BACKGROUND: Long-term remote ischemic conditioning (RIC) has been proven to be beneficial in multiple diseases, such as cerebral and cardiovascular diseases. However, the hyperacute and acute effects of a single RIC stimulus are still not clear. Quantitative proteomic analyses of plasma proteins following RIC application have been conducted in preclinical and clinical studies but exhibit high heterogeneity in results due to wide variations in experimental setups and sampling procedures. Hence, this study aimed to explore the immediate effects of RIC on plasma proteome in healthy young adults to exclude confounding factors of disease entity, such as medications and gender. METHODS: Young healthy male participants were enrolled after a systematic physical examination and 6-month lifestyle observation. Individual RIC sessions included five cycles of alternative ischemia and reperfusion, each lasting for 5 min in bilateral forearms. Blood samples were collected at baseline, 5 min after RIC, and 2 h after RIC, and then samples were processed for proteomic analysis using liquid chromatography-tandem mass spectrometry method. RESULTS: Proteins related to lipid metabolism (e.g., Apolipoprotein F), coagulation factors (hepatocyte growth factor activator preproprotein), members of complement cascades (mannan-binding lectin serine protease 1 isoform 2 precursor), and inflammatory responses (carboxypeptidase N catalytic chain precursor) were differentially altered at their serum levels following the RIC intervention. The most enriched pathways were protein glycosylation and complement/coagulation cascades. CONCLUSIONS One-time RIC stimulus may induce instant cellular responses like anti-inflammation, coagulation, and fibrinolysis balancing, and lipid metabolism regulation which are protective in different perspectives. Protective effects of single RIC in hyperacute and acute phases may be exploited in clinical emergency settings due to apparently beneficial alterations in plasma proteome profile. Furthermore, the beneficial effects of long-term (repeated) RIC interventions in preventing chronic cardiovascular diseases among general populations can also be expected based on our study findings.
Young Adult ; Humans ; Male ; Proteome ; Cardiovascular Diseases ; Proteomics ; Ischemia ; Blood Coagulation

Due to the failure of multiple translational researches, Stroke Therapy Academic Industry Roundtable (STAIR) recommends the use of large animal models of focal cerebral ischemia for preclinical researches. Especially, stroke treatment has currently entered a new era of vascular recanalization. Large animals commonly used in acute ischemic stroke models include dogs, swine, sheep, and non-human primates, which can be used to simulate various aspects of cerebral ischemia and reperfusion (vascular recanalization) in patients. Although large animals have significant advantages due to their proximity to humans in anatomy and physiology, there are also issues with anatomical and physiological specificity and ethical limitations. This article summarizes the large animal ischemic stroke models prepared by craniotomy and endovascular intervention, hoping to help researchers select the most appropriate large animal ischemic stroke model, and then promote the development of stroke translational research.

Because the clinical studies of neuroprotective drugs ended in failure, the Stroke Treatment Academy Industry Roundtable recommended the use of non-human primates for preclinical research on stroke. Non-human primates are the bridge between basic experiment and clinical research, and the experimental results are of great reference value. However, non-human primate stroke models have a variety of neurological deficits and behavioral evaluation methods, and the scoring methods also have their own emphases. It is easy to have differences in the evaluation, or there are deficiencies in the scale itself, resulting in inaccurate scoring, which directly affects the experimental results and the implementation of subsequent research. This article summarizes the neurological deficits and behavioral evaluation methods of non-human primate stroke model.

Over the preceding decades, there have been substantial advances in our knowledge of the pathophysiology of stroke. One such advance has been an increased understanding of the multifarious crosstalk in which the nervous and immune systems engage in order to maintain homeostasis. By interrupting the immune-nervous nexus, it is thought that stroke induces change in both systems. Additionally, it has been found that both innate and adaptive immunosuppression play protective roles against the effects of stroke. The release of danger-/damage-associated molecular patterns (DAMPs) activates Toll-like receptors (TLRs), contributing to the harmful inflammatory effects of ischemia/reperfusion injury after stroke; the Tyro3, Axl, and MerTK (TAM)/Gas6 system, however, has been shown to suppress inflammation via downstream signaling molecules that inhibit TLR signaling. Anti-inflammatory cytokines have also been found to promote neuroprotection following stroke. Additionally, adaptive immunosuppression merits further consideration as a potential endogenous protective mechanism. In this review, we highlight recent studies regarding the effects and mechanism of immunosuppression on the pathophysiology of stroke, with the hope that a better understanding of the function of both of innate and adaptive immunity in this setting will facilitate the development of effective therapies for post-stroke inflammation.

