With the popularization of cardiopulmonary resuscitation (CPR) technology, the success rate of restoration of spontaneous circulation (ROSC) is gradually improved, and the survival rate and neurological outcome of patients with cardiac arrest are improved. Currently, therapeutic methods for cerebral resuscitation after cardiac arrest are limited. In addition to mild hypothermia for clinical application, the majority of drugs remain in the animal experimental stage. Finding effective brain protection drugs has become a hot spot in the field of brain resuscitation research. This article will review the pharmaceutical progress of research for cerebral resuscitation after cardiac arrest, so that we can study the brain protection mechanism of these drugs better and more targeted.
Cerebrovascular Circulation/drug effects* ; Heart Arrest/drug therapy* ; Humans ; Pharmaceutical Research/trends* ; Resuscitation/methods*

Betacoronavirus ; COVID-19 ; Coronavirus ; Coronavirus Infections/therapy* ; Humans ; Pandemics ; Pneumonia, Viral/therapy* ; SARS-CoV-2

AlM: To measure ocular biometric values with the degree of axial myopia and determine the relationship between the differences using the Lenstar 900.
METHODS:Totally 413 myopes (826 eyes) were enrolled in this study and were divided into 3 groups: low myopia (myopia <3. 00 diopters, 104 eyes), moderate myopia ( myopia =3. 00-6. 00 diopters, 500 eyes) and high myopia ( myopia > 6. 00 diopters, 222 eyes ). Central corneal thickness ( CCT ) , aqueous depth ( AD ) , lens thickness (LT), axial length (AL) were measured by Lenstar 900. The parameters were tested using analysis of variance and the relations among SE, AL, LT were analyzed.
RESULTS: There were significant difference both in AL (F=206.16, P<0.01) and AD (F=4.764, P<0.05) and no significant difference both in CCT and LT between these myopia groups. With analysis of Person, the Spherical equivalent ( SE) shows a significantly positive correlation with AL (r=0. 662, P<0. 01) and AD (r=0. 095, P<0. 05), no correlation with CCT and LT. AL shows a significantly positive correlation with AD (r=0. 347, P<0. 01) and CCT (r=0.126, P<0.01), negative correlation with LT (r=-0.265, P<0. 01). LT shows a significantly negative correlation with AD (r=-0. 496, P<0. 01).
CONCLUSlON: Along with the diopters increasing in myopia, the axial length and aqueous depth continue to increase. Spherical equivalent ( SE) shows a significantly positive correlation with AD. AL shows positive correlation with SE, AD and CCT and negative correlation with LT. LT shows a significantly negative correlation with AD.

This article deals with the influence of shear stress on endothelial NO synthesis, and the role of caveolae in shear stress-induced eNOS activation. Human umbilical vascular endothelial cells (HUVEC) were cultured and exposed to different levels of laminal shear stress and Filipin, the perfused cultures were collected, and NO(2-)/NO(3-) was detected using nitrate reduction method. The structure of caveolae was observed through transmission electron microscopy (TEM). The level of NO(2-)-/NO(3-) was found to increase with the elevation of shear stress level (P < 0.01). It was the highest at 1.5 N/m2. After treatment with Filipin, the level of NO produced by HUVEC decreased significantly (P < 0.01), but after recovery and shear without Filipin, the level of NO synthesis bounded back (P < 0.01). It was then concluded that shear stress can induce endothelial NO synthesis and caveolae plays a key role in shear stress-induced eNOS activation.
Caveolae ; physiology ; Cells, Cultured ; Endothelium, Vascular ; cytology ; Filipin ; pharmacology ; Humans ; Nitric Oxide Synthase Type III ; metabolism ; Shear Strength ; Umbilical Veins ; cytology

