Phenotypic and genetic characterization of hypervirulent Klebsiella pneumoniae in patients with liver abscess and ventilator-associated pneumonia.

Ventilator-associated pneumonia (VAP) and pyogenic liver abscess (PLA) due to Klebsiella pneumoniae infection can trigger life-threatening malignant consequences, however, there are few studies on the strain-associated clinical pathogenic mechanisms between VAP and PLA. A total of 266 patients consist of 129 VAP and 137 PLA were included for analysis in this study. We conducted a comprehensive survey for the two groups of K. pneumoniae isolates, including phenotypic experiments, clinical epidemiology, genomic analysis, and instrumental analysis, i.e., to obtain the genomic differential profile of K. pneumoniae strains responsible for two distinct infection outcomes. We found that PLA group had a propensity for specific underlying diseases, especially diabetes and cholelithiasis. The resistance level of VAP was significantly higher than that of PLA (78.57% vs. 36%, P < 0.001), while the virulence results were opposite. There were also some differences in key signaling pathways of biochemical processes between the two groups. The combination of iucA, rmpA, hypermucoviscous phenotype, and ST23 presented in K. pneumoniae infection is more important and highly prudent for timely treatment. The present study may contribute a benchmark for the K. pneumoniae clinical screening, epidemiological surveillance, and effective therapeutic strategies.

AQMDRL: Automatic Quality of Service Architecture Based on Multistep Deep Reinforcement Learning in Software-Defined Networking.

Software-defined networking (SDN) has become one of the critical technologies for data center networks, as it can improve network performance from a global perspective using artificial intelligence algorithms. Due to the strong decision-making and generalization ability, deep reinforcement learning (DRL) has been used in SDN intelligent routing and scheduling mechanisms. However, traditional deep reinforcement learning algorithms present the problems of slow convergence rate and instability, resulting in poor network quality of service (QoS) for an extended period before convergence. Aiming at the above problems, we propose an automatic QoS architecture based on multistep DRL (AQMDRL) to optimize the QoS performance of SDN. AQMDRL uses a multistep approach to solve the overestimation and underestimation problems of the deep deterministic policy gradient (DDPG) algorithm. The multistep approach uses the maximum value of the n-step action currently estimated by the neural network instead of the one-step Q-value function, as it reduces the possibility of positive error generated by the Q-value function and can effectively improve convergence stability. In addition, we adapt a prioritized experience sampling based on SumTree binary trees to improve the convergence rate of the multistep DDPG algorithm. Our experiments show that the AQMDRL we proposed significantly improves the convergence performance and effectively reduces the network transmission delay of SDN over existing DRL algorithms.

Emerging Trends and Hot Topics in Cardiopulmonary Resuscitation Research: A Bibliometric Analysis from 2010 to 2019.

BACKGROUND Cardiopulmonary resuscitation (CPR) is a topic of great scientific and clinical interest that has received much attention in the past decade. Our study aimed to predict the trends in CPR research activities and evaluate hot topics via bibliometric means, quantitatively and qualitatively. MATERIAL AND METHODS All data were collected from a search of the Web of Science Core Collection on May 12, 2020. Retrieved information was investigated with bibliometric analysis by CiteSpace and VOSviewer software and the Online Analysis Platform of Literature Metrology to analyze and predict the trends and hotspots in this field. RESULTS Our search returned a total of 9563 articles and reviews on CPR published from 2010 through 2019. The number of original research studies on CPR has been increasing annually. The journal Resuscitation published the greatest number of manuscripts involved CPR, and the leading country and institution with regard to contributions on CPR were the United States and the University of Pennsylvania. Keyword co-occurrence/co-citation-cluster analysis showed that the most popular terms associated with CPR occurred in the manner of cluster labels, such as therapeutic hypothermia and treatment recommendation, among others. In addition, palliative care, sepsis, extracorporeal membrane oxygenation, and brain injury were identified as new foci through burst detection analysis. CONCLUSIONS Our study showed that the scientific research focus on CPR is switching from traditional therapeutic treatments to a public health practice, with in-depth understanding and development of CPR-related techniques expanding over the past decade. These results demonstrate trends in the CPR research and detected the possible neo-foci for ensuing research.

Pyogenic Liver Abscess: A Retrospective Study of 105 Cases in an Emergency Department from East China.

