BACKGROUND:Good neurological outcome after cardiac arrest(CA) is hard to achieve for clinicians.Experimental and clinical evidence suggests that therapeutic mild hypothermia is beneficial.This study aimed to assess th...BACKGROUND:Good neurological outcome after cardiac arrest(CA) is hard to achieve for clinicians.Experimental and clinical evidence suggests that therapeutic mild hypothermia is beneficial.This study aimed to assess the effectiveness and safety of therapeutic mild hypothermia in patients successfully resuscitated from CA using a meta-analysis.METHODS:We searched the MEDLINE(1966 to April 2012),OVID(1980 to April 2012),EMBASE(1980 to April 2012),Chinese bio-medical literature & retrieval system(CBM)(1978 to April 2012),Chinese medical current contents(CMCC)(1995 to April 2012),and Chinese medical academic conference(CMAC)(1994 to April 2012).Studies were included if 1) the study design was a randomized controlled trial(RCT);2) the study population included patients successfully resuscitated from CA,and received either standard post-resuscitation care with normothermia or mild hypothermia;3) the study provided data on good neurologic outcome and survival to hospital discharge.Relative risk(RR) and 95%confidence interval(CI) were used to pool the effect.RESULTS:The study included four RCTs with a total of 417 patients successfully resuscitated from CA.Compared to standard post-resuscitation care with normothermia,patients in the hypothermia group were more likely to have good neurologic outcome(RR=1.43,95%CI 1.14-1.80,P=0.002) and were more likely to survive to hospital discharge(RR=1.32,95%CI 1.08-1.63,P=0.008).There was no significant difference in adverse events between the normothermia and hypothermia groups(P>0.05),nor heterogeneity and publication bias.CONCLUSION:Therapeutic mild hypothermia improves neurologic outcome and survival in patients successfully resuscitated from CA.展开更多
Through investigating the effect of mild hypothermia on activity of nitric oxide snythase (NOS) in cortical neurons and glycemia levels of neonatal rats with hypoxic ischemic brain damage (HIBD). We studied the mechan...Through investigating the effect of mild hypothermia on activity of nitric oxide snythase (NOS) in cortical neurons and glycemia levels of neonatal rats with hypoxic ischemic brain damage (HIBD). We studied the mechanism of protecting hypoxic ischemic neurons of mild hypothermia. We established neonatal rat HIBD models, used NOS immunohistochemistry and glycemia determination by micromethod. The number of cortical NOS positive neurons after hypoxic ischemia was significantly decreased as compared with controls. The glycemia levels was significantly increased than that controls. No significant difference was found in number of cortical NOS positive neurons and glycemia levels between 31℃ and 34℃ mild hypothemia. The results imply that hypothermia can decrease overproduction of NO through inhibiting the increase of the activity of NOS, and increase the glycemia levels, thus protect the hypoxic ischemic neurons.展开更多
To study the effect of mild hypothermia on glucose metabolism and glycerol of brain tissue in patients with severe traumatic brain injury (sTBI).Methods All 33 patients with sTBI(GCS≤8) were randomly divided into hyp...To study the effect of mild hypothermia on glucose metabolism and glycerol of brain tissue in patients with severe traumatic brain injury (sTBI).Methods All 33 patients with sTBI(GCS≤8) were randomly divided into hypothermic group and control group.Microdialysis catheters were inserted into the cerebral cortex of perilesion,relative normal brain tissue and subcutaneous tissue of abdomen in order to analyze the concentrations of lactate/pyruvate (L/P),lactate/glucose (L/G) and the glycerol(Gly) in extracellular fluid (ECF).Results In comparison with the control group,the concentration of L/G,L/P and Gly in periphery and that of L/P in ECF of the “normal brain tissue” were significantly decreased in the hypothermic group.In control group,concentration of L/G,L/P and Gly in periphery were higher than those in relative normal brain.In the hypothermic group,L/P concentration in periphery was higher than that in relative normal brain.Conclusion Mild hypothermia protects brain by decreasing concentrations of L/G,L/P and Gly in periphery and L/P concentration in “normal brain tissue”.The energy crisis and membrane phospholipid breakage in periphery are easier to happen after TBI,where mild hypothermia exerts significant protgective role.12 refs,3 tabs.展开更多
Cold-inducible RNA-binding protein(CIRP), a key regulatory protein, could be facilitated by mild hypothermia in the brain, heart and liver. This study observed the effects of mild hypothermia at 31 ± 0.5℃ on tra...Cold-inducible RNA-binding protein(CIRP), a key regulatory protein, could be facilitated by mild hypothermia in the brain, heart and liver. This study observed the effects of mild hypothermia at 31 ± 0.5℃ on traumatic brain injury in rats. Results demonstrated that mild hypothermia suppressed apoptosis in the cortex, hippocampus and hypothalamus, facilitated CIRP m RNA and protein expression in these regions, especially in the hypothalamus. The anti-apoptotic effect of mild hypothermia disappeared after CIRP silencing. There was no correlation between mitogen-activated extracellular signal-regulated kinase activation and CIRP silencing. CIRP silencing inhibited extracellular signal-regulated kinase-1/2 activation. These indicate that CIRP inhibits apoptosis by affecting extracellular signal-regulated kinase-1/2 activation, and exerts a neuroprotective effect during mild hypothermia for traumatic brain injury.展开更多
