Preconditioning Research Articles

Brain Ischemic Tolerance Triggered by Preconditioning Involves Modulation of Tumor Necrosis Factor-α-Stimulated Gene 6 (TSG-6) in Mice Subjected to Transient Middle Cerebral Artery Occlusion.

Ischemic preconditioning (PC) induced by a sub-lethal cerebral insult triggers brain tolerance against a subsequent severe injury through diverse mechanisms, including the modulation of the immune system. Tumor necrosis factor (TNF)-α-stimulated gene 6 (TSG-6), a hyaluronate (HA)-binding protein, has recently been involved in the regulation of the neuroimmune response following ischemic stroke. Thus, we aimed at assessing whether the neuroprotective effects of ischemic PC involve the modulation of TSG-6 in a murine model of transient middle cerebral artery occlusion (MCAo). The expression of TSG-6 was significantly elevated in the ischemic cortex of mice subjected to 1 h MCAo followed by 24 h reperfusion, while this effect was further potentiated (p < 0.05 vs. MCAo) by pre-exposure to ischemic PC (i.e., 15 min MCAo) 72 h before. By immunofluorescence analysis, we detected TSG-6 expression mainly in astrocytes and myeloid cells populating the lesioned cerebral cortex, with a more intense signal in tissue from mice pre-exposed to ischemic PC. By contrast, levels of TSG-6 were reduced after 24 h of reperfusion in plasma (p < 0.05 vs. SHAM), but were dramatically elevated when severe ischemia (1 h MCAo) was preceded by ischemic PC (p < 0.001 vs. MCAo) that also resulted in significant neuroprotection. In conclusion, our data demonstrate that neuroprotection exerted by ischemic PC is associated with the elevation of TSG-6 protein levels both in the brain and in plasma, further underscoring the beneficial effects of this endogenous modulator of the immune system.

Realizing the gravity of the simulation: adaptation to simulated hypogravity leads to altered predictive control

Accurate predictive abilities are important for a wide variety of animal behaviors. Inherent to many of these predictions is an understanding of the physics that underlie the behavior. Humans are specifically attuned to the physics on Earth but can learn to move in other environments (e.g., the surface of the Moon). However, the adjustments made to their physics-based predictions in the face of altered gravity are not fully understood. The current study aimed to characterize the locomotor adaptation to a novel paradigm for simulated reduced gravity. We hypothesized that exposure to simulated hypogravity would result in updated predictions of gravity-based movement. Twenty participants took part in a protocol that had them perform vertically targeted countermovement jumps before (PRE), during, and after (POST) a physical simulation of hypogravity. Jumping in simulated hypogravity had different neuromechanics from the PRE condition, with reduced ground impulses (p ≤ .009) and muscle activity prior to the time of landing (i.e., preactivation; p ≤ .016). In the 1 g POST condition, muscle preactivation remained reduced (p ≤ .033) and was delayed (p ≤ .008) by up to 33% for most muscles of the triceps surae, reflecting an expectation of hypogravity. The aftereffects in muscle preactivation, along with little-to-no change in muscle dynamics during ground contact, point to a neuromechanical adaptation that affects predictive, feed-forward systems over feedback systems. As such, we conclude that the neural representation, or internal model, of gravity is updated after exposure to simulated hypogravity.

The impact of commingling preconditioned calves on mortality, morbidity and performance in a feedlot

Bovine respiratory disease (BRD) is the most important disease in the North American beef industry, causing substantial eco­nomic losses due to morbidity and mortality, including treat­ments, reduced performance, and increased antimicrobial use. Preconditioning (PC) to mitigate BRD was proposed as early as 1967 and constitutes management practices that reduce stressors and optimize resilience through vaccination against bacterial and viral pathogens, optimized timing of dehorning, castration, best weaning strategy, and training calves to eat from a bunk and drink from a water source at least 45 d before transport to the feedlot. Despite proven profits for precondi­tioning of beef calves, PC hasn’t been established in the current beef industry. Besides the lack of premiums paid, there is also the question if commingling of PC and auction-derived (AD) calves in the feedlot can hamper PC calves’ expected growth and health advantages. Therefore, our objective was to evalu­ate the impact of optimally preconditioned calves on mortality, morbidity and average daily gain (ADG) during the first 40 days in the feedlot when PC calves where commingled with different proportions of AD calves (25, 50, 75%).

Skeletal Muscle Heat Shock Protein Content and the Repeated Bout Effect.

