaemia equal what has been observed in other species. One consequence of these high muscle blood flows is that the human heart cannot support an optimal blood flow in whole body exercise (arms and legs combined) and sympathetically mediated vasoconstriction, also in arterioles feeding active limb muscles, contributes to matching peripheral resistance in order to maintain blood pressure. Respiratory muscles appear to have a higher priority for a blood flow than limb and torso muscles. There is no consensus in regard to which locally produced substances elicit the vasodilatation when muscle contracts. In addition to NO, data are presented for various metabolites of arachidonic acid and also on ATP, possibly released from the red cells. Using blockers of nitric oxide synthase ( l -NMMA or l -NAME) and the enzymes producing epoxyeicosatrienoic acid (EET) (sulpaphenozole or tetraetylammonium chloride) or prostaglandins (indomethacin), muscle blood flow may be reduced by up to 25–40%. Evaluating the exact role of ATP has to await further studies in humans and especially the use of specific ATP receptor blockers.     

Exercise gas transport determinants in elderly normotensive and hypertensive humans

This study examined the effect of the phenylalkylamine calcium channel blocker verapamil, on resting left ventricular (LV) function and O2 uptake rate (VO2) during exercise at maximal and submaximal work rates. Nine older hypertensive (71 years; OH), 10 older sedentary normotensive (69 years; OS), 10 older active (71 years; OA) and 10 young (24 years; Y) individuals volunteered. Studies were completed in the control condition and 4-6 h following 240 mg verapamil SR per os. Resting LV systolic (fractional shortening; FS) and diastolic (early: late (E/A) flow velocity ratio and isovolumic relaxation time (IVRT) were measured by Doppler echocardiography. Maximal oxygen uptake (VO2,max) and, on subsequent test days, four transitions to and from a 6 min square wave exercise perturbation at a sub-anaerobic threshold intensity of 40 W (OH, OS, OA) or 100 W (Y) for determination of VO2 kinetics were performed on a cycle ergometer. Breath-by-breath VO2 transients were fitted with a monoexponential equation, starting at phase 2 of the response, while heart rate (HR) was fitted from phase 1, for the determination of the time constant of VO2 (tau VO2) and HR (tau HR). Baseline left ventricular FS was significantly greater in the OS (32%), OA (34%) and Y (34%) than in the OH (23%) groups, while E/A was significantly greater in the OA (1.16) and Y (2.34) than in the OH (0.9) and OS (0.82) groups (P < 0.05). Baseline VO2,max was higher and tau VO2 faster in the young (41.4 ml kg-1 min-1; 25.2 s) than in the older groups and in the OA (28.8 ml kg-1 min-1; 44.3 s) than in both OH (20.8 ml kg-1 min-1; 71.3 s) and OS (22.0 ml kg-1 min-1; 59.5 s) groups (P < 0.05). Heart rate kinetics showed similar differences to VO2 kinetics among the groups. After verapamil, no significant changes in FS, E/A or IVRT were observed in the OA and Y groups. In the OH group, FS (32%) and E/A (1.15) increased while IVRT decreased significantly (from 0.103 to 0.07; P < 0.05). In the OS group, only E/A increased significantly (0.82 to 1.0; P < 0.05). None of the exercise variables (VO2,max, tau VO2 or tau HR) were altered for the OA or Y groups. VO2,max increased (from 20.8 to 22.8 ml kg-1 min-1) in the OH and (from 22.0 to 24.1 ml kg-1 min-1) in the OS (P < 0.05). tau VO2 was accelerated from 71.3 to 49.2 s in the OH group and from 59.5 to 48.2 s in the OS group (P < 0.05). These results suggest that VO2 responses at maximal and submaximal work rates may be dependent upon the initial cardiac pump function of the study population.     