Using the latency of paw withdrawal (PWL) from a noxious thermal stimulus as a measure of hyperalgesia, the effects of i.p. injection of meptazinol and its isomers, 112824 and 112825, on carrageenan-induced thermal hyperalgesia were studied in awaked carrageenan-inflamed rats. Peripheral inflammation was induced by intraplantar (i.pl.) injection of carrageenan (2 mg/100 microl) into one hindpaw in rats. Carrageenan produced marked inflammation (edema and erythema) and thermal hyperalgesia in the injected paws, which peaked at 3 h after injection and showed little change in magnitude for another 3 h. Injection of 0.1 mg/kg meptazinol (i.p.) at 3 h after carrageenan had no effect on the PWLs of either inflamed or non-inflamed hindpaw during the next 100 min (P>0.05, n=8). At the dosage of 1 and 10 mg/kg, meptazinol produced marked anti-nociception and anti-hyperalgesia in non-inflamed and inflamed hindpaw, respectively (P<0.05, n=8-11). The prolonging effect of meptazinol on PWL in inflamed hindpaw was more potent than that in non-inflamed hindpaw. Pre-administration of 1.5 mg/kg naloxone significantly antagonized meptazinol-induced anti-nociception and anti-hyperalgesia. Intraperitoneal injection of an isomer of meptazinol, 112825 (1.5 mg/kg), but not 112824 (1 mg/kg), markedly increased the PWL of the non-inflamed hindpaw. Nevertheless, both the isomers produced similar anti-hyperalgesic effect to that of meptazinol (P<0.05, n=8), which was completely reversed by naloxone (1.5 mg/mg). The results suggest that meptazinol and its isomers have anti-nociceptive and anti-hyperalgesic properties with the former more potent. The effects are mainly mediated by mu opioid receptors. This study provides an important clue for extending clinical utilization of meptazinol and its isomers.
Analgesics, Opioid ; pharmacology ; Animals ; Carrageenan ; Hyperalgesia ; chemically induced ; physiopathology ; Inflammation ; chemically induced ; Isomerism ; Male ; Meptazinol ; pharmacology ; Nociceptors ; drug effects ; Pain ; physiopathology ; Pain Measurement ; methods ; Rats ; Rats, Sprague-Dawley

Objective To compare the differences in cardiac functions and myocardial injury between asphyxia and trans-oesophageal pacing induced rat cardiac arrest models.Methods Healthy adult male Sprague-Dawley (SD) rats were randomly divided into sham group,asphyxia group and electrical stimulation group by random number table.The rats in the latter two groups were randomly divided into two subgroups (24 hours and 72 hours)according to the sampling time after successful resuscitation,with 6 rats in each group.All rats were mechanically ventilated for 20 minutes,in electrical stimulation group,cardiac arrest was induced by trans-oesophageal cardiac pacing for about 3 minutes (intensity 30 V,frequency 50 Hz,pulse duration 2 ms),and in asphyxia group,cardiac arrest was induced by clipping trachea for about 3 minutes.Cardiopulmonary resuscitation (CPR) was initiated 4 minutes after cardiac arrest.Echocardiographic examination was performed at 2 hours after return of spontaneous circulation (ROSC) with cardiac color ultrasound apparatus.Cardiac tissues were harvested at 24 hours and 72 hours after ROSC,hematoxylin-eosin (HE) staining was performed,and myocardial damage was observed under light microscope.The levels of cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP) in serum were determined by enzyme-linked immunosorbent assay (ELISA).Results There was no significant difference in ROSC rate between the asphyxia group and electrical stimulation group [94.4％ (17/18) vs.88.9％ (16/18),P ＞ 0.05].The heart rate (HR),mean arterial pressure (MAP),left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) at 2 hours after ROSC in asphyxia group and electrical stimulation group were significantly lower than those in sham group [HR (bpm):401.50± 19.76,370.67± 18.63 vs.430.17± 18.38,MAP (mmHg,1 mmHg =0.133 kPa):107.17± 12.92,92.50±9.35 vs.125.67±5.72,LVEF:0.60±0.02,0.54±0.03 vs.0.63±0.01,LVFS:(48.40±2.52)％,(40.33±3.32)％ vs.(55.47 ± 2.38)％,all P ＜ 0.05],and the decrease in electrical stimulation group was more significant (all P ＜ 0.05).Compared with sham group,the levels of cTnI and BNP in serum of electrical stimulation group were significantly increased at 24 hours after ROSC [cTnI (ng/L):51.57±13.04 vs.38.23±5.57,BNP (ng/L):1 919.61±823.22 vs.977.47 ±445.18,both P ＜ 0.05],but there was no significant difference in cTnI or BNP of serum between asphyxia group and sham group [cTnI (ng/L):46.84 ± 11.04 vs.38.23 ± 5.57,BNP (ng/L):1 144.13±390.05 vs.977.47 ± 445.18,both P ＞ 0.05].There was no significant difference in cTnI or BNP of serum at 72 hours after ROSC among all the groups.The results of HE stain showed that the pathological injury of myocardium in electrical stimulation group was more serious than that in asphyxia group,characterized by more severe myocardial edema and partial myocardial cell lysis.Conclusion The cardiac function after cardiac arrest-CPR was decreased in both asphyxia group and electrical stimulation group,but electrical stimulation had a heavier cardiac function injury than asphyxia.

