Antifibrotic Effects of Vibratory Stimulation

Extracellular matrix (ECM) is a dynamic and complex environment characterized by biophysical, mechanical and biochemical properties specific for each tissue. Cells constantly experience dynamic mechanical loadings that include compression, shear, tension, hydrostatic pressure, and interstitial fluid flow. Through the process of mechano-chemical conversion, mechanical stimulation activates intracellular biochemical signaling that affects many aspects of cell behavior including cell proliferation and differentiation, as well as ECM deposition and organization during development, wound healing, and pathological diseases. Despite significant advances in understanding the dynamic relationship between mechanical forces and matrix remodeling, many of the unique mechanisms and associated responses to various physical stimuli remain to be elucidated. Fibrosis is a complex disease predominantly characterized by excessive and abnormal fibrous ECM deposition that leads to the failure of various organs: lung, liver, kidney and skin. During the normal wound healing process, injured tissue progresses through phases of hemostasis, acute inflammation, granulation tissue/fibroproliferative, matrix formation, and remodeling. Collectively, the fibro-proliferative stage terminates with the restoration of ECM homeostasis and the disappearance of myofibroblasts, probably through apoptosis. However, the chronic presence of diverse injuries, commonly involving the abnormal persistence of several profibrotic cytokines results in sustained myofibroblast activation, excessive ECM deposition, scar formation, and organ failure. Specifically, transforming growth factor-β (TGF-β) is a master switch that activates critical downstream molecules in the progression of fibrotic disease. Although various strategies designed to interfere with TGF-β expression, receptor binding, and signal transduction have been studied, a clinically safe and effective therapy has not yet been developed. The superficial layer of the lamina propria (SLLP) in the human vocal folds experiences a unique mechanical microenvironment of high frequency vibration during voice production. The presence of macrophages/myofibroblasts in the SLLP of healthy patients suggests that the mechanical stresses imposed during routine speech result in repetitive microtrauma, which is generally repaired without permanent alterations in vocal fold matrix composition or vocal quality. In addition, mechanical forces have recently been shown to alter the fibrotic phenotype in fibrotic fibroblasts. Therefore, the objective of this research is to understand the mechanisms regulating fibroblast matrix metabolism in the SLLP and investigate the potential of vibratory stimulation for treatment of fibrotic diseases. First, we characterized the transcriptional and translational changes of human dermal fibroblasts in response to vibratory stimulation and demonstrated that vibratory stimulation led to the down-regulation of the TGF-β signaling through reduced expression of TGF-β receptors and Smad signal transduction molecules and increased expression of SMAD7, ubiquitin ligases, and SIK1 and SKIL, transcriptional repressors responsible for signaling inhibition. Second, we then investigated the effects of variable vibratory regimes defined by varying frequency, amplitude, and duration on the expression of ECM-related transcripts in human dermal fibroblast and found significant dose-dependent and temporal changes in mRNA expression levels of HA-related molecules and profibrotic cytokines, while type I and III collagen expression was consistently down-regulated across a broad range of parameters. Finally, we tested the potential therapeutic efficacy of vibration for reversing the fibrotic phenotype in scleroderma-derived fibroblasts. These studies showed that vibratory stimulation significantly reduced the mRNA levels of sclerotic pathogenic targets and collagen synthesis and accumulation. These studies, therefore, suggest that vibration can be used as a clinical mechanotherapy for a wide range of fibrotic diseases such as systemic sclerosis and idiopathic pulmonary fibrosis

Intracranial EEG fluctuates over months after implanting electrodes in human brain.

