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Background: Cardiac arrest/cardiopulmonary resuscitation (CA/CPR) represents one of the devastating medical emergencies and is associated with high mortality and neuro-disability. Post-cardiac arrest syndrome (PCAS) is mechanistically ascribed to acute systemic ischemia/reperfusion(I/R) injury. The lncRNA/microRNA/mRNA networks have been found to play crucial roles in the pathogenesis of the hypoxia-responsive diseases. Nonetheless, the precise molecular mechanisms by which lncRNA/miRNA/mRNA axes are involved in the astrocyte-microglia crosstalk in CA/CPR have not been fully elucidated. Methods: We collected and purified the exosomes from the blood of CA/CPR patients and supernatant of OGD/R-stimulated astrocytes. On the basis of microarray analysis, bioinformatic study, and luciferase activity determination, we speculated that lncRNA GAS5/miR-137 is implicated in the astrocyte-microglia crosstalk under the insult of systemic I/R injury. The regulation of lncRNA GAS5/miR-137 on INPP4B was examined by cellular transfection in OGD/R cell culture and by lateral ventricle injection with miR-137 agomir in CA/CPR mice model. Flow cytometry and immunofluorescence staining were performed to detect the microglial apoptosis, M1/M2 phenotype transformation, and neuroinflammation. Neurological scoring and behavior tests were conducted in CA/CPR group, with miR-137 agomir lateral-ventricle infusion and in their controls. Results: In all the micRNAs, miR-137 was among the top 10 micRNAs that experienced greatest changes, in both the blood of CA/CPR patients and supernatant of OGD/R-stimulated astrocytes. Bioinformatic analysis revealed that miR-137 was sponged by lncRNA GAS5, targeting INPP4B, and the result was confirmed by Luciferase activity assay. qRT-PCR and Western blotting showed that lncRNA GAS5 and INPP4B were over-expressed whereas miR-137 was downregulated in the blood of CA/CPR patients, OGD/R-stimulated astrocytes, and brain tissue of CA/CPR mice. Silencing lncRNA GAS5 suppressed INPP4B expression, but over-expression of miR-137 negatively modulated its expression. Western blotting exhibited that PI3K and Akt phosphorylation was increased when lncRNA GAS5 was silenced or miR-137 was over-expressed. However, PI3K and Akt phosphorylation was notably suppressed in the absence of miR-137, almost reversing their phosphorylation in the silencing lncRNA GAS5 group. Then we found that GAS5 siRNA or miR-137 mimic significantly increased cell viability and alleviated apoptosis after OGD/R injury. Furthermore, over-expression of miR-137 attenuated microglial apoptosis and neuroinflammation in CA/CPR mice model, exhibiting significantly better behavioral tests after CA/CPR. Conclusion: LncRNA GAS5/miR-137 may be involved in the astrocyte-microglia communication that inhibits PI3K/Akt signaling activation via regulation of INPP4B during CA/CPR.

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Paro Cardíaco/metabolismo , Hipoxia-Isquemia Encefálica/metabolismo , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Astrocitos/metabolismo , Reanimación Cardiopulmonar , Comunicación Celular/fisiología , Femenino , Paro Cardíaco/complicaciones , Humanos , Hipoxia-Isquemia Encefálica/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Daño por Reperfusión