Because the inhibition of Nogo proteins can promote neurite growth and nerve cell differentiation, a cell-scaffold complex seeded with Nogo receptor(Ng R)-silenced neural stem cells and Schwann cells may be able to im...Because the inhibition of Nogo proteins can promote neurite growth and nerve cell differentiation, a cell-scaffold complex seeded with Nogo receptor(Ng R)-silenced neural stem cells and Schwann cells may be able to improve the microenvironment for spinal cord injury repair. Previous studies have found that mild hypothermia helps to attenuate secondary damage in the spinal cord and exerts a neuroprotective effect. Here, we constructed a cell-scaffold complex consisting of a poly(D,L-lactide-co-glycolic acid)(PLGA) scaffold seeded with Ng R-silenced neural stem cells and Schwann cells, and determined the effects of mild hypothermia combined with the cell-scaffold complexes on the spinal cord hemi-transection injury in the T9 segment in rats. Compared with the PLGA group and the Ng R-silencing cells + PLGA group, hindlimb motor function and nerve electrophysiological function were clearly improved, pathological changes in the injured spinal cord were attenuated, and the number of surviving cells and nerve fibers were increased in the group treated with the Ng R-silenced cell scaffold + mild hypothermia at 34°C for 6 hours. Furthermore, fewer pathological changes to the injured spinal cord and more surviving cells and nerve fibers were found after mild hypothermia therapy than in injuries not treated with mild hypothermia. These experimental results indicate that mild hypothermia combined with Ng R gene-silenced cells in a PLGA scaffold may be an effective therapy for treating spinal cord injury.展开更多
Several studies have demonstrated that mild hypothermia exhibits a neuroprotective role and it can inhibit endothelial cell apoptosis following ischemia/reperfusion injury by decreasing caspase-3 expression. It is hyp...Several studies have demonstrated that mild hypothermia exhibits a neuroprotective role and it can inhibit endothelial cell apoptosis following ischemia/reperfusion injury by decreasing caspase-3 expression. It is hypothesized that mild hypothermia exhibits neuroprotective effects on neurons exposed to ischemia/reperfusion condition produced by oxygen-glucose deprivation. Mild hypothermia significantly reduced the number of apoptotic neurons, decreased the expression of pro-apoptotic protein Bax and increased mitochondrial membrane potential, with the peak of anti-apoptotic effect appearing between 6 and 12 hours after the injury. These findings indicate that mild hypothermia inhibits neuronal apoptosis following ischemia/reperfusion injury by protecting the mitochondria and that the effective time window is 6–12 hours after ischemia/reperfusion injury.展开更多
Fractional anisotropy values in diffusion tensor imaging can quantitatively reflect the consistency of nerve fibers after brain damage, where higher values generally indicate less damage to nerve fibers. Therefore, we...Fractional anisotropy values in diffusion tensor imaging can quantitatively reflect the consistency of nerve fibers after brain damage, where higher values generally indicate less damage to nerve fibers. Therefore, we hypothesized that diffusion tensor imaging could be used to evaluate the effect of mild hypothermia on diffuse axonal injury. A total of 102 patients with diffuse axonal injury were randomly divided into two groups: normothermic and mild hypothermic treatment groups. Patient's modified Rankin scale scores 2 months after mild hypothermia were significantly lower than those for the normothermia group. The difference in average fractional anisotropy value for each region of interest before and after mild hypothermia was 1.32–1.36 times higher than the value in the normothermia group. Quantitative assessment of diffusion tensor imaging indicates that mild hypothermia therapy may be beneficial for patients with diffuse axonal injury.展开更多
BACKGROUND: It is widely accepted that mild hypothermia can protect against injury to cerebral ischemia/reperfusion. OBJECTIVE: To observe the effects of mild hypothermia on microtubule-associated protein 2 (MAP2) exp...BACKGROUND: It is widely accepted that mild hypothermia can protect against injury to cerebral ischemia/reperfusion. OBJECTIVE: To observe the effects of mild hypothermia on microtubule-associated protein 2 (MAP2) expression in the hippocampal dentate gyrus in rats following cerebral ischemia/reperfusion. Also, to study neuronal ultrastructural changes in the dentate gyrus to investigate the mechanism of the protection against injury to cerebral ischemia/reperfusion conferred by mild hypothermia. DESIGN, TIME AND SETTING: This randomized grouping, neural cell morphology trial was performed at the Laboratory Animal Center of Yijishan Hospital between March and June 2007. MATERIALS: Eighty-five healthy male Sprague Dawley rats were randomly allocated to three groups: mild hypothermia (n = 40), normothermia (n = 40), and sham-operated (n = 5). METHODS: Cerebral ischemia/reperfusion injury was induced by the suture method in the mild hypothermia and normothermia groups, with a threading depth of 180.5 mm. In the sham-operated group, the suture was inserted 15 mm, with no vascular ligation, and was followed by reperfusion 2 hours later. In the sham-operated and normothermia groups, the rat rectal temperature was maintained at 36–37 ℃; in the mild hypothermia group, it was controlled at 32–33 ℃. MAIN OUTCOME MEASURES: The hippocampal dentate gyrus was serially sectioned for hematoxylin-eosin staining and MAP2 immunohistochemistry. Ultrastructural changes and the MAP2 absorbance value of the hippocampal dentate gyrus were examined by transmission electron microscopy. RESULTS: The sham-operated group exhibited approximately normal ultrastructure of neurons in the bilateral hippocampal dentate gyrus. In the normothermia group, ischemic hippocampal dentate gyrus neurons were found with markedly fewer normal mitochondria, greatly proliferated rough endoplasmic reticulum, and a swollen and dysmorphic Golgi. In the mild hypothermia group, at each corresponding time point, these abnormal changes were noticeably alleviated. The number of necrotic mitochondria, as well as the degree of degeneration, was obviously reduced compared with the normothermia group. At days 6, 8 and 10 following reperfusion, the normothermia group exhibited lower neurological function scores than the mild hypothermia group (P < 0.05). In the normothermia group, the absorbance value of MAP2 expression in the ischemic hippocampal dentate gyrus was significantly decreased compared with the sham-operated group (P < 0.01), was slightly increased at 4 days, and reached a peak on day 8. The mild hypothermia group showed an absorbance value of MAP2 expression in the ischemic hippocampal dentate gyrus similar to the normothermia group, but it reached a peak on day 6. On days 1, 2, 4 and 6 following reperfusion, MAP2 expression was lower in the mild hypothermia group than in the sham-operated group, but it was higher than the normothermia group (P < 0.05). CONCLUSION: Mild hypothermia applied in early ischemia can alleviate brain injury. This may be due to an enhancement of MAP2 expression.展开更多
