Σάββατο, 16 Φεβρουαρίου 2019

Thyroid hormone receptor function in maturing ovine cardiomyocytes

Key points

Plasma thyroid hormone (T3) concentrations rise near the end of gestation and are known to inhibit proliferation and stimulate maturation of cardiomyocytes before birth. Thyroid hormone receptors are required for thyroid hormone action in fetal cardiomyocytes. Loss of TRα1 abolishes T3 signalling through ERK and AKT in fetal cardiomyocytes. The expression of thyroid receptors alpha 1 (TRα1) and beta 1 (TRβ1) in ovine fetal myocardium increases with age, though TRα1 levels always remain higher than those of TRβ1. Near term fetal cardiac myocytes are more sensitive than younger myocytes to thyroid receptor blockade by antagonist, NH3, and to effects of TRα1/α2 siRNA. While T3 is known to abrogate ovine cardiomyocyte proliferation stimulated by IGF‐1, this effect is mediated through genomic action of thyroid hormone receptors, with little evidence for non‐genomic mechanisms.

Abstract

We have previously shown that the late‐term rise in tri‐iodo‐L‐thyronine, (T3) in fetal sheep, leads to inhibition of proliferation and promotion of maturation in cardiomyocytes. This study was designed to determine whether these T3‐induced changes are mediated through thyroid receptors (TR) or by non‐genomic mechanisms. Fetal cardiomyocytes were isolated from 102 ± 3 and 135 ± 1 days gestational age (dGA) sheep (n = 7/age; term ∼145dGA). Cells were treated with T3 (1.5 nm), IGF‐1 (1μg/ml) or a combination in the presence of TR antagonist NH3 (100 nm) or following siRNA knockdown of TRα1/α2. Proliferation was quantified by BrdU uptake (10μM). Western blots measured protein levels of ERK, AKT, TRα1/β1, and p21. Age specific levels of TRα1/β1 were measured in normal hearts from fetuses (95dGA (n = 8), 135dGA (n = 7)), neonates (n = 8), and adult ewes (n = 7). TRα1 protein levels were consistently > 50% more than TRβ1 at each gestational age (p < 0.05). T3 reduced IGF‐1 stimulated proliferation by ∼50% in 100dGA and by ∼75% in 135dGA cardiomyocytes (p < 0.05). NH3 blocked the T3+IGF‐1 reduction of BrdU uptake without altering the phosphorylation of ERK or AKT at both ages. NH3 did not suppress T3‐induced p21 expression in 100dGA cardiomyocytes though in 135dGA cardiomyocytes, NH3 alone reduced BrdU uptake (−28%, p < 0.05) as well as T3‐induced p21 (−75%, p < 0.05). In both ages, siRNA knockdown of TRα1/α2 blocked the T3+IGF‐1 reduction of BrdU uptake and dramatically reduced ERK and AKT signalling in 135dGA cardiomyocytes. In conclusion, TRs are required for normal proliferation and T3 signalling in fetal ovine cardiomyocytes, and the sensitivity to TR blockade is age‐dependent.

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PKA phosphorylation underlies functional recruitment of sarcolemmal SK2 channels in ventricular myocytes from hypertrophic hearts

Key points summary

Small‐conductance Ca2+‐activated K+ (SK) channels expressed in ventricular myocytes are dormant in health yet become functional in cardiac disease. SK channels are voltage independent and their gating is controlled by intracellular [Ca2+] in a biphasic manner. Submicromolar [Ca2+] activates the channel via constitutively‐bound calmodulin, while higher [Ca2+] exerts inhibitory effect during depolarization. Using a rat model of cardiac hypertrophy induced by thoracic aortic banding, we found that functional upregulation of SK2 channels in hypertrophic rat ventricular cardiomyocytes is driven by PKA phosphorylation. Using site‐directed mutagenesis, we identified Serine‐465 as the site to confer PKA‐dependent effects on SK2 channel function. PKA phosphorylation attenuates ISK rectification by reducing the Ca2+/voltage‐dependent inhibition of SK channels without changing their sensitivity to activating submicromolar [Ca2+]i. This mechanism underlies the functional recruitment of SK channels not only in cardiac disease but also in normal physiology, contributing to repolarization under conditions of enhanced adrenergic drive.

Abstract

Small‐conductance Ca2+‐activated K+ (SK) channels expressed in ventricular myocytes (VMs) are dormant in health yet become functional in cardiac disease. We sought to test the hypothesis that posttranslational modifications of SK channels in conditions accompanied by enhanced adrenergic drive play a central role in disease‐related activation of the channels. We investigated this phenomenon using a rat model of hypertrophy induced by thoracic aortic banding (TAB). Western blot analysis using anti‐pan‐Serine/Threonine antibodies demonstrated enhanced phosphorylation of immunoprecipitated SK2 channels in VMs from TAB rats vs. Shams, which was reversible by incubation of the VMs with PKA inhibitor H89 (1 μmol/L). Patch‐clamped VMs under basal conditions from TABs but not Shams exhibited outward current sensitive to the specific SK inhibitor Apamin (100 nmol/L) which was eliminated by inhibition of PKA (PKI, 1 μmol/L). Beta‐adrenergic stimulation (isoproterenol, 100 nmol/L) evoked ISK in VMs from Shams, resulting in shortening of action potentials in VMs and ex vivo optically mapped Sham hearts. Using adenoviral gene transfer, WT and mutant SK2 channels were overexpressed in adult rat VMs, revealing Serine‐465 as the site that elicits PKA‐dependent phosphorylation effects on SK2 channel function. Concurrent confocal Ca2+ imaging experiments established that PKA phosphorylation lessens rectification of ISK via reduction Ca2+/voltage‐dependent inhibition of the channels at high [Ca2+] without affecting their sensitivity to activation by Ca2+ in submicromolar range. In conclusion, upregulation of SK channels in diseased VMs is mediated by hyperadrenergic drive in cardiac hypertrophy, with functional effects on the channel conferred by PKA‐dependent phosphorylation at Serine‐465.

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CaMKII Does not Control Mitochondrial Ca2+ Uptake in Cardiac Myocytes

Key points

Mitochondrial Ca2+ uptake stimulates the Krebs cycle to regenerate the reduced forms of pyridine nucleotides (NADH, NADPH and FADH2) required for ATP production and ROS elimination. It was previously proposed that Ca2+/calmodulin‐dependent protein kinase II (CaMKII) regulates mitochondrial Ca2+ uptake via MCU phosphorylation. We used two mouse models with either global deletion of CaMKIIδ (CaMKIIδ KO) or cardiomyocyte‐specific deletion of CaMKIIδ and γ (CaMKIIδ/γ DKO) to interrogate whether CaMKII controls mitochondrial Ca2+ uptake in isolated mitochondria and during β‐adrenergic stimulation in cardiac myocytes. CaMKIIδ/γ controlled neither Ca2+ uptake, respiration nor ROS emission in isolated cardiac mitochondria nor in isolated cardiac myocytes during β‐adrenergic stimulation and pacing. Our results argue against a relevant role of CaMKII for mitochondrial Ca2+ uptake in cardiac myocytes under physiological conditions.

Abstract

Mitochondria are the main source of ATP and reactive oxygen species (ROS) in cardiac myocytes. Furthermore, activation of the mitochondrial permeability transition pore (mPTP) induces programmed cell death. These processes are essentially controlled by Ca2+, which is taken up into mitochondria via the Ca2+ uniporter (MCU). It was recently proposed that Ca2+/calmodulin‐dependent protein kinase II (CaMKII) regulates Ca2+ uptake by interacting with the MCU, thereby affecting mPTP activation and programmed cell death. Here, we addressed the role of CaMKII under physiological conditions in which mitochondrial Ca2+ uptake matches energy supply to demand of cardiac myocytes. To this end, we measured mitochondrial Ca2+ uptake in isolated mitochondria and cardiac myocytes harvested from cardiomyocyte‐specific CaMKII δ and γ double KO (CaMKIIδ/γ DKO) and global CaMKIIδ KO mice. To simulate a physiological workload increase, cardiac myocytes were subjected to β‐adrenergic stimulation (by isoproterenol superfusion) and increase in stimulation frequency (from 0.5 to 5 Hz). No differences in mitochondrial Ca2+ accumulation were detected in isolated mitochondria or cardiac myocytes from both CaMKII KO models compared with wild‐type (WT) littermates. Mitochondrial redox state and ROS production were unchanged in CaMKIIδ/γ DKO, whereas we observed a mild oxidation of mitochondrial redox state and an increase in H2O2 emission from CaMKIIδ KO cardiac myocytes exposed to an increase in workload. In conclusion, our results argue against a relevant regulation of mitochondrial Ca2+ uptake via the MCU or mPTP activation by CaMKII in cardiac myocytes under physiological conditions.