BACKGROUND: Pyogenic liver abscesses have become common in emergency departments (EDs) in recent years in Shanghai, China due to a variety of risk factors contributory to the disease. OBJECTIVE: To review our experience in managing pyogenic liver abscesses to aid in the current management of this complex condition. METHODS: This retrospective study was conducted to collect and analyze information from adult patients diagnosed with liver hepatic abscesses who were admitted to Ren Ji Hospital during the period from January 1, 2010 to December 31, 2015. The demographic data, etiology, underlying diseases, clinical presentation, imaging features, laboratory examinations, microbiological tests, treatment, and clinical outcomes were analyzed. RESULTS: The data of a total 105 patients were retrospectively analyzed. The mean age of the patients was 62.0 ± 13.5 years. The etiology was predominantly hepatobiliary disease (43/105, 40.1%) or diabetes mellitus (42/105, 40.0%). During hospitalization, 12 patients (11.4%) with septic shock required intensive care. One patient died, yielding a 0.9% fatality rate. In addition to empiric antimicrobial therapy, 66/105 (62.9%) patients underwent ultrasound-guided percutaneous drainage of the liver abscess at diagnosis. Only 3 patients required surgical intervention. Bacterial culture of pyogenic fluids revealed 25 positive results of 66 cases (37.9%). Among them, Klebsiella pneumoniae was the primary pathogen detected in 15 cases (60.0%). CONCLUSIONS: Pyogenic liver abscesses have become common in EDs in Shanghai, China. The early recognition of the disease, prompt use of empirical antimicrobial therapy, initiation of drainage in the appropriate patients, and controlling the underlying conditions were crucial for preventing severe sepsis and improving the outcome.

Remote ischemic pre- and postconditioning improve postresuscitation myocardial and cerebral function in a rat model of cardiac arrest and resuscitation.

OBJECTIVES: Cardiac arrest and resuscitation are models of whole body ischemia reperfusion injury. Postresuscitation myocardial and cerebral dysfunction are major causes of high mortality and morbidity. Remote ischemic postconditioning has been proven to provide potent protection of the heart and brain against ischemia reperfusion injury. In this study, we investigated the effects of remote ischemic postconditioning on postresuscitation myocardial and cerebral function in a rat model of cardiac arrest and resuscitation. DESIGN: Prospective, randomized, controlled experimental study. SETTING: University-affiliated animal research institution. SUBJECTS: Twenty-eight healthy male Sprague-Dawley rats. INTERVENTIONS: The animals were randomized into four groups: 1) remote ischemic preconditioning initiated 40 minutes before induction of ventricular fibrillation, 2) remote ischemic postconditioning initiated coincident with the start of cardiopulmonary resuscitation, 3) remote ischemic postconditioning initiated 5 minutes after successful resuscitation, and 4) control. Remote ischemic pre- and postconditioning was induced by four cycles of 5 minutes of limb ischemia, followed by 5 minutes of reperfusion. Ventricular fibrillation was induced and untreated for 6 minutes while defibrillation was attempted after 8 minutes of cardiopulmonary resuscitation. The animals were then monitored for 4 hours and observed for an additional 68 hours after resuscitation. MEASUREMENTS AND MAIN RESULTS: Hemodynamic measurements and myocardial function, including cardiac output, left ventricular ejection fraction, and myocardial performance index, were measured at baseline and hourly for 4 hours after resuscitation. Postresuscitation cerebral function was evaluated by neurologic deficit score at 24-hour intervals for a total of 72 hours. Consequently, significantly better myocardial and cerebral function with a longer duration of survival were observed in the three groups treated with remote ischemic pre- and postconditioning. CONCLUSIONS: In a rat model of cardiac arrest and resuscitation, remote ischemic pre-and postconditioning attenuated postresuscitation myocardial and cerebral dysfunction and improved the duration of survival.

Improved cardiac and neurologic outcomes with postresuscitation infusion of cannabinoid receptor agonist WIN55, 212-2 depend on hypothermia in a rat model of cardiac arrest.