The "Repeated Bout Effect" (RBE) occurs when a skeletal muscle is preconditioned with a few lengthening contractions (LC) prior to exposing the muscle to a greater number of LC. The preconditioning (PC) results in significantly less damage and preservation of force. Since it takes only a few LC to increase muscle heat shock protein (HSP) content, it was of interest to examine the relationship between HSPs and the RBE. To do this, one tibialis anterior (TA) muscle from Sprague-Dawley rats (n = 5/group) was preconditioned with either 0, 5, or 15 lengthening contractions (LC) and exposed to a treatment of 60 LC 48 h later. Preconditioning TA muscles with 15 LC, but not 5 LC, significantly elevated muscle αB-crystallin (p < 0.05), HSP25 (p < 0.05), and HSP72 content (p < 0.001). These preconditioned TA muscles also showed a significantly (p < 0.05) reduced loss of active torque throughout the subsequent 60 LC. While there was a trend for all preconditioned muscles to maintain higher peak torque levels throughout the 60 LC, no significant differences were detected between the groups. Morphologically, preconditioned muscles appeared to show less discernible muscle fiber damage. In conclusion, an elevated skeletal muscle HSP content from preconditioning may contribute to the RBE.

Preconditioning-Induced Facilitation of Lactate Release from Astrocytes Is Essential for Brain Ischemic Tolerance.

A sublethal ischemic episode [termed preconditioning (PC)] protects neurons in the brain against a subsequent severe ischemic injury. This phenomenon is known as brain ischemic tolerance and has received much attention from researchers because of its robust neuroprotective effects. We have previously reported that PC activates astrocytes and subsequently upregulates P2X7 receptors, thereby leading to ischemic tolerance. However, the downstream signals of P2X7 receptors that are responsible for PC-induced ischemic tolerance remain unknown. Here, we show that PC-induced P2X7 receptor-mediated lactate release from astrocytes has an indispensable role in this event. Using a transient focal cerebral ischemia model caused by middle cerebral artery occlusion, extracellular lactate levels during severe ischemia were significantly increased in mice who experienced PC; this increase was dependent on P2X7 receptors. In addition, the intracerebroventricular injection of lactate protected against cerebral ischemic injury. In in vitro experiments, although stimulation of astrocytes with the P2X7 receptor agonist BzATP had no effect on the protein levels of monocarboxylate transporter (MCT) 1 and MCT4 (which are responsible for lactate release from astrocytes), BzATP induced the plasma membrane translocation of these MCTs via their chaperone CD147. Importantly, CD147 was increased in activated astrocytes after PC, and CD147-blocking antibody abolished the PC-induced facilitation of astrocytic lactate release and ischemic tolerance. Taken together, our findings suggest that astrocytes induce ischemic tolerance via P2X7 receptor-mediated lactate release.

Efforts to Improve the Skills of Finding Mandate in Poetry Through Multiple Choice Test Techniques in the High Classes

This research is based on the difficulties encounteredstudents' experience in writing poetry.This research aims to improve capabilitiesa student at SDN 053978 Tanjung IbusThis is done to provide motivation to students in learning to write poetry and provide a real learning experience that writing poetry using the acrostic technique can help students learn more actively, creatively andpleasant.Class 5 research subjects were 25 students consisting of 13 male students and 12 female students.The research was carried out using classroom action procedures (PTK). The data collection technique uses obsequential techniquesrvation and test. Research result found that in the initial or pre conditions The cycle of students' poetry writing abilities does not yet meet the minimum completeness criteria..

Behavioral activity patterns but not hair cortisol concentrations explain steers' transition-related stress in the first 6wk in the feedlot.