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Validity and reliability of lower‐limb pulse‐wave velocity assessments using an oscillometric technique

NEW FINDINGS

What is the central question of this study? There is growing interest on the effects of sedentarism on central and peripheral cardiovascular health. To permit further investigation, including in larger epidemiological studies, there is a need to identify arterial health assessment tools that are valid (accurate) and reliable (precise), yet practical. What is the main finding and its importance? Lower‐limb vascular health (femoral‐ankle pulse‐wave velocity) can be determined in a supine position with accuracy and precision using an oscillometric‐based device. This technology may help further the understanding of the pathological mechanisms linking cardiovascular disease to sedentarism, including the interaction between peripheral and central vasculature.

ABSTRACT

Background

There is a growing interest in the deleterious effects of sedentary behaviour on lower‐limb arterial health. To permit further investigation, including in larger epidemiological studies, there is a need to identify lower‐limb arterial health assessment tools that are valid and reliable, yet simple to administer.

Purpose

This study sought to determine the validity and between‐day reliability of femoral‐ankle pulse‐wave velocity (faPWV) measures obtained using an oscillometric‐based device (SphygmocCor XCEL) in supine and seated positions. Doppler ultrasound (US) was used as the criterion.

Methods

A total of 47 healthy adults were recruited for validity (n = 32) and reliability (n = 15) analyses. Validity was determined by measuring faPWV in seated and supine positions using the XCEL and US devices, in a randomised order. Between‐day reliability was determined by measuring seated and supine faPWV using the XCEL on 3 different mornings, separated by a maximum of 7 days.

Results

The validity criteria (absolute standard error of estimate [aSEE] < 1.0 m s−1) was met in the supine (aSEE = 0.8 m s−1, 95% CI: 0.4‐1.0), but not the seated (aSEE = 1.2 m s−1, 95% CI: 1.1, 1.2) position. Intras‐class correlation coefficient estimates revealed the XCEL demonstrated good reliability in the supine position (ICC = 0.83, 95% CI: 0.65, 0.93), but poor reliability in the seated position (ICC = 0.29, 95% CI: 0.23, 0.63).

Conclusions

The oscillometric XCEL device can be used to determine lower‐limb PWV with acceptable validity and reliability in the conventionally recommended supine position, but not the seated position.

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Cover Image

Journal of Oral Rehabilitation Cover Image

The cover image, by Min Yu and Xuemei Gao, is based on the Original Article Tongue pressure distribution of individual normal occlusions and exploration of related factors DOI: 10.1111/joor.12741.




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Issue Information



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Cataractogenic load – a concept to study the contribution of ionizing radiation to accelerated aging in the eye lens

Publication date: Available online 15 February 2019

Source: Mutation Research/Reviews in Mutation Research

Author(s): Alice Uwineza, Alexia A. Kalligeraki, Nobuyuki Hamada, Miguel Jarrin, Roy A. Quinlan

Abstract

Ionizing radiation (IR) damages DNA and other macromolecules, including proteins and lipids. Most cell types can repair DNA damage and cycle continuously their macromolecules as a mechanism to remove defective proteins and lipids. In those cells that lack nuclei and other organelles, such as lens fiber cells and mammalian erythrocytes, IR-induced damage to macromolecules is retained because they cannot be easily replenished. Whilst the life span for an erythrocyte is several months, the life span of a human lens is decades. There is very limited turnover in lens macromolecules, therefore the aging process greatly impacts lens structure and function over its lifetime. The lens is a tissue where biomolecular longevity, lifelong retention of its components and continued growth are integral to its homeostasis. These characteristics make the lens an excellent model to study the contribution of retained macromolecular damage over time. Epidemiological data have revealed a significant association between exposure to IR, the loss of lens optical function and the formation of cataracts (cataractogenesis) later in life. Lifestyle, genetic and environmental factors all contribute to cataractogenesis due to their effect on the aging process. Cataract is an iconic age-related disease in humans. IR is a recognised cause of cataract and the occupational lens dose limit is reduced from 150 to 20 mGy / year averaged over 5 years (ICRP Publication 118). Understanding the effects of low dose IR on the lens and its role in cataractogenesis is therefore very important. So we redefine "cataractogenic load" as a term to account for the combined lifestyle, genetic and environmental processes that increase biomolecular damage to lens macromolecules. These processes weaken metabolic defenses, increase post-translational protein modifications, and alter the lipid structure and content of the lens. IR exposure is a significant insult to the lens because of free radical generation and the ensuing oxidative stress. We support the concept that damage caused by IR compounds the aging process by increasing the cataractogenic load, hereby accelerating lens aging and its loss of function.



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A through year behavior of 137Cs in a Japanese flowering cherry tree in relation to that of potassium

Publication date: June 2019

Source: Journal of Environmental Radioactivity, Volume 202

Author(s): Toshihiro Yoshihara, Vasyl Yoschenko, Kenji Watanabe, Koji Keitoku

Abstract

To understand the transfer of radiocesium (137Cs) in inside of deciduous trees, changes in 137Cs activity concentrations, primarily derived from the Fukushima accident in March 2011, were observed in the upper parts of a Japanese flowering cherry tree (Prunus x yedoensis cv. Somei-Yoshino) between 2015 and 2018. The sampling of the foliar parts occurred over the entire leaf life span from winter bud to litterfall and those of the branches were distinguished based on emergence years (2017, 2016, 2015, 2014–2011, and 2010/before). First, every tissue demonstrated a clear seasonal variation in 137Cs activity concentration. Second, a synchrony of seasonal variations in 137Cs activity concentration with those in the biological analogue of K concentration was observed in foliar parts during their growth season, but not in branches nor during the other seasons. With respect to the timing of changes in each tissue with tree phenology, it is possible that K and 137Cs alternate between leaves and branches via the same translocation mechanisms. The resorption efficiencies (i.e., 1 − [the concentrations in the last litterfall]/[the maximum concentrations in green leaves]) of K and 137Cs were 76% and 46% in average, respectively. In addition, both leaf buds and branches played an important role as reservoirs during dormancy. The buds storage ratio before and after bud burst (i.e., [the inventories in buds at the end of defoliation]/[those before and after bud burst]) for K were 0.57 and 0.10 in median, respectively, and those for and 137Cs were 1.14 and 0.14 in median, respectively. Consequently, the transfer of 137Cs in inside of trees was still visible seven years after deposition, even though the annual reduction in 137Cs activity concentration was apparent in each tissue.



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Evaluation of body size and temperature on 137Cs uptake in marine animals

Publication date: June 2019

Source: Journal of Environmental Radioactivity, Volume 202

Author(s): Derin M. Thomas, Nicholas S. Fisher

Abstract

137Cs bioaccumulation and retention in seven different marine animal species, including crustaceans, mollusc larvae, and fish larvae were compared under different temperature conditions (10 °C, 18 °C and 25 °C). Replicate animals were experimentally exposed to 0.5 nM 137Cs dissolved in filtered seawater for 3 days, and their 137Cs contents were periodically measured using gamma spectrometry. Among the seven species, 137Cs bioconcentration factors ranged from 14 to 239 at the end of the exposure periods. Following uptake, the137Cs loss rate constants from the animals ranged from 5 to 50% d−1 and were unaffected by temperature or animal size. The 137Cs bioconcentration factors were directly related to animal size and hence their surface: volume ratios, consistent with the conclusion that Cs sorption from the aqueous phase is the principal uptake mechanism in these animals. With the exception of gastropods, temperature had no major influence on Cs uptake and efflux in the experimental species.



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Effect of ionizing radiation on physiological and molecular processes in plants

Publication date: June 2019

Source: Journal of Environmental Radioactivity, Volume 202

Author(s): Sergey V. Gudkov, Marina A. Grinberg, Vladimir Sukhov, Vladimir Vodeneev

Abstract

The study of effects of ionizing radiation (IR) on plants is important in relation to several problems: (I) the existence of zones where background radiation – either natural or technogenic – is increased; (II) the problems of space biology; (III) the use of IR in agricultural selection; (IV) general biological problems related to the fundamental patterns and specifics of the effects of IR on various living organisms. By now, researchers have accumulated and systematized a large body of data on the effects of IR on the growth and reproduction of plants, as well as on the changes induced by IR at the genetic level. At the same time, there is a large gap in understanding the mechanisms of IR influence on the biochemical and physiological processes – despite the fact that these processes form the basis determining the manifestation of IR effects at the level of the whole organism. On the one hand, the activity of physiological processes determines the growth of plants; on the other, it is determined by changes at the genetic level. Thus, it is the study of IR effects at the physiological and biochemical levels that can give the most detailed and complex picture of IR action in plants.