Exercise and coronary vascular remodelling in the healthy heart

In this review the evidence for structural adaptations of the coronary circulation in the healthy adult heart in response to exercise and training is examined. Previously, it was thought that expansion of the coronary arteries and resistance vasculature occurred without angiogenesis. Detailed studies of the time course of coronary vascular remodelling now reveal that capillary proliferation is an integral response to exercise training, but is disguised by concurrent transformation of capillaries into arterioles by 'arteriolarization'. Increases in numbers of small arterioles < 30 micro m in diameter are accompanied by expansion in calibre of resistance and large coronary arteries. Stimuli related to increases in blood flow--shear stress and wall tension--and to mechanical deformation of the myocardium--stretch and compression--provide the main impetus for coronary vascular remodelling. Despite the technical difficulties of measuring such parameters in the heart in vivo, intervention studies using specific exercise components such as vasodilator, inotropic and chronotropic manipulations have allowed some insight into the differential regional effects of haemodynamic factors throughout the vascular tree. It remains to establish more clearly the involvement of mediators such as nitric oxide and growth factors in the temporal relationship to endothelial and smooth muscle growth and proliferation so that the endogenous attributes of exercise can be exploited for therapeutic purposes.     

Hypoxia and training-induced adaptation of hormonal responses to exercise in humans

To establish whether or not hypoxia influences the training-induced adaptation of hormonal responses to exercise, 21 healthy, untrained subjects [26 (2) years, mean (SE)] were studied in three groups before and after 5 weeks' training (cycle ergometer, 45 min· day^–1, 5 days· week^–1). Group 1 trained at sea level at 70% maximal oxygen uptake ( O_2max), group 2 in a hypobaric chamber at a simulated altitude of 2500 m at 70% of altitude O_2max, and group 3 at a simulated altitude of 2500 m at the same absolute work rate as group 1. Arterial blood was sampled before, during and at the end of exhaustive cycling at sea level (85% of pretraining of O_2max). O₂ increased by 12 (2)% with no significant difference between groups, whereas endurance improved most in group 1 (P < 0.05). Training-induced changes in response to exercise of noradrenaline, adrenaline, growth hormone, -endorphin, glucagon, and insulin were similar in the three groups. Concentrations of erythropoietin and 2,3-diphosphoglycerate at rest did not change over the training period. In conclusion, within 5 weeks of training, no further adaptation of hormonal exercise responses takes place if intensity is increased above 70% O_2max. Furthermore, hypoxia per se does not add to the training-induced hormonal responses to exercise.     

Balance control and adaptation during vibratory perturbations in middle-aged and elderly humans

The objective was to investigate if healthy elderly people respond and adapt differently to postural disturbances compared to middle-aged people. Thirty middle-aged (mean age 37.8 years, range 24–56 years) and forty healthy elderly subjects (mean age 74.6 years, range 66–88 years) were tested with posturography. Body sway was evoked by applying pseudorandom vibratory stimulation to the belly of the gastrocnemius muscles of both legs simultaneously. The tests were performed both with eyes open and eyes closed. The anteroposterior body sway was measured with a force platform and analyzed with a method that considers the adaptive changes of posture and stimulation responses. The results showed that middle-aged people generally used a different postural control strategy as compared to the elderly. The elderly responded more rapidly to vibratory perturbation, used more high-frequency (>0.1 Hz) motions and the motion dynamics had a higher degree of complexity. Moreover, the elderly had diminished ability to use visual information to improve balance control. Altogether, despite having an effective postural control adaptation similar to that of middle-aged people, the elderly had more difficultly in withstanding balance perturbations. These findings suggest that the balance control deterioration associated with aging cannot be fully compensated for by postural control adaptation.     

Chronic neural adaptation induced by long-term resistance training in humans

While it is known that resistance training causes changes in the central nervous system (CNS) in the initial stages of training, there have been few studies of cumulative or sustained neural adaptation to resistance training beyond the initial periods. To further investigate this we compared the electromyographic (EMG) response to transcranial magnetic stimulation (TMS) during voluntary contractions of ten subjects who have been training for more than 2 years, resistance-training (RT) group, and ten subjects that have never participated in resistance training (NT). The active motor threshold for biceps brachii was obtained during voluntary elbow flexion at 10% of maximal voluntary contraction (MVC). TMS was also delivered at 100% of the maximal stimulator output while the participants exerted forces ranging from 10 to 90% of MVC. Evoked force, motor-evoked potential (MEP) amplitude and latency from biceps brachii was recorded for each condition to explore changes in corticospinal excitability. The evoked force was significantly lower in the RT group in comparison with the NT group between 30 and 70% of MVC intensity (P<0.05). At 90% of MVC, nine subjects from the RT group showed an absence in the evoked force while this occurred in only five subjects from the NT group. The MEP amplitude and latency changed significantly (P<0.001) with increasing levels of contraction, without significant difference between groups. These results indicate that changes in the CNS are sustained in the log-term practices of resistance training and permit a higher voluntary activation at several intensities of the MVC.     

