Project description:Acetaminophen (APAP) overdose accounts for the highest incidence of acute liver failure, despite the availability of an antidote i.e. N-acetylcysteine. This calls for alternative strategies to manage APAP-induced liver injury (AILI). Therapeutic hypothermia has been explored in past studies for hepatoprotection, but these phenomenal reports lack clarification of its optimal window for application, and mechanistic effects in specific AILI. Hence, we conducted an in vitro study with transforming growth factor-α transgenic mouse hepatocytes cell line, TAMH, and human liver hepatocytes cell line, L-02, where cells were conditioned with deep (25°C) or moderate (32°C) hypothermia before, during or after APAP toxicity. Cell viability was evaluated as a hallmark of cytoprotection, along with cell death. Simultaneously, cold shock proteins (CSPs) and heat shock proteins expressions were monitored; key liver functions including drug-metabolizing ability and hepatic clearance were also investigated. Herein, we demonstrated significant hepatoprotection with 24-hour moderate hypothermic conditioning during AILI and this effect sustained for at least 24 hours of rewarming. Such liver preservation was associated with a CSP-RNA-binding motif protein 3 (RBM3) as its knockdown promptly abolished the cytoprotective effects of hypothermia. With mild and reversible liver perturbations, hypothermic therapy appears promising and its RBM3 involvement deserves future exploration.
Project description:Although therapeutic hypothermia (TH) is the standard of care for hypoxic ischaemic encephalopathy in high-income countries, the safety and efficacy of this therapy in low-income and middle-income countries (LMICs) is unknown. We aimed to describe the feasibility of TH using a low-cost servo-controlled cooling device and the short-term outcomes of the cooled babies in LMIC.DesignWe recruited babies with moderate or severe hypoxic ischaemic encephalopathy (aged <6 hours) admitted to public sector tertiary neonatal units in India over a 28-month period. We administered whole-body cooling (set core temperature 33.5°C) using a servo-controlled device for 72 hours, followed by passive rewarming. We collected the data on short-term neonatal outcomes prior to hospital discharge.ResultsEighty-two babies were included-61 (74%) had moderate and 21 (26%) had severe encephalopathy. Mean (SD) hypothermia cooling induction time was 1.7 hour (1.5) and the effective cooling time 95% (0.08). The mean (SD) hypothermia induction time was 1.7 hour (1.5 hour), core temperature during cooling was 33.4°C (0.2), rewarming rate was 0.34°C (0.16°C) per hour and the effective cooling time was 95% (8%). Twenty-five (51%) babies had gastric bleeds, 6 (12%) had pulmonary bleeds and 21 (27%) had meconium on delivery. Fifteen (18%) babies died before discharge from hospital. Heart rate more than 120 bpm during cooling (P=0.01) and gastric bleeds (P<0.001) were associated with neonatal mortality.ConclusionsThe low-cost servo-controlled cooling device maintained the core temperature well within the target range. Adequately powered clinical trials are required to establish the safety and efficacy of TH in LMICs.Clinical trial registration numberNCT01760629.
Project description:IntroductionThe precise temperature for optimal neuroprotection in infants with neonatal encephalopathy is unclear. Our aim was to assess systemic effects of whole-body cooling to 35 °C, 33.5 °C, and 30 °C in a piglet model of perinatal asphyxia.MethodsTwenty-eight anesthetized male piglets aged <24 h underwent hypoxia-ischemia (HI) and were randomized to normothermia or cooling to rectal temperature (Trec) 35 °C, 33.5 °C, or 30 °C during 2-26 h after insult (n = 7 in each group). HR, MABP, and Trec were recorded continuously.ResultsFive animals cooled to 30 °C had fatal cardiac arrests. During 30 °C cooling, heart rate (HR) was lower vs. normothermia (P < 0.001). Although mean arterial blood pressure (MABP) did not vary between groups, more fluid boluses were needed at 30 °C than at normothermia (P < 0.02); dopamine use was higher at 30 °C than at normothermia or 35 °C (P = 0.005 and P = 0.02, respectively). Base deficit was increased at 30 °C at 12, 24, and 36 h vs. all other groups (P < 0.05), pH was acidotic at 36 h vs. normothermia (P = 0.04), and blood glucose was higher for the 30 °C group at 12 h vs. the normothermia and 35 °C groups (P < 0.05). Potassium was lower at 12 h in the 30 °C group vs. the 33.5 °C and 35 °C groups. There was no difference in cortisol level between groups.DiscussionCooling to 30 °C led to metabolic derangement and more cardiac arrests and deaths than cooling to 33.5 °C or 35 °C. Inadvertent overcooling should be avoided.