The review focuses on the effects of radiation on the essential physiological processes, including photosynthesis, respiration, long-distance transport, the functioning of the hormonal system, and various biosynthetic processes. On the basis of a large body of experimental data, we analyze dose and time dependences of the IR-induced effects – which are qualitatively similar – on various physiological and biochemical processes. We also consider the sequence of stages in the development of those effects and discuss their mechanisms, as well as the cause-effect relationships between them. The primary IR-induced physicochemical reactions include the formation of various forms of reactive oxygen species (ROS) and are the cause of the observed changes in the functional activity of plants. The review emphasizes the role of hydrogen peroxide, a long-lived ROS, not only as a damaging agent, but also as a mediator – a universal intracellular messenger, which provides for the mechanism of long-distance signaling. A supposition is made that IR affects physiological processes mainly by violating the regulation of their activity. The violation seems to become possible due to the fact that there exists a crosstalk between different signaling systems of plants, such as ROS, calcium, hormonal and electrical systems. As a result of both acute and chronic irradiation, an increase in the level of ROS can influence the activity of a wide range of physiological processes – by regulating them both at the genetic and physiological levels. To understand the ways, by which IR affects plant growth and development, one needs detailed knowledge about the mechanisms of the processes that occur at the (i) genetic and (ii) physiological levels, as well as their interplay and (iii) knowledge about regulation of these processes at different levels.



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Fit-for-purpose modelling of radiocaesium soil-to-plant transfer for nuclear emergencies: a review

Publication date: May 2019

Source: Journal of Environmental Radioactivity, Volume 201

Author(s): Talal Almahayni, Nicholas A. Beresford, Neil M.J. Crout, Lieve Sweeck

Abstract

Numerous radioecological models have been developed to predict radionuclides transfer from contaminated soils to the food chain, which is an essential step in preparing and responding to nuclear emergencies. However, the lessons learned from applying these models to predict radiocaesium (RCs) soil-to-plant transfer following the Fukushima accident in 2011 renewed interest in RCs transfer modelling. To help guide and prioritise further research in relation to modelling RCs transfer in terrestrial environments, we reviewed existing models focussing on transfer to food crops and animal fodders.

To facilitate the review process, we categorised existing RCs soil-to-plant transfer models into empirical, semi-mechanistic and mechanistic, though several models cross the boundaries between these categories. The empirical approach predicts RCs transfer to plants based on total RCs concentration in soil and an empirical transfer factor. The semi-mechanistic approach takes into account the influence of soil characteristics such as clay and exchangeable potassium content on RCs transfer. It also uses ʻbioavailableʼ rather than total RCs in soil. The mechanistic approach considers the physical and chemical processes that control RCs distribution and uptake in soil-plant systems including transport in the root zone and root absorption kinetics.

Each of these modelling approaches has its advantages and disadvantages. The empirical approach is simple and requires two inputs, but it is often associated with considerably uncertainty due to the large variability in the transfer factor. The semi-mechanistic approach factorises more soil and plant parameters than the empirical approach; therefore, it is applicable to a wider range of environmental conditions. The mechanistic approach is instrumental in understanding RCs mobility and transfer in soil-plant systems; it also helps to identify influential soil and plant parameters. However, the comlexity and the large amount of specific parameters make this approach impractical for nuclear emergency preparedness and response purposes.

We propose that the semi-mechanistic approach is sufficiently robust and practical, hence more fit for the purpose of planning and responding to nuclear emergencies compared with the empirical and mechanistic approaches. We recommend further work to extend the applicability of the semi-mechanistic approach to a wide range of plants and soils.



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Cognitive Behavioral Therapy for Acute Post-trauma Distress: A Randomized, Controlled, Proof-of-Concept Study among Hospitalized Adults with Burns

Publication date: Available online 15 February 2019

Source: Archives of Physical Medicine and Rehabilitation

Author(s): James A. Fauerbach, Amanda K. Gehrke, Shawn T. Mason, Neda F. Gould, Stephen M. Milner, Julie Caffrey

Abstract
Objective

(1) To evaluate the feasibility of conducting a randomized controlled trial (RCT) of the Safety, Meaning, Activation and Resilience Training (SMART) intervention versus Non-Directive Supportive Psychotherapy (NDSP) in an acutely hospitalized adult burn survivor sample; (2) To assess the preliminary impact of SMART on Acute Stress Disorder (ASD)/Posttraumatic Stress Disorder (PTSD) and Major Depress Disorder (MDD) symptom reduction as secondary prevention.

Design

Proof-of-concept, parallel group, RCT design.

Setting

Regional burn center.

Participants

Acutely injured, hospitalized adult burn survivors.

Interventions

SMART is a manualized, 4-session cognitive behavioral therapy-based psychological intervention targeting ASD/PTSD and MDD symptoms. NDSP is a manualized, 4-session protocol.

Main Outcome Measures

Davidson Trauma Scale (DTS; diagnostic proxy for ASD/PTSD; clinical cutoff = 40-higher score = higher severity) and the Patient Health Questionnaire-9 (PHQ-9; diagnostic proxy for MDD; clinical cutoff = 10-higher score = higher severity) at pre-treatment, immediate post-treatment, and 1-month post-treatment.

Results

Burn survivors (n= 50) were randomly assigned to SMART (n = 28) or NDSP (n = 22). Due to drop out and missing data, final sample size was 40, SMART (n = 21) and NDSP (n = 19). At baseline, median DTS scores and PHQ-9 scores were above clinical cutoffs and did not differ across groups. At 1-week and 1-month post-treatment, median DTS and PHQ-9 scores were beneath clinical cutoffs in the SMART group; scores remained above clinical cutoffs in the NDSP group at these time points.

Conclusions

It is feasible to conduct an RCT of SMART in hospitalized adult burn survivors. SMART has the potential to yield clinically significant outcomes. Additional studies are needed to replicate and extend these findings.



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Adaptive Sports Medicine: A Clinical Guide

No abstract available

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Impaired Thermoregulatory Function during Dynamic Exercise in Multiple Sclerosis

imageIntroduction Impairments in sudomotor function during passive whole-body heating have been reported in multiple sclerosis (MS), a demyelinating disease of the CNS that disrupts autonomic function. However, the capability of the thermoregulatory system to control body temperature during exercise has never been assessed in MS. Thus, the aim of the present study was to test the hypothesis that thermoregulatory function is impaired in MS patients compared with healthy controls (CON) exercising at similar rates of metabolic heat production. Methods Sweating and skin blood flow responses were compared between 12 individuals diagnosed with relapsing-remitting MS (9 females, 3 males) and 12 sex-, age-, mass-, and BSA-matched CON during a single bout of cycling exercise (rate of metabolic heat production: ∼4.5 W·kg−1) for 60 min in a climate-controlled room (25°C, 30% RH). Results Individuals with MS exhibited an attenuated increase in cumulative whole-body sweat loss after 30 min (MS, 72 ± 51 g; CON, 104 ± 37 g; P = 0.04) and 60 min (MS, 209 ± 94 g; CON, 285 ± 62 g; P = 0.02), as well as lower sweating thermosensitivity (MS, 0.49 ± 0.26 mg·cm−2·min−1·°C−1; CON, 0.86 ± 0.30 mg·cm−2·min−1·°C−1; P = 0.049). Despite evidence for thermoregulatory dysfunction, there were no differences between MS and CON in esophageal or rectal temperatures at 30- or 60-min time points (P > 0.05). Cutaneous vasculature responses were also not different in MS compared with CON (P > 0.05). Conclusion Taken together, MS blunts sweating responses during exercise while cutaneous vasculature responses are preserved. Altered mechanisms of body temperature regulation in persons with MS may lead to temporary worsening of disease symptoms and limit exercise tolerance under more thermally challenging conditions.