Repeated core temperature elevation induces conduit artery adaptation in humans

Purpose

Shear stress is a known stimulus to vascular adaptation in humans. However, it is not known whether thermoregulatory reflex increases in blood flow and shear can induce conduit artery adaptation.

Methods

Ten healthy young volunteers therefore underwent 8 weeks of 3 × weekly bouts of 30 min lower limb heating (40 °C) during which the upper body was not directly heated. Throughout each leg heating session, a pneumatic cuff was placed on one forearm and inflated to unilaterally restrict reflex-mediated blood flow responses.

Results

Each bout of leg heating significantly increased brachial artery shear rate in the uncuffed arm (96 ± 97 vs 401 ± 96 l/s, P < 0.01), whereas no change was apparent in the cuffed arm (83 ± 69 vs 131 ± 76 l/s, P = 0.67). Repeated episodic exposure to leg heating enhanced brachial artery endothelial function (measured by flow-mediated dilation) in the uncuffed arm from week 0 (5.2 ± 1.9 %) to week 4 (7.7 ± 2.6 %, P < 0.05), before returning to baseline levels by week 8. No adaptation was evident in the cuffed arm.

Conclusions

We conclude that repeated increases in core temperature, induced via lower limb heating, resulted in upper limb conduit artery vascular adaptation which was dependent upon increases in shear stress. To our knowledge this is the first study to establish a beneficial systemic impact of thermoregulatory reflexes on conduit artery function in humans.     

High-altitude adaptation in humans: from genomics to integrative physiology

About 1.2 to 33% of high-altitude populations suffer from Monge’s disease or chronic mountain sickness (CMS). Number of factors such as age, sex, and population of origin (older, male, Andean) contribute to the percentage reported from a variety of samples. It is estimated that there are around 83 million people who live at altitudes > 2500 m worldwide and are at risk for CMS. In this review, we focus on a human “experiment in nature” in various high-altitude locations in the world—namely, Andean, Tibetan, and Ethiopian populations that have lived under chronic hypoxia conditions for thousands of years. We discuss the adaptive as well as mal-adaptive changes at the genomic and physiological levels. Although different genes seem to be involved in adaptation in the three populations, we can observe convergence at genetic and signaling, as well as physiological levels. What is important is that we and others have shown that lessons learned from the genes mined at high altitude can be helpful in better understanding and treating diseases that occur at sea level. We discuss two such examples: EDNRB and SENP1 and their role in cardiac tolerance and in the polycythemic response, respectively.     

Asymmetric short-term adaptation of the vertical vestibulo-ocular reflex in humans