OBJECTIVE: Implanting subdural and penetrating electrodes in the brain causes acute trauma and inflammation that affect intracranial electroencephalographic (iEEG) recordings. This behavior and its potential impact on clinical decision-making and algorithms for implanted devices have not been assessed in detail. In this study we aim to characterize the temporal and spatial variability of continuous, prolonged human iEEG recordings. APPROACH: Intracranial electroencephalography from 15 patients with drug-refractory epilepsy, each implanted with 16 subdural electrodes and continuously monitored for an average of 18 months, was included in this study. Time and spectral domain features were computed each day for each channel for the duration of each patient\u27s recording. Metrics to capture post-implantation feature changes and inflexion points were computed on group and individual levels. A linear mixed model was used to characterize transient group-level changes in feature values post-implantation and independent linear models were used to describe individual variability. MAIN RESULTS: A significant decline in features important to seizure detection and prediction algorithms (mean line length, energy, and half-wave), as well as mean power in the Berger and high gamma bands, was observed in many patients over 100 d following implantation. In addition, spatial variability across electrodes declines post-implantation following a similar timeframe. All selected features decreased by 14-50% in the initial 75 d of recording on the group level, and at least one feature demonstrated this pattern in 13 of the 15 patients. Our findings indicate that iEEG signal features demonstrate increased variability following implantation, most notably in the weeks immediately post-implant. SIGNIFICANCE: These findings suggest that conclusions drawn from iEEG, both clinically and for research, should account for spatiotemporal signal variability and that properly assessing the iEEG in patients, depending upon the application, may require extended monitoring

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality

Effects of Short Term Stretching on Ankle Stiffness and Range of Motion in People with Multiple Sclerosis

Hypertonia is seen in 85% of people with Multiple Sclerosis (pwMS) resulting in disability and functional restrictions. Hypertonia can be caused by increases in passive stiffness and enhanced stretch reflexes (spasticity) and is frequently managed clinically using passive stretches. However, the optimal parameters of stretching such as the applied torque and stretch duration remain unclear. During commonly prescribed ankle plantarflexor stretches pwMS produced higher torques when standing in a weight bearing position compared to stretches applied using the upper limbs. Stretches could be held for 120 seconds on average and stretch duration was mainly limited by fatigue. People with higher disability tended to favour more supported stretching positions. The effects of stretching for either 30 or 10 minutes using a customised motor at three torque levels covering the range that MS participants could produce was investigated. Compared to the 10 minute stretch, greater reductions in passive stiffness and greater increases in range of movement (ROM) were seen immediately following the 30 minute stretch with the effects being sustained for the 30 minute post stretch period. Higher levels of applied torque resulted in a greater change in ROM however; there was no effect of applied torque on passive stiffness. Stretch reflex mediated stiffness was unaffected by the stretching intervention and showed transient post stretch increases. Ultrasonography was used to investigate changes in muscle–tendon length and strain in pwMS and controls and following stretching. PwMS showed evidence of stiffer muscles and increased tendon length at baseline compared to controls. Following a 10 minute stretch overall muscle length did not increase in pwMS, although increases in strain in the musculotendinous junction region were observed suggesting that more proximal regions of the muscle was likely to have contributed significantly to overall stiffness. This work highlights that stretch duration and levels of applied torque are critical factors in determining the effectiveness of stretches. The pathological mechanisms underlying hypertonia at a molecular and structural level and the effects of stretching on components of the musculo-tendinous structure and on functional ability should be ascertained.Multiple Sclerosis Societ

Effects of inhaled therapies on pulmonary hypertension and right ventricular function in cardiac surgery