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Effect of Ice Slurry Ingestion on Cardiovascular Drift and V˙O2max during Heat Stress

imageExternal body cooling by fan airflow mitigates the decrease in maximal oxygen uptake (V˙O2max) associated with cardiovascular (CV) drift during cycling in hot conditions. It remains unknown whether internal body cooling via ice slurry ingestion elicits a similar response. Purpose This study aimed to test the hypothesis that ice slurry ingestion attenuates the magnitude of CV drift and accompanying decrement in V˙O2max during heat stress. Methods Eight men completed a graded exercise test on a cycle ergometer in 22°C to measure V˙O2max. Then on three separate occasions (in randomly assigned counterbalanced treatment orders), they cycled at 60% V˙O2max in hot conditions (35°C, 40% RH) for 15 min, 45 min with tepid (23°C) fluid ingestion (45FL), or 45 min with ice (−1°C) slurry ingestion (45ICE), followed immediately by measurement of V˙O2max. The purpose of the separate 15- and 45-min trials was to measure CV drift and V˙O2max over the same time interval. Results The increase in heart rate between 15 and 45 min was twice as large in 45FL (8.6%) compared with 45ICE (4.6%; P = 0.02). Stroke volume declined by 6.2% in 45FL but was maintained with 45ICE (P = 0.02). V˙O2peak decreased from 15 to 45 min by 8.6% and 9.0% in 45FL and 45ICE, respectively, but was not different between conditions (P = 0.79). Conclusion Although ice slurry ingestion attenuated CV drift more than fluid ingestion, it did not mitigate the decline in V˙O2max. Contrary to previous findings, when ice slurry is ingested, changes in heart rate may not reflect changes in relative metabolic intensity during prolonged exercise in the heat.

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Exercise-induced Changes in Soluble ST2 Concentrations in Marathon Runners

imagePurpose Previous studies have suggested that extreme endurance exercise may induce cardiac microdamage that could lead to subsequent myocardial fibrosis. Soluble suppression of tumorigenicity 2 (sST2) is a cardiac biomarker for assessment of myocardial fibrosis, inflammation, and strain. We evaluated baseline and exercise-induced sST2 concentrations in a heterogeneous cohort of marathon runners to identify predictors for sST2 concentrations. Methods Ninety-two runners supplied demographic data, health status, physical activity levels, and marathon experience. Before (baseline) and immediately after (finish) the marathon, blood was collected for analysis of sST2 and cardiac troponin I (cTnI). Results Eighty-two participants (45 ± 8 yr, 79% male) finished the race in 227 ± 28 min at 92% (88%–94%) of their predicted maximum heart rate (exercise intensity). sST2 concentrations increased in all runners, from 34 (25–46) ng·mL−1 to 70 (53–87) ng·mL−1 (P

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Chronic Adherence to a Ketogenic Diet Modifies Iron Metabolism in Elite Athletes

imagePurpose The short-term restriction of carbohydrate (CHO) can potentially influence iron regulation via modification of postexercise interleukin-6 (IL-6) and hepcidin levels. This study examined the effect of a chronic ketogenic low-CHO high-fat (LCHF) diet on iron status and iron-regulatory markers in elite athletes. Methods International-level race walkers (n = 50) were allocated to one of three dietary interventions: (i) a high-CHO diet (n = 16), (ii) a periodized CHO availability (n = 17), or (iii) an LCHF diet (n = 17) while completing a periodized training program for 3 wk. A 19- to 25-km race walking test protocol was completed at baseline and after adaptation, and changes in serum ferritin, IL-6, and hepcidin concentrations were measured. Results from high-CHO and periodized CHO were combined into one group (CHO; n = 33) for analysis. Results The decrease in serum ferritin across the intervention period was substantially greater in the CHO group (37%) compared with the LCHF (23%) group (P = 0.021). After dietary intervention, the postexercise increase in IL-6 was greater in LCHF (13.6-fold increase; 95% confidence interval [CI] = 7.1–21.4) than athletes adhering to a CHO-rich diet (7.6-fold increase; 95% CI = 5.5–10.2; P = 0.033). Although no significant differences occurred between diets, CI values indicate that 3 h postexercise hepcidin concentrations were lower after dietary intervention compared with baseline in CHO (β = −4.3; 95% CI = −6.6 to −2.0), with no differences evident in LCHF. Conclusion Athletes who adhered to a CHO-rich diet experienced favorable changes to the postexercise IL-6 and hepcidin response, relative to the LCHF group. Lower serum ferritin after 3 wk of additional dietary CHO might reflect a larger more adaptive hematological response to training.

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Regional Vastus Medialis and Vastus Lateralis Activation in Females with Patellofemoral Pain

imageIntroduction This study aimed to investigate whether regional activation patterns in the vasti muscles differ between females with and without patellofemoral pain (PFP), and whether muscle activation patterns correlate with knee extension strength. Methods Thirty-six females with PFP and 20 pain-free controls performed a standardized knee flexion–extension task. The activation of vastus medialis (VM) and vastus lateralis (VL) was collected using high-density surface EMG and analyzed using principal component (PC) analysis. Spatial locations and temporal coefficients of the PC, and the percent variance they explain, were compared between groups and between the concentric and the eccentric phases of the movement. Correlations were assessed between PC features and knee extension strength. Results The spatial weights of PC1 (general vasti activation) and PC2 (reflecting vastus-specific activation) were similar between groups (R > 0.95). Activation patterns in PFP were less complex than controls. Fewer PC features were necessary to reconstruct 90% of the signal for PFP participants in the concentric phase (P

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Editorial Note to Batterham and Hopkins Letter and Sainani Response

No abstract available

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Caffeine Augments the Prothrombotic but Not the Fibrinolytic Response to Exercise

imageCaffeine, a popular ergogenic supplement, induces neural and vascular changes that may influence coagulation and/or fibrinolysis at rest and during exercise. Purpose The purpose of this study was to assess the effect of a single dose of caffeine on measures of coagulation and fibrinolysis before and after a single bout of high-intensity exercise. Methods Forty-eight men (age, 23 ± 3 yr; body mass index, 24 ± 3 kg·m−2) completed two trials, with 6 mg·kg−1 of caffeine (CAFF) or placebo (PLAC), in random order, followed by a maximal cycle ergometer test. Plasma concentrations of fibrinogen, factor VIII antigen, active tissue plasminogen activator (tPA:c), tissue plasminogen activator antigen (tPA:g), and active plasminogen activator inhibitor-1 (PAI-1:c) were assessed at baseline and immediately after exercise. Results Exercise led to significant changes in tPA:c (Δ 8.5 ± 4.36 IU·mL−1 for CAFF, 6.6 ± 3.7 for PLAC), tPA:g (Δ 2.4 ± 3.2 ng·mL−1 for CAFF, 1.9 ± 3.1 for PLAC), fibrinogen (Δ 30.6 ± 61.4 mg·dL−1 for CAFF, 28.1 ± 66.4 for PLAC), and PAI-1:c (Δ −3.4 ± 7.9 IU·mL−1 for CAFF, −4.0 ± 12.0 for PLAC) (all P

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Effects of Joint Kinetics on Energy Cost during Repeated Vertical Jumping

imagePurpose The present study was designed to investigate the effects of lower limb joint kinetics on energy cost during jumping. Methods Eight male middle and long-distance runners volunteered for the study. The subjects were asked to repeat vertical jumps at a frequency of 2 Hz for 3 min on a force platform in three different surface inclination conditions: Incline (+8°), Level (0°), and Decline (−8°). Sagittal plane kinematics were obtained using a high-speed video camera. Simultaneously, ground reaction forces and EMG of the lower limb muscles were recorded. Energy cost was calculated using steady-state oxygen uptake, respiratory ratio, and vertical distance of the body. Results In all conditions, energy cost correlated positively with total mechanical work of the knee joint (r = 0.636, P

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Exercise Training Increases Metaboreflex Control in Patients with Obstructive Sleep Apnea

imageIntroduction/Purpose We demonstrated that patients with obstructive sleep apnea (OSA) have reduced muscle metaboreflex control of muscle sympathetic nerve activity (MSNA). In addition, exercise training increased muscle metaboreflex control in heart failure patients. Objective We tested the hypothesis that exercise training would increase muscle metaboreflex control of MSNA in patients with OSA. Methods Forty-one patients with OSA were randomized into the following two groups: 1) nontrained (OSANT, n = 21) and 2) trained (OSAT, n = 20). Muscle sympathetic nerve activity was assessed by microneurography technique, muscle blood flow (FBF) by venous occlusion plethysmography, heart rate by electrocardiography, and blood pressure with an automated oscillometric device. All physiological variables were simultaneously assessed at rest, during isometric handgrip exercise at 30% of the maximal voluntary contraction, and during posthandgrip muscle ischemia (PHMI). Muscle metaboreflex sensitivity was calculated as the difference in MSNA between PHMI and the rest period. Patients in the OSAT group underwent 72 sessions of moderate exercise training, whereas patients in the OSANT group were clinical follow-up for 6 months. Results The OSANT and OSAT groups were similar in anthropometric, neurovascular, hemodynamic and sleep parameters. Exercise training reduced the baseline MSNA (34 ± 2 bursts per minute vs 25 ± 2 bursts per minute; P