Objective:To compare the severity of brain injury between asphyxia and electrical stimulation induced cardiac arrest in rats.Methods:Forty-two healthy male Sprague-Dawley (SD) rats were randomized into sham group ( n = 6), asphyxia group ( n = 18) and electrical stimulation group ( n = 18). Rats in each group were given invasive mechanical ventilation and femoral blood vessels catheterization for monitoring blood pressure and fluid infusion. In the asphyxia group, the tracheal tube was clamped to induce cardiac arrest, and in the electrical stimulation group, the esophageal electrical stimulation was used to induce cardiac arrest, and cardiopulmonary resuscitation (CPR) was performed 4 minutes after cardiac arrest. In the sham group, only tracheal intubation and femoral artery intubation were performed after anesthesia, but cardiac arrest was not induced. Animals were allowed to survive until 72 hours after resuscitation, and survival analysis was performed using Kaplan-Meier curves. At 24 hours and 72 hours after resuscitation, the neurological deficit score (NDS) was measured. The vena cava blood was collected, and the brain injury associated serum biomarkers, neuron-specific enolase (NSE) and S100B, were detected by enzyme-linked immunosorbent assay (ELISA). The brain tissues were then harvested to perform hematoxylin-eosin (HE) staining for observing pathological changes in the hippocampal CA1 area with light microscopy. Results:Cardiac arrest was successfully induced in both the asphyxia group and the electrical stimulation group, 94.4% (17/18) and 88.9% (16/18) animals were resuscitated successfully in the two groups respectively. Kaplan-Meier curves analysis showed that 72-hour cumulative survival rate was similar in the asphyxia group and the electrical stimulation group (Log-Rank test: χ2 = 0.040, P = 0.841). Both asphyxia group and electrical stimulation group had higher NDS score than sham group at 24 hours after resuscitation (37.50±4.26, 32.17±4.02 vs. 8.33±2.33, both P < 0.01). NDS score showed a downwards trend at 72 hours after resuscitation in both model groups, and the decline was more significant in the electrical stimulation group, which was significantly different as compared with asphyxia group (14.00±2.89 vs. 26.33±4.84, P < 0.05). ELISA results showed that the levels of serum NSE at 24 hours after resuscitation in the asphyxia and electrical stimulation groups were significantly higher than those in the sham group (μg/L: 1.02±0.07, 1.02±0.02 vs. 0.87±0.02, both P < 0.05). NSE kept increasing at 72 hours after resuscitation in the asphyxia group, which showed significant difference as compared with sham group (μg/L: 1.03±0.05 vs. 0.87±0.02, P < 0.01). But it had almost recovered to the normal level in the electrical stimulation group without significant difference as compared with sham group (μg/L: 0.96±0.04 vs. 0.87±0.02, P > 0.05). There was no significant difference in S100B level at different time points after resuscitation among three groups. It was displayed under light microscope that there was no significant neuronal damage in the hippocampal CA1 area in the two model groups at 24 hours after resuscitation as compared with the sham group. At 72 hours, there were certain damages in the hippocampal CA1 area in both model groups, which were more obvious in the asphyxia group. Conclusions:Both cardiac arrest models induced by asphyxia and electrical stimulation show a certain degree of brain injuries after resuscitation. Brain injuries are more severe in asphyxia-induced cardiac arrest compared with trans-esophageal electrical stimulation method.