Stress during the transition of beef steers from ranch to feedlot may depend on steer source and preconditioning. The interplay between physiological and behavioral patterns of preconditioned (PC) and auction-derived (AD) steers, particularly after commingling, is poorly understood. Our objective was to evaluate whether hair cortisol (HC) concentrations were related to the health and performance of PC and AD steers and study behavioral activities after commingling over 6wk in a feedlot. Steers, sourced either from ranch (PC, n = 250) or local auction (AD, n = 250), were assigned into 1 of 5 pens, 100% PC (100PC); 75% PC 25% AD (75PC); 50% PC 50% AD (50PC); 25% PC 75% AD (25PC), and 100% AD (0PC), each pen containing 100 steers. Pen was the experimental unit and individual steers were the observational unit where physiological and behavioral changes were measured. The study subsampled 225 steers (PC = 113 and AD = 112) which were equipped with CowManager ear tags to record behaviors. On day 40, hair samples from each steer were collected by clipping hair close to the skin. Data were analyzed using multiple linear, logistic regression, or multilevel negative binomial regression models depending on the outcomes. There was no difference in HC concentrations (day 40) between PC and AD steers (P = 0.66), and no association with Bovine Respiratory Disease (BRD)-related morbidity (P = 0.08) or average daily gain (ADG) (P = 0.44). After adjusting for source and commingling effects, HC concentrations did not affect time spent eating (P = 0.83), ruminating (P = 0.20), active (P = 0.89), or non-active (P = 0.32). PC steers spent more time eating and ruminating over weeks 1 to 4 (P < 0.01) and weeks 1 to 3, respectively (P < 0.05), and more time being active over weeks 1 and 2 compared to AD steers (P < 0.001), but less time being non-active than AD steers on weeks 1 to 3 (P < 0.001). Steers in 100PC and 50PC pens spent more time eating than steers in 0PC (P < 0.001), whereas steers in 25PC spent less time eating than steers in 0PC (P < 0.001). Steers in 0PC spent the most time being not active (P < 0.01). In conclusion, preconditioned steers spent more time eating, ruminating, and being active and less time being not active over the first 3wk in the feedlot, regardless of commingling. The HC concentrations did not identify potentially lower stress related to ranch transfer and were neither associated with BRD-related morbidity nor ADG.

The effect of paired associative stimulation with a high-intensity cortical component and a high-frequency peripheral component on heart rate and heart rate variability in healthy subjects.

A novel protocol for paired associative stimulation (PAS), called high PAS, consists of high-intensity transcranial magnetic stimulation (TMS) and high-frequency peripheral nerve stimulation (PNS). High PAS was developed for spinal cord injury rehabilitation and targets plastic changes in stimulated pathways in the corticospinal tract, which improves motor function. As therapy interventions can last many weeks, it is important to fully understand the effects of high PAS, including its effect on the cardiovascular system. Heart rate variability (HRV) has been used to measure changes in both sympathetic and parasympathetic systems. We used short-term HRV measurements to evaluate the effects of one 20-min session of high PAS on 17 healthy individuals. HRV was recorded for 5 min before (PRE), during (STIM), immediately after (POST), 30 min after (POST30), and 60 min after (POST60) the stimulation. Five participants repeated the HRV setup with sham stimulation. A significant decrease in low-frequency (LF) power (n.u.) (p = 0.002), low-frequency to high-frequency (HF) ratio (p = 0.017), in Poincaré plot [the standard deviation of RR intervals perpendicular to (SD1) and along (SD2) the line of identity SD2/SD1 ratio p < 0.001], and an increase in HF power (n.u.) (p = 0.002) were observed between PRE and STIM conditions; these changes were fully reversible immediately after stimulation. PRE to POST by 3% (p = 0.015) and continued to decline until POST60 by 5% (p = 0.011). LF power (ms2) (p = 0.017) and SD2 (p = 0.015) decreased from PRE to STIM and increased from PRE to POST (p = 0.025 and p = 0.017, respectively). The results from sham PAS exhibited a trend similar to active high-PAS stimulation. High PAS does not have sustained effects during 60-min follow-up on cardiovascular functions, as measured by HRV. None of the short-term results indicates activation of the sympathetic nervous system in healthy individuals. Observed changes in HRV indicate higher parasympathetic activity during stimulation, which is reversible, and is plausibly explained by the fact that the participants spend 20 min without moving, talking, or using phones while being stimulated.

Assessing effectiveness of heart rate variability biofeedback to mitigate mental health symptoms: a pilot study.

Introduction: The increasing burden on mental health has become a worldwide concern especially due to its substantial negative social and economic impact. The implementation of prevention actions and psychological interventions is crucial to mitigate these consequences, and evidence supporting its effectiveness would facilitate a more assertive response. Heart rate variability biofeedback (HRV-BF) has been proposed as a potential intervention to improve mental wellbeing through mechanisms in autonomic functioning. The aim of this study is to propose and evaluate the validity of an objective procedure to assess the effectiveness of a HRV-BF protocol in mitigating mental health symptoms in a sample of frontline HCWs (healthcare workers) who worked in the COVID-19 pandemic. Methods: A prospective experimental study applying a HRV-BF protocol was conducted with 21 frontline healthcare workers in 5weekly sessions. For PRE-POST intervention comparisons, two different approaches were used to evaluate mental health status: applying (a) gold-standard psychometric questionnaires and (b) electrophysiological multiparametric models for chronic and acute stress assessment. Results: After HRV-BF intervention, psychometric questionnaires showed a reduction in mental health symptoms and stress perception. The electrophysiological multiparametric also showed a reduction in chronic stress levels, while the acute stress levels were similar in PRE and POST conditions. A significant reduction in respiratory rate and an increase in some heart rate variability parameters, such as SDNN, LFn, and LF/HF ratio, were also observed after intervention. Conclusion: Our findings suggest that a 5-session HRV-BF protocol is an effective intervention for reducing stress and other mental health symptoms among frontline HCWs who worked during the COVID-19 pandemic. The electrophysiological multiparametric models provide relevant information about the current mental health state, being useful for objectively evaluating the effectiveness of stress-reducing interventions. Further research could replicate the proposed procedure to confirm its feasibility for different samples and specific interventions.