BACKGROUND: Cardiac arrest(CA) is a common and serious event in emergency medicine. Despite recent improvements in resuscitation techniques, the survival rate of patients with CA is unchanged. The present study was un...BACKGROUND: Cardiac arrest(CA) is a common and serious event in emergency medicine. Despite recent improvements in resuscitation techniques, the survival rate of patients with CA is unchanged. The present study was undertaken to observe the effect of mild hypothermia(MH) on the reactive oxygen species(ROS) and the effect of neurological function and related mechanisms.METHODS: Sixty-five healthy male Sprague Dawley(SD) adult rats were randomly(random number) divided into 2 groups: blank control group(n=5) and CPR group(n=60). CA was induced by asphyxia. The surviving rats were randomly(random number) divided into two groups: normothermia CPR group(NT) and hypothermia CPR group(HT). Normothermia of 37 °C was maintained in the NT group after return of spontaneous circulation(ROSC), hypothermal intervention of 32 °C was carried out in the HT group for 4 hours immediately after ROSC. Both the NT and HT groups were then randomly divided into 2 subgroups 12 hours and 24 hours after ROSC(NT-12, NT-24, HT-12, HT-24 subgroups). During observation, the neurological defi cit scores(NDSs) was recorded, then the bilateral hippocampi were obtained from rats' head, and monoplast suspension of fresh hippocampus tissue was made immediately to determine the level of intracellular ROS by flow cytometry. Transmission electron microscope was used to observe the ultramicro changes of cellular nucleus and mitochondria. Reverse transcription-polymerase chain reaction(RT-PCR) was used to determine the expression of caspase-3 m RNA, and western-blotting(WB) was used to determine the level of LC3 in frozen hippocampus tissue. Measured data were analyzed with paired sample t test and One-Way ANOVA.RESULTS: Of 60 rats with CA, 44(73%) were successfully resuscitated and 33(55%) survived until the end of the experiment. The NDSs of rats in the NT and HT groups were more signifi cantly reduced than those in the BC group(F=8.107, P<0.05), whereas the NDSs of rats in the HT-12 and HT-24 subgroups were significantly increased in comparison with those NDSs of rats in the NT-12 and NT-24 subgroups, respectively(t=9.692, P<0.001; t=14.374, P<0.001). The ROS in hippocampus nerve cells in the NT and HT groups signifi cantly increased compared to the BC group(F=16.824, P<0.05), whereas the ROS in the HT-12 and HT-24 subgroups significantly reduced compared with that ROS in the NT-12 and NT-24 subgroups, respectively(t=9.836, P<0.001; t=7.499, P<0.001). The expression of caspase-3 m RNA in hippocampus nerve cells in the NT and HT groups were signifi cantly increased compared to the BC group(F=24.527, P<0.05), whereas the expression of caspase-3 m RNA in rats of the HT-12 and HT-24 subgroups was signifi cantly reduced compared to the NT-12 and NT-24 subgroups, respectively(t=6.935, P<0.001; t=4.317, P<0.001). The expression of LC3B-II/I in hippocampus nerve cells of rats in the NT and HT groups signifi cantlyincreased compared to the BC group(F=6.584, P<0.05), whereas the expression of LC3B-II/I in rats of the HT-12 and HT-24 subgroups significantly reduced compared to the NT-12 and NT-24 subgroups, respectively(t=10.836, P<0.001; t=2.653, P=0.02). Ultrastructure damage of nucleus and mitochondria in the NT group was more evident than in the BC group, and eumorphism of nucleus and mitochondria were maintained in rats of the HT group compared with the NT group.CONCLUSION: Mild hypothermia lessened the injury of nerve cells and improved the neurological function of rats that survived from cardiac arrest by reducing the ROS production of nerve cells and inhibiting the expression of caspase-3 m RNA and LC3, leading to cellular apoptosis and massive autophagy in rats that survived from cardiac arrest after CPR.展开更多
BACKGROUND: Matrix metalloproteinase-9 (MMP-9) expression increases with intracerebral hemorrhage, and participates in the pathophysiological processes of secondary brain injury after intracerebral hemorrhage. OBJECTI...BACKGROUND: Matrix metalloproteinase-9 (MMP-9) expression increases with intracerebral hemorrhage, and participates in the pathophysiological processes of secondary brain injury after intracerebral hemorrhage. OBJECTIVE: To investigate the effects of mild hypothermia on MMP-9 expression and brain edema in the perihematomal region of experimental intracerebral hemorrhage rats. DESIGN, TIME AND SETTING: The randomized, controlled experiment was performed at the Central Laboratory of Shandong Provincial Hospital between May and September 2007. MATERIALS: Seventy-two, Wistar, male rats, 12-weeks old, were used for this study. Rabbit anti-MMP-9 primary antibody was purchased from Boster, China. METHODS: Wistar rats were equally and randomly divided into normothermia and mild hypothermia groups. The two groups each comprised control, 6-hour intracerebral hemorrhage, 24-hour intracerebral hemorrhage, 48-hour intracerebral hemorrhage, 72-hour intracerebral hemorrhage, and 1-week intracerebral hemorrhage subgroups, with six rats in each subgroup. Rat models of intracerebral hemorrhage were established by injecting 100 μL of autologous blood into the rat caudate nucleus. Rats in the mild hypothermia group received four hours of local mild hypothermia immediately following the injection. Intracerebral temperature was maintained at (33 ± 0.5) ℃. Subsequently, intracerebral temperature was spontaneously recovered at 25 ℃. Rats in the control subgroup were not injected with autologous blood and received only with intracerebral hemorrhage. MAIN OUTCOME MEASURES: Brain water content and MMP-9 expression surrounding the hematoma region. RESULTS: MMP-9 expression increased at 6 hours, and brain edema reached a peak at 48 hours after intracerebral hemorrhage. MMP-9 expression was significantly decreased in the mild hypothermia group compared with the normothermia group at each time point (P < 0.05). CONCLUSION: Mild hypothermia can significantly inhibit MMP-9 overexpression and relieve brain edema following intracerebral hemorrhage.展开更多