Project description:IntroductionThis study aimed to assess the effects of different temperature settings of hypothermic circulatory arrest (HCA) on intestinal barrier function in a piglet model.MethodsTwenty Wuzhishan piglets were randomly assigned to 40 min of HCA at 18°C (DHCA group, n = 5), 40 min of HCA at 24°C (MHCA group, n = 5), normothermic cardiopulmonary bypass (CPB group, n = 5) or sham operation (SO group, n = 5). Serum D-lactate (SDL) and lipopolysaccharide (LPS) levels were determined. Microdialysis parameters (glucose, lactate, pyruvate and glycerol) in the intestinal dialysate were measured. After 180 min of reperfusion, intestinal samples were harvested for real-time polymerase chain reaction and western blotting measurements for E-cadherin and Claudin-1.ResultsHigher levels of SDL and LPS were detected in the DHCA group than in the MHCA group (P < 0.001). Both MHCA and DHCA groups exhibited lower glucose levels, higher lactate and glycerol levels and a higher lactate to pyruvate (L/P) ratio compared with the CPB group (p<0.05); the DHCA group had higher lactate and glycerol levels and a higher L/P ratio (p<0.05) but similar glucose levels compared to the MHCA group. No significant differences in E-cadherin mRNA or protein levels were noted. Upregulation of claudin-1 mRNA levels was detected in both the DHCA and MHCA animals' intestines (P < 0.01), but only the DHCA group exhibited a decrease in claudin-1 protein expression (P < 0.01).ConclusionHCA altered the energy metabolism and expression of epithelial junctions in the intestine. Moderate hypothermia (24°C) was less detrimental to the markers of normal functioning of the intestinal barrier than deep hypothermia (18°C).
Project description:To examine the predictive ability of stage of hypoxic-ischemic encephalopathy (HIE) for death or moderate/severe disability at 18 months among neonates undergoing hypothermia.Stage of encephalopathy was evaluated at <6 hours of age, during study intervention, and at discharge among 204 participants in the National Institute of Child Health and Human Development Neonatal Research Network Trial of whole body hypothermia for HIE. HIE was examined as a predictor of outcome by regression models.Moderate and severe HIE occurred at <6 hours of age among 68% and 32% of 101 hypothermia group infants and 60% and 40% of 103 control group infants, respectively. At 24 and 48 hours of study intervention, infants in the hypothermia group had less severe HIE than infants in the control group. Persistence of severe HIE at 72 hours increased the risk of death or disability after controlling for treatment group. The discharge exam improved the predictive value of stage of HIE at <6 hours for death/disability.On serial neurologic examinations, improvement in stage of HIE was associated with cooling. Persistence of severe HIE at 72 hours and an abnormal neurologic exam at discharge were associated with a greater risk of death or disability.