OBJECTIVES: To investigate the mechanisms of improved myocardial and neurological function and survival following i.v. administration of cannabinoid receptor agonist, WIN55, 212-2 in a rat model of cardiac arrest. DESIGN: Prospective randomized controlled experimental study. SETTING: University-affiliated research institute. SUBJECTS: Thirty male Sprague-Dawley rats. INTERVENTIONS: Ventricular fibrillation was electrically induced in 30 male Sprague-Dawley rats weighing between 450 and 550 g. Cardiopulmonary resuscitation was initiated after 6 minutes of untreated ventricular fibrillation. The precordial compression was performed with a pneumatically driven mechanical chest compressor. No pharmacological agent was used during cardiopulmonary resuscitation. After 8 minutes of cardiopulmonary resuscitation, up to three 2-J defibrillations were attempted. The animals were then randomized into three groups: 1) WIN55, 212-2 hypothermia, 2) WIN55, 212-2 with normal body temperature, and 3) placebo control. Either WIN55, 212-2 (1.0 mg/kg/hr) or saline placebo was continuously infused for 2 hours. Except for the WIN55, 212-2 hypothermia group, the body temperature in the other two groups was maintained at 37.0 ± 0.2°C using an external heating lamp. Postresuscitation myocardial function was measured by echocardiogram. Neurological deficit scores and survival time were observed for up to 72 hours. MEASUREMENTS AND MAIN RESULTS: Blood temperatures decreased from 37°C to 33°C in 4 hours in animals in WIN55, 212-2 hypothermia group. Myocardial function, as measured by cardiac output, ejection fraction, and myocardial performance index, was significantly impaired in all animals after successful resuscitation when compared with the baseline values. There was a significant improvement in myocardial function in the animals treated with WIN55, 212-2 hypothermia beginning at 1 hour after start of infusion. However, no improvement was observed in the groups of WIN55, 212-2 with normal body temperature and placebo control. WIN55, 212-2 hypothermia group was associated with significantly improved neurologic deficit scores and survival time when compared with placebo control group and WIN55, 212-2 with normal body temperature group. CONCLUSIONS: In a rat model of cardiac arrest, better postresuscitation myocardial function, neurological deficit scores, and longer duration of survival were observed by the pharmacologically induced hypothermia with WIN55, 212-2. The improved outcomes of cardiopulmonary resuscitation following administration of WIN55, 212-2 appeared to be the results from its temperature reduction effects.

The effects of the rate of postresuscitation rewarming following hypothermia on outcomes of cardiopulmonary resuscitation in a rat model.

OBJECTIVE: To investigate the optimal rewarming rate following therapeutic hypothermia in a rate model of cardiopulmonary resuscitation. Both clinical and laboratory studies have demonstrated that mild therapeutic hypothermia following cardiopulmonary resuscitation improves myocardial and neurologic outcomes of cardiac arrest. However, the optimal rewarming strategy following therapeutic hypothermia remains to be explored. DESIGN: Prospective randomized controlled experimental study. SETTING: University-affiliated research institution. SUBJECTS: Twenty-three healthy male Sprague-Dawley rats. INTERVENTIONS: Four groups of Sprague-Dawley rats were randomized: 1) normothermia group (control), 2) rewarming rate at 2°C/hr, 3) rewarming rate at 1°C/hr, and 4) rewarming rate at 0.5°C/hr. Ventricular fibrillation was induced and untreated for 8 minutes, and defibrillation was attempted after 8 minutes of cardiopulmonary resuscitation. For the 2, 1, and 0.5°C/hr groups, rapid cooling was started at the beginning of cardiopulmonary resuscitation. On reaching the target cooling temperature of 33°C ± 0.2°C, the temperature was maintained with the aid of a cooling blanket until 4 hours after resuscitation. Rewarming was then initiated at the rate of 2.0, 1.0, or 0.5°C/hr, respectively, until the body temperature reached 37°C ±0.2°C. Blood samples were drawn at baseline and postresuscitation of 4, 6, 8, 10, and 12 hours for the measurements of blood gas and serum biomarkers. MEASUREMENTS AND MAIN RESULTS: Blood temperature significantly decreased in the hypothermic groups from cardiopulmonary resuscitation to postresuscitation 4 hours. Significantly better cardiac output, ejection fraction, myocardial performance index, reduced neurologic deficit scores, and longer duration of survival were observed in the 1 and 0.5°C/hr groups. The increased serum concentration of troponin I, interleukin-6, and tumor necrosis factor-α was partly attenuated in the 1 and 0.5°C/hr groups when compared with the control and 2°C/hr groups. CONCLUSIONS: This study demonstrated that the severity of myocardial, cerebral injuries, and inflammatory reaction after cardiopulmonary resuscitation was reduced when mild therapeutic hypothermia was applied. A rewarming rate at 0.5-1°C/hr did not alter the beneficial effects of therapeutic hypothermia. However, a rapid rewarming rate at 2°C/hr abolished the beneficial effects of hypothermia.

On approximating a new generalization of traveling salesman problem.