Au Canada, on estime que 30 000 chirurgies cardiaques sont effectuées chaque année (1). L'insuffisance ventriculaire droite demeure une complication courante chez les patients subissant une chirurgie cardiaque. L'incidence de l’insuffisance ventriculaire droite périopératoire aiguë sévère peut aller de 0,1 % après une cardiotomie à 20 à 30 % après l'implantation d'un dispositif d'assistance ventriculaire gauche (2). La survenue d'une défaillance ventriculaire droite est encore plus fréquente en présence d'hypertension pulmonaire. Les conséquences de l'insuffisance ventriculaire droite en chirurgie cardiaque comprennent une détérioration périopératoire et des effets indésirables tels qu'un sevrage difficile de la circulation extracorporelle, une utilisation accrue d'agents vasoactifs intraveineux, et un risque accru de mortalité. Par conséquent, le diagnostic et le traitement de l’hypertension pulmonaire et de la dysfonction ventriculaire droite sont essentiels dans la période périopératoire pour éviter les complications. La surveillance simultanée et en continue des courbes de pression de l’artère pulmonaire et du ventricule droit à l'aide du cathétérisme de l'artère pulmonaire est un outil de surveillance important chez les patients en chirurgie cardiaque pour la détection précoce d'un dysfonctionnement du ventricule droit et pour évaluer la réponse au traitement. Les stratégies thérapeutiques dans ce contexte devraient se concentrer sur la réduction de la postcharge du ventricule droit et l'amélioration de la fonction du ventricule droit tout en évitant l'hypotension systémique. Les hypothèses de cette thèse sont les suivantes : 1) les vasodilatateurs inhalés sont supérieurs aux agents administrés par voie intraveineuse pour le traitement et la gestion de l’hypertension pulmonaire en chirurgie cardiaque, 2) la combinaison d'époprosténol inhalé et de la milrinone inhalée (iE&iM) est une stratégie efficace pour faciliter le sevrage de la circulation extracorporelle et pour réduire les besoins en inotropes intraveineux, 3) tous les patients n'ont pas une réponse vasodilatatrice positive à la combinaison de l’iE&iM, 4) la réponse à l’iE&iM est associée à des changements des courbes de pression du ventricule droit et de l’artère pulmonaire, et 5) le gradient de la chambre de chasse du ventricule droit et la vitesse d’augmentation de la pression intraventriculaire droite (dP/dt) ont le potentiel d'être des marqueurs pharmacodynamiques de la réponse au traitement. Le travail compris dans cette thèse consiste en 3 études. La première est une revue systématique et méta-analyse d'essais contrôlés randomisés démontrant que l'administration de vasodilatateurs inhalés pour le traitement de l’hypertension pulmonaire pendant la chirurgie cardiaque est associée à une amélioration de la performance du ventricule droit comparé aux agents administrés par voie intraveineuse. La deuxième étude est une analyse de cohorte rétrospective de 128 patients recevant l’iE&iM avant la circulation extracorporelle. Cette étude a démontré une réponse vasodilatatrice au traitement par l’iE&iM chez 77% des patients. Une réponse favorable était associée à un sevrage facile de la circulation extracorporelle plus fréquent et à une utilisation plus faible d'inotropes intraveineux. De plus, cette étude a également démontré qu'une hypertension pulmonaire plus sévère est prédictive d'une réponse vasodilatatrice pulmonaire positive, tandis qu'un European System for Cardiac Operative Risk Evaluation score (EuroSCORE) II élevé est un prédicteur de non-réponse au traitement. La dernière étude de cette thèse est une étude de cohorte prospective incluant 26 patients recevant iE&iM avec surveillance continue de la courbe de pression du ventricule droit démontrant l'innocuité et l'efficacité de cette approche thérapeutique dans l'amélioration de la fonction ventriculaire droite.In Canada there is an estimated 30,000 cardiac surgeries that are performed each year (1). Right ventricular failure (RVF) remains a common complication in patients undergoing cardiac surgery. The incidence of severe acute perioperative RVF can range from 0.1% after cardiotomy to 20-30% after left ventricular assist device implantation (2). The occurrence of RVF is even more frequent in the presence of pulmonary hypertension (PH). Consequences of RVF in cardiac surgery include perioperative deterioration and adverse outcomes such as difficult separation from cardiopulmonary bypass (CPB), increased use of intravenous (IV) vasoactive agents and an increased risk of mortality. Therefore, the diagnosis and treatment of PH and right ventricular (RV) dysfunction is essential in the perioperative period to circumvent complications. Continuous and simultaneous monitoring of both pulmonary artery pressure (Ppa) and RV pressure (Prv) waveforms using pulmonary artery catheterization is an important monitoring tool in cardiac surgery patients for early detection of RV dysfunction and for evaluating response to treatment. Therapeutic strategies in this context should focus on reducing RV afterload and improving RV function while avoiding systemic hypotension. The hypotheses of this thesis are the following: 1) inhaled aerosolized vasodilators are superior to IV administered agents for the treatment and management of PH in cardiac surgery, 2) the combination of inhaled epoprostenol and inhaled milrinone (iE&iM) is an effective strategy to facilitate separation from CPB and reduce the requirements for IV inotropes, 3) not all patients have a positive vasodilator response to iE&iM, 4) response to iE&iM is associated with changes in RV and PA pressure waveforms, and 5) RV outflow tract (RVOT) gradient and RV maximal rate of pressure rise during early systole (dP/dt) have the potential to be pharmacodynamic markers of response to treatment. The work comprised in this thesis consist of 3 studies. The first is a systematic review and meta-analysis of randomized controlled trials showing that administration of inhaled vasodilators for the treatment of PH during cardiac surgery is associated with improved RV performance compared to IV administered agents. The second study is a retrospective cohort analysis of 128 patients receiving iE&iM before CPB. This study showed that 77% of patients have a vasodilator response to iE&iM treatment. A favorable vasodilator response was associated with more frequent easy separation from CPB and lower use of IV inotropes post-CPB. In addition, more severe PH at baseline is shown to be predictive of a positive pulmonary vasodilator response while high European System for Cardiac Operative Risk Evaluation score (EuroSCORE) II is a predictor of non-response to treatment. The last study of this thesis is a prospective cohort study including 26 patients receiving iE&iM with continuous monitoring of Prv waveform demonstrating the safety and efficacy of this treatment approach in improving RV function