Impacts of commingling preconditioned and auction-derived beef calves on bovine respiratory disease related morbidity, mortality, and weight gain.

Stressors predisposing to bovine respiratory disease (BRD) upon arrival in the feedlot, include the ranch to feedlot transition and mixing cattle from multiple sources. Preconditioning (PC) reduces multiple stressors, but commingling PC and auction-derived (AD) calves in a feedlot may increase BRD risk. Our objective was to evaluate PC calf performance over the first 40 days in the feedlot and determine impacts of commingling with varying proportions of AD calves (25, 50, and 75%). Calves were either preconditioned at one ranch (n = 250) or mixed-source and bought from a local auction (n = 250). At arrival, calves were assigned into 1 of 5 pens: 100 PC, 75 PC, 50 PC, 25 PC, and 0 PC, reflecting the percentage of PC calves in a 100-head pen. Over 40 days, morbidity in pen 100 PC was lower compared to 0 PC (24 vs. 50%, P < 0.001) and varied in commingled pens, being highest (63%) in 25 PC and least (21%) in 50 PC (P < 0.05). There were 3 AD deaths in 0 PC and 2 deaths in 25 PC. The AD calves in 0 PC were 3 times more likely to get BRD than PC calves in 100 PC; however, AD calves gained 0.49 kg/d more than PC calves (P < 0.0001). Ignoring pen placement, AD calves were 2.76 times more likely to get BRD but gained 0.27 kg/d more than PC calves (P < 0.0001). Commingling did not affect morbidity of PC (P = 0.5) or AD calves (P = 0.96), implying commingling did not affect health. Calves in 25 PC were 3.39 times more likely to get BRD than those in the 100 PC (P < 0.001). Furthermore, 25 PC calves gained the most (1.08 kg/d), followed by 50 PC (0.62 kg/d) and 75 PC (0.61 kg/d), compared to 100 PC (P < 0.05). Calf weight at arrival modified ADG (P < 0.05). In conclusion, PC calves had lower morbidity over the first 40 days, irrespective of commingling. With larger variations in arrival weight, there was no advantage of PC for ADG in the first 40 days. The unknown weaning strategies and comparable arrival weights of AD calves may have contributed to greater ADG in AD calves.

Citrate pre conditioning inhibits ap optosis and protects rat myocardium from ischemia reperfusion injury by activating PI3K/Akt signaling pathway

Purpose: To study the influence of citric acid pre-exposure on apoptosis and heart tissue ischemia-reperfusion lesion, and the involvement of PI3K/Akt signal route in this process.&#x0D; Methods: Eighty-four male Sprague-Dawley (SD) rats were randomly divided into a sham group, model group, pretreatment group, and inhibitor group, with 21 rats in each group. Changes in myocardial infarction area were determined using TCC staining, while TUNEL assay was performed to assess apoptosis of cardiomyocytes in the rats. Expression levels of p-Akt, ppi3k, Bcl-2, Bax, and caspase-3 were assayed by Western blotting.&#x0D; Results: The levels of Bax and caspase-3 were higher in model rats than in sham group, while concentrations of Bcl-2, p-Akt, and p-pi3k were significantly reduced. In pre-treated and inhibitor-exposed rats, caspase-3 and Bax levels were significantly down-regulated, relative to corresponding levels in model rats, but Bcl-2, p-pi3k, and p-Akt were significantly up-regulated (p &lt; 0.05). In inhibitor-exposed rats, Bax and caspase-3 were higher than levels in pretreatment rats, but p-pi3k, Bcl-2, and p-Akt concentrations were significantly decreased (p &lt; 0.05).&#x0D; Conclusion: Citric acid pretreatment in rats activates PI3K/Akt signal pathway, inhibits cardiomyocyte apoptosis, protects the myocardium from ischemia-reperfusion injury, and improves cardiac function. The potential of citric acid pretreatment for its protective effect against myocardial injury due to ischemia-reperfusion should be further investigated.