The current best-known performance guarantees for the extensively studied Traveling Salesman Problem (TSP) of determinate approximation algorithms is 32, achieved by Christofides' algorithm 47 years ago. This paper investigates a new generalization problem of the TSP, termed the Minimum-Cost Bounded Degree Connected Subgraph (MBDCS) problem. In the MBDCS problem, the goal is to identify a minimum-cost connected subgraph containing n=|V| edges from an input graph G=(V,E) with degree upper bounds for particular vertices. We show that for certain special cases of MBDCS, the aim is equivalent to finding a minimum-cost Hamiltonian cycle for the input graph, same as the TSP. To appropriately solve MBDCS, we initially present an integer programming formulation for the problem. Subsequently, we propose an algorithm to approximate the optimal solution by applying the iterative rounding technique to solution of the integer programming relaxation. We demonstrate that the returned subgraph of our proposed algorithm is one of the best guarantees for the MBDCS problem in polynomial time, assuming P≠NP. This study views the optimization of TSP as finding a minimum-cost connected subgraph containing n edges with degree upper bounds for certain vertices, and it may provide new insights into optimizing the TSP in future research.

Impact of acupuncture on ischemia/reperfusion injury: Unraveling the role of miR-34c-5p and autophagy activation.

We have previously reported that the expression of miR-34c-5p was up-regulated during acupuncture treatment in the setting of a cerebral ischemia/reperfusion injury (CIRI), indicating that miR-34c-5p plays an important role in healing from a CIRI-induced brain injury. This study sought to evaluate the effects of acupuncture on miR-34c-5p expression and autophagy in the forward and reverse directions using a rat focal cerebral ischemia/reperfusion model. After 120 minutes of middle cerebral artery occlusion and reperfusion, rats were treated with acupuncture at the "Dazhui" (DU20), "Baihui" (DU26) and "Renzhong" (DU14) points. Neurologic function deficit score, cerebral infarct area ratio, neuronal apoptosis and miR-34c-5p expression were evaluated 72 hr after treatment. The autophagy agonist RAPA and the antagonist 3MA were used to evaluate the neuro protective effects of autophagy-mediated acupuncture. We found that acupuncture treatment improved autophagy in the brain tissue of CIRI rats. Acupuncture reversed the negative effects of 3MA on CIRI, and acupuncture combined with RAPA further enhanced autophagy. We also found that acupuncture could increase miR-34c-5p expression in hippocampal neurons after ischemia/reperfusion. Acupuncture and a miR-34c agomir were able to enhance autophagy, improve neurologic deficits, and reduce the cerebral infarct area ratio and apoptosis rate by promoting the expression of miR-34c-5p. Silencing miR-34c resulted in a significantly reduced activating effect of acupuncture on autophagy and increased apoptosis, neurologic deficit symptoms, and cerebral infarct area ratio. This confirms that acupuncture can upregulate miR-34c-5p expression, which is beneficial in the treatment of CIRI.

The present/null polymorphism in the GSTT1 gene and the risk of lung cancer in Chinese population.

The present/null polymorphism in the GSTT1 gene has been implicated in susceptibility to lung cancer in Chinese population. A large number of studies have reported inconclusive results. The aim of the current study was to investigate the relationship between the present/null polymorphism in the GSTT1 gene and lung cancer risk in Chinese population by meta-analysis. The Pubmed, Embase, CNKI, and Wanfang databases were searched. The statistical analysis was performed by using Revman4.2 and Stata10.0. In summary, a total of 2,211 lung cancer cases and 3,115 controls in 18 case-control studies were included for data analysis. The results suggested that the null genotype carriers may contribute to increased risk of lung cancer in Chinese population when compared with the present genotype carriers (odds ratio = 1.24, 95% confidence interval = 1.02-1.49). The current meta-analysis suggested that the present/null polymorphism in the GSTT1 gene might contribute to the risk of lung cancer in Chinese population. Future studies are needed to validate these results.

Thromboelastography Parameters in Urosepsis: A Retrospective Study.

Thromboelastography (TEG) is usually used to monitor coagulation disorder clinically. It is unclear whether TEG has association with urosepsis and sepsis-induced coagulopathy (SIC). The purpose of this study was to investigate the clinical significance of TEG parameters in urosepsis. 90 patients who were admitted to the Emergency Ward and Emergency Intensive Care Unit (EICU) of Ren Ji Hospital affiliated to Shanghai Jiao Tong University School of Medicine due to urinary infection from February 2014 to February 2022 were retrospectively studied. Urosepsis patients and non-sepsis patients were separately investigated according to the final discharge diagnosis and Sepsis 3.0. At the same time, patients with urosepsis were further divided into groups of SIC and non-SIC based on the definition of SIC. The data of clinical features, laboratory biomarkers, and TEG parameters were collected and analyzed. There were significant differences in white blood cell count, C-reactive protein (CRP), platelet count, procalcitonin (PCT), fibrinogen (FIB), international normalized ratio (INR), prothrombin time (PT), D-dimer, and incidence of urinary tract obstruction between the urosepsis group and non-sepsis group (P < 0.05). In the comparison with non-sepsis group, K value was significantly lower (P = 0.006), while α-angle (P = 0.003) and clot index (CI) (P = 0.048) were significantly higher in urosepsis group. The area under the K value curve excluding urosepsis was 0.667. The areas under CI and α-angle curves for diagnosing urosepsis were 0.682 and 0.621, respectively. The patients in SIC group had significantly higher K value, lower α-angle, and maximum amplitude (MA) than those in non-SIC group (P < 0.05). Coagulopathy is prone to occur in patients with urosepsis. TEG is helpful for assessment of hypercoagulable state in urosepsis and prediction of hypocoagulability in SIC patients implying the dynamic process of DIC.

