Clinical Applications of Iso-Inertial, Eccentric-Overload (YoYo™) Resistance Exercise

In the quest for a viable non-gravity dependent method to “lift weights” in space, our laboratory introduced iso-inertial resistance (YoYo™) exercise using spinning flywheel(s), more than 25 years ago. After being thoroughly tested in individuals subjected to various established spaceflight analogs, a multi-mode YoYo™ exercise apparatus was eventually installed on the International Space Station in 2009. The method, applicable to any muscle group, provides accommodated resistance and optimal muscle loading through the full range of motion of concentric actions, and brief episodes of eccentric overload. This exercise intervention has found terrestrial applications and shown success in enhancing sports performance and preventing injury and aiding neurological or orthopedic rehabilitation. Research has proven that this technique offers unique physiological responses not possible with other exercise hardware solutions. This paper provides a brief overview of research that has made use, and explored the efficacy, of this method in healthy sedentary or physically active individuals and populations suffering from muscle wasting, disease or injury. While the collective evidence to date suggests YoYo™ offers a potent stimulus to optimize the benefits of resistance exercise, systematic research to support clinical use of this method has only begun to emerge. Thus, we also offer perspectives on unresolved issues, unexplored applications for clinical conditions, and how this particular exercise paradigm could be implemented in future clinical research and eventually being prescribed. Fields of particular interest are those aimed at promoting muscle health by preventing injury or combating muscle wasting and neurological or metabolic dysfunction due to aging or illness, or those serving in rehabilitation following trauma and/or surgery

Muscle, functional and cognitive adaptations after flywheel resistance training in stroke patients : a pilot randomized controlled trial

Resistance exercise (RE) improves neuromuscular function and physical performance after stroke. Yet, the effects of RE emphasizing eccentric (ECC; lengthening) actions on muscle hypertrophy and cognitive function in stroke patients are currently unknown. Thus, this study explored the effects of ECC-overload RE training on skeletal muscle size and function, and cognitive performance in individuals with stroke. Thirty-two individuals with chronic stroke (≥6 months post-stroke) were randomly assigned into a training group (TG; n = 16) performing ECC-overload flywheel RE of the more-affected lower limb (12 weeks, 2 times/week; 4 sets of 7 maximal closed-chain knee extensions; <2 min of contractile activity per session) or a control group (CG; n = 16), maintaining daily routines. Before and after the intervention, quadriceps femoris volume, maximal force and power for each leg were assessed, and functional and dual task performance, and cognitive functions were measured. Quadriceps femoris volume of the more-affected leg increased by 9.4 % in TG. Muscle power of the more-affected, trained (48.2 %), and the less-affected, untrained limb (28.1 %) increased after training. TG showed enhanced balance (8.9 %), gait performance (10.6 %), dual-task performance, executive functions (working memory, verbal fluency tasks), attention, and speed of information processing. CG showed no changes. ECC-overload flywheel resistance exercise comprising 4 min of contractile activity per week offers a powerful aid to regain muscle mass and function, and functional performance in individuals with stroke. While the current intervention improved cognitive functions, the cause-effect relationship, if any, with the concomitant neuromuscular adaptations remains to be explored. Clinical Trial

Metabolic adaptations in skeletal muscle after 84 days of bed rest with and without concurrent flywheel resistance exercise