Abstract WMP112: Type 2 Diabetes Dampens Neuroprotection Against Ischemic Injury By Lipopolysaccharide-Induced Preconditioning

Introduction: Evidence suggests that lipopolysaccharide ( LPS ) preconditioning (PC) provides neuroprotection by inducing tolerance to subsequent lethal ischemia. Ischemic tolerance (IT) declines with age, yet it is unclear whether metabolic disease like type 2 diabetes (T2DM) also interfere with IT. The current study sought to determine whether T2DM reduces neuroprotection induced by LPS PC, and the molecular mechanisms underlying the dampened IT. Methods: Male and female diabetic db/db and control db/+ mice (8-10 months of age) were i.p. injected with Toll-like receptor (TLR)4 ligand LPS at 0.2 mg/kg or saline. Stroke was induced 3 days later by permanent distal occlusion of middle cerebral artery and temporary occlusion of ipsilateral common carotid artery for 60 min. Sensory and motor function was evaluated 1 day after stroke by a combination of tests. Infarct size was determined 3 days after stroke following TTC staining. The effect of LPS PC on the phenotypes of leukocytes in the brain parenchyma after stroke was quantified by Fluorescent activated cell sorter (FACS) 2 days after stroke with a panel of markers for subsets of myeloid cells. Transcriptome was determined by RNAseq of isolated monocytes from peripheral blood mononuclear cells. Differentially expressed genes were examined for distinct biological pathways via enrichment analysis. Results: LPS PC significantly reduced infarct in db/+ mice by one third and improved neurological scores, but it did not protect the db/db mice from stroke. FACS data showed that LPS PC reduced the number of Ly6G+ cells in db/+ but not db/db brains, suggesting that LPS PC curbed stroke-induced infiltration of neutrophils in the brain parenchyma. Pathway analysis suggests that diabetic mice exhibited down-regulated pathways in interferon signaling. The expression of Jak-Stat signaling (such as Stat1), MHC antigen presentation (H2A family), and Toll-like receptor (TLR) signaling (such as Irf7) were also reduced in diabetic mice after stroke. Conclusions: The dampened IT in the diabetic mice induced by LPS-PC is associated with increased neutrophil infiltration after stroke compared to control mice. Ongoing studies will seek toovercome the underlying defective molecular mechanisms in T2DM.

Feeding behaviour and activity of beef calves during the first week at the feedlot: Impact of calf source and commingling ratios

Preconditioned (PC) calves have reduced morbidity, mortality and improved performance compared to auction-derived (AD) and non-preconditioned calves; however, there is limited research on the impacts of commingling PC and AD calves at the feedlot. Commingling calves from various sources is known to be highly stressful and can impact performance on arrival at the feedlot. Therefore, the first objective was to assess feeding behaviour (time spent eating and ruminating) and activity of PC beef calves during the first 7 days after arrival at the feedlot compared to ranch-sourced (RS) and AD calves. The second objective was to assess the impacts of commingling PC calves with various proportions of AD calves (25, 50, 75 %) on feeding behaviour and activity in that same time frame. A subset of 45 calves per pen for PC, AD, and commingled pens, and 20 RS calves were equipped with CowManager® tags on arrival. This technology detects ear movement through a sensor in the tag linked to eating, ruminating, active and not active. On average, in the first 7 days at the feedlot, PC calves spent 11 % more time eating than RS and 15 % more time than AD calves. PC calves spent 5 % less time active compared to RS (P < 0.000), and there was no significant difference in activity compared to AD. PC calves spent 4 % less time not active compared to RS (P = 0.017) and 15 % less time inactive compared to AD calves (P < 0.001). There was no difference among PC, RS and AD in overall time spent ruminating. When comparing PC calves from 100 % PC and commingled pens, 100 % PC calves spent 5 % more time eating compared to a 75 % ratio PC and 5 % more time eating compared to a 25 % ratio PC pen. However, time spent eating was not significantly different between 100 % PC and 50 % ratio PC. Furthermore, PC calves had increased time spent eating and less time spent active and not active during the first 7 days after arrival at the feedlot compared to RS and AD calves. When commingled with AD calves, PC calves had more time spent eating and reduced time spent active and not active; therefore, PC calves have exhibited increased feeding behaviour also after being commingled with AD calves at the feedlot. The current study acknowledges the limitations of the field experiment that not all confounding variables could be controlled for, explicitly pen effect due to the lack of replication of pens across groups.