BACKGROUND: Previous studies have confirmed the neuroprotective effect of mild hypothermia on ischemic brain injury. OBJECTIVE: To investigate the effects of mild hypothermia on intercellular adhesion molecule-1 expre...BACKGROUND: Previous studies have confirmed the neuroprotective effect of mild hypothermia on ischemic brain injury. OBJECTIVE: To investigate the effects of mild hypothermia on intercellular adhesion molecule-1 expression and serum interleukin-6 levels in ischemic brain tissues of focal brain ischemia rats, and to explore the neuroprotective effects of mild hypothermia on ischemic brain injury. DESIGN, TIME AND SETTING: A randomized, controlled, neurobiological experiment was performed at the Central Laboratory, First Affiliated Hospital, Xinxiang Medical College, China from February to July 2006. MATERIALS: Thirty healthy, adult, Sprague Dawley rats were used to establish middle cerebral artery occlusion models using the suture method. The immunohistochemistry (streptavidin-biotin-peroxidase complex method) kit was purchased from Boster, China. Interleukin-6 radioimmunoassay was supplied by Institute of Radioimmunity, Technology Development Center, General Hospital of Chinese PLA. METHODS: The rats were equally and randomly assigned into mild hypothermia and control groups, and middle cerebral artery occlusion models were established. The rectal temperature was maintained at (37 ± 0.5) ℃ in the control group. In the mild hypothermia group, the rectal temperature was maintained at (33 ± 1) ℃. MAIN OUTCOME MEASURES: At 12 hours after model establishment, the ischemic brain hemispheres were coronally sliced at the level of the optic chiasm. The number of intercellular adhesion molecule-1-positive vessels per high-power field was observed with an optical microscope. Serum interleukin-6 levels were measured by radioimmunoassay. RESULTS: Compared with the control group, intercellular adhesion molecule-1 and serum interleukin-6 expressions were significantly decreased in ischemic brain tissues of the mild hypothermia group (P < 0.01). CONCLUSION: Mild hypothermia exhibits a neuroprotective effect by reducing serum interleukin-6 and intercellular adhesion molecule-1 expression following cerebral ischemia.展开更多
The influence of mild hypothermia on neural cell apoptosis remains poorly understood. Therefore, the present study established rat models of diffuse axonal injury (DAI) at 33 ℃. Morris water maze results demonstrated...The influence of mild hypothermia on neural cell apoptosis remains poorly understood. Therefore, the present study established rat models of diffuse axonal injury (DAI) at 33 ℃. Morris water maze results demonstrated significantly better learning and memory functions in DAI rats with hypothermia compared with DAI rats with normothermia. Expression of apoptotic protease activating factor-1 in the hippocampal CA1 region was significantly lower in the DAI hypothermia group compared with the DAI normothermia group. Expression of apoptotic protease activating factor-1 positively correlated with latency, but negatively correlated with platform location times and time of swimming in the quadrant area. Results suggested that post-traumatic mild hypothermia in a rat model of DAI could provide cerebral protection by attenuating expression of apoptotic protease activating factor-1.展开更多
Objective: To study the changes of partial pressure of brain tissue oxygen (PbtO 2) and brain temperature in acute phase of severe head injury during mild hypothermia therapy and the clinical significance. Methods: On...Objective: To study the changes of partial pressure of brain tissue oxygen (PbtO 2) and brain temperature in acute phase of severe head injury during mild hypothermia therapy and the clinical significance. Methods: One hundred and sixteen patients with severe head injury were selected and divided into a mild hypothermia group (n=58), and a control group (n=58) according to odd and even numbers of hospitalization. While mild hypothermia therapy was performed PbtO 2 and brain temperature were monitored for 1 7 days (mean=86 hours), simultaneously, the intracranial pressure, rectum temperature, cerebral perfusion pressure, PaO 2 and PaCO 2 were also monitored. The patients were followed up for 6 months and the prognosis was evaluated with GOS (Glasgow outcome scale). Results: The mean value of PbtO 2 within 24 hour monitoring in the 116 patients was 13.7 mm Hg ± 4.94 mm Hg , lower than the normal value (16 mm Hg ± 40 mm Hg ) The time of PbtO 2 recovering to the normal value in the mild hypothermia group was shortened by 10± 4.15 hours compared with the control group (P< 0.05 ). The survival rate of the mild hypothermia group was 60.43 %, higher than that of the control group ( 46.55 %). After the recovery of the brain temperature, PbtO 2 increased with the rise of the brain temperature. Conclusions: Mild hypothermia can improve the survival rate of severe head injury. The technique of monitoring PbtO 2 and the brain temperature is safe and reliable, and has important clinical significance in judging disease condition and instructing clinical therapy.展开更多
Objective: To study the effects of mild hypothermia on cerebral oxygen partial pressure, carbon dioxide partial pressure, pH and body temperature （PbrO2, PbrCO2, pHbr and BT） in patients with acute severe head injur...Objective: To study the effects of mild hypothermia on cerebral oxygen partial pressure, carbon dioxide partial pressure, pH and body temperature （PbrO2, PbrCO2, pHbr and BT） in patients with acute severe head injury. Methods: Thirty-eight patients with acute severe head injury were treated with mild hypothermia, meantime PbrO2, PbrCO2, pHbr and BT were monitored in order to study the changes of PbrO2, PbrCO2, pHbr and BT. Results: In patients with acute head injury, mild hypothermia obviously increased PbrO2, decreased PbrCO2 and CO2 accumulation and acidosis in brain tissue. BT was 1℃-（1.5）℃ higher than rectal temperature（RT） after injury. The BT and RT were decreased when the patients were treated with mild hypothermia, but at the same time the difference between BT and RT was increased. Conclusions: In patients with acute severe head injury the direct monitoring of PbrO2, PbrCO2, pHbr and BT was safe and reliable, and is helpful in estimating prognosis and mild hypothermia therapy.展开更多