Objective:To compare the therapeutic effects and safety of dexmedetomidine and midazolam on patients with severe coronavirus disease 2019 (COVID-19) who received non-invasive ventilation.Methods:Patients with COVID-19 who needed non-invasive ventilation in one critical care medicine ward of Wuhan Jinyintan Hospital during the team support period from the department of critical care medicine of Renmin Hospital of Wuhan University from January 23rd to February 15th in 2020 were investigated retrospectively. Ramsay score, mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR), arterial oxygen partial pressure (PaO 2) before sedation and at 1, 12, 24 hours after sedation, sleep time were collected, and the side effects such as excessive sedation, fall of tongue, abdominal distension, aspiration, bradycardia, escalation to invasive mechanical ventilation during 24 hours were also collected. According to different sedative drugs, patients were divided into the control group (without sedative drugs), dexmedetomidine group and midazolam group. The changes of indicators among the three groups were compared. Results:Fourteen patients were injected with dexmedetomidine (loading dose of 1 μg/kg for 10 minutes, maintained at 0.2-0.7 μg·kg -1·h -1); 9 patients were injected with midazolam (loading dose of 0.05 mg/kg for 2 minutes, maintained at 0.02-0.10 mg·kg -1·h -1); 12 patients didn't use sedative drugs due to limitations of previous hospital or patients' rejection. In dexmedetomidine group and midazolam group, the Ramsay score was maintained at 2-3 points after sedation, which were higher than those of control group at different time points after sedation, and there was no significant difference between dexmedetomidine group and midazolam group. MAP of dexmedetomidine group and midazolam group decreased gradually after sedation. MAP after 1-hour sedation was significantly lower than that before sedation, and MAP after 24 hours sedation was significantly lower than that in the control group [mmHg (1 mmHg = 0.133 kPa): 109.7±11.5, 107.1±12.3 vs. 121.1±13.3, both P < 0.05]. HR decreased gradually after sedation treatment, which was significantly lower after 12 hours of sedation than that before sedation, and HR in dexmedetomidine group was significantly lower than that in control group after 12 hours of sedation (bpm: 84.0±13.9 vs. 92.8±15.4 at 12 hours; 81.0±16.7 vs 92.6±12.7 at 24 hours, both P < 0.05). PaO 2 increased and RR decreased in all three groups after ventilation. PaO 2 in dexmedetomidine group and midazolam group were significantly higher than that in the control group after 12 hours of sedation [cmH 2O (1 cmH 2O = 0.098 kPa): 79.0±6.5, 79.0±8.9 vs. 70.0±7.8, both P < 0.05]; the decreases of RR in dexmedetomidine group and midazolam group were significant than that in control group after 1 hour of sedation (bpm: 34.0±3.9, 33.8±4.6 vs. 39.0±3.6, both P < 0.05). There were no differences of MAP, HR, PaO 2 and RR between dexmedetomidine group and midazolam group at different time points. The sleep duration in dexmedetomidine group and midazolam group were significantly longer than that in the control group (hours: 4.9±1.9, 5.8±2.4 vs. 3.0±1.8, both P < 0.05), but there was no difference between dexmedetomidine group and midazolam group ( P > 0.05). Adverse events occurred in all three groups. In midazolam group, there were 2 cases of excessive sedation with fall of tongue and abdominal distension, including 1 case of aspiration, 1 case receiving intubation due to refractory hypoxemia and 1 case due to unconsciousness. In dexmedetomidine group, there were 2 cases of bradycardia, 1 case of intubation due to refractory hypoxemia. In control group, 4 cases underwent intubation due to refractory hypoxemia. Conclusions:Non-invasive mechanical ventilation is an important respiratory support technology for patients with severe COVID-19. Appropriate sedation can increase the efficiency of non-invasive mechanical ventilation. Dexmedetomidine is more effective and safer than midazolam in these patients, but attention should be paid to HR and blood pressure monitoring.

Ischemia/reperfusion (I/R) caused by cardiac arrest (CA) and subsequent cardiopulmonary resuscitation (CPR) was the primary cause of post-cardiac arrest syndrome (PCAS), including post-cardiac arrest myocardial dysfunction and post-cardiac arrest brain injury. Disturbance of endoplasmic reticulum proteostasis, so-called endoplasmic reticulum stress (ERS) was one of the pathological changes induced by I/R injury. The unfolded protein response (UPR) was an adaptive response triggered by ERS in cells. Modulating the UPR arms to alleviate ERS to promote cell survival was promising for attenuating I/R injury. Activating the activating transcription factor6 (ATF6) signaling pathway, one of the arms of the UPR, confers protection against I/R injury in multiple tissues by restoring endoplasmic reticulum proteostasis and reducing oxygen free radicals. This article reviewed the structural characteristics and biological function of ATF6 and focused on its essential role in cardiac and cerebral I/R injury as well as potential therapeutic targets, hoping to provide new ideas for the effective treatment of PCAS.