Mapping the research trends and hot topics of ventricular arrhythmia: A bibliometric analysis from 2001 to 2020.

Background: Studies of ventricular arrhythmia (VA) have drawn much scholarly attention over the past two decades. Our study aimed to assess the current situation and detect the changing research trends of VA quantitatively and qualitatively. Materials and methods: All the information used in our statistical and bibliometric analysis were collected and summarized from papers retrieved from the Web of Science Core Collection (WoSCC) database on December 22, 2021 using certain criteria. Visual analytics were realized using CiteSpace, VOSviewer, the bibliometrix R package, and the bibliometric online analysis platform. Results: A total of 6,897 papers (6,711 original articles, 182 proceedings papers, three book chapters, and one data paper) were published in 796 journals that concentrated on the research areas of cardiovascular and critical care medicine. The most productive country and influential institution was the USA and the Mayo Clinic, respectively. Heart Rhythm (551 articles and 8,342 local citations) published the most manuscripts. The keyword co-occurrence and co-citation network of references analyses revealed that the most popular terms were ventricular tachycardia, ventricular fibrillation, catheter ablation, implantable cardioverter defibrillator (ICD), and sudden cardiac death (SCD). Further, the burst detection analysis demonstrated that topics strongly associated with clinical prognosis, such as meta-analysis, long-term outcomes, and impact, were new concerns. Conclusion: Our study offers a comprehensive picture of VA research and provides profound insights into the current research status. Moreover, we show that new topics within the VA research field have focused more on prognosis and evidence-based clinical guidelines.

Protection Against Post-resuscitation Acute Kidney Injury by N-Acetylcysteine via Activation of the Nrf2/HO-1 Pathway.

Background and Objective: Acute kidney injury (AKI), the common complication after cardiopulmonary resuscitation (CPR), seriously affects the prognosis of cardiac arrest (CA) patients. However, there are limited studies on post-resuscitation AKI. In addition, it has been demonstrated that N-acetylcysteine (N-AC) as an ROS scavenger, has multiorgan-protective effects on systemic and regional ischaemia-reperfusion injuries. However, no studies have reported its protective effects against post-resuscitation AKI and potential mechanisms. This study aimed to clarify the protective effects of N-AC on post-resuscitation AKI and investigate whether its potential mechanism was mediated by activating Nrf-2/HO-1 pathway in the kidney. Methods: We established cardiac arrest models in rats. All animals were divided into four groups: the sham, control, N-AC, and ZnPP groups. Animals in each group except for the ZnPP group were assigned into two subgroups based on the survival time: 6 and 48 h. The rats in the control, N-AC, and ZnPP groups underwent induction of ventricular fibrillation (VF), 8 min untreated VF and cardiopulmonary resuscitation. Renal function indicators, were detected using commercial kits. Renal pathologic changes were assessed by haematoxylin-eosin (HE) staining. Oxidative stress and inflammatory responses were measured using the corresponding indicators. Apoptosis was evaluated using terminal uridine nick-end labeling (TUNEL) staining, and expression of proteins associated with apoptosis and the Nrf-2/HO-1 pathway was measured by western blotting. Results: N-AC inhibited post-resuscitation AKI. We observed that N-AC reduced the levels of biomarkers of renal function derangement; improved renal pathological changes; and suppressed apoptosis, oxidative stress, and inflammatory response. Additionally, the production of ROS in the kidneys markedly decreased by N-AC. More importantly, compared with the control group, N-AC further upregulated the expression of nuclear Nrf2 and endogenous HO-1 in N-AC group. However, N-AC-determined protective effects on post-resuscitation AKI were markedly reversed after pretreatment of the HO-1 inhibitor zinc protoporphyrin (ZnPP). Conclusions: N-AC alleviated renal dysfunction and prolonged survival in animal models of CA. N-AC partially exerts beneficial renal protection via activation of the Nrf-2/HO-1 pathway. Altogether, all these findings indicated that N-AC as a common clinical agent, may have the potentially clinical utility to improve patients the outcomes in cardiac arrest.