Mild therapeutic hypothermia has been shown to mitigate cerebral ischemia, reduce cerebral edema, and improve the prognosis of patients with cerebral ischemia. Adipose-derived stem cell-based therapy can decrease neur...Mild therapeutic hypothermia has been shown to mitigate cerebral ischemia, reduce cerebral edema, and improve the prognosis of patients with cerebral ischemia. Adipose-derived stem cell-based therapy can decrease neuronal death and infiltration of inflammatory cells, exerting a neuroprotective effect. We hypothesized that the combination of mild therapeutic hypothermia and adipose-derived stem cells would be neuroprotective for treatment of stroke. A rat model of transient middle cerebral artery occlusion was established using the nylon monofilament method. Mild therapeutic hypothermia(33°C) was induced after 2 hours of ischemia. Adipose-derived stem cells were administered through the femoral vein during reperfusion. The severity of neurological dysfunction was measured by a modified Neurological Severity Score Scaling System. The area of the infarct lesion was determined by 2,3,5-triphenyltetrazolium chloride staining. Apoptotic neurons were detected by terminal deoxynucleotidyl transferase-mediated d UTP-biotin nick end labeling(TUNEL) staining. The regeneration of microvessels and changes in the glial scar were detected by immunofluorescence staining. The inflammatory responses after ischemic brain injury were evaluated by in situ staining using markers of inflammatory cells. The expression of inflammatory cytokines was measured by reverse transcription-polymerase chain reaction. Compared with mild therapeutic hypothermia or adipose-derived stem cell treatment alone, their combination substantially improved neurological deficits and decreased infarct size. They synergistically reduced the number of TUNEL-positive cells and glial fibrillary acidic protein expression, increased vascular endothelial growth factor levels, effectively reduced inflammatory cell infiltration and down-regulated the m RNA expression of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α and interleukin-6. Our findings indicate that combined treatment is a better approach for treating stroke compared with mild therapeutic hypothermia or adipose-derived stem cells alone.展开更多
文摘BACKGROUND:Good neurological outcome after cardiac arrest(CA) is hard to achieve for clinicians.Experimental and clinical evidence suggests that therapeutic mild hypothermia is beneficial.This study aimed to assess the effectiveness and safety of therapeutic mild hypothermia in patients successfully resuscitated from CA using a meta-analysis.METHODS:We searched the MEDLINE(1966 to April 2012),OVID(1980 to April 2012),EMBASE(1980 to April 2012),Chinese bio-medical literature & retrieval system(CBM)(1978 to April 2012),Chinese medical current contents(CMCC)(1995 to April 2012),and Chinese medical academic conference(CMAC)(1994 to April 2012).Studies were included if 1) the study design was a randomized controlled trial(RCT);2) the study population included patients successfully resuscitated from CA,and received either standard post-resuscitation care with normothermia or mild hypothermia;3) the study provided data on good neurologic outcome and survival to hospital discharge.Relative risk(RR) and 95%confidence interval(CI) were used to pool the effect.RESULTS:The study included four RCTs with a total of 417 patients successfully resuscitated from CA.Compared to standard post-resuscitation care with normothermia,patients in the hypothermia group were more likely to have good neurologic outcome(RR=1.43,95%CI 1.14-1.80,P=0.002) and were more likely to survive to hospital discharge(RR=1.32,95%CI 1.08-1.63,P=0.008).There was no significant difference in adverse events between the normothermia and hypothermia groups(P>0.05),nor heterogeneity and publication bias.CONCLUSION:Therapeutic mild hypothermia improves neurologic outcome and survival in patients successfully resuscitated from CA.
文摘Through investigating the effect of mild hypothermia on activity of nitric oxide snythase (NOS) in cortical neurons and glycemia levels of neonatal rats with hypoxic ischemic brain damage (HIBD). We studied the mechanism of protecting hypoxic ischemic neurons of mild hypothermia. We established neonatal rat HIBD models, used NOS immunohistochemistry and glycemia determination by micromethod. The number of cortical NOS positive neurons after hypoxic ischemia was significantly decreased as compared with controls. The glycemia levels was significantly increased than that controls. No significant difference was found in number of cortical NOS positive neurons and glycemia levels between 31℃ and 34℃ mild hypothemia. The results imply that hypothermia can decrease overproduction of NO through inhibiting the increase of the activity of NOS, and increase the glycemia levels, thus protect the hypoxic ischemic neurons.
文摘To study the effect of mild hypothermia on glucose metabolism and glycerol of brain tissue in patients with severe traumatic brain injury (sTBI).Methods All 33 patients with sTBI(GCS≤8) were randomly divided into hypothermic group and control group.Microdialysis catheters were inserted into the cerebral cortex of perilesion,relative normal brain tissue and subcutaneous tissue of abdomen in order to analyze the concentrations of lactate/pyruvate (L/P),lactate/glucose (L/G) and the glycerol(Gly) in extracellular fluid (ECF).Results In comparison with the control group,the concentration of L/G,L/P and Gly in periphery and that of L/P in ECF of the “normal brain tissue” were significantly decreased in the hypothermic group.In control group,concentration of L/G,L/P and Gly in periphery were higher than those in relative normal brain.In the hypothermic group,L/P concentration in periphery was higher than that in relative normal brain.Conclusion Mild hypothermia protects brain by decreasing concentrations of L/G,L/P and Gly in periphery and L/P concentration in “normal brain tissue”.The energy crisis and membrane phospholipid breakage in periphery are easier to happen after TBI,where mild hypothermia exerts significant protgective role.12 refs,3 tabs.
基金supported by the National Natural Science Foundation of China,No.81303091
文摘Cold-inducible RNA-binding protein(CIRP), a key regulatory protein, could be facilitated by mild hypothermia in the brain, heart and liver. This study observed the effects of mild hypothermia at 31 ± 0.5℃ on traumatic brain injury in rats. Results demonstrated that mild hypothermia suppressed apoptosis in the cortex, hippocampus and hypothalamus, facilitated CIRP m RNA and protein expression in these regions, especially in the hypothalamus. The anti-apoptotic effect of mild hypothermia disappeared after CIRP silencing. There was no correlation between mitogen-activated extracellular signal-regulated kinase activation and CIRP silencing. CIRP silencing inhibited extracellular signal-regulated kinase-1/2 activation. These indicate that CIRP inhibits apoptosis by affecting extracellular signal-regulated kinase-1/2 activation, and exerts a neuroprotective effect during mild hypothermia for traumatic brain injury.