Anatomical and electrophysiological studies have demonstrated up–down asymmetries in vertical ocular motor pathways. We investigated whether these asymmetries extend to the capacity for short-term adaptation of the vertical vestibulo-ocular reflex (VVOR) in humans. Specifically, we asked whether smooth pursuit signals are sufficient to asymmetrically adapt the VVOR. Healthy human subjects (N=8), positioned 90° left-ear-down and fixating with their eyes upon a small laser dot (diameter: 0.1°) projected on a sphere (distance: 1.4 m) were trained toward low VVOR gain for 30 min with symmetric and asymmetric visual VVOR cancellation paradigms, while being oscillated (0.2 Hz, ±20°) on a motorized turntable about the interaural earth-vertical axis. During asymmetric VVOR cancellation, the target was head-fixed in either the pitch-up or pitch-down half-cycles of oscillation (=trained direction) and space-fixed during the other half-cycles (=untrained direction). During symmetric VVOR cancellation, the target was head-fixed throughout the oscillations. Before and after adaptation, the pitch-up and pitch-down VOR gains were assessed during turntable oscillation in complete darkness. Before adaptation, average gains of pitch-up (0.75±0.15 SD) and pitch-down (0.79±0.19 SD) VOR were not significantly different (paired t test: P>0.05). On an average, relative gain reductions induced by selective pitch-up (pitch-up VOR: 32%; pitch-down VOR: 21%) and pitch-down (pitch-up VOR: 18%; pitch-down VOR: 30%) VOR cancellation were significantly (P<0.05) larger in the trained than in the untrained direction. Symmetric visual VVOR cancellation led to a significantly (P<0.01) larger relative gain reduction of the pitch-down (41%) than the pitch-up (33%) VOR. None of the paradigms led to significant changes of phase or offset. We conclude that, in human subjects, the smooth pursuit system is capable to asymmetrically decrease the gain of the VVOR equally well in both the upward and downward direction. The unexpected asymmetric decrease of the VVOR gain after symmetric visual cancellation may be related to the directional preferences of vertical gaze–velocity sensitive Purkinje cells in the flocculus for the downward direction.This work was supported by Swiss National Science Foundation (3231-051938.97/31-63465.00/#3200BO-1054534), and Betty and David Koetser Foundation for Brain Research (Zurich, Switzerland).     

Exercise intensity-dependent contribution of beta-adrenergic receptor-mediated vasodilatation in hypoxic humans

We previously reported that hypoxia-mediated reductions in alpha-adrenoceptor sensitivity do not explain the augmented vasodilatation during hypoxic exercise, suggesting an enhanced vasodilator signal. We hypothesized that beta-adrenoceptor activation contributes to augmented hypoxic exercise vasodilatation. Fourteen subjects (age: 29 +/- 2 years) breathed hypoxic gas to titrate arterial O(2) saturation (pulse oximetry) to 80%, while remaining normocapnic via a rebreath system. Brachial artery and antecubital vein catheters were placed in the exercising arm. Under normoxic and hypoxic conditions, baseline and incremental forearm exercise (10% and 20% of maximum) was performed during control (saline), alpha-adrenoceptor inhibition (phentolamine), and combined alpha- and beta-adrenoceptor inhibition (phentolomine/propranolol). Forearm blood flow (FBF), heart rate, blood pressure, minute ventilation, and end-tidal CO(2) were determined. Hypoxia increased heart rate (P < 0.05) and minute ventilation (P < 0.05) at rest and exercise under all drug infusions, whereas mean arterial pressure was unchanged. Arterial adrenaline (P < 0.05) and venous noradrenaline (P < 0.05) were higher with hypoxia during all drug infusions. The change (Delta) in FBF during 10% hypoxic exercise was greater with phentolamine (Delta306 +/- 43 ml min(-1)) vs. saline (Delta169 +/- 30 ml min(-1)) or combined phentolamine/propranolol (Delta213 +/- 25 ml min(-1); P < 0.05 for both). During 20% hypoxic exercise, DeltaFBF was greater with phentalomine (Delta466 +/- 57 ml min(-1); P < 0.05) vs. saline (Delta346 +/- 40 ml min(-1)) but was similar to combined phentolamine/propranolol (Delta450 +/- 43 ml min(-1)). Thus, in the absence of overlying vasoconstriction, the contribution of beta-adrenergic mechanisms to the augmented hypoxic vasodilatation is dependent on exercise intensity.     

