Carbon monoxide inhalation increases microparticles causing vascular and CNS dysfunction

We hypothesized that circulating microparticles (MPs) play a role in pro-inflammatory effects associated with carbon monoxide (CO) inhalation. Mice exposed for 1 h to 100 ppm CO or more exhibit increases in circulating MPs derived from a variety of vascular cells as well as neutrophil activation. Tissue injury was quantified as 2000 kDa dextran leakage from vessels and as neutrophil sequestration in the brain and skeletal muscle; and central nervous system nerve dysfunction was documented as broadening of the neurohypophysial action potential (AP). Indices of injury occurred following exposures to 1000 ppm for 1 h or to 1000 ppm for 40 min followed by 3000 ppm for 20 min. MPs were implicated in causing injuries because infusing the surfactant MP lytic agent, polyethylene glycol telomere B (PEGtB) abrogated elevations in MPs, vascular leak, neutrophil sequestration and AP prolongation. These manifestations of tissue injury also did not occur in mice lacking myeloperoxidase. Vascular leakage and AP prolongation were produced in naïve mice infused with MPs that had been obtained from CO poisoned mice, but this did not occur with MPs obtained from control mice. We conclude that CO poisoning triggers elevations of MPs that activate neutrophils which subsequently cause tissue injuries.     

Effect of Liandouqingmai recipe on quality of life and inflammatory reactions of patients with coronary heart disease

OBJECTIVE： To observe the effect of Liandouqingmai recipe（Chinese herbal medicine compound preparation） on the quality of life（QOL） and inflammatory reaction of patients with coronary heart disease（CHD）.METHODS： A total of 101 CHD patients were randomized into two groups： treatment group（n=45）receiving standard treatment for CHD plus Liandouqingmai recipe, and control group（n=56） receiving standard treatment only. The control group contained 16 normal healthy subjects. Changes in hs-C-reactive protein（CRP）, peripheral blood leucocytes（PBL）, and interleukin（IL）-6 and IL-10 levels were measured. The Seattle Angina Questionnaire（SAQ） was used to determine patient QOL before and after treatment for 2 weeks.RESULTS： Before treatment, SAQ scores [physical limitation（PL）, angina stability（AS）, angina frequen-cy（AF）, treatment satisfaction（TS）, and disease perception（DP）] were not statistically different between groups. After treatment, AS and DP levels of controls were significantly increased compared with the other groups, while PL, AS, AF, TS, and DP levels of the treatment group were significantly increased compared with controls. Treatment group SAQ scores（PL, AS, AF, TS, and DP） were significantly higher than for controls. CHD patient IL-6 and IL-10 levels were significantly higher than controls.Before treatment, mean levels of IL-6, hs-CRP and PBL of the two groups were not statistically different. After treatment, mean levels of IL-6, IL-10,hs-CRP and PBL of the two groups were significantly decreased compared with their before treatment values, and levels of IL-6, hs-CRP, and PBL of the treatment group were lower than controls. Although mean IL-10 levels of both groups decreased, there was no significant difference in between-group and in-group comparisons before and after treatment. Mean levels of IL-6 and IL-10 in the normal group were lower than in CHD patients.SAQ scores of QOL were negatively associated with the inflammatory index（IL-6/IL     

SLIC-1/sorting nexin 20: a novel sorting nexin that directs subcellular distribution of PSGL-1