As metabolic changes in human skeletal muscle after long-term (simulated) spaceflight are not well understood, this study examined the effects of long-term microgravity, with and without concurrent resistance exercise, on skeletal muscle oxidative and glycolytic capacity. Twenty-one men were subjected to 84 days head-down tilt bed rest with (BRE; n = 9) or without (BR; n = 12) concurrent flywheel resistance exercise. Activity and gene expression of glycogen synthase, glycogen phosphorylase (GPh), hexokinase, phosphofructokinase-1 (PFK-1), and citrate synthase (CS), as well as gene expression of succinate dehydrogenase (SDH), vascular endothelial growth factor (VEFG), peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1α), and myostatin, were analyzed in samples from m. vastus lateralis collected before and after bed rest. Activity and gene expression of enzymes controlling oxidative metabolism (CS, SDH) decreased in BR but were partially maintained in BRE. Activity of enzymes regulating anaerobic glycolysis (GPh, PFK-1) was unchanged in BR. Resistance exercise increased the activity of GPh. PGC-1α and VEGF expression decreased in both BR and BRE. Myostatin increased in BR but decreased in BRE after bed rest. The analyses of these unique samples indicate that long-term microgravity induces marked alterations in the oxidative, but not the glycolytic, energy system. The proposed flywheel resistance exercise was effective in counteracting some of the metabolic alterations triggered by 84-day bed rest. Given the disparity between gene expression vs. enzyme activity in several key metabolic markers, posttranscriptional mechanisms should be explored to fully evaluate metabolic adaptations to long-term microgravity with/without exercise countermeasures in human skeletal muscle

REPORTES CLINICOS: INFECCION RINOSINUSAL PROBADA POR Aspergillus flavus Y PROBABLE INFECCION PULMONAR POR Emericella nidulans EN PACIENTES INMUNODEPRIMIDOS

En los ultimos 20 años la incidencia de aspergilosis invasiva ha aumentado  entre 5 y 10 veces, presentando una mortalidad que varía desde un 60 a 98% dependiendo de su localización, enfermedad de base(inmunodepresión), diagnóstico y tratamiento precoz. A pesar que se ha logrado un importante avance en estos dos últimos decenios, aproximadamente un 50% de los casos se diagnostican post mortem. Se reportan dos casos de aspergilosis (probada y probable) en pacientesinmunodeprimidos de 21 y 44 años respectivamente. El primer caso corresponde a una infección rinosinusal en una paciente con leucemia linfoblastica, con un cuadro clínico caracterizado por aumento de volumen facial  izquierdo, compromiso progresivo del estado general yequímosis en región periorbitaria. La endoscopia nasal detectó abundante secreción y tejido friable amarillento sugerente de infección micótica. Las muestras de tejidos enviadas al laboratorio para exámen directo y cultivos arrojaron presencia de hifas en la mucosa y crecimientoabundante de Aspergillus flavus. Se inició terapia con itraconazol, cambiándose posteriormente a voriconazol, con respuesta favorable y disminución del dolor y volumen facial. Sin embargo, la paciente fallece al 10º día del ingreso debido a su mal estado general, avance de la falla medular y posterior insuficiencia respiratoria. El segundo caso corresponde a una probable infección pulmonar en una paciente con cáncer de mama en tratamiento quimioterápico. La paciente ingresó conel diagnóstico de neutropenia febril y probable neumonia de etiología bacteriana, fue tratada con antimicrobianos tanto en el hospital comunal como en el de base. Sin embargo, presentó una evolución tórpida, cursando posteriormente con hemoptisis, insuficiencia respiratoriay compromiso de conciencia. Se tomaron muestras de secreción endotraqueal las que fueron enviadas para estudio bacteriológico(TBC) y micológico, además de hemo y urocultivos. Los resultados de los examenes efectuados fueron negativos, excepto todos los cultivosmicológicos que tempranamente (4 días) detectaron un amplio crecimiento de Aspergillus (Emericella) nidulans. Al momento del informe micológico la paciente había fallecido en el hospital base

Extracellular vesicle characteristics and micro RNA content in cerebral palsy and typically developed individuals at rest and in response to aerobic exercise.