基金supported by a grant from the Application Basis and Front Technology Projects of Tianjin(Science and Technology Foundation of Tianjin),No.12JCYBJC18000
文摘Because the inhibition of Nogo proteins can promote neurite growth and nerve cell differentiation, a cell-scaffold complex seeded with Nogo receptor(Ng R)-silenced neural stem cells and Schwann cells may be able to improve the microenvironment for spinal cord injury repair. Previous studies have found that mild hypothermia helps to attenuate secondary damage in the spinal cord and exerts a neuroprotective effect. Here, we constructed a cell-scaffold complex consisting of a poly(D,L-lactide-co-glycolic acid)(PLGA) scaffold seeded with Ng R-silenced neural stem cells and Schwann cells, and determined the effects of mild hypothermia combined with the cell-scaffold complexes on the spinal cord hemi-transection injury in the T9 segment in rats. Compared with the PLGA group and the Ng R-silencing cells + PLGA group, hindlimb motor function and nerve electrophysiological function were clearly improved, pathological changes in the injured spinal cord were attenuated, and the number of surviving cells and nerve fibers were increased in the group treated with the Ng R-silenced cell scaffold + mild hypothermia at 34°C for 6 hours. Furthermore, fewer pathological changes to the injured spinal cord and more surviving cells and nerve fibers were found after mild hypothermia therapy than in injuries not treated with mild hypothermia. These experimental results indicate that mild hypothermia combined with Ng R gene-silenced cells in a PLGA scaffold may be an effective therapy for treating spinal cord injury.
文摘Several studies have demonstrated that mild hypothermia exhibits a neuroprotective role and it can inhibit endothelial cell apoptosis following ischemia/reperfusion injury by decreasing caspase-3 expression. It is hypothesized that mild hypothermia exhibits neuroprotective effects on neurons exposed to ischemia/reperfusion condition produced by oxygen-glucose deprivation. Mild hypothermia significantly reduced the number of apoptotic neurons, decreased the expression of pro-apoptotic protein Bax and increased mitochondrial membrane potential, with the peak of anti-apoptotic effect appearing between 6 and 12 hours after the injury. These findings indicate that mild hypothermia inhibits neuronal apoptosis following ischemia/reperfusion injury by protecting the mitochondria and that the effective time window is 6–12 hours after ischemia/reperfusion injury.
基金supported by the Natural Science Foundation of Guangdong Province in China,No.10151600101000002
文摘Fractional anisotropy values in diffusion tensor imaging can quantitatively reflect the consistency of nerve fibers after brain damage, where higher values generally indicate less damage to nerve fibers. Therefore, we hypothesized that diffusion tensor imaging could be used to evaluate the effect of mild hypothermia on diffuse axonal injury. A total of 102 patients with diffuse axonal injury were randomly divided into two groups: normothermic and mild hypothermic treatment groups. Patient's modified Rankin scale scores 2 months after mild hypothermia were significantly lower than those for the normothermia group. The difference in average fractional anisotropy value for each region of interest before and after mild hypothermia was 1.32–1.36 times higher than the value in the normothermia group. Quantitative assessment of diffusion tensor imaging indicates that mild hypothermia therapy may be beneficial for patients with diffuse axonal injury.
基金the Natural Scientific Research Foundation of Education Department of Anhui Province, No. 2005KJ298
文摘BACKGROUND: It is widely accepted that mild hypothermia can protect against injury to cerebral ischemia/reperfusion. OBJECTIVE: To observe the effects of mild hypothermia on microtubule-associated protein 2 (MAP2) expression in the hippocampal dentate gyrus in rats following cerebral ischemia/reperfusion. Also, to study neuronal ultrastructural changes in the dentate gyrus to investigate the mechanism of the protection against injury to cerebral ischemia/reperfusion conferred by mild hypothermia. DESIGN, TIME AND SETTING: This randomized grouping, neural cell morphology trial was performed at the Laboratory Animal Center of Yijishan Hospital between March and June 2007. MATERIALS: Eighty-five healthy male Sprague Dawley rats were randomly allocated to three groups: mild hypothermia (n = 40), normothermia (n = 40), and sham-operated (n = 5). METHODS: Cerebral ischemia/reperfusion injury was induced by the suture method in the mild hypothermia and normothermia groups, with a threading depth of 180.5 mm. In the sham-operated group, the suture was inserted 15 mm, with no vascular ligation, and was followed by reperfusion 2 hours later. In the sham-operated and normothermia groups, the rat rectal temperature was maintained at 36–37 ℃; in the mild hypothermia group, it was controlled at 32–33 ℃. MAIN OUTCOME MEASURES: The hippocampal dentate gyrus was serially sectioned for hematoxylin-eosin staining and MAP2 immunohistochemistry. Ultrastructural changes and the MAP2 absorbance value of the hippocampal dentate gyrus were examined by transmission electron microscopy. RESULTS: The sham-operated group exhibited approximately normal ultrastructure of neurons in the bilateral hippocampal dentate gyrus. In the normothermia group, ischemic hippocampal dentate gyrus neurons were found with markedly fewer normal mitochondria, greatly proliferated rough endoplasmic reticulum, and a swollen and dysmorphic Golgi. In the mild hypothermia group, at each corresponding time point, these abnormal changes were noticeably alleviated. The number of necrotic mitochondria, as well as the degree of degeneration, was obviously reduced compared with the normothermia group. At days 6, 8 and 10 following reperfusion, the normothermia group exhibited lower neurological function scores than the mild hypothermia group (P < 0.05). In the normothermia group, the absorbance value of MAP2 expression in the ischemic hippocampal dentate gyrus was significantly decreased compared with the sham-operated group (P < 0.01), was slightly increased at 4 days, and reached a peak on day 8. The mild hypothermia group showed an absorbance value of MAP2 expression in the ischemic hippocampal dentate gyrus similar to the normothermia group, but it reached a peak on day 6. On days 1, 2, 4 and 6 following reperfusion, MAP2 expression was lower in the mild hypothermia group than in the sham-operated group, but it was higher than the normothermia group (P < 0.05). CONCLUSION: Mild hypothermia applied in early ischemia can alleviate brain injury. This may be due to an enhancement of MAP2 expression.