Over the preceding decades, there have been substantial advances in our knowledge of the pathophysiology of stroke. One such advance has been an increased understanding of the multifarious crosstalk in which the nervous and immune systems engage in order to maintain homeostasis. By interrupting the immune-nervous nexus, it is thought that stroke induces change in both systems. Additionally, it has been found that both innate and adaptive immunosuppression play protective roles against the effects of stroke. The release of danger-/damage-associated molecular patterns (DAMPs) activates Toll-like receptors (TLRs), contributing to the harmful inflammatory effects of ischemia/reperfusion injury after stroke; the Tyro3, Axl, and MerTK (TAM)/Gas6 system, however, has been shown to suppress inflammation via downstream signaling molecules that inhibit TLR signaling. Anti-inflammatory cytokines have also been found to promote neuroprotection following stroke. Additionally, adaptive immunosuppression merits further consideration as a potential endogenous protective mechanism. In this review, we highlight recent studies regarding the effects and mechanism of immunosuppression on the pathophysiology of stroke, with the hope that a better understanding of the function of both of innate and adaptive immunity in this setting will facilitate the development of effective therapies for post-stroke inflammation.

Objective: To report the clinical features of anti-MDA5 antibody positive juvenile dermatomyositis (JDM) complicated with severe interstitial lung disease (ILD). Methods: The clinical data of three patients, who was admitted to the Department of Rheumatology and Immunology, Children's Hospital of the Capital Institute of Pediatrics from September 2016 to July 2017, with anti-melanoma differentiation associated gene 5 (MDA5) antibody positive JDM complicated with ILD were retrospectively extracted and analyzed. Meanwhile, PubMed database, CNKI, Wanfang database and China Biology Medicine disc (from their establishment to February 2019) with the key words "juvenile dermatomyositis" "interstitial lung disease" , and "anti-MAD5 antibody" both in English and Chinese were searched. Results: There were 2 females and 1 male (P1-P3), aged from 10 years 3 months to13 years 4 months, the time from onset to diagnosis were 2 months, 4 months and 10 months. All presented with rash. One of them had decreased muscle strength, and two had decreased activity tolerance. Creatine kinase was 588, 915 and 74 U/L, and serum ferritin were 1 792, >2 000 and 195.4 μg/L. All three patients had positive anti-MDA5 antibodies. At the time of diagnosis, all of them had ILD, pneumothorax and mediastinal emphysema, but had no respiratory symptoms. All three patients received oral methylprednisolone and cyclophosphamide pulse therapy, while human immunoglobulin was given only to P1 and P2. P1 developed rapid progressive pulmonary interstitial disease (RPILD) and died of respiratory failure after 2 months. While P2 and P3 were followed up for 1 to 2 years, who had complete remission, as anti-MDA5 antibody turned to negative and ILD improved significantly. Ten related reports in literature were retrieved, without reported Chinese cases, and most cases initiated with rash and very likely complicated with arthritis. Some of them were more likely to have ILD rather than muscle weakness. It also showed that Japanese JDM children had higher rate of positive anti-MDA5 antibody than patients from the U.S. and U.K., and are more susceptible to ILD and RPILD. The mortality rate of patients with RPILD is extremely high. Conclusions The cases of JDM with positive anti-MDA5 antibody mainly presented with rash and mild muscle weakness, and could be complicated with ILD, pneumothorax and mediastinal emphysema without respiratory symptoms at early stage. Anti-MDA5 antibody titer is related to disease activity and can turn to negative after treatment.

In recent years, for patients with acute ischemic stroke due to large vessel occlusion, intravascular mechanical thrombectomy has become the most recommended treatment method. Determining whether there is ischemic penumbra or not is very important for the selection of patients who are suitable for endovascular mechanical thrombectomy. In addition, the ischemic penumbra also provides guidance for extending the time window of traditional intravenous thrombolytic therapy. This article reviews the imaging evaluation methods of ischemic penumbra.