Immunomodulatory Effects of Massage in Skeletal Muscle

The inflammatory process is a critical component of the repair and regeneration of skeletal muscle following injury. The influx of innate immune cells following injury is intricate, and temporal nature. Although required for proper repair and regeneration, the inflammatory process has been shown to exacerbate initial damage, prolonging the healing process. Complementary Alternative Medicine (CAM) treatments, such as massage therapy, are a promising substitute for pharmaceutical modulation of the inflammatory response, and recent studies into the efficacy of massage have begun to report the physiological benefits of massage application following injury. Nonetheless, there is a significant lack of sound mechanistic investigations into massage application and its effects on unperturbed tissue. To gain insight to its potential influences on healthy skeletal muscle, massage was applied at three different magnitudes of load in vivo. Using a custom fabricated device for cyclic compressive loading, Wistar rats receiving massage had an increased expression in genes associated with the immune response; a significant change in the macrophage populations within the muscle tissue; and demonstrated a systemic effect marked by the increase of immune cells in the non-massaged limb. Further elucidating the systemic and immunomodulatory effects of massage, Long Evans rats receiving non-constrained eccentric exercise followed by a single 30minute bout of massage, displayed a significant crossover effect just 6 hours post exercise through the modulation of inflammatory cells in the non-massaged limb. Together these investigations suggest that mechanotransductive properties of massage can promote modulation of the immune response absent of pharmaceuticals

TrkB-enhancer Facilitates Functional Recovery After Traumatic Brain Injury

Brain-derived neurotrophic factor (BDNF), a key player in regulating synaptic strength and learning, is dysregulated following traumatic brain injury (TBI), suggesting that stimulation of BDNF signaling pathways may facilitate functional recovery. This study investigates whether CN2097, a peptidomimetic ligand which targets the synaptic scaffold protein, postsynaptic density protein 95, to enhance downstream signaling of tropomyosin-related kinase B, a receptor for BDNF, can improve neurological function after TBI. Moderate to severe TBI elicits neuroinflammation and c-Jun-N-terminal kinase (JNK) activation, which is associated with memory deficits. Here we demonstrate that CN2097 significantly reduces the post-traumatic synthesis of proinflammatory mediators and inhibits the posttraumatic activation of JNK in a rodent model of TBI. The recordings of field excitatory post-synaptic potentials in the hippocampal CA1 subfield demonstrate that TBI inhibits the expression of long-term potentiation (LTP) evoked by high-frequency stimulation of Schaffer collaterals, and that CN2097 attenuates this LTP impairment. Lastly, we demonstrate that CN2097 significantly improves the complex auditory processing deficits, which are impaired after injury. The multifunctionality of CN2097 strongly suggests that CN2097 could be highly efficacious in targeting complex secondary injury processes resulting from neurotrauma

