内源性一氧化碳对内毒素休克肺组织和肾组织保护作用的实验研究

目的：研究内毒素休克时内源性一氧化碳（CO）对肺组织和肾组织的保护作用及其机制;方法：采用盲肠结扎穿孔（CLP）的方法建立大鼠内毒素休克模型,通过免疫组化、光镜下组织形态学观察及超氧化物岐化酶活性、丙二醛含量的测定进行研究;结果：治疗组肺组织和肾组织病变明显减轻,炎症反应及脂质过氧化程度减轻;结论：内毒素休克时内源性CO对肺组织和肾组织具有保护作用,且此保护作用与其抑制炎症反应和抗氧化作用有重要关系。     

Analysis of peripheral blood lymphocyte subsets and prognosis in patients with septic shock

The purpose of the study is to study the relationship between peripheral blood lymphocyte subset proportion and prognosis in patients with septic shock. Fifty‐two patients with septic shock, admitted to the intensive care unit between March 2007 and December 2010, were enrolled in this study. Peripheral blood lymphocyte subset proportions were measured using flow cytometry. The percentage of CD3⁺CD4⁺ T lymphocytes and CD19⁺ lymphocytes, CD4⁺/CD8⁺ T cell ratio were substantially lower in patients with septic shock compared to the control group (P < 0.01). The percentage of CD3⁺CD8⁺ T lymphocytes did not differ significantly between the two groups (P > 0.05). The percentage of CD16⁺CD56⁺ lymphocytes was higher in patients with septic shock than in the control group (P < 0.01). Compared with the survivor group, the percentage of CD3⁺CD4⁺ T lymphocytes and CD19⁺ lymphocytes, CD4⁺/CD8⁺ T cell ratio were clearly lower in the non‐survivor group (P < 0.01). There was no difference in the percentage of CD3⁺CD8⁺ T lymphocytes between the non‐survivor and survivor groups (P > 0.05). The percentage of CD16⁺CD56⁺ lymphocytes was higher in the non‐survivor group than in the survivor group (P < 0.05). The total maximum SOFA score and the delta SOFA score were much higher in the non‐survivor group than in the survivor group (P < 0.01). Immune imbalance occurs in patients with septic shock. Peripheral blood lymphocyte subset proportion and SOFA scores can be used to assess the treatment and prognosis of septic shock.     

Soluble TREM-1 as a diagnostic and prognostic biomarker in patients with septic shock: an observational clinical study

Objectives: The impact of TREM-1-mediated inflammation was investigated in different inflammatory settings.

Methods: Secondary analyses of an observational clinical pilot study, including 60 patients with septic shock, 30 postoperative controls and 30 healthy volunteers.

Results: Plasma levels of sTREM-1 were found to identify patients with septic shock more effectively than procalcitonin and C-reactive protein. Moreover, sTREM-1 was identified to be an early predictor for survival in patients with septic shock.

Conclusion: Due to its diagnostic as well as prognostic value in sepsis syndrome, implementation of sTREM-1 measurements in routine diagnostics should be taken into account.     

LDL apheresis as an alternate method for plasma LPS purification in healthy volunteers and dyslipidemic and septic patients

Lipopolysaccharide (LPS) is a key player for innate immunity activation. It is therefore a prime target for sepsis treatment, as antibiotics are not sufficient to improve outcome during septic shock. An extracorporeal removal method by polymyxin (PMX) B direct hemoperfusion (PMX-DHP) is used in Japan, but recent trials failed to show a significant lowering of circulating LPS levels after PMX-DHP therapy. PMX-DHP has a direct effect on LPS molecules. However, LPS is not present in a free form in the circulation, as it is mainly carried by lipoproteins, including LDLs. Lipoproteins are critical for physiological LPS clearance, as LPSs are carried by LDLs to the liver for elimination. We hypothesized that LDL apheresis could be an alternate method for LPS removal. First, we demonstrated in vitro that LDL apheresis microbeads are almost as efficient as PMX beads to reduce LPS concentration in LPS-spiked human plasma, whereas it is not active in PBS. We found that PMX was also adsorbing lipoproteins, although less specifically. Then, we found that endogenous LPS of patients treated by LDL apheresis for familial hypercholesterolemia is also removed during their LDL apheresis sessions, with both electrostatic-based devices and filtration devices. Finally, LPS circulating in the plasma of septic shock and severe sepsis patients with gram-negative bacteremia was also removed in vitro by LDL adsorption. Overall, these results underline the importance of lipoproteins for LPS clearance, making them a prime target to study and treat endotoxemia-related conditions.     

Mortality in cardiogenic shock is stronger associated to clinical factors than contemporary biomarkers reflecting neurohormonal stress and inflammatory activation

Abstract

Purpose

To validate the IABP-SHOCK II risk score in a Danish cohort and assess the association between the IABP-SHOCK II risk score and admission concentration of biomarkers reflecting neurohormonal – (Copeptin, Pro-atrial natriuretic peptide (proANP), Mid-regional pro-adrenomedullin (MRproADM)) and inflammatory (ST2) activation in patients with CS complicating ST segment elevation myocardial infarction (STEMI).     