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BackgroundThe novel coronavirus (CoV) severe acute respiratory syndrome (SARS)-CoV-2 outbreak started at the end of 2019 in Wuhan, China, and spread over 100 countries. SARS-CoV-2 uses the membrane protein Angiotensin I converting enzyme 2(ACE2) as a cell entry receptor. Indeed, it was reported that the balance of Renin-Angiotensin System (RAS), regulated by both ACE and ACE2, was altered in COVID-19 patients. It is controversial, however, whether commonly used anti-hypertensive drugs Angiotensin I converting enzyme inhibitor (ACEI) and Angiotensin II receptor blocker (ARB) shall be continued in the confirmed COVID-19 patients. This study was designed to investigate any difference in disease severity between COVID-19 patients with hypertension comorbidity. The included COVID-19 patients used ACEI, ARB, calcium channel blockers (CCB), beta blockers (BB), or thiazide to treat preexisting hypertension prior to the hospital were compared to patients who did not take any of those drugs. MethodsIn this multicentre retrospective study, clinical data of 511 COVID-19 patients were analyzed. Patients were categorized into six sub-groups of hypertension comorbidity based on treatment using one of anti-hypertension drugs (ACEI, ARB, CCB, BB, thiazide), or none. A meta-analysis was performed to evaluate the use of ACEI and ARB associated with pneumonia using published studies. FindingsAmong the elderly (age>65) COVID-19 patients with hypertension comorbidity, the risk of COVID-19-S (severe disease) was significantly decreased in patients who took ARB drugs prior to hospitalization compared to patients who took no drugs (OR=0{middle dot}343, 95% CI 0{middle dot}128-0{middle dot}916, p=0{middle dot}025). The meta-analysis showed that ARB use has positive effects associated with morbidity and mortality of pneumonia. InterpretationElderly (age>65) COVID-19 patients with hypertension comorbidity who are taking ARB anti-hypertension drugs may be less likely to develop severe lung disease compared to patients who take no anti-hypertension drugs. FundingNational Natural Science Foundation of China, Chinese Academy of Medical Sciences Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for articles published up to March 15, 2020 using keywords "2019-nCoV", "SARS-CoV-2", "novel coronavirus", and COVID-19 AND "ARB", and "angiotensin II receptor blocker" for papers published in both English and Chinese. We found three papers: one from our group, published in Science China Life Science that demonstrated an elevated Angiotensin II level in blood samples from COVID-19 patients; another a perspective article in Chinese recommending ACEI and ARBs as potential remedies for SARS-CoV-2 infections; the third a retrospective study in Chinese identifying no significant difference between ACEI/ARB associated with outcomes in 112 COVID-19 patients with CVD comorbidity. The International society of Hypertension stated on March 16th, 2020: "there are no clinical data in human to show that ACE-inhibitors or ARBs either improve or worsen susceptibility to COVID-19 infection nor do they affect the outcomes of those infected". Added value of this studyWe retrospectively reviewed different types of anti-hypertensive drugs taken by COVID-19 patients with hypertension comorbidity prior to entering the hospital. We discovered that ARB hypertensive drugs were associated with a decreased risk of severe disease in elderly (age>65) COVID-19 patients (OR=0{middle dot}343, 95% CI 0{middle dot}128-0{middle dot}916, p=0{middle dot}025), the first evidence of ARBs association to COVID-19 infections in human. We conducted a meta-analysis in the literature and found that ARB has positive effects associated with morbidity and mortality of pneumonia. Implications of all the available evidenceARB drugs are widely used in the population with hypertension. Treatments with ACEI and ARBs should be continuous according to medical guidelines. RCT trials of ARB associated with morbidity and mortality of SARS-CoV-2 infection are recommended in the future.

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Objective To analysis of multiple myeloma (MM) and non-MM patients with the same clinical manifestations but significant differences in laboratory findings at the first visit to the Emergency Medicine Department suggesting that patient should be rule out the possibilities of suffering from MM by the attending physicians engaging in a specialty other than hematology as soon as possible to avoid misdiagnosis of MM.Methods Retrospective analysis of clinical features of MM cases from February 2013 to December 2016.Patients with renal dysfunction (serum creatinine ≥ 177 mmol/L),infection,bone pain and anemia were divided into four groups.The non-MM patients with the same clinical symptoms were enrolled as control group.SPSS22.0 and Medcalce 15.10 software were used for analyzing the distinct difference and diagnostic validity of routine laboratory tests in patients with MM and non-MM.Results ①The patients with serum creatinine≥ 177 mmol/L,and unexplained renal insufficiency with blood Ca2+ ＞ 2.39mmol/L,ALB ≤ 30.31 g/L and Hb≤84 g/L should be investigated the possibility of MM.②The patient with poor response to the conventional treatment and unexplained infection with IgM ＜0.42 g/L and ALB≤32.7 g/L or ESR ＞ 82 mm/h and Hb ＜ 100 g/L should be investigated the possibility of MM.③The male patients with the first symptom in bone and joint pain associated with bone damage with urinary protein and blood,and the emergence of Ca2+ ＞ 2.39 mmol/L,ALB ＜ 37.5 g/L,Hb ＜ 104 g/L and TT ＞ 19.8 s were suggested to detect MM.④The poor respose to conventional treatment,unexplained anemia (Hb≤90 g/L),IgM ＜ 0.51 g/L,ALB ＜ 34.1 g/L and GLB ＞ 46.4 g/L suggested to detect MM.Conclusions On the basis of symptoms such as renal insufficiency,infection,bone pain,anemia,routine blood laboratory findings of high calcium,low IgM,low albumin,and high globulin,it was recommended that bone marrow biopsy be made to detect MM.