[Acupuncture mediated miR-34c-5p regulates the autophagy of hippocampal neurons in rats with cerebral ischemia/reperfusion injury].

OBJECTIVE: To observe the effect of acupuncture on the expression of miR-34c-5p, autophagy-related proteins and apoptosis rate in hippocampus of rats with cerebral ischemia/reperfusion injury (CI/RI), so as to explore its mechanism in regulating autophagy in hippocampal neurons in CI/RI rats. METHODS: SD rats were randomly divided into sham operation, model, medication and acupuncture groups, with 20 rats in each group. The rat model of CI/RI was established by occlusion of the middle cerebral artery. In the acupuncture group, "Dazhui" (GV14), "Baihui" (GV20) and "Shuigou" (GV26) were punctured with filiform needles and stimulated manually once every 15 min, for 30 min. The rats of the medication group were intraperito-neally injected with edaravone (5 mg/kg). The treatment was conducted once every 12 h for a total of 7 times. The neurological de-ficit score of all the rats were evaluated according to Garcia's methods, and TTC staining was employed to assess the cerebral ischemic area (percentage of cerebral infarct area, CIA). Transmission electron microscopy (TEM) was used to observe the ultrastructural changes of hippocampal neurons. The expression of hippocampal miR-34c-5p was measured by real-time PCR, and the protein expressions of hippocampal LC3B, Beclin1 and p62 were measured by Western blot. The apoptosis rate of ischemic brain tissue was observed by TUNEL staining. RESULTS: Compared with the sham operation group, the neurological deficit score, the expressions of miR-34c-5p, Beclin1, p62 and LC3B-Ⅱ/LC3B-Ⅰ were significantly decreased (P<0.01, P<0.05), and the CIA and the apoptosis rate significantly increased (P<0.01) in the model group. Compared with the model group, the neurological deficit scores, the expressions of miR-34c-5p, Beclin1, p62 and LC3B-Ⅱ/LC3B-Ⅰ were significantly increased (P<0.01, P<0.05), and the CIA and the apoptosis rate significantly decreased (P<0.01) in the medication and acupuncture groups. Compared with the medication group, the expression of miR-34c-5p was significantly increased (P<0.01). The results of electron microscope showed that the neurons in the acupuncture and medication groups were less damaged than those in the model group, the cells showed mild edema, and the structures were relatively complete. Some normal organelles could be seen, and autophagy bodies, autophagy lysosomes and their encapsulated organelles could still be observed. CONCLUSION: Acupuncture can improve the neurological deficit and reduce the area of cerebral infarction in CI/RI rats, which is closely with its effect in promoting hippocampal neuronal autophagy and anti-apoptosis via up-regulating the expression of miR-34c-5p.

[PTEN impedes EMT during chick embryo gastrulation].

PTEN has been considered as one of the important anti-oncogenes, which possesses very wide biological activities. Endogenous PTEN genes begin to express in epiblast during chick embryo gastrulation, and then the expression extends to neural plate and mesoderm. This suggests that PTEN might be involved in cell migration, proliferation, and differentiation during early embryo development. In this study, we employed in vivo approach to explore if endogenous PTEN participates in EMT (Epithelial-mesenchymal transition) in early chick embryo. PTEN was initially detected to highly express in primitive streak during chick gastrulation, in which EMT occurs, and subsequently mesoderm structure such as somites etc. Then, overexpression of both Wt PTEN-GFP and Wt PTEN-GFP positive transplantation of primitive streak resulted in cell accumulation in primitive streak in the development hereafter, indicating that EMT was blocked in both of our assays, either whole embryo transfection of Wt PTEN-GFP or transplantation of Wt PTEN-GFP primary streak tissue. Finally down-regulation of PTEN gene in one side using PTEN siRNA led to reduce the more number of mesoderm cells in PTNE siRNA side than normal side, which suggests that PTEN gene is probably involved in regulating EMT process in development of early embryonic gastrulation.

Renoprotective effects of levosimendan on acute kidney injury following cardiac arrest via anti-inflammation, anti-apoptosis, and ERK activation.