Objective To investigate the neuroprotective effect and its mechanism of local hypothermia combined with nicotinamide phosphoribosyltransferase (NAMPT) on cerebral ischemia-reperfusion injury in rats.Methods Fifty-four Sprague-Dawley rats were randomly divided into sham operation group,model group,NAMPT group,local hypothermia group,and combined treatment group (NAMPT + local hypothermia).A rat model of local cerebral ischemia-reperfusion was induced by suture method.Infarct volume and cerebral edema volume were assessed by 2,3,5-triphenyltetrazolium chloride staining after 2 h cerebral ischemia and 24 h reperfusion in rats.Evans blue staining was used to assess the extent of blood-brain barrier damage,and a 12-point scale was used to assess neurological deficits.Results The infarct volume in the local hypothermia group,NAMPT group,and combination treatment group was significantly lower than that in the model group (all P ＜0.05).The infarct volume in the combination treatment group was significantly lower than that in the NAMPT group (P ＜0.05).The infarct volume in the combination treatment group was lower than that in the local hypothermia group,but it did not reach statistical significance.The neurological function scores of the local hypothermia group,NAMPT group,and combination treatment group were significantly lower than those of the model group (all P ＜0.05).The score of the combined treatment group was significantly lower than that of the NAMPT group and the local hypothermia group (all P＜0.05).Evans blue leakage in the local hypothermia group,NAMPT group,and combination treatment group was lower than that in the model group (all P ＜0.05),but the differences between each treatment group were not statistically significant.Conclusion NAMPT and local hypothermia combination therapy showed better neuroprotective effects on cerebral ischemia-reperfusion injury,suggesting that the combination therapy had clinical transformation prospects.

Objective To report the clinical features of anti?MDA5 antibody positive juvenile dermatomyositis (JDM) complicated with severe interstitial lung disease (ILD). Methods The clinical data of three patients, who was admitted to the Department of Rheumatology and Immunology, Children's Hospital of the Capital Institute of Pediatrics from September 2016 to July 2017, with anti?melanoma differentiation associated gene 5 (MDA5) antibody positive JDM complicated with ILD were retrospectively extracted and analyzed. Meanwhile, PubMed database, CNKI, Wanfang database and China Biology Medicine disc (from their establishment to February 2019) with the key words "juvenile dermatomyositis""interstitial lung disease", and"anti?MAD5 antibody"both in English and Chinese were searched. Results There were 2 females and 1 male (P1-P3), aged from 10 years 3 months to13 years 4 months, the time from onset to diagnosis were 2 months, 4 months and 10 months. All presented with rash. One of them had decreased muscle strength, and two had decreased activity tolerance. Creatine kinase was 588, 915 and 74 U/L, and serum ferritin were 1 792, >2 000 and 195.4 μg/L. All three patients had positive anti?MDA5 antibodies. At the time of diagnosis, all of them had ILD, pneumothorax and mediastinal emphysema, but had no respiratory symptoms. All three patients received oral methylprednisolone and cyclophosphamide pulse therapy, while human immunoglobulin was given only to P1 and P2. P1 developed rapid progressive pulmonary interstitial disease (RPILD) and died of respiratory failure after 2 months. While P2 and P3 were followed up for 1 to 2 years, who had complete remission, as anti?MDA5 antibody turned to negative and ILD improved significantly. Ten related reports in literature were retrieved, without reported Chinese cases, and most cases initiated with rash and very likely complicated with arthritis. Some of them were more likely to have ILD rather than muscle weakness. It also showed that Japanese JDM children had higher rate of positive anti?MDA5 antibody than patients from the U. S. and U. K., and are more susceptible to ILD and RPILD. The mortality rate of patients with RPILD is extremely high. Conclusions The cases of JDM with positive anti?MDA5 antibody mainly presented with rash and mild muscle weakness, and could be complicated with ILD, pneumothorax and mediastinal emphysema without respiratory symptoms at early stage. Anti?MDA5 antibody titer is related to disease activity and can turn to negative after treatment.

The Stroke Therapy Academic Industry Roundtable(STAIR)committee has suggested that nonhuman primates(NHPs)should be used for preclinical stroke studies owing to previous translational failures. Ischemia induced by endovascular method closely mimics thromboembolic or thrombotic cerebrovascular occlusion in patients. This method also shows potential for endovascular treatment. This review provides a detailed summary of NHP models using endovascular method,including advantages and disadvantages,and potential applications. Additionally,we also provide further analysis based on different kinds of emboli,infract size,and abnormal hemodynamics. Selection of the optimum model will pave the way for translational research.