FOXE1 polymorphisms and chronic exposure to nitrates in drinking water cause metabolic dysfunction,thyroid abnormalities,and genotoxic damage in women

Nitrates in drinking water has been associated to adverse health effects, including changes in glucose and lipid levels, thyroid hormone imbalance and adverse reproductive effects. We analyzed metabolic and thyroid hormone alterations and genotoxic damage in women with chronic exposure to nitrates in drinking water. The concentration of nitrates in drinking water was quantified and according to this parameter, participants were divided into three exposure scenarios. Blood and urine samples were collected from 420 women living in Durango, Mexico and biomarkers were determined. We found nitrates concentrations in drinking water above the permissible limit (>50 mg/L), and an increase in the percentage of methemoglobin (p=0.0001), nitrite in blood plasma and urine (p=0.0001), glucose (p=0.0001), total cholesterol (p=0.001), LDL (p=0.001) and triglycerides (p=0.0001). We also found alterations in TSH (p=0.01), fT3 (p=0.0003), T4T (p=0.01) and fT4 (p=0.0004) hormones. Frequency of subclinical hypothyroidism was 8.33%; differences in FOXE1 (rs965513, rs1867277) genotypes distribution were found and both polymorphisms were associated with a decrease in TSH. A high percentage of micronucleus in binucleate lymphocyte cells was found (35%, p=0.0001). In conclusion, the chronic exposure to nitrates in water for human consumption caused metabolic and hormonal alterations and genotoxic damage in women.     

Methyl‐CpG‐binding protein 2 polymorphisms and vulnerability to autism

The methyl‐binding protein gene, MECP2, is a candidate for involvement in autism through its implication as a major causative factor in Rett syndrome that has similarities to autism. Rare mutations in MECP2 have also been identified in autistic individuals. We have examined the possible broader involvement of MECP2 as a predisposing factor in the disorder. Analysis of polymorphic markers spanning the gene and comprising both microsatellites and single nucleotide polymorphisms (SNPs) by the transmission disequilibrium test in two collections of families (219 in total), one in the USA and one in the UK, has provided evidence for significant association (P = 0.009) for a three‐marker SNP haplotype of MECP2 with autism/autism spectrum disorders. This association is supported by association of both Single Sequence Repeat (SSR) and SNP single markers located at the 3′ end of the MECP2 locus and flanking sequence, the most significant being that of an indel marker located in intron 2 (P = 0.001 – Bonferroni corrected P = 0.006). This suggests that one or more functional variants of MECP2 existing at significant frequencies in the population may confer increased risk of autism/autism spectrum disorders and warrants further investigation in additional independent samples.     

Heparanase-enhanced Shedding of Syndecan-1 and Its Role in Driving Disease Pathogenesis and Progression

Both heparanase and syndecan-1 are known to be present and active in disease pathobiology. An important feature of syndecan-1 related to its role in pathologies is that it can be shed from the surface of cells as an intact ectodomain composed of the extracellular core protein and attached heparan sulfate and chondroitin sulfate chains. Shed syndecan-1 remains functional and impacts cell behavior both locally and distally from its cell of origin. Shedding of syndecan-1 is initiated by a variety of stimuli and accomplished predominantly by the action of matrix metalloproteinases. The accessibility of these proteases to the core protein of syndecan-1 is enhanced, and shedding facilitated, when the heparan sulfate chains of syndecan-1 have been shortened by the enzymatic activity of heparanase. Interestingly, heparanase also enhances shedding by upregulating the expression of matrix metalloproteinases. Recent studies have revealed that heparanase-induced syndecan-1 shedding contributes to the pathogenesis and progression of cancer and viral infection, as well as other septic and non-septic inflammatory states. This review discusses the heparanase/shed syndecan-1 axis in disease pathogenesis and progression, the potential of targeting this axis therapeutically, and the possibility that this axis is widespread and of influence in many diseases.     

Alteration of plasma phospholipid fatty acid profile in patients with septic shock

In septic shock patients, alterations of plasma phospholipid fatty acid profile have never been described. The purpose of this monocentric, non-interventional, observational prospective study was to describe this fatty acid profile in the early phase of septic shock in intensive care unit. Thirty-seven adult patients with septic shock were included after the first day of stay in intensive care unit, before any form of artificial nutritional support. Plasma phospholipid fatty acid composition was determined by gas chromatography. All biological data from patients with septic shock were compared with laboratory reference values. Patients presented hypocholesterolemia and hypertriglyceridemia. They had low concentrations of phospholipid fatty acids specifically n-6 and n-3 polyunsaturated fatty acids (PUFAs) with a high n-6/n-3 ratio. Plasma phospholipid PUFA concentrations were strongly correlated with cholesterolemia. PUFAs/SFAs (saturated fatty acids) and PUFAs/MUFAs (monounsaturated fatty acids) ratios were low because of low percentage of n-6 and n-3 PUFAs and high percentage of SFAs and MUFAs. Low levels of plasma long chain PUFAs (≥20 carbons) were significantly associated with mortality at 28th day. In conclusion, plasma phospholipid FA profile of septic patients is very characteristic, close to that of acute respiratory distress syndrome and mortality is associated with long chain PUFA decrease. This profile could be explained by numerous non-exclusive physio-pathological processes 1) an activation of hepatic de novo lipogenesis that could contribute to hepatic steatosis, 2) an elevated adipose tissue lipolysis, 3) an increased free radical attack of FA by oxidative stress, 4) an over-production of inflammatory lipid mediators.     

RAAS,ACE2 and COVID-19; a mechanistic review

The use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in coronavirus disease 2019 (COVID-19) patients has been claimed as associated with the risk of COVID-19 infection and its subsequent morbidities and mortalities. These claims were resulting from the possibility of upregulating the expression of angiotensin-converting enzyme 2 (ACE2), facilitation of SARS-CoV-2 entry, and increasing the susceptibility of infection in such treated cardiovascular patients. ACE2 and renin-angiotensin-aldosterone system (RAAS) products have a critical function in controlling the severity of lung injury, fibrosis, and failure following the initiation of the disease. This review is to clarify the mechanisms beyond the possible deleterious effects of angiotensin II (Ang II), and the potential protective role of angiotensin 1–7 (Ang 1–7) against pulmonary fibrosis, with a subsequent discussion of the latest updates on ACEIs/ARBs use and COVID-19 susceptibility in the light of these mechanisms and biochemical explanation.