18P Adoptive cell therapy (ACT) with bispecific gamma delta TCR+ invariant TCR+ NKT-like cells for multiple myeloma (MM): Comparison of preconditioning (PC) on outcome

AVM0703 (AVM) is the subject of an actively enrolling US trial in relapsed/refractory (R/R) no-option Non-Hodgkin’s Lymphoma (NHL), with drug related adverse events limited to grades 1-3 and durable complete (CR) and partial responses (PR) to date. Acute supra-pharmacologic doses (>6 mg/kg) of AVM0703 mobilized endogenous bispecific gdTCR+ invTCR+ Natural Killer T-like cells (AVM_NKT) (PCT/US21/19773) in mice, humanized mice and clinical trial patients1. An ACT model was conducted to verify the direct tumor killing activity of AVM0703 induced novel immune cells (AVM_NKT) and to determine the effect of different PC on tumor killing of the ACT. MOPC315 (Balb/c) MM cells were inoculated into the flank as single cell suspensions. When tumor volume reached ∼400mm3 well-established tumors, mice were PC’d with human equivalent dose (HED) cyclophosphamide-fludarabine (CyFlu HED 500/30 mg/mm2), with Placebo (PL) or with AVM0703 HED 18 mg/kg. ACT splenocytes (3.3M) from mice dosed with PL or AVM were iv injected 48 hours later (PL_ACT had 8,240 AVM_NKT and AVM_ACT had 150,000). The next day (13-16 hours later) the mice were euthanized and remaining live MOPC cells were measured in the tumor, spleen, bone marrow, thymus and blood by flow cytometry. PC was necessary for AVM_ACT effect since there was no difference in live MOPC cells between AVM_ACT versus PL_ACT in mice PC’d with PL. AVM PC was equivalent to CyFlu PC against MOPC in tumor and spleen when AVM_ACT were transferred. Neither AVM nor CyFlu PC (with AVM_ACT) reduced MOPC in blood, bone marrow or thymus compared to PL PC. Repeat daily AVM and CyFlu dosing for PC will be explored in subsequent studies.Table: 18PPCPlaceboAVMAVMCyFluCyFluACTAVMPlaceboAVMPlaceboAVM* P<0.05 versus Placebo PC with Placebo ACTTumor***Spleen***BloodBone marrow*Thymus Open table in a new tab AVM0703 could be a less-toxic PC agent before CarT or other ACT. 1 Blood 2021:138(S1) 4557

Effect of Heat Shock Preconditioning on Pressure Injury Prevention via Hsp27 Upregulation in Rat Models.

Pressure injury (PI) prevention is a huge industry and involves various interventions. Temperature and moisture are important factors for wound healing; however, the active mechanism by which “moist heat” affects PI prevention has not yet been clarified. Thus, we explored the protective and therapeutic effects of hydrotherapy on PI based on the preconditioning (PC) principle, which might be useful for clinical practice. This study aimed to investigate the preventive mechanisms of heat shock preconditioning on PIs in rat models. The experiment was performed in the basic medical laboratory of Nagano College of Nursing in Japan. Ten rats were divided into two groups, with five rats in each group. Rats in the control group were not bathed. Rats in the preconditioning group (PC group) were bathed with hot tap-water. Bathing was conducted thrice a week. After bathing for 4 weeks, the PI model was constructed on the rats’ dorsal skin. The skin temperature, skin moisture, and area of ulcers were compared between the two groups. In vitro, we investigated the expression of heat shock protein 27 (Hsp27) in 6, 12, and 24 h after the PI model was constructed through Western blot analysis. Ulcers occurred in the control group 24 h after the PI model constructed, wheras the PC group exhibited ulcers after 36 h. The ulcer area was larger in the control group than that in the PC group after 24 h (all p < 0.05). The temperatures of PI wounds in the control group decreased and were lower than those in the PC group after 1, 6, 12, 36, and 48 h (all p < 0.05). However, the skin moisture levels of PI wounds increased in the control group and were higher than those in the PC group at the same time (all p < 0.05). Using Western blot analysis, hydrotherapy preconditioning showed the potential to increase Hsp27 expression after pressure was released (p < 0.05). We determine that heat shock preconditioning had a preventive effect on PIs in rat models, a result that may be associated with their actions in the upregulation of Hsp27.

Moderate Ethanol-Preconditioning Offers Ischemic Tolerance Against Focal Cerebral Ischemic/Reperfusion: Role of Large Conductance Calcium-Activated Potassium Channel.