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Energy Expenditure during Extreme Endurance Exercise: The Giro d’Italia

imagePurpose Little data are available on doubly labeled water (DLW) assessed total daily energy expenditure (TDEE) during extreme endurance exercise. Doubly labeled water is considered the gold standard to measure TDEE, but different calculations are being used, which may have a large impact on the results. The aim of the current study was to measure TDEE during the Giro d'Italia and apply two different calculation methods. Methods Seven male cyclists (age, 28 ± 5 yr; body mass index, 22.1 ± 2.1 kg·m−2) completed the 24-d professional cycling race "Giro d'Italia" in which a total distance of 3445 km was covered, including 10 mountain stages. Total daily energy expenditure was measured over the entire duration of the race, with the ingestion of DLW at three different time points. To calculate TDEE and body composition, the isotope dilution space was calculated using two different techniques, the "plateau" and "intercept" technique. Results The %fat mass at baseline was 7.8% and 16.8% with the plateau and intercept technique respectively and did not significantly change over the course of the race. Total daily energy expenditure was on average 32.3 ± 3.4 MJ·d−1 using the plateau technique versus 28.9 ± 3.2 using the intercept technique, resulting in an average physical activity level (PAL) of 4.37 ± 0.43 versus 3.91 ± 0.39, respectively. The dilution space ratio was on average 1.030 with the plateau and 1.060 with the intercept technique. Conclusions Given that the observed dilution space ratio with the plateau technique is similar as the expected ratio from literature and the % fat mass of 7.8% is more realistic for the athletes being studied, we propose the application of the plateau rather than the intercept method, when using DLW during extreme endurance exercise.

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Sucrose but Not Nitrate Ingestion Reduces Strenuous Cycling–induced Intestinal Injury

imagePurpose Strenuous exercise induces intestinal injury, which is likely related to splanchnic hypoperfusion and may be associated with gastrointestinal complaints commonly reported during certain exercise modalities. Increasing circulating nitric oxide (NO) levels or inducing postprandial hyperemia may improve splanchnic perfusion, thereby attenuating intestinal injury during exercise. Therefore, we investigated the effects of both dietary nitrate ingestion and sucrose ingestion on splanchnic perfusion and intestinal injury induced by prolonged strenuous cycling. Methods In a randomized crossover manner, 16 well-trained male athletes (age, 28 ± 7 yr; Wmax, 5.0 ± 0.3 W·kg−1) cycled 60 min at 70% Wmax after acute ingestion of sodium nitrate (NIT; 800 mg NO3), sucrose (SUC; 40 g), or a water placebo (PLA). Splanchnic perfusion was assessed by determining the gap between gastric and arterial pCO2 (gapg-apCO2) using gastric air tonometry. Plasma intestinal fatty acid–binding protein (I-FABP) concentrations, reflecting enterocyte damage, were assessed every 20 min during and up to 60 min of postexercise recovery. Results The exercise protocol resulted in splanchnic hypoperfusion, as gapg-apCO2 levels increased during exercise (P

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The Problems with “The Problem with ‘Magnitude-Based Inference’”

No abstract available

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Adenosine Triphosphate Production of Muscle Mitochondria after Acute Exercise in Lean and Obese Humans

imageIntroduction Current evidence indicates mitochondrial dysfunction in humans with obesity. Acute exercise appears to enhance mitochondrial function in the muscle of nonobese humans, but its effects on mitochondrial function in muscle of humans with obesity are not known. We sought to determine whether acute aerobic exercise stimulates mitochondrial function in subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria in humans with obesity. Methods We assessed maximal adenosine triphosphate production rate (MAPR) and citrate synthase (CS) activity in isolated SS and IMF mitochondria from subjects with body mass index 32 kg·m−2 (median age, 29 yr; interquartile range, 20–39 yr) before and 3 h after a 45-min cycling exercise at an intensity corresponding to 65% HR reserve. The SS and IMF mitochondria were isolated from muscle biopsies using differential centrifugation. Maximal adenosine triphosphate production rate and CS activities were determined using luciferase-based and spectrophotometric enzyme-based assays, respectively. Results Exercise increased MAPR in IMF mitochondria in both nonobese subjects and subjects with obesity (P 0.05). Exercise increased MAPR supported by complex II in SS mitochondria, in both groups (P 0.05). Citrate synthase–specific activity increased in SS mitochondria in response to exercise only in nonobese subjects (P

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Response

No abstract available

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The 24-Hour Activity Cycle: A New Paradigm for Physical Activity

imageThe physiologic mechanisms by which the four activities of sleep, sedentary behavior, light-intensity physical activity, and moderate-to-vigorous physical activity (MVPA) affect health are related, but these relationships have not been well explored in adults. Research studies have commonly evaluated how time spent in one activity affects health. Because one can only increase time in one activity by decreasing time in another, such studies cannot determine the extent that a health benefit is due to one activity versus due to reallocating time among the other activities. For example, interventions to improve sleep possibly also increase time spent in MVPA. If so, the overall effect of such interventions on risk of premature mortality is due to both more MVPA and better sleep. Further, the potential for interaction between activities to affect health outcomes is largely unexplored. For example, is there a threshold of MVPA minutes per day, above which adverse health effects of sedentary behavior are eliminated? This article considers the 24-h Activity Cycle (24-HAC) model as a paradigm for exploring inter-relatedness of health effects of the four activities. It discusses how to measure time spent in each of the four activities, as well as the analytical and statistical challenges in analyzing data based on the model, including the inevitable challenge of confounding among activities. The potential usefulness of this model is described by reviewing selected research findings that aided in the creation of the model and discussing future applications of the 24-HAC model.

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Team Physician, Team Subspecialist: A Potential Scientific Conflict of Interest?

No abstract available

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Longitudinal Associations of Fitness, Motor Competence, and Adiposity with Cognition

imagePurpose The purpose of this study was to investigate the longitudinal associations of cardiorespiratory fitness (CRF), motor competence (MC), and body fat percentage (BF%) with cognition in children. Methods Altogether, 371 children (188 boys and 183 girls) 6–9 yr of age at baseline participated in this 2-yr follow-up study. We assessed CRF by maximal cycle ergometer test, computed the MC score from the z-scores of the 50-m shuttle run, static balance, and box and block test results, measured BF% by dual-energy x-ray absorptiometry, and assessed cognition using the Raven's Coloured Progressive Matrices (RCPM) score. The associations were studied by linear regression analysis and repeated-measures ANCOVA. Results In boys, a higher MC score (β = −0.161, 95% confidence interval [CI] = −0.314 to −0.009), a shorter 50-m shuttle run test duration (β = 0.152, 95% CI = 0.007–0.296), and a higher number of cubes moved in the Box and block test (β = −0.161, 95% CI = −0.309 to −0.013) at baseline were associated with a smaller increase in the RCPM score during follow-up. These associations were largely explained by the RCPM score at baseline. However, boys in the highest third (mean difference = 2.5, 95% CI for difference = 0.66–4.33) and the middle third (mean difference = 2.1, 95% CI for difference = 0.39–3.82) of the MC score at baseline had a higher RCPM score over the 2-yr follow-up than boys in the lowest third. CRF, MC, or adiposity was not associated with the RCPM score in girls. Changes in CRF, MC, or BF% were not associated with changes in cognition. Conclusions Higher MC at baseline predicted better cognition during the first two school years in boys but not in girls. CRF or adiposity was not associated with cognition in boys or girls.