基金supported by a grant from a science andtechnology project"Health of Science and Education"of Suzhouin 2013(KJXW2013026)
文摘BACKGROUND: Cardiac arrest(CA) is a common and serious event in emergency medicine. Despite recent improvements in resuscitation techniques, the survival rate of patients with CA is unchanged. The present study was undertaken to observe the effect of mild hypothermia(MH) on the reactive oxygen species(ROS) and the effect of neurological function and related mechanisms.METHODS: Sixty-five healthy male Sprague Dawley(SD) adult rats were randomly(random number) divided into 2 groups: blank control group(n=5) and CPR group(n=60). CA was induced by asphyxia. The surviving rats were randomly(random number) divided into two groups: normothermia CPR group(NT) and hypothermia CPR group(HT). Normothermia of 37 °C was maintained in the NT group after return of spontaneous circulation(ROSC), hypothermal intervention of 32 °C was carried out in the HT group for 4 hours immediately after ROSC. Both the NT and HT groups were then randomly divided into 2 subgroups 12 hours and 24 hours after ROSC(NT-12, NT-24, HT-12, HT-24 subgroups). During observation, the neurological defi cit scores(NDSs) was recorded, then the bilateral hippocampi were obtained from rats' head, and monoplast suspension of fresh hippocampus tissue was made immediately to determine the level of intracellular ROS by flow cytometry. Transmission electron microscope was used to observe the ultramicro changes of cellular nucleus and mitochondria. Reverse transcription-polymerase chain reaction(RT-PCR) was used to determine the expression of caspase-3 m RNA, and western-blotting(WB) was used to determine the level of LC3 in frozen hippocampus tissue. Measured data were analyzed with paired sample t test and One-Way ANOVA.RESULTS: Of 60 rats with CA, 44(73%) were successfully resuscitated and 33(55%) survived until the end of the experiment. The NDSs of rats in the NT and HT groups were more signifi cantly reduced than those in the BC group(F=8.107, P<0.05), whereas the NDSs of rats in the HT-12 and HT-24 subgroups were significantly increased in comparison with those NDSs of rats in the NT-12 and NT-24 subgroups, respectively(t=9.692, P<0.001; t=14.374, P<0.001). The ROS in hippocampus nerve cells in the NT and HT groups signifi cantly increased compared to the BC group(F=16.824, P<0.05), whereas the ROS in the HT-12 and HT-24 subgroups significantly reduced compared with that ROS in the NT-12 and NT-24 subgroups, respectively(t=9.836, P<0.001; t=7.499, P<0.001). The expression of caspase-3 m RNA in hippocampus nerve cells in the NT and HT groups were signifi cantly increased compared to the BC group(F=24.527, P<0.05), whereas the expression of caspase-3 m RNA in rats of the HT-12 and HT-24 subgroups was signifi cantly reduced compared to the NT-12 and NT-24 subgroups, respectively(t=6.935, P<0.001; t=4.317, P<0.001). The expression of LC3B-II/I in hippocampus nerve cells of rats in the NT and HT groups signifi cantlyincreased compared to the BC group(F=6.584, P<0.05), whereas the expression of LC3B-II/I in rats of the HT-12 and HT-24 subgroups significantly reduced compared to the NT-12 and NT-24 subgroups, respectively(t=10.836, P<0.001; t=2.653, P=0.02). Ultrastructure damage of nucleus and mitochondria in the NT group was more evident than in the BC group, and eumorphism of nucleus and mitochondria were maintained in rats of the HT group compared with the NT group.CONCLUSION: Mild hypothermia lessened the injury of nerve cells and improved the neurological function of rats that survived from cardiac arrest by reducing the ROS production of nerve cells and inhibiting the expression of caspase-3 m RNA and LC3, leading to cellular apoptosis and massive autophagy in rats that survived from cardiac arrest after CPR.
基金the Project of Shandong Provincial Health Department, No.2007HW093 the Project of Shandong Provincial Science and Technology Department,No. 003130103
文摘BACKGROUND: Matrix metalloproteinase-9 (MMP-9) expression increases with intracerebral hemorrhage, and participates in the pathophysiological processes of secondary brain injury after intracerebral hemorrhage. OBJECTIVE: To investigate the effects of mild hypothermia on MMP-9 expression and brain edema in the perihematomal region of experimental intracerebral hemorrhage rats. DESIGN, TIME AND SETTING: The randomized, controlled experiment was performed at the Central Laboratory of Shandong Provincial Hospital between May and September 2007. MATERIALS: Seventy-two, Wistar, male rats, 12-weeks old, were used for this study. Rabbit anti-MMP-9 primary antibody was purchased from Boster, China. METHODS: Wistar rats were equally and randomly divided into normothermia and mild hypothermia groups. The two groups each comprised control, 6-hour intracerebral hemorrhage, 24-hour intracerebral hemorrhage, 48-hour intracerebral hemorrhage, 72-hour intracerebral hemorrhage, and 1-week intracerebral hemorrhage subgroups, with six rats in each subgroup. Rat models of intracerebral hemorrhage were established by injecting 100 μL of autologous blood into the rat caudate nucleus. Rats in the mild hypothermia group received four hours of local mild hypothermia immediately following the injection. Intracerebral temperature was maintained at (33 ± 0.5) ℃. Subsequently, intracerebral temperature was spontaneously recovered at 25 ℃. Rats in the control subgroup were not injected with autologous blood and received only with intracerebral hemorrhage. MAIN OUTCOME MEASURES: Brain water content and MMP-9 expression surrounding the hematoma region. RESULTS: MMP-9 expression increased at 6 hours, and brain edema reached a peak at 48 hours after intracerebral hemorrhage. MMP-9 expression was significantly decreased in the mild hypothermia group compared with the normothermia group at each time point (P < 0.05). CONCLUSION: Mild hypothermia can significantly inhibit MMP-9 overexpression and relieve brain edema following intracerebral hemorrhage.