P-Selectin glycoprotein ligand-1 (PSGL-1) is a mucin-like glycoprotein expressed on the surface of leukocytes that serves as the major ligand for the selectin family of adhesion molecules and functions in leukocyte tethering and rolling on activated endothelium and platelets. Previous studies have implicated the highly conserved cytoplasmic domain of PSGL-1 in regulating outside-in signaling of integrin activation. However, molecules that physically and functionally interact with this domain are not completely defined. Using a yeast two-hybrid screen with the cytoplasmic domain of PSGL-1 as bait, a novel protein designated selectin ligand interactor cytoplasmic-1 (SLIC-1) was isolated. Computer-based homology search revealed that SLIC-1 was the human orthologue for the previously identified mouse sorting nexin 20. Direct interaction between SLIC-1 and PSGL-1 was specific as indicated by co-immunoprecipitation and motif mapping. Colocalization experiments demonstrated that SLIC-1 contains a Phox homology domain that binds phosphoinositides and targets the PSGL-1/SLIC-1 complex to endosomes. Deficiency in the murine homologue of SLIC-1 did not modulate PSGL-1-dependent signaling nor alter neutrophil adhesion through PSGL-1. We conclude that SLIC-1 serves as a sorting molecule that cycles PSGL-1 into endosomes with no impact on leukocyte recruitment.     

Requirements for CD8 T-cell migration into the human arterial wall

Atherosclerotic lesions develop in the arterial intima. Among the leukocytes that accumulate in advanced atherosclerotic plaques, CD8 T cells play a quantitatively important role. They may be involved in disease progression and plaque destabilization, leading to plaque rupture or erosion. These events finally precipitate cardiovascular events. Therefore, we wished to determine the accessibility of the human arterial wall, particularly the arterial intima, for CD8-positive, cytotoxic T lymphocytes. We quantified the number of CD8-positive T cells in the arterial wall using human arterial tissue microarrays. The conditions for efficient cytotoxic T-lymphocyte migration into the arterial wall were determined in an in vitro tissue invasion assay. The invasion pattern of resting or activated cytotoxic T-lymphocyte clones was morphometrically analyzed by confocal microscopy. CD8 T cells represented up to 50% of the lymphocytes in advanced atherosclerotic lesions. Resting CD8-positive cytotoxic T lymphocytes were able to migrate into the arterial intima when it was affected by advanced lesions but not at the earliest stages of the disease. After T-cell receptor and/or proinflammatory cytokine activation, cytotoxic T lymphocytes migrated efficiently into the arterial intima, even in the healthy or mildly affected sites. This in vitro tissue invasion assay mimics conditions under which effector cytotoxic T lymphocytes migrate into the arterial wall to reach similar cell densities as observed in arterial tissue sections from autopsies. Interference with T-cell activation may be important to inhibit cytotoxic T-lymphocyte invasion into the unaffected, healthy artery but may not prevent cytotoxic T-lymphocyte invasion into arteries that are severely affected by atherosclerotic lesions.     

Immunological,paracrine and endocrine aspects of testicular immune privilege

Protection of the spermatogenic cells from the host immune response is fundamental to male fertility. Significantly, this protection extends to the tolerance of foreign tissue grafts placed within the testicular environment, a phenomenon that is called ‘immune privilege’. This privilege of the testis appears to involve several levels of immune control, encompassing the normal mechanisms of immune tolerance, antigen sequestration behind the blood–testis barrier, reduced immune activation, localised immunosuppression and antigen-specific immunoregulation. Central to these regulatory processes are the somatic cells of the testis, particularly the Sertoli cells, and testicular secretions, including androgens, cytokines, peptides and bioactive lipids. Failure of these protective mechanisms, which may be precipitated by trauma, inflammation or infection, or as the consequence of genetic factors, can lead to androgen deficiency, infertility and autoimmunity.     

Use of Machine Learning and Artificial Intelligence to predict SARS-CoV-2 infection from Full Blood Counts in a population