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Professional Dancers Distinct Biomechanical Pattern during Multidirectional Landings

imagePurpose This study aimed to compare lower extremity (LE) biomechanics between professional dancers (PD) and nondancers (ND) during multidirectional single-leg landings. Methods Fifteen PD (27 ± 7 yr, 1.69 ± 0.1 m, 57.8 ± 9.3 kg) and 15 ND (25 ± 5 yr, 1.69 ± 0.1 m, 66 ± 10.2 kg) performed single-leg jumps in three directions: 1) lateral, 2) diagonal, and 3) forward. Dominant LE biomechanical data were collected using a motion capture system. Data were processed in Visual3D. LE kinematic (hip, knee, and ankle joint angles in sagittal and frontal planes, and range of motion [ROM]) and kinetics (hip and knee internal joint moments and vertical ground reaction force) variables were analyzed at initial contact (IC), peak vertical ground reaction force (PvGRF), and peak knee flexion (PKF). Repeated-measures ANOVA was conducted (P

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Walking Pace Is Associated with Lower Risk of All-Cause and Cause-Specific Mortality

imagePurpose Walking pace is associated with all-cause and cardiovascular disease (CVD) mortality. Whether this association extends to other health outcomes and whether it is independent of total amount of time walked are currently unknown. Therefore, the aim of this study was to investigate whether usual walking pace is associated with a range of health outcomes. Methods UK Biobank participants (318,185 [54%] women) age 40 to 69 yr were included. Walking pace and total walking time were self-reported. The outcomes comprised: all-cause mortality as well as incidence and mortality from CVD, respiratory disease and cancer. The associations were investigated using Cox proportional hazard models. Results Over a mean of 5.0 yr [ranging from 3.3 to 7.8], 5890 participants died, 18,568 developed CVD, 5430 respiratory disease and 19,234 cancer. In a fully adjusted model, compared to slow pace walkers, men and women, respectively, with a brisk pace having lower risk of mortality from all-causes (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.69–0.90 and HR, 0.73; 95% CI, 0.62–0.85), CVD (HR, 0.62; 95% CI, 0.50–0.76 and HR, 0.80; 95% CI, 0.73–0.88), respiratory disease (HR, 0.58; 95% CI, 0.43–0.78 and HR, 0.66; 95% CI, 0.57–0.77), chronic obstructive pulmonary disease (HR, 0.26; 95% CI, 0.12–0.56 and HR, 0.28; 95% CI, 0.16–0.49). No associations were found for all-cause cancer, colorectal, and breast cancer. However, brisk walking was associated with a higher risk of prostate cancer. Conclusions Walking pace is associated with lower risk of a wide range of important health conditions, independently of overall time spent walking.

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A quantitative taxonomy of human hand grasps

A proper modeling of human grasping and of hand movements is fundamental for robotics, prosthetics, physiology and rehabilitation. The taxonomies of hand grasps that have been proposed in scientific literature...

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The actin ‘A‐Triad's’ role in contractile regulation in health and disease

Abstract

Striated muscle contraction is regulated by Ca2+‐dependent modulation of myosin cross‐bridge binding to F‐actin by the thin filament troponin (Tn)‐tropomyosin (Tm) complex. In the absence of Ca2+, Tn binds to actin and constrains Tm to an azimuthal location where it sterically occludes myosin binding sites along the thin filament surface. This limits force production and promotes muscle relaxation. In addition to Tn‐actin interactions, inhibitory Tm positioning requires associations between other thin filament constituents. For example, the actin "A‐triad", composed of residues K326, K328, and R147, forms numerous, highly favorable electrostatic contacts with Tm that are critical for establishing its inhibitory azimuthal binding position. Here, we review recent findings, including the identification and interrogation of modifications within and proximal to the A‐triad that are associated with disease and/or altered muscle behaviour, which highlight the surface feature's role in F‐actin‐Tm interactions and contractile regulation.

This article is protected by copyright. All rights reserved



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You are as fast as your motor neurons: Speed of recruitment and maximal discharge of motor neurons determine the maximal rate of force development in humans

Key points

We propose and validate a method to accurately identify the activity of populations of motor neurons during contractions at maximal rate of force development in humans. The behaviour of the motor neuron pool during rapid voluntary contractions in humans is presented. We show with this approach that the motor neuron recruitment speed and maximal motor unit discharge rate largely explains the individual ability in generating rapid force contractions. The results also indicate that the synaptic inputs received by the motor neurons before force is generated dictate human potential to generate force rapidly. This is the first characterization of the discharge behaviour of a representative sample of human motor neurons during rapid contractions.

Abstract

During rapid contractions motor neurons are recruited in a short burst and begin to discharge at high frequencies (up to > 200 Hz). Here we studied the behaviour of relatively large populations of motor neurons during rapid (explosive) contractions in humans applying a new approach to accurately identify motor neuron activity simultaneous to measuring rate of force development. The activity of spinal motor neurons was assessed by high‐density EMG decomposition from the tibialis anterior muscle of 20 men during isometric explosive contractions. The speed of motor neuron recruitment and the instantaneous motor unit discharge rate were analysed as a function of the impulse (the time‐force integral) and the maximal rate of force development. The peak of motor unit discharge rate occurred before force generation and discharge rates decreased thereafter. The maximal motor unit discharge rate was associated to the explosive force variables, at the whole population level (R2 = 0.71 (0.12), P<0.001). Moreover, the peak motor unit discharge and maximal rate of force variables were correlated with an estimate of the supraspinal drive, that was measured as the speed of motor unit recruitment before the generation of afferent feedback (P<0.05). We showed for the first time the full association between the effective neural drive to the muscle and human maximal rate of force development. The results obtained in this study indicate that the variability in the maximal contractile explosive force of the human tibialis anterior muscle is determined by the neural activation preceding force generation.

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Different patterns of movement-related cortical oscillations in patients with myoclonus and in patients with spinocerebellar ataxia

Publication date: Available online 16 February 2019

Source: Clinical Neurophysiology

Author(s): E. Visani, C. Mariotti, L. Nanetti, A. Mongelli, A. Castaldo, F. Panzica, S. Franceschetti, L. Canafoglia

Abstract
Objective

To assess whether different patterns of EEG rhythms during a Go/No-go motor task characterize patients with cortical myoclonus (EPM1) or with spinocerebellar ataxia (SCA).

Methods

We analyzed event-related desynchronization (ERD) and synchronization (ERS) in the alpha and beta-bands during visually cued Go/No-go task in 22 patients (11 with EPM1, 11 with SCA) and 11 controls.

Results

In the Go condition, the only significant difference was a reduced contralateral beta-ERS in the EPM1 patients compared with controls; in the No-go condition, the EPM1 patients showed prolonged alpha-ERD in comparison with both controls and SCA patients, and reduced or delayed alpha- and beta-ERS in comparison with controls. In both conditions, the SCA patients, unlike EPM1 patients and controls, showed minimal or absent lateralization of alpha- and beta-ERD.

Conclusions

EPM1 patients showed abnormal ERD/ERS dynamics, whereas SCA patients mainly showed defective ERD lateralization.

Significance

A different behavior of ERS/ERD distinguished the two patient groups: the pattern observed in EPM1 suggests a prominent defect of inhibition occurring in motor cortex contralateral to activated segment, whereas the pattern observed in SCA suggested a defective lateralization attributable to the damage of cerebello-cortical network, which is instead marginal in patients with cortical myoclonus.



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Neuro-Oncology Diet and risk of glioma

Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool
Abstract
Background
Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985–2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors.
Methods
A multi-institutional retrospective institutional review board–approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively.
Results
The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0–1.0, 1.5–2.0, 2.5–3, and 3.5–4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively.
Conclusion
The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com.


Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients
Abstract
Background
Peptide vaccines offer the opportunity to elicit glioma-specific T cells with tumor killing ability. Using antigens eluted from the surface of glioblastoma samples, we designed a phase I/II study to test safety and immunogenicity of the IMA950 multipeptide vaccine adjuvanted with poly-ICLC in HLA-A2 + glioma patients.
Methods
Adult patients with newly diagnosed glioblastoma (n=16) and grade III astrocytoma (n=3) were treated with radiochemotherapy followed by IMA950/poly-ICLC vaccination. The first 6 patients received IMA950 (9 MHC class I and 2 MHC class II peptides) i.d. and poly-ICLC i.m. After protocol amendment, IMA950 and poly-ICLC were mixed and injected s.c. (n=7) or i.m. (n=6). Primary endpoints were safety and immunogenicity. Secondary endpoints were overall survival, progression-free survival at 6 and 9 months, and vaccine-specific peripheral CD4 and CD8 T cell responses.
Results
The IMA950/poly-ICLC vaccine was safe and well tolerated. Four patients presented cerebral edema with rapid recovery. For the first 6 patients, vaccine-induced CD8 T cell responses were restricted to a single peptide and CD4 responses were absent. After optimization of vaccine formulation, we observed multipeptide CD8 and sustained Th1 CD4 T cell responses. For the entire cohort, CD8 T cell responses to a single or multiple peptides were observed in 63.2% and 36.8% of patients, respectively. Median overall survival was 19 months for glioblastoma patients.
Conclusion
We provide, in a clinical trial, using cell surface-presented antigens, insights into optimization of vaccines generating effector T cells for glioma patients.
Trial registration
Clinicaltrials.gov NCT01920191.