Faecal carriage of optrA-positive enterococci in asymptomatic healthy humans in Hangzhou,China

ObjectivesTo investigate the faecal carriage of optrA-positive enterococci among asymptomatic healthy humans in Hangzhou, China, and to characterize the genetic context of optrA.MethodsA total of 3458 stool samples from healthy individuals were collected and cultured on a selective medium containing 10 mg/L florfenicol and resulting enterococci were screened for the presence of optrA by PCR. OptrA variants were determined by amino acid sequence comparison with the original OptrA from Enterococcus faecalis E349. Whole genome sequencing and PCR mapping were performed to obtain and analyse the genetic environment of optrA.ResultsSimilar optrA carriage rates (～3.5%) were detected in samples from adults (55/1558) and children (66/1900). Linezolid resistance rates for E. faecalis, Enterococcus faecium and other Enterococcus species were 58.5% (38/65), 42.3% (11/26) and 0% (0/31), respectively. Nineteen OptrA variants exhibiting different linezolid MICs were identified. Isolates carrying wild-type OptrA and variants RDK, KLDP, KD, D, RDKP, and EDP generally demonstrated linezolid MICs ≥8 mg/L. The OptrA variants, with fexA upstream and erm(A) downstream, were flanked by IS1216E at one or both ends. The fexA-optrA(wild-type) was located downstream of a Tn554 transposon, and was inserted into the radC gene. The EDM variant was detected in 31/73 enterococci with linezolid MICs ≤4 mg/L. Despite the variable genetic context, Tn558-araC-optrA(EDM)-erm(A)-met was the most common gene array.ConclusionsThis study revealed a correlation between linezolid MIC, genetic context and OptrA variant. Intestinal colonization of healthy individuals by optrA-positive enterococci is a concern, and active epidemiological surveillance of optrA is warranted.     

Exercise and the immune system: regulation, integration, and adaptation

Stress-induced immunological reactions to exercise have stimulated much research into stress immunology and neuroimmunology. It is suggested that exercise can be employed as a model of temporary immunosuppression that occurs after severe physical stress. The exercise-stress model can be easily manipulated experimentally and allows for the study of interactions between the nervous, the endocrine, and the immune systems. This review focuses on mechanisms underlying exercise-induced immune changes such as neuroendocrinological factors including catecholamines, growth hormone, cortisol, beta-endorphin, and sex steroids. The contribution of a metabolic link between skeletal muscles and the lymphoid system is also reviewed. The mechanisms of exercise-associated muscle damage and the initiation of the inflammatory cytokine cascade are discussed. Given that exercise modulates the immune system in healthy individuals, considerations of the clinical ramifications of exercise in the prevention of diseases for which the immune system has a role is of importance. Accordingly, drawing on the experimental, clinical, and epidemiological literature, we address the interactions between exercise and infectious diseases as well as exercise and neoplasia within the context of both aging and nutrition.     

Functional adaptation of reactive saccades in humans: a PET study

It is known that the saccadic system shows adaptive changes when the command sent to the extraocular muscles is inappropriate. Despite an abundance of supportive psychophysical investigations, the neurophysiological substrate of this process is still debated. The present study addresses this issue using H2(15)O positron emission tomography (PET). We contrasted three conditions in which healthy human subjects were required to perform saccadic eye movements toward peripheral visual targets. Two conditions involved a modification of the target location during the course of the initial saccade, when there is suppression of visual perception. In the RAND condition, intra-saccadic target displacement was random from trial-to-trial, precluding any systematic modification of the primary saccade amplitude. In the ADAPT condition, intra-saccadic target displacement was uniform, causing adaptive modification of the primary saccade amplitude. In the third condition (stationary, STAT), the target remained at the same location during the entire trial. Difference images reflecting regional cerebral-blood-flow changes attributable to the process of saccadic adaptation (ADAPT minus RAND; ADAPT minus STAT) showed a selective activation in the oculomotor cerebellar vermis (OCV; lobules VI and VII). This finding is consistent with neurophysiological studies in monkeys. Additional analyses indicated that the cerebellar activation was not related to kinematic factors, and that the absence of significant activation within the frontal eye fields (FEF) or the superior colliculus (SC) did not represent a false negative inference. Besides the contribution of the OCV to saccadic adaptation, we also observed, in the RAND condition, that the saccade amplitude was significantly larger when the previous trial involved a forward jump than when the previous trial involved a backward jump. This observation indicates that saccade accuracy is constantly monitored on a trial-to-trial basis. Behavioral measurements and PET observations (RAND minus STAT) suggest that this single-trial control of saccade amplitude may be functionally distinct from the process of saccadic adaptation.