ATP-sensitive potassium channels (KATPs) have protective effects in ischemia-reperfusion-induced injuries and can be activated by levosimendan. This study investigated the effects of levosimendan on renal injury, inflammation, apoptosis, and survival in a rat model of acute kidney injury (AKI) following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Rats underwent a 5-min asphyxia-based CA and resuscitation. The rats were treated with levosimendan after successful resuscitation. Renal functions, histological changes, inflammatory responses, and apoptosis were examined. NRK-52E cells treated by hypoxia/reoxygenation (H/R) were used to establish an in vitro CA-CPR model. Rats in the CA-induced AKI group had a low survival rate and increased levels of creatinine, blood urea nitrogen, and proinflammatory cytokines, as well as increased tubular injury. These results were significantly reversed after treatment with levosimendan. Levosimendan downregulated the expression of the apoptosis-related proteins Bax, cleaved caspase-3, and cleaved caspase-9, as well as upregulated Bcl-2 and p-ERK expression in vivo and in vitro. Thus, our data suggest that levosimendan reduces mortality and AKI following CA and CPR via suppression of inflammation and apoptosis, and activation of ERK signaling.

Levosimendan in rats decreases acute kidney injury after cardiopulmonary resuscitation by improving mitochondrial dysfunction.

BACKGROUND: Acute kidney injury (AKI), the most common complication after cardiac resuscitation, is highly prevalent and harmful. There is increasing evidence that levosimendan can improve cardiac output, increase renal blood flow, and prevent AKI. As a novel calcium sensitizer, levosimendan may exert its protective effect via mitochondria. METHODS: Rat models of asphyxia-induced cardiac arrest and cardiopulmonary resuscitation (CPR) were set up. Thirty healthy adult male SD rats were randomly divided into CPR group (CPR group, n=10), levosimendan-treated group (levo group, n=10), and sham-operated group (sham group, n=10). Twelve hours after CPR, serum renal function indicators were measured, the kidney injury and mitochondrial morphological changes were observed. Oxygen uptake of the mitochondria, mitochondrial adenosine triphosphate (ATP) and mitochondrial free Ca2+ concentration were measured. Oxidative stress-related indicator levels in rat kidney tissues were further detected to analyze the differences in apoptosis rates among these three groups. Mitochondrial optic atrophy 1 (Opa1), dynamin-related protein 1 (Drp1), and apoptosis-related proteins were detected using Western blotting. RESULTS: Compared with the sham group, the CPR group had a significant increase in renal tissue damage. PAS staining and HE stains confirmed that CPR led to renal histopathological damage and destruction of the mitochondrial structure. Levosimendan improved the histopathological and ultrastructural damages of kidneys. Further analysis revealed that mitochondrial ATP content, NADH dehydrogenase, succinate dehydrogenase/cytochrome C oxidase, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (CSH-Px) decreased. Free Ca2+ concentration and malondialdehyde (MDA) significantly increased (all P<0.05) in the kidney tissues of rats in the CPR group. However, mitochondrial ATP content, NADH dehydrogenase, succinate dehydrogenase/cytochrome C oxidase, SOD, CAT, and CSH-Px increased, whereas free Ca2+ concentration and MDA decreased (all P<0.05) in the levo group. The apoptosis rate increased in the CPR group. There were significantly increased levels of Drp1 protein levels, and significantly decreased Opa1 expression (all P<0.05). However, the levo group showed the opposite effects (all P<0.05). CONCLUSIONS: Levosimendan can alleviate AKI following CPR, which may be achieved by improving mitochondrial dysfunction and suppressing the mitochondrial apoptosis pathway.

Efficacy and safety of dissimilar acupuncture intervention time-points in treating stroke: a systematic review and network meta-analysis.

BACKGROUND: Impairment of motor function and activities of daily living is very common in post-stroke patients. Acupuncture has been used in stroke for a long time. Although growing evidence supports the beneficial effects of acupuncture, there is still no clear conclusion on the optimal intervention time-point for acupuncture in stroke. Thus, we tried to assess the efficacy and safety of dissimilar acupuncture intervention time-points by network meta-analysis (NMA). METHODS: A retrieval was performed in several databases from beginning to October 2020. We only enrolled randomized controlled trials (RCTs) testing acupuncture for stroke, and the outcome indicators measured were Fugl-Meyer assessment (FMA) score, Barthel Index (BI), and adverse events. RESULTS: Thirty-eight trials involving 3,836 participants were included in this NMA, the vast majority of which had a low or unclear risk of selection bias, detection bias, reporting bias, attrition bias, but had a high risk of performance bias. The results showed as following: (I) acupuncture treatment (Acu) is significantly more effective than non-acupuncture treatment (Non-Acu) with a good safety. (II) In terms of FMA, acupuncture within 48 h post-stroke (Acu I) was superior to acupuncture within 2-15 d post-stroke (Acu II) [standard mean difference (SMD): 7.17; 95% confidence interval (CI), 1.11 to 13.22], acupuncture within 16-30 d post-stroke (Acu III) (SMD: 20.73; 95% CI, 13.68 to 27.78), acupuncture within 1 month to half a year post-stroke (Acu IV) (SMD: 26.95; 95% CI, 14.88 to 39.02). As for BI, Acu I was the optimal time-point, comparing with Acu III (SMD: 15.18; 95% CI, 8.97 to 21.39) and Acu IV (SMD: 22.88; 95% CI, 11.07 to 34.69). (III) Results of ranking indicated that Acu was better than Non-Acu at a similar stage in improving FMA and BI, while Acu I was the optimal intervention time-point, followed by Acu II. CONCLUSIONS: Although the credibility of our conclusions is low, our NMA indicates that acupuncture can be beneficial for stroke survivors with good safety. In terms of improvement in FMA score and BI, the soon use of acupuncture the better the efficacy. The optimal acupuncture intervention time-point for stroke is within 48 h post-stroke, and the significant validity period lasts until 15 days after onset.