Recent Developments and Future Directions in Adult Lower-Grade Gliomas: Society for Neuro-Oncology (SNO) and European Association of Neuro-Oncology (EANO) Consensus
Abstract
The finding that most grade II and III gliomas harbor isocitrate dehydrogenase (IDH) mutations conveying a relatively favorable and fairly similar prognosis in both tumor grades highlights that these tumors represent a fundamentally different entity from IDH wild-type gliomas exemplified in most glioblastoma. Herein we review the most recent developments in molecular neuropathology leading to reclassification of these tumors based upon IDH and 1p/19q status, as well as the potential roles of methylation profiling and CDKN2A/B deletional analysis. We discuss the epidemiology, clinical manifestations, benefit of surgical resection, and neuroimaging features of lower-grade gliomas as they relate to molecular subtype, including advanced imaging techniques such as 2-hydroxyglutarate magnetic resonance spectroscopy and amino acid PET scanning. Recent, ongoing and planned studies of radiation therapy and both cytotoxic and targeted chemotherapies are summarized, including both small molecule and immunotherapy approaches specifically targeting the mutant IDH protein.


Diet and risk of glioma: combined analysis of three large prospective studies in the UK and USA
Abstract
Background
Available evidence on diet and glioma risk comes mainly from studies with retrospective collection of dietary data. To minimise possible differential dietary recall between those with and without glioma, we present findings from three large prospective studies.
Methods
Participants included 692,176 from (UK) Million Women Study, 470,780 from (US) NIH-AARP Study, and 99,148 from (US) PLCO Study. Cox regression yielded study-specific adjusted relative risks for glioma in relation to 15 food groups, 14 nutrients, and 3 dietary patterns, which were combined, weighted by inverse-variances of the relative risks. Separate analyses by <5 and ≥5 years follow-up assessed potential biases related to changes of diet before glioma diagnosis.
Results
The 1,262,104 participants, mean age 60.6 (SD5.5) at baseline, were followed for 15.4 million person-years (mean 12.2 years/participant), during which 2,313 incident gliomas occurred, at mean age 68.2 (SD6.4). Overall, there was weak evidence for increased glioma risks associated with increasing intakes of total fruit, citrus fruit, and fibre, and healthy dietary patterns, but these associations were generally null after excluding the first 5 years of follow-up. There was little evidence for heterogeneity of results by study or by sex.
Conclusions
The largest prospective evidence to date suggests little, if any, association between major food groups, nutrients, or common healthy dietary patterns, and glioma incidence. With the statistical power of this study and the comprehensive nature of the investigation here, it seems unlikely we have overlooked major effects of diet on risk of glioma that would be of public health concern.




Highlights from the Literature


Forthcoming Meetings
Edited by Albert H. Kim and Jennie W. Taylor

Glioblastoma: a prognostic value of AMT-PET?
See the article by John et al, pp. 264–273.

Old meet new—the path to combination treatments in pediatric low-grade gliomas
See the article by Poore et al, pp. 252–263.

Disparities along the glioblastoma clinical trials landscape
We read with interest the recent work by Vanderbeek et al1 regarding the current clinical trials landscape for glioblastoma (GBM) patients. An unexplored dimension of their analysis centers on disparities and demographic discrepancies between clinical trial participants and the broader GBM population. We therefore examined clinical trials with published results as highlighted by the authors, totaling 51 trials.1 While most of these trials reported details regarding patient age (48/51, 94%) and gender (47/51, 92%), only 14 trials (27%) provided information regarding ethnicity and/or race in either peer-reviewed publications or ClinicalTrials.gov. The rate of reporting ethnicity/race was particularly low among phase I/II studies (9/43, 21%) compared with phase III trials (5/8, 63%, chi-squared test P = 0.02).

Multimodal imaging-defined subregions in newly diagnosed glioblastoma: impact on overall survival
Abstract
Background
Although glioblastomas are heterogeneous brain-infiltrating tumors, their treatment is mostly focused on the contrast-enhancing tumor mass. In this study, we combined conventional MRI, diffusion-weighted imaging (DWI), and amino acid PET to explore imaging-defined glioblastoma subregions and evaluate their potential prognostic value.
Methods
Contrast-enhanced T1, T2/fluid attenuated inversion recovery (FLAIR) MR images, apparent diffusion coefficient (ADC) maps from DWI, and alpha-[11C]-methyl-L-tryptophan (AMT)-PET images were analyzed in 30 patients with newly diagnosed glioblastoma. Five tumor subregions were identified based on a combination of MRI contrast enhancement, T2/FLAIR signal abnormalities, and AMT uptake on PET. ADC and AMT uptake tumor/contralateral normal cortex (T/N) ratios in these tumor subregions were correlated, and their prognostic value was determined.
Results
A total of 115 MRI/PET-defined subregions were analyzed. Most tumors showed not only a high-AMT uptake (T/N ratio > 1.65, N = 27) but also a low-uptake subregion (N = 21) within the contrast-enhancing tumor mass. High AMT uptake extending beyond contrast enhancement was also common (N = 25) and was associated with low ADC (r = −0.40, P = 0.05). Higher AMT uptake in the contrast-enhancing tumor subregions was strongly prognostic for overall survival (hazard ratio: 7.83; 95% CI: 1.98–31.02, P = 0.003), independent of clinical and molecular genetic prognostic variables. Nonresected high-AMT uptake subregions predicted the sites of tumor progression on posttreatment PET performed in 10 patients.
Conclusions
Glioblastomas show heterogeneous amino acid uptake with high-uptake regions often extending into non-enhancing brain with high cellularity; nonresection of these predict the site of posttreatment progression. High tryptophan uptake values in MRI contrast-enhancing tumor subregions are a strong, independent imaging marker for longer overall survival.


Supratotal resection in glioma: a systematic review
Abstract
Background
Emerging evidence suggests survival benefit from resection beyond all MRI abnormalities present on T1-enhanced and T2‒fluid attenuated inversion recovery (FLAIR) modalities in glioma (supratotal resection); however, the quality of evidence is unclear. We addressed this question via systematic review of the literature.
Methods
EMBASE, MEDLINE, Scopus, and Web of Science databases were queried. Case studies, reviews or editorials, non-English, abstract-only, brain metastases, and descriptive works were excluded. All others were included.
Results
Three hundred and nine unique references yielded 41 studies for full-text review, with 7 included in the final analysis. Studies were mostly of Oxford Center for Evidence-Based Medicine Level 4 quality. A total of 88 patients underwent supratotal resection in a combined cohort of 492 patients (214 males and 278 females, age 18 to 82 years). Fifty-one supratotal resections were conducted on high-grade gliomas, and 37 on low-grade gliomas. Karnofsky performance status, overall survival, progression-free survival, neurological deficits postoperatively, and anaplastic transformation were the main measured outcomes. No randomized controlled trials were identified. Preliminary low-quality support was found for supratotal resection in increasing overall survival and progression-free survival for both low-grade and high-grade glioma.
Conclusion
The literature suggests insufficient evidence for carte blanche application of supratotal resection, particularly in lower-grade gliomas where neurological deficits can result in long-term disability. While the preliminary studies discussed here, containing data from only a few centers, have reported increased progression-free and overall survival, these claims require validation in prospective research studies involving larger patient populations with clearly defined appropriate outcome metrics in order to reduce potential bias.


Uncommon low-grade brain tumors
Abstract
The 2016 World Health Organization (WHO) classification of primary central nervous system (CNS) tumors includes numerous uncommon (representing ≤1% of tumors) low-grade (grades I–II) brain neoplasms with varying clinical behaviors and outcomes. Generally, gross tumor or maximal safe resection is the primary treatment. Adjuvant treatments, though their exact role is unknown, may be considered individually based on pathological subtypes and a proper assessment of risks and benefits. Targetable mutations such as BRAF (proto-oncogene B-Raf), TRAIL (tumor necrosis factor apoptosis inducing ligand), and PDGFR (platelet derived growth factor receptor) have promising roles in future management.