Since December 2019 the novel coronavirus SARS-CoV-2 has been identified as the cause of the pandemic COVID-19. Early symptoms overlap with other common conditions such as common cold and Influenza, making early screening and diagnosis are crucial goals for health practitioners. The aim of the study was to use machine learning (ML), an artificial neural network (ANN) and a simple statistical test to identify SARS-CoV-2 positive patients from full blood counts without knowledge of symptoms or history of the individuals. The dataset included in the analysis and training contains anonymized full blood counts results from patients seen at the Hospital Israelita Albert Einstein, at São Paulo, Brazil, and who had samples collected to perform the SARS-CoV-2 rt-PCR test during a visit to the hospital. Patient data was anonymised by the hospital, clinical data was standardized to have a mean of zero and a unit standard deviation. This data was made public with the aim to allow researchers to develop ways to enable the hospital to rapidly predict and potentially identify SARS-CoV-2 positive patients.We find that with full blood counts random forest, shallow learning and a flexible ANN model predict SARS-CoV-2 patients with high accuracy between populations on regular wards (AUC = 94–95%) and those not admitted to hospital or in the community (AUC = 80–86%). Here, AUC is the Area Under the receiver operating characteristics Curve and a measure for model performance. Moreover, a simple linear combination of 4 blood counts can be used to have an AUC of 85% for patients within the community. The normalised data of different blood parameters from SARS-CoV-2 positive patients exhibit a decrease in platelets, leukocytes, eosinophils, basophils and lymphocytes, and an increase in monocytes.SARS-CoV-2 positive patients exhibit a characteristic immune response profile pattern and changes in different parameters measured in the full blood count that are detected from simple and rapid blood tests. While symptoms at an early stage of infection are known to overlap with other common conditions, parameters of the full blood counts can be analysed to distinguish the viral type at an earlier stage than current rt-PCR tests for SARS-CoV-2 allow at present. This new methodology has potential to greatly improve initial screening for patients where PCR based diagnostic tools are limited.     

放射性脑损伤炎症反应机制的研究进展

放射性脑损伤（radiation-induced brain injury, RBI）的发生机制仍不明确,目前多项研究认为炎症反应起重要作用。活性氧类的产生,炎症介质的释放,神经元、胶质细胞、周细胞的相互作用以及外周白细胞的募集等共同促进放射性脑损伤的发生发展。本文就放射性脑损伤炎症反应机制的研究进展进行综述。     

Flow cytometry assessment of leukocyte functions in vascular pathologies

Intravascular activation of leukocytes has been shown to be involved in a wide range of different and apparently unrelated clinical situations, such as systemic inflammatory response syndrome, ischemia/reperfusion, disseminated intravascular coagulation, atherosclerosis... All of them involve to different degrees many steps of the inflammation process, with leukocyte accumulation and release of toxic species. Haemostasis, leukocyte functions and their cross-talk are summarized in this paper, as well as the most popular methods used for studying leukocyte functions in vascular pathologies. The strengths and present limitations of flow cytometry are analyzed in comparison with the biochemical and functional approaches.     

Sepiapterin reduces postischemic injury in the rat heart

A reduced availability of tetrahydrobiopterin (BH4), an essential cofactor for NO-synthesis, is causally involved in the development of endothelial dysfunction associated with ischemia/reperfusion. We, therefore, investigated the effect of sepiapterin, a substrate for BH4 synthesis, on postischemic injury in myocardial infarction and myocardial stunning. In rats, myocardial stunning was induced by repetitive ischemia (5×10-min ligature of the left coronary artery, 5×20-min reperfusion) and myocardial infarction by 50-min ligature and 60-min reperfusion. Myocardial blood flow was determined by H₂-clearance, regional myocardial function by pulsed Doppler and infarct size by tetrazolium staining. Myeloperoxidase (MPO) activity was measured as a marker of neutrophil extravasation. cGMP was determined in rat serum as an indicator of increased NO synthesis. In animals treated with sepiapterin, regional myocardial function was significantly improved in both myocardial stunning and infarction and infarct size was significantly reduced. MPO activity decreased with sepiapterin treatment in both models. The systemic level of cGMP was reduced both following myocardial stunning and myocardial infarction in the control group. Pretreatment with sepiapterin induced a significant increase of cGMP level at the end of the protocol in both models. Substitution of sepiapterin reduces postischemic injury both in myocardial stunning and infarction apparently by ameliorating the availability of NO, thereby attenuating the activation of neutrophils in ischemia/reperfusion.