文摘BACKGROUND: Previous studies have confirmed the neuroprotective effect of mild hypothermia on ischemic brain injury. OBJECTIVE: To investigate the effects of mild hypothermia on intercellular adhesion molecule-1 expression and serum interleukin-6 levels in ischemic brain tissues of focal brain ischemia rats, and to explore the neuroprotective effects of mild hypothermia on ischemic brain injury. DESIGN, TIME AND SETTING: A randomized, controlled, neurobiological experiment was performed at the Central Laboratory, First Affiliated Hospital, Xinxiang Medical College, China from February to July 2006. MATERIALS: Thirty healthy, adult, Sprague Dawley rats were used to establish middle cerebral artery occlusion models using the suture method. The immunohistochemistry (streptavidin-biotin-peroxidase complex method) kit was purchased from Boster, China. Interleukin-6 radioimmunoassay was supplied by Institute of Radioimmunity, Technology Development Center, General Hospital of Chinese PLA. METHODS: The rats were equally and randomly assigned into mild hypothermia and control groups, and middle cerebral artery occlusion models were established. The rectal temperature was maintained at (37 ± 0.5) ℃ in the control group. In the mild hypothermia group, the rectal temperature was maintained at (33 ± 1) ℃. MAIN OUTCOME MEASURES: At 12 hours after model establishment, the ischemic brain hemispheres were coronally sliced at the level of the optic chiasm. The number of intercellular adhesion molecule-1-positive vessels per high-power field was observed with an optical microscope. Serum interleukin-6 levels were measured by radioimmunoassay. RESULTS: Compared with the control group, intercellular adhesion molecule-1 and serum interleukin-6 expressions were significantly decreased in ischemic brain tissues of the mild hypothermia group (P < 0.01). CONCLUSION: Mild hypothermia exhibits a neuroprotective effect by reducing serum interleukin-6 and intercellular adhesion molecule-1 expression following cerebral ischemia.
基金a grant from Department of Public Health of Heibei Province, No. 20100134
文摘The influence of mild hypothermia on neural cell apoptosis remains poorly understood. Therefore, the present study established rat models of diffuse axonal injury (DAI) at 33 ℃. Morris water maze results demonstrated significantly better learning and memory functions in DAI rats with hypothermia compared with DAI rats with normothermia. Expression of apoptotic protease activating factor-1 in the hippocampal CA1 region was significantly lower in the DAI hypothermia group compared with the DAI normothermia group. Expression of apoptotic protease activating factor-1 positively correlated with latency, but negatively correlated with platform location times and time of swimming in the quadrant area. Results suggested that post-traumatic mild hypothermia in a rat model of DAI could provide cerebral protection by attenuating expression of apoptotic protease activating factor-1.
文摘Objective: To study the changes of partial pressure of brain tissue oxygen (PbtO 2) and brain temperature in acute phase of severe head injury during mild hypothermia therapy and the clinical significance. Methods: One hundred and sixteen patients with severe head injury were selected and divided into a mild hypothermia group (n=58), and a control group (n=58) according to odd and even numbers of hospitalization. While mild hypothermia therapy was performed PbtO 2 and brain temperature were monitored for 1 7 days (mean=86 hours), simultaneously, the intracranial pressure, rectum temperature, cerebral perfusion pressure, PaO 2 and PaCO 2 were also monitored. The patients were followed up for 6 months and the prognosis was evaluated with GOS (Glasgow outcome scale). Results: The mean value of PbtO 2 within 24 hour monitoring in the 116 patients was 13.7 mm Hg ± 4.94 mm Hg , lower than the normal value (16 mm Hg ± 40 mm Hg ) The time of PbtO 2 recovering to the normal value in the mild hypothermia group was shortened by 10± 4.15 hours compared with the control group (P< 0.05 ). The survival rate of the mild hypothermia group was 60.43 %, higher than that of the control group ( 46.55 %). After the recovery of the brain temperature, PbtO 2 increased with the rise of the brain temperature. Conclusions: Mild hypothermia can improve the survival rate of severe head injury. The technique of monitoring PbtO 2 and the brain temperature is safe and reliable, and has important clinical significance in judging disease condition and instructing clinical therapy.
文摘Objective: To study the effects of mild hypothermia on cerebral oxygen partial pressure, carbon dioxide partial pressure, pH and body temperature （PbrO2, PbrCO2, pHbr and BT） in patients with acute severe head injury. Methods: Thirty-eight patients with acute severe head injury were treated with mild hypothermia, meantime PbrO2, PbrCO2, pHbr and BT were monitored in order to study the changes of PbrO2, PbrCO2, pHbr and BT. Results: In patients with acute head injury, mild hypothermia obviously increased PbrO2, decreased PbrCO2 and CO2 accumulation and acidosis in brain tissue. BT was 1℃-（1.5）℃ higher than rectal temperature（RT） after injury. The BT and RT were decreased when the patients were treated with mild hypothermia, but at the same time the difference between BT and RT was increased. Conclusions: In patients with acute severe head injury the direct monitoring of PbrO2, PbrCO2, pHbr and BT was safe and reliable, and is helpful in estimating prognosis and mild hypothermia therapy.
基金supported by the National Natural Science Foundation of China,No.81371301
文摘Mild therapeutic hypothermia has been shown to mitigate cerebral ischemia, reduce cerebral edema, and improve the prognosis of patients with cerebral ischemia. Adipose-derived stem cell-based therapy can decrease neuronal death and infiltration of inflammatory cells, exerting a neuroprotective effect. We hypothesized that the combination of mild therapeutic hypothermia and adipose-derived stem cells would be neuroprotective for treatment of stroke. A rat model of transient middle cerebral artery occlusion was established using the nylon monofilament method. Mild therapeutic hypothermia(33°C) was induced after 2 hours of ischemia. Adipose-derived stem cells were administered through the femoral vein during reperfusion. The severity of neurological dysfunction was measured by a modified Neurological Severity Score Scaling System. The area of the infarct lesion was determined by 2,3,5-triphenyltetrazolium chloride staining. Apoptotic neurons were detected by terminal deoxynucleotidyl transferase-mediated d UTP-biotin nick end labeling(TUNEL) staining. The regeneration of microvessels and changes in the glial scar were detected by immunofluorescence staining. The inflammatory responses after ischemic brain injury were evaluated by in situ staining using markers of inflammatory cells. The expression of inflammatory cytokines was measured by reverse transcription-polymerase chain reaction. Compared with mild therapeutic hypothermia or adipose-derived stem cell treatment alone, their combination substantially improved neurological deficits and decreased infarct size. They synergistically reduced the number of TUNEL-positive cells and glial fibrillary acidic protein expression, increased vascular endothelial growth factor levels, effectively reduced inflammatory cell infiltration and down-regulated the m RNA expression of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α and interleukin-6. Our findings indicate that combined treatment is a better approach for treating stroke compared with mild therapeutic hypothermia or adipose-derived stem cells alone.