Objective:To study the crosstalk between the activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1) - X-box binding protein 1 (XBP1) pathway in oxygen-glucose deprivation/reoxygenation (OGD/R)-injured mouse hippocampal neuronal cell line HT22.Methods:The OGD/R-injured HT22 cell model was used to observe the changes of the indicators of endoplasmic reticulum stress (ERS), cell viability, and apoptosis at different OGD/R time points (0, 3, 6, 12, and 24 hours). HT22 cells in the logarithmic growth phase were randomized into blank control group, control+ATF6 activator (AA147) group, control+IRE1 inhibitor (4μ8c) group, OGD/R model group, OGD/R+AA147 group and OGD/R+4μ8c group (10 μmol/L AA147 or 16 μmol/L 4μ8c was given during the whole process in the AA147 group and 4μ8c group). Western blotting was used to detect the expression of ERS-related proteins [glucose-regulated protein 78 (GRP78), phosphorylated-inositol-requiring enzyme 1 (p-IRE1), and phosphorylated-eukaryotic translation initiation factor-2α (p-eIF2α)], and apoptosis-related proteins (Bcl-2, Bax, caspase-3, and cleaved caspase-3). The mRNA of ERS-related genes, and ATF6 [homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 (Herpud1), protein disulfide isomerase associated 4 (Pdia4) and Sel-1 suppressor of lin-12-like (Sel1L)] and spliced XBP1 [XBP1s, include DnaJ heat shock protein family member B9 (Erdj4), Sec24 related gene family, member D (Sec24d) and signal sequence receptor, gamma (Ssr3)] induced transcriptional response-related genes were measured by real-time quantitative polymerase chain reaction (RT-qPCR). A cell counting kit-8 (CCK-8) assay was used to detect the viability of HT22 cells. Immunofluorescence was utilized to test the expression of cleaved caspase-3.Results:Compared with the blank control group, the expression of ERS-related proteins p-IRE1 and p-eIF2α were significantly increased at 12 hours and 3 hours following OGD/R, respectively (p-IRE1/β-actin: 2.09±0.10 vs. 1.00±0.00, p-eIF2α/β-actin: 1.39±0.11 vs. 1.00±0.00, both P < 0.01). The mRNA expressions of ERS-related genes [ATF6, XBP1s, unspliced XBP1 (XBP1u), activating transcription factor 4 (ATF4), CCAAT/EBP homologous protein (CHOP)] were also upregulated in different OGD/R timepoint in HT22 cells, which indicated ERS was activated in OGD/R-stimulated HT22 cells. Compared with the OGD/R model group, the expression of protein p-IRE1 was not changed, but the mRNA of XBP1s and XBP1u were obviously downregulated in the OGD/R+AA147 group [XBP1s (2 -ΔΔCt): 0.76 (0.71, 0.92) vs. 1.13 (1.03, 1.29), XBP1u (2 -ΔΔCt): 0.29±0.05 vs. 0.52±0.04, both P < 0.01], whereas the expressions of XBP1s-induced transcriptional response downstream genes did not change significantly. Compared with the OGD/R model group, the protein of short-form ATF6 (sATF6) and GRP78 were not changed after administration of 4μ8c, neither was the mRNA expression of ATF6-induced transcriptional response-related genes. These results showed that the mRNA expression of XBP1s and XBP1u were inhibited by AA147-induced activation of ATF6, but no crosstalk was observed between the transcriptional response induced by ATF6 and XBP1s. Compared with the blank control group, the cell viability decreased significantly at OGD/R 3 hours [(44.64±5.12) % vs. (99.13±5.76) %, P < 0.01], the ratios of apoptosis-related proteins Bax/Bcl-2 and cleaved caspase-3/caspase-3 were significantly increased at OGD/R 3 hours and OGD 0 hour, respectively (Bax/Bcl-2: 6.15±1.65 vs. 1.00±0.00, cleaved caspase-3/caspase-3: 17.48±2.75 vs. 1.00±0.00, both P < 0.01), which indicated that apoptosis was activated in OGD/R-treated HT22 cells. Compared with the OGD/R model group, the cell viability decreased significantly [(36.52±17.78)% vs. (69.90±9.43)%, P < 0.01], and the ratios of Bax/Bcl-2 and cleaved caspase-3/caspase-3 were significantly upregulated in the OGD/R+AA147 group in HT22 cells (Bax/Bcl-2: 2.06±0.31 vs. 1.10±0.25, cleaved caspase-3/caspase-3: 3.35±0.59 vs. 0.55±0.09, both P < 0.01). Conclusion:Under our experimental conditions, no obvious crosstalk between the transcriptional response induced by ATF6 and XBP1s was observed, while ATF6 activation induced by AA147 suppressed mRNA expression of XBP1s and XBP1u and promoted cell death in OGD/R-treated HT22 cells.