Acute and short-term normobaric hypoxic conditioning on psycho-physiological responses in obese populations

This thesis investigated the psycho-physiological responses of obese individuals during and following acute and short-term hypoxic conditioning, including both passive and active modalities. Study one determined psycho-physiological responses to passive hypoxic conditioning (FiO2= 12.0%) consisting of varying hypoxic and normoxic cycles in obese individuals. It was found that perceptions of breathlessness following short (15 × 2 mins hypoxia/2 mins normoxia) cycles was lowest (-7%) for up to 60 mins post-exposure compared to long cycles (5 × 6 mins hypoxia/6 mins normoxia), whilst the extent of desaturation in arterial oxygen satura tion was greater in the latter than the former (-4%). The fndings of this study later informed the interval work/rest duration of exercising in hypoxia for obese individuals. Study two assessed psycho-physiological responses of trained runners during a perceptually regulated interval running session (4 × 4 mins at a rating of perceived exertion equal to 16, 3mins recovery) in hypoxic (FiO2 = 15.0%) and normoxic conditions. The main findings show that a slower treadmill velocity (-6%) was required to maintain a rating of perceived exertion equal to 16 in hypoxia than normoxia. Whilst physiological responses were matched between conditions (i.e., heart rate and muscle oxygenation), exercise-related sensations (i.e., perceived recovery [-21%], motivation [-21%], breathlessness [+22%%], limb discomfort [+11%%] and pleasure [-31%]) were negatively impacted more so during hypoxia compared to normoxia. The findings of this study provided an intial insight regarding the influence of hypoxia on the perceptually-regulated exercise model in trained runners prior to utilisation in an obese population. Study three assessed psycho-physiological responses of obese individuals during a perceptually-regulated interval walking session (15 × 2 mins walking, 2 mins recovery, based on the findings of study one) in hypoxic (FiO2 = 13.0%) and normoxic conditions. Further, during an additional third condition, the psycho-physiological responses from hypoxia were isolated with the velocity selected during this trial matched in normoxic conditions. Similar to study three, a slower treadmill velocity (-2%) was required to maintain a rating of perceived exertion equal to 14 in hypoxia than normoxia. Physiological responses were more pronounced during hypoxia compared to normoxia (i.e., higher heart rate [+6%] and lower muscle oxygenation [-6%]), whilst perceptions of limb discomfort were lower (-21%) in the former than the latter. In the absence of hypoxia at the same velocity, perceptions of limb discomfort were matched to perceptually-regulated walking in hypoxia, but the physiological stress was lower (i.e., heart rate [-5%]). The findings of this study provided indication of the acute effects of perceptually-regulated interval walking in hypoxia prior to implementation of this protocol design on a regular, short-term basis. Study four examined the psycho-physiological responses of obese individuals to a short-term training intervention (utilising the same session protocol of study three, eight sessions in two weeks) in hypoxic (FiO2 = 13.0%) and normoxic conditions. A similar perceptually-regulated velocity, physiological stress (i.e., heart rate) and exercise-related sessions (i.e., perceived recovery, motivation, breathlessness, limb discomfort and pleasure) were recorded during training between conditions. Improvements in perceived mood state (+12%), exercise-selfefficacy (+11%) and energy expenditure (+10%) were reported after training independent of condition, whilst resting blood glucose levels were only enhanced after hypoxic training (-15%). Collectively, obese individuals may benefit in terms of psycho-physiological responses from exercising at a perceptually-regulated intensity in hypoxia more so than normoxia. These benefits (acute and short-term) could be potentiated largely due to the optimisation of cycle variations of hypoxia/normoxia and exercise/rest durations