The mechanism underlying moderate ethanol (EtOH)-preconditioning (PC) against ischemic brain injury remains unclear. We evaluated the role of large conductance calcium-sensitive potassium (BKCa) channels in EtOH-PC. Almost one hundred and ninetynormal adult SD rats (8 to 10weeks, 320-350g) were enrolled in this study. Ischemic/reperfusion (I/R) brain injury was induced in rats by middle cerebral artery occlusion for 2h followed by reperfusion for 24h. EtOH or the BKCa channel opener, NS11021, was administered 24h before I/R with or without pre-treatment with the BKCa channel blocker, paxilline. Infarct volumes were measured by tissue staining and imaging, and neurological functions were assessed by a scoring system. The expression of BKCa channel subunit α was detected by Western blotting, and cell apoptosis was assessed using staining. Prior (24h) administration of ethanol that produced a peak plasma concentration of ~ 45mg/dl in rats would offer neuroprotection after cerebral I/R. In addition, the expression of BKCa channel α-subunit was significantly increased 24h after EtOH-PC (n = 10; control: 2.00 ± 0.09, EtOH: 1.00 ± 0.06; P < 0.5). Compared to I/R, EtOH-PC enhanced the expression of BKCa channel α-subunit both in the penumbra (n = 10; 24h: I/R: 1.25 ± 0.10, EtOH-PC + I/R: 1.99 ± 0.12; P < 0.01; 4h: I/R: 1.03 ± 0.03, EtOH-PC + I/R: 1.49 ± 0.05; P < 0.001) and infarct core (n = 10; 4h: I/R: 1.04 ± 0.04, EtOH-PC + I/R: 1.42 ± 0.05; P < 0.001), improved the neurological function (n = 10; I/R: 14.00 (12.75-15.00), EtOH-PC + I/R: 7.00 (4.75-8.25); P < 0.001), attenuated the apoptosis (n = 10; I/R: 26.80 ± 0.69, EtOH-PC + I/R: 8.46 ± 0.31; P < 0.001), and decreased the infarct volume (n = 10; I/R: 244.00 ± 26.24, EtOH-PC + I/R: 70.09 ± 14.69; P < 0.001) after experimental cerebral I/R. These changes were reversed by paxilline administration. The moderate EtOH-PC protects against I/R-induced brain damage dependent on the upregulation BKCa channels.

Effect of 3 vs. 3 Soccer Small-Sided Game on Various Performance, Inflammatory, Muscle Damage and Hormonal Indicators in Semi-Professional Players.

The purpose of this study was to examine the effect of a soccer small-sided game (SSG) on performance, inflammatory, muscle damage and hormonal indicators. Twenty-two male soccer players participated and were assigned to either experimental (EXP = 12) or control (CON = 10) groups. Subjective fatigue (RPE) and lactate (La¯) were measured during the SSG; vertical squat jump (SJ), 20-m sprint, creatine kinase (CK), interleukin-6 (IL-6), cortisol (C), and testosterone (T) were measured before (PRE), after (POST), 24 h, 48 h, and 72 h after the SSG in the EXP group. The heart rate during the SSG reached 92 ± 3% of their HRmax, whereas La¯ and RPE reached 13.02 ± 1.60 mmol·L−1 and 15 ± 1 after SSG, respectively. The IL-6, different among measurements (F (1.04, 11.50) = 504.82, p < 0.001), peaked (3.52 ± 0.43 pg·mL−1 [95%CI; 3.28–3.77]) after the SSG and returned to baseline 24 h later. The CK, different among measurements (F (1.76, 19.32) = 93.96, p < 0.001), peaked (536.58 ± 124.73U·L−1 [95%CI; 466.01–607.15]) 24 h after the SSG and remained significantly higher than PRE condition in POST and up to 72 h later. The T/C ratio, significantly different among measurements (F (1.73, 19.05) = 12.12, p < 0.001), was at its lowest (0.44 ± 0.16 [95%CI; 0.35–0.54]) immediately after the SSG (p < 0.05) and returned to baseline after 24 h. It seems that 48 h (at the most) after an SSG is adequate time for players to recover, and a high training load should be avoided sooner than 24 h after an SSG.

May unpredictable events affect monkey welfare under human care?