Project description:Hypothermia is a promising therapeutic strategy for severe vasospasm and other types of non-thrombotic cerebral ischemia, but its clinical application is limited by significant systemic side effects. We aimed to develop an intraventricular device for the controlled cooling of the cerebrospinal fluid, to produce a targeted hypothermia in the affected cerebral hemisphere with a minimal effect on systemic temperature. An intraventricular cooling device (acronym: V-COOL) was developed by in silico modelling, in vitro testing, and in vivo proof-of-concept application in healthy Wistar rats (n = 42). Cerebral cortical temperature, rectal temperature, and intracranial pressure were monitored at increasing flow rate (0.2 to 0.8 mL/min) and duration of application (10 to 60 min). Survival, neurological outcome, and MRI volumetric analysis of the ventricular system were assessed during the first 24 h. The V-COOL prototyping was designed to minimize extra-cranial heat transfer and intra-cranial pressure load. In vivo application of the V-COOL device produced a flow rate-dependent decrease in cerebral cortical temperature, without affecting systemic temperature. The target degree of cerebral cooling (- 3.0 °C) was obtained in 4.48 min at the flow rate of 0.4 mL/min, without significant changes in intracranial pressure. Survival and neurological outcome at 24 h showed no significant difference compared to sham-treated rats. MRI study showed a transient dilation of the ventricular system (+ 38%) in a subset of animals. The V-COOL technology provides an effective, rapid, selective, and safe cerebral cooling to a clinically relevant degree of - 3.0 °C.
Project description:Using state-of-the-art technology, interactions of eye, head and intersegmental body movements were analyzed for the first time during multiple twisting somersaults of high-level gymnasts. With this aim, we used a unique combination of a 16-channel infrared kinemetric system; a three-dimensional video kinemetric system; wireless electromyography; and a specialized wireless sport-video-oculography system, which was able to capture and calculate precise oculomotor data under conditions of rapid multiaxial acceleration. All data were synchronized and integrated in a multimodal software tool for three-dimensional analysis. During specific phases of the recorded movements, a previously unknown eye-head-body interaction was observed. The phenomenon was marked by a prolonged and complete suppression of gaze-stabilizing eye movements, in favor of a tight coupling with the head, spine and joint movements of the gymnasts. Potential reasons for these observations are discussed with regard to earlier findings and integrated within a functional model.
Project description:IntroductionNeurovascular decoupling is a common consequence after brain injuries like sports-related concussion. Failure to appropriately match cerebral blood flow (CBF) with increases in metabolic demands of the brain can lead to alterations in neurological function and symptom presentation. Therapeutic hypothermia has been used in medicine for neuroprotection and has been shown to improve outcome. This study aimed to examine the real time effect of selective head cooling on healthy controls and concussed athletes via magnetic resonance spectroscopy (MRS) and arterial spin labeling (ASL) measures.Methods24 participants (12 controls; 12 concussed) underwent study procedures including the Post-Concussion Symptom Severity (PCSS) Rating Form and an MRI cooling protocol (pre-cooling (T1 MPRAGE, ASL, single volume spectroscopy (SVS)); during cooling (ASL, SVS)).ResultsResults showed general decreases in brain temperature as a function of time for both groups. Repeated measures ANOVA showed a significant main effect of time (F = 7.94, p < 0.001) and group (F = 22.21, p < 0.001) on temperature, but no significant interaction of group and time (F = 1.36, p = 0.237). CBF assessed via ASL was non-significantly lower in concussed individuals at pre-cooling and generalized linear mixed model analyses demonstrated a significant main effect of time for the occipital left ROI (F = 11.29, p = 0.002) and occipital right ROI (F = 13.39, p = 0.001). There was no relationship between any MRI metric and PCSS symptom burden.DiscussionThese findings suggest the feasibility of MRS thermometry to monitor alterations of brain temperature in concussed athletes and that metabolic responses in response to cooling after concussion may differ from controls.
Project description:We aimed to investigate whether selective head-neck cooling could shorten recovery after sports-related concussions (SRCs). In a nonrandomized study of 15 Swedish professional ice hockey teams, 29 concussed players received immediate head and neck cooling for ≥30 min (initiated at 12.3 ± 9.2 min post-SRC by a portable cooling system), and 52 SRC controls received standard management. Players receiving head-neck cooling had shorter time to return-to-play than controls (7 vs 12.5 days, p < 0.0001), and 7% in the intervention group versus 25% in the control group were out of play for ≥3 weeks (p = 0.07). Immediate selective head-neck cooling is a promising option in the acute management of SRC that should be addressed in larger cohorts.