In this study, the properties of circulating extracellular vesicles (EVs) were examined in cerebral palsy (CP) and typically developed (TD) individuals at rest and after aerobic exercise, focusing on the size, concentration, and microRNA cargo of EVs. Nine adult individuals with CP performed a single exercise bout consisting of 45 min of Frame Running, and TD participants completed either 45 min of cycling (n = 10; TD EX) or were enrolled as controls with no exercise (n = 10; TD CON). Blood was drawn before and 30 min after exercise and analyzed for EV concentration, size, and microRNA content. The size of EVs was similar in CP vs. TD, and exercise had no effect. Individuals with CP had an overall lower concentration (~25%, p \u3c 0.05) of EVs. At baseline, let-7a, let-7b and let-7e were downregulated in individuals with CP compared to TD (p \u3c 0.05), while miR-100 expression was higher, and miR-877 and miR-4433 lower in CP compared to TD after exercise (p \u3c 0.05). Interestingly, miR-486 was upregulated ~2-fold in the EVs of CP vs. TD both at baseline and after exercise. We then performed an in silico analysis of miR-486 targets and identified the satellite cell stemness factor Pax7 as a target of miR-486. C2C12 myoblasts were cultured with a miR-486 mimetic and RNA-sequencing was performed. Gene enrichment analysis revealed that several genes involved in sarcomerogenesis and extracellular matrix (ECM) were downregulated. Our data suggest that circulating miR-486 transported by EVs is elevated in individuals with CP and that miR-486 alters the transcriptome of myoblasts affecting both ECM- and sarcomerogenesis-related genes, providing a link to the skeletal muscle alterations observed in individuals with C

Metabolic adaptations in skeletal muscle after 84 days of bed rest with and without concurrent flywheel resistance exercise

As metabolic changes in human skeletal muscle after long-term (simulated) spaceflight are not well understood, this study examined the effects of long-term microgravity, with and without concurrent resistance exercise, on skeletal muscle oxidative and glycolytic capacity. Twenty-one men were subjected to 84 days head-down tilt bed rest with (BRE; n 9) or without (BR; n 12) concurrent flywheel resistance exercise. Activity and gene expression of glycogen synthase, glycogen phosphorylase (GPh), hexokinase, phosphofructokinase-1 (PFK-1), and citrate synthase (CS), as well as gene expression of succinate dehydrogenase (SDH), vascular endothelial growth factor (VEFG), peroxisome proliferator-activated receptor gamma coactivator- 1 (PGC-1 ), and myostatin, were analyzed in samples from m.vastus lateralis collected before and after bed rest. Activity and gene expression of enzymes controlling oxidative metabolism (CS, SDH) decreased in BR but were partially maintained in BRE. Activity of enzymes regulating anaerobic glycolysis (GPh, PFK-1) was unchanged in BR. Resistance exercise increased the activity of GPh. PGC-1 and VEGF expression decreased in both BR and BRE. Myostatin increased in BR but decreased in BRE after bed rest. The analyses of these unique samples indicate that long-term microgravity induces marked alterations in the oxidative, but not the glycolytic, energy system. The proposed flywheel resistance exercise was effective in counteracting some of the metabolic alterations triggered by 84-day bed rest. Given the disparity between gene expression vs. enzyme activity in several key metabolic markers, posttranscriptional mechanisms should be explored to fully evaluate metabolic adaptations to long-term microgravity with/without exercise countermeasures in human skeletal muscle

Substantial and Reproducible Individual Variability in Skeletal Muscle Outcomes in the Cross-Over Designed Planica Bed Rest Program

To evaluate the individual responses in skeletal muscle outcomes following bed rest, data from three studies (21-day PlanHab; 10-day FemHab and LunHab) were combined. Subjects (n = 35) participated in three cross-over campaigns within each study: normoxic (NBR) and hypoxic bed rest (HBR), and hypoxic ambulation (HAMB; used as control). Individual variability (SDIR) was investigated as √(SD (Formula presented.) –SD (Formula presented.)), where SDExp and SDCon are the standard deviations of the change score (i.e., post – pre) in the experimental (NBR and HBR) and the control (HAMB) groups, respectively. Repeatability and moderators of the individual variability were explored. Significant SDIR was detected for knee extension torque, and thigh and calf muscle area, which translated into an individual response ranging from 3 to −17% for knee extension torque, −2 to −12% for calf muscle area, and −1 to −8% for thigh muscle area. Strong correlations were found for changes in NBR vs. HBR (i.e., repeatability) in thigh and calf muscle area (r = 0.65–0.75, P < 0.0001). Change-scores in knee extension torque, and thigh and calf muscle area strongly correlated with baseline values (P < 0.001; r between −0.5 and −0.9). Orthogonal partial least squares regression analysis explored if changes in the investigated variables could predict calf muscle area alterations. This analysis indicated that 43% of the variance in calf muscle area could be attributed to changes in all of the other variables. This is the first study using a validated methodology to report clinically relevant individual variability after bed rest in knee extension torque, calf muscle area, and (to a lower extent) thigh muscle area. Baseline values emerged as a moderator of the individual response, and a global bed rest signature served as a moderately strong predictor of the individual variation in calf muscle area alterations