This study aimed at evaluating the effects of unpredictability on behavioral and clinical aspects of Geoffroy's woolly monkey (Lagothrix cana cana) - a frugivorous Amazonian primate species - under human care. We studied seven individuals subjected to five conditions: two control conditions (PRE and POST; 10 days each), and three experimental conditions in which unpredictability was associated to food presentation. Each experimental condition had three intensities (stages): spatial unpredictability (food offer in unusual, changing places; S1, S2, S3), temporal unpredictability (food offer in unusual, changing times; T1, T2, T3), and spatial and temporal unpredictability combined (C1, C2, C3). Each stage lasted 10 days. Behaviors were collected using scan sampling in 24 five-minute daily sessions, with records taken every 20 s. A Behavioral Diversity Index (BDI) was also calculated daily, and welfare assessment was performed at each stage, with the use of the Five Domains Model. Condition T promoted an increase in exploration, and reductions in behaviors indicative of dysfunction, surveillance, maintenance, and in affiliative interactions. In condition S, we found an increase in foraging, and reductions in maintenance behaviors and agonistic interactions. Finally, in condition C, we recorded increases in exploration, and reductions in behaviors indicative of dysfunction, surveillance, maintenance, affiliative and agonistic interactions. Most of these effects have been correlated to improved welfare. The Five Domains Model evaluation also supported an improvement in welfare levels in all experimental stages, compared to PRE condition. Our behavioral and welfare assessment results pointed that unpredictability promoted an improvement in the welfare levels for the animals studied, and is recommended for the maintenance of the species under human care.

First-in-human clinical trial of an oncolytic adenovirus armed with TNFa and IL-2 in patients with advanced melanoma receiving adoptive cell transfer of tumor-infiltrating lymphocytes.

TPS9590 Background: The long-term complete remission experienced by some cancer patients after receiving immunotherapies, such as adoptively transferred tumor-infiltrating lymphocytes (ACT-TIL), represent the ideal outcome to pursue for the development of therapies for oncology. At the same time, those responses are limited to a minority of treated patients, and adverse events resulting from preconditioning chemotherapy and postconditioning IL2 are a rather common scenario. TILT-123 is an oncolytic adenovirus (Ad5/3-E2F-D24-TNFa-IRES-IL2) designed to enable T-cell therapies and checkpoint inhibition against cancer. Ultimately, the aim of this approach is to expand the proportion of patients benefiting from immunotherapies. Extensive preclinical studies with this technology showed that the virus repolarizes the tumor’s immune microenvironment in a way that favors T-cell presence and their activity against tumor cells. When TILT-123 was used together with TILs in preclinical in vivo models, animals had a higher chance to display curative results while showing reduced toxicity as the use of TILT-123 replaces the pre and post conditioning (Havunen R. et al Mol Ther Oncolytics 2016, Santos J.M. Mol Ther 2018). A Phase I clinical trial (NCT04217473) is ongoing to evaluate safety of the approach in advanced melanoma patients. Extensive biological assays of patient aim to characterize viral transduction of tumors through the intravenous and intratumoral routes, and the recruitment of activated lymphocytes to tumors in order to elucidate the immunological impact of the drug. Methods: The primary aim of NCT04217473 is to evaluate safety of TILT-123 in advanced melanoma patients. Refractory or recurrent stage III/IV patients, which cannot be treated with curative intent with available therapies, and are eligible for ACT-TIL therapy, can potentially participate in the study. TILT-123 administration begins while the manufacturing of ACT-TILs takes place and continues after the TIL-therapy is administered to the patient. In contrast with standard ACT-TIL therapy, patients are not conditioned with lymphodepletion or IL-2 in this approach. Patients must present at least one biopsiable/operable tumor for the generation of TILs and another injectable lesion for intratumoral administration of TILT-123. The open label, dose escalation trial has the main endpoint of establishing TILT-123 safety by day 36 (prior to TIL administration), which is based on the incidence of adverse events, severe adverse events, vital signs, ECG, and safety laboratory results. Secondary endpoints include safety and tolerability after TIL therapy has been administered, evaluation of antitumor responses and studies of tumor immune repolarization. Cohorts 1-3 have been completed without DLTs. Enrollment in cohort 4 was initiated in December 2021. Clinical trial information: NCT04217473.

The impact of action observation on the intention for action engagement

ABSTRACT Based on the embodiment theory of action and the shared neural networks between action execution and action observation, we investigate how an acute bout of exercise and action observation might differently modulate proneness for exercise. We used a visual analog scale to assess proneness for exercise and collected salivary cortisol pre and post conditions to investigate if cortisol secretion subtends proneness for exercise derived from seeing and doing. Thirty University students (16 Active and 14 Sedentary) volunteered to participate in all 3 conditions (Control; Action Execution; and Action Observation). Crucially, we find that the mere observation of action leads to a greater enhancement of proneness for exercise when compared to action execution. Increased proneness for exercise, however, is not associated with higher cortisol secretion linked to cortical motor activity brought about by embodiment. We suggest that the decisional motivation process is cognitive and top-down and not bottom-up as embodiment theories would suggest. Moreover, we did not find any difference between active and sedentary participants in cortisol secretion across conditions, suggesting a complex interaction between intensity and chronicity on perceived exertion and cortisol secretion. Crucially, our findings contribute to further our understanding of the mechanisms of exercise engagement.