Different acupuncture intervention time-points for improving capacity in motor function and activities of daily living after stroke: A protocol for systematic review and network meta-analysis.

BACKGROUND: The incidence of stroke has been found in an increasing trend worldwide, resulting in significant negative effects and severe impairments to survivors in terms of motor function and activities of daily living. Acupuncture therapy has been widely used in the clinical treatment of stroke for a long time, meanwhile, the efficacy has been confirmed by many studies. However, the optimal intervention time-point of acupuncture in stroke is controversial. Therefore, the purpose of our study is to provide scientific evidence and reasonable suggestions for this issue. METHODS: A computer-based retrieval will be employed in 7 electronic databases: EMBASE Database, PubMed, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang databases, Chinese Scientific Journals Database (VIP) and China Biological Medicine Database (CBM), from the establishment date of each database throughout October 2020. Only randomized controlled trials of acupuncture for stroke will be recruited and language is limited to English or Chinese. The outcomes we focus on include the Fugl-Meyer Assessment score and the Barthel Index. Additionally, safety assessments such as adverse events and drop-out cases may also be taken into consideration. The network meta-analysis will be performed based on the Bayesian framework and literature selection will be conducted by 2 trained reviewers. All data analysis will be calculated by Revman5.3, WinBUGS 1.4.3, Stata13.0, and R software 3.6.1. The Assessment of heterogeneity, inconsistency, subgroup, sensitivity, and publication bias will also be done under the guidelines of Cochrane Collaboration's tool. RESULTS: The results of this study will be submitted to a peer-reviewed journal for publication. CONCLUSION: This network meta-analysis will provide evidence-based references to evaluate the efficacy of different acupuncture intervention time-points during the treatment of stroke. Furthermore, it will help the clinicians to formulate appropriate medical plans and improve clinical efficacy. TRIALS REGISTRATION NUMBER: INPLASY2020120060.

Levosimendan Ameliorates Post-resuscitation Acute Intestinal Microcirculation Dysfunction Partly Independent of its Effects on Systemic Circulation: A Pilot Study on Cardiac Arrest in a Rat Model.

BACKGROUND: Cardiac arrest (CA) is recognized as a life-threatening disease; however, the initial resuscitation success rate has increased due to advances in clinical treatment. Levosimendan has shown potential benefits in CA patients. However, its exact function on intestinal and systemic circulation in CA or post-cardiac arrest syndrome (PCAS) remained unclear. This study preliminarily investigated the link between dynamic changes in intestine and systemic hemodynamics post-resuscitation after levosimendan administration. METHODS: Twenty-five rats were randomized into three groups: sham control group (n = 5), levosimendan group (n = 10), and vehicle group (n = 10). Intestinal microcirculation was observed using a sidestream dark-field imaging device at baseline and each hour of the return of spontaneous circulation (≤6 h). Systemic hemodynamics, serum indicators of cardiac injury, and tissue perfusion/metabolism were measured by echo-cardiography, a biological signal acquisition system, and an enzyme-linked immunosorbent assay, respectively. RESULTS: Myocardial injury and global and intestinal perfusion/metabolism were significantly improved by levosimendan treatment. There was no statistically significant difference in the mean arterial pressure values between the vehicle and levosimendan groups (P > 0.05). The intestinal and systemic circulation measurements showed poor correlation (Pearson r-value of variable combinations in the levosimendan group was much less than 0.75; P < 0.01, levosimendan vs. vehicle group). CONCLUSIONS: Levosimendan significantly reduced the cardiac injury and corrected the metabolic status in an experimental rat model of ventricular fibrillation induced CA and cardiopulmonary resuscitation. Levosimendan may ameliorate PCAS-induced intestinal microcirculation dysfunction, partly independent of its effects on macrocirculation.