Outcomes following stereotactic radiosurgery for small to medium-sized brain metastases are exceptionally dependent upon tumor size and prescribed dose
Abstract
Background
At our institution, we have historically treated brain metastasis (BM) ≤2 cm in eloquent brain with a radiosurgery (SRS) lower prescription dose (PD) to reduce the risk of radionecrosis (RN). We sought to evaluate the impact of this practice on outcomes.
Methods
We analyzed a prospective registry of BM patients treated with SRS between 2008 and 2017. Incidences of local failure (LF) and RN were determined and Cox regression was performed for univariate and multivariate analyses (MVAs).
Results
We evaluated 1533 BM ≤2 cm. Median radiographic follow-up post SRS was 12.7 months (1.4–100). Overall, the 2-year incidence of LF was lower for BM treated with PD ≥21 Gy (9.3%) compared with PD ≤15 Gy (19.5%) (sub–hazard ratio, 2.3; 95% CI: 1.4–3.7; P = 0.0006). The 2-year incidence of RN was not significantly higher for the group treated with PD ≥21 Gy (9.5%) compared with the PD ≤15 Gy group (7.5%) (P = 0.16). MVA demonstrated that PD (≤15 Gy) and tumor size (>1 cm) were significantly correlated (P < 0.05) with higher rates of LF and RN, respectively. For tumors ≤1 cm, when comparing PD ≤15 Gy with ≥21 Gy, the risks of LF and RN are equivalent. However, for lesions >1 cm, PD ≥21 Gy is associated with a lower incidence of LF without significantly increasing the risk of RN.
Conclusion
Our results indicate that rates of LF or RN following SRS for BM are strongly correlated with size and PD. Based on our results, we now, depending upon the clinical context, consider increasing PD to 21 Gy for BM in eloquent brain, excluding the brainstem.


Sex difference of mutation clonality in diffuse glioma evolution
Abstract
Background
Sex differences in glioma incidence and outcome have been previously reported but remain poorly understood. Many sex differences that affect the cancer risk were thought to be associated with cancer evolution.
Methods
In this study, we used an integrated framework to infer the timing and clonal status of mutations in ~600 diffuse gliomas from The Cancer Genome Atlas (TCGA) including glioblastomas (GBMs) and low-grade gliomas (LGGs), and investigated the sex difference of mutation clonality.
Results
We observed higher overall and subclonal mutation burden in female patients with different grades of gliomas, which could be largely explained by the mutations of the X chromosome. Some well-established drivers were identified showing sex-biased clonality, such as CDH18 and ATRX. Focusing on glioma subtypes, we further found a higher subclonal mutation burden in females than males in the majority of glioma subtypes, and observed opposite clonal tendency of several drivers between male and female patients in a specific subtype. Moreover, analysis of clinically actionable genes revealed that mutations in genes of the mitogen-activated protein kinase (MAPK) signaling pathway were more likely to be clonal in female patients with GBM, whereas mutations in genes involved in the receptor tyrosine kinase signaling pathway were more likely to be clonal in male patients with LGG.
Conclusions
The patients with diffuse glioma showed sex-biased mutation clonality (eg, different subclonal mutation number and different clonal tendency of cancer genes), highlighting the need to consider sex as an important variable for improving glioma therapy and clinical care.


Corrigendum to “Symposia” [Int. J. Psychophysiol. 131S(2018)S9–S68]

Publication date: Available online 16 February 2019

Source: International Journal of Psychophysiology

Author(s): P. Ermakov, E. Vorobyeva



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An examination of the moderating effects of neurophysiology on treatment outcomes from cognitive training in schizophrenia-spectrum disorders

Publication date: Available online 15 February 2019

Source: International Journal of Psychophysiology

Author(s): Michael W. Best, Melissa Milanovic, Amanda L. Shamblaw, Abi Muere, Laura J. Lambe, Irene K. Hong, Mashal K. Haque, Christopher R. Bowie

Abstract
Background

Impairments in neurocognition and community functioning are core features of schizophrenia and cognitive training techniques have been developed with the aim of improving these impairments. While cognitive training has produced reliable improvements in neurocognition and functioning, little is known about factors that moderate treatment response. Electroencephalographic (EEG) measures provide a neurophysiological indicator of cognitive functions that may moderate treatment outcomes from cognitive training.

Methods

Data from a clinical trial comparing two cognitive training approaches in schizophrenia-spectrum disorders were utilized in the current report. Cluster analysis was conducted to identify participant clusters based on baseline P300, mismatch negativity (MMN), and theta power during an n-back task, and the EEG measures were also examined as continuous predictors of treatment response.

Results

Three clusters were identified based on the baseline EEG variables; however, there were no significant differences in treatment response across the three clusters. Higher P300 amplitude and theta power during the n-back at baseline were significantly associated with greater improvements in a cognitive composite score post-treatment. None of the EEG measures were significantly associated with treatment outcomes in specific cognitive domains or community functioning. Change in EEG measures from baseline to post-treatment was not significantly associated with durability of cognitive or functional change at 12-week follow-up.

Conclusions

Clusters derived from the EEG measures were not significantly associated with either neurocognitive or functional outcomes. P300 and n-back theta power may be associated with learning-related processes, which are important for acquisition and retention of skills during cognitive training programs. Future research should aim to identify at an individual level who is likely to respond to specific forms of cognitive enhancement.



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Corrigendum to “The human phenotype of ornithine decarboxylase superactivity: a new syndrome”



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CNOT2 as the critical gene for phenotypes of 12q15 microdeletion syndrome

Chromosome 12q15 microdeletion syndrome is characterized by intellectual disability and dysmorphic facial features, but the associations between each of the deleted genes and the phenotypes of 12q15 microdeletion syndrome remain unclear. Recently, the smallest region of overlap in 16 previously reported patients was used to define three candidate genes for the 12q15 microdeletion syndrome: CNOT2, KCNMB4, and PTPRB. Among these three candidate genes, CNOT2 maintains the structural integrity of the carbon catabolite repressor 4 (CCR4)‐negative on TATA (NOT) complex, which plays a key role in regulating global gene expression, and is essential for the enzymatic activity of the CCR4‐NOT complex. Disruption of the CCR4‐NOT complex results in dysregulation of global gene expression, and is associated with various human disease processes, including neuronal diseases. Therefore, CNOT2 haploinsufficiency might account for the neurological features of the 12q15 microdeletion syndrome. Herein, we document a 12‐yearold female patient with mild intellectual disability and multiple structural abnormalities including cleft lip and palate and 2–3 toe syndactyly. She exhibited dysmorphic facial features such as upslanting and short palpebral fissures, micrognathia, low‐set ears, and hypoplastic antihelix. A microarray analysis showed a de novo 1.32‐Mb deletion within 12q15 that included CNOT2 and 14 other genes. Remapping of the 12q15 deletion region in the 16 previously reported patients together with that in the newly identified patient indicated that CNOT2 is the only gene that is commonly deleted. These findings suggest that CNOT2 is the prime candidate for the neurological phenotypes of the 12q15 microdeletion syndrome.



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Involvement of the Na,K‐ATPase isoforms in control of cerebral perfusion

New Findings

What is the topic of this review? This review considers the role of the Na,K‐ATPase in cerebrovascular function and how it might be changed in familial hemiplegic migraine type 2 (FHM2). The primary focus will be involvement of the Na,K‐ATPase isoforms in regulation of cerebrovascular tone. What advances does it highlight? The review discusses three overall distinct mechanisms whereby the Na,K‐ATPase might be capable of regulating cerebrovascular tone. Furthermore, it discusses how changes in the Na,K‐ATPase in cerebral arteries might affect brain perfusion and thereby be involved in the FHM2 pathology.

Abstract

FHM2 has been characterized by biphasic changes in cerebral blood flow during a migraine attack; initial hypoperfusion followed by abnormal hyperperfusion of the affected hemisphere. We suggested that FHM2‐associated loss‐of‐function mutation(s) in the Na,K‐ATPase α2 isoform may be responsible for these biphasic changes in several ways. We found that reduced expression of the α2 isoform leads to sensitization of the contractile machinery to intracellular Ca2+ ([Ca2+]i) via Src kinase dependent signal transduction. This change in sensitivity may be the underlying mechanism for both abnormally potentiated vasoconstriction and exaggerated vasorelaxation. Moreover, functional significance of the Na,K‐ATPase α2 isoform in astrocytes provides for the possibility of elevated extracellular potassium signaling from astrocytic endfeet to the vascular wall in neurovascular coupling.

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