R2 prime (R2') magnetic resonance imaging for post-myocardial infarction intramyocardial haemorrhage quantification.

To assess whether R2* is more accurate than T2* for the detection of intramyocardial haemorrhage (IMH) and to evaluate whether T2' (or R2') is less affected by oedema than T2* (R2*), and thus more suitable for the accurate identification of post-myocardial infarction (MI) IMH. Reperfused anterior MI was performed in 20 pigs, which were sacrificed at 120 min, 24 h, 4 days, and 7 days. At each time point, cardiac magnetic resonance (CMR) T2- and T2*-mapping scans were recorded, and myocardial tissue samples were collected to quantify IMH and myocardial water content. After normalization by the number of red blood cells in remote tissue, histological IMH increased 5.2-fold, 10.7-fold, and 4.1-fold at Days 1, 4, and 7, respectively. The presence of IMH was correlated more strongly with R2* (r = 0.69; P = 0.013) than with T2* (r = -0.50; P = 0.085). The correlation with IMH was even stronger for R2' (r = 0.72; P = 0.008). For myocardial oedema, the correlation was stronger for R2* (r = -0.63; P = 0.029) than for R2' (r = -0.50; P = 0.100). Multivariate linear regressions confirmed that R2* values were significantly explained by both IMH and oedema, whereas R2' values were mostly explained by histological IMH (P = 0.024) and were little influenced by myocardial oedema (P = 0.262). Using CMR mapping with histological validation in a pig model of reperfused MI, R2'more accurately detected IMH and was less influenced by oedema than R2* (and T2*). Further studies are needed to elucidate whether R2' is also better suited for the characterization of post-MI IMH in the clinical setting.This study was partially supported by a competitive grant from the Carlos III Institute of Health-Fondo de Investigacion Sanitaria and the European Regional Development Fund (ERDF/FEDER) (PI16/02110), the Spanish Ministry of Science, Innovation and Universities (MICIU), ERDF/FEDER SAF2013-49663-EXP, by the Comunidad de Madrid (S2017/BMD-3867 RENIM-CM) and cofunded with European structural and investment funds. This study forms part of a Master Research Agreement between the CNIC and Philips Healthcare. This research program is part of an institutional agreement between FIIS Fundacion Jimenez Diaz and the CNIC. The CNIC is supported by the Ministry of Science, Innovation and Universities MICIU the Instituto de Salud Carlos III (ISCiii), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (award SEV-2015-0505). X.R. has received support from the DYSEC-CNIC CARDIOJOVEN fellowship program. R.F.-J. is a recipient of funding from the European Union Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie (Agreement No. 707642).S

First measurement of the CP-violating phase in B0s→J/ψ( → e+e−)ϕ decays

A flavour-tagged time-dependent angular analysis of B0 s → J/ψφ decays is presented where the J/ψ meson is reconstructed through its decay to an e +e − pair. The analysis uses a sample of pp collision data recorded with the LHCb experiment at centre-of-mass energies of 7 and 8 TeV, corresponding to an integrated luminosity of 3 fb−1 . The CP-violating phase and lifetime parameters of the B0 s system are measured to be φs = 0.00 ± 0.28 ± 0.05 rad, ∆Γs = 0.115 ± 0.045 ± 0.011 ps−1 and Γs = 0.608 ± 0.018 ± 0.011 ps−1 where the first uncertainty is statistical and the second systematic. This is the first time that CP-violating parameters are measured in the B0 s → J/ψφ decay with an e +e − pair in the final state. The results are consistent with previous measurements in other channels and with the Standard Model predictions