Imbalance between procoagulant factors and natural coagulation inhibitors contributes to hypercoagulability in the critically ill COVID-19 patient: clinical implications.

OBJECTIVE: Coronavirus Disease-2019 (COVID-19) predisposes patients to thrombosis which underlying mechanisms are still incompletely understood. We sought to investigate the balance between procoagulant factors and natural coagulation inhibitors in the critically ill COVID-19 patient and to evaluate the usefulness of hemostasis parameters to identify patients at risk of venous thromboembolic event (VTE). PATIENTS AND METHODS: We conducted an observational study recording VTEs defined as deep vein thrombosis or pulmonary embolism using lower limb ultrasound (92% of the patients), computed tomography pulmonary angiography (6%) and both tests (2%). We developed a comprehensive analysis of hemostasis. RESULTS: Ninety-two consecutive mechanically ventilated COVID-19 patients (age, 62 years [53-69] (median [25th-75th percentiles]); M/F sex ratio, 2.5; body-mass index, 28 kg/m2 [25-32]; past hypertension (52%) and diabetes mellitus (30%)) admitted to the Intensive Care Unit (ICU) from 03/11/2020 to 5/05/2020, were included. When tested, patients were receiving prophylactic (74%) or therapeutic (26%) anticoagulation. Forty patients (43%) were diagnosed with VTE. Patients displayed inflammatory and prothrombotic profile including markedly elevated plasma fibrinogen (7.7 g/L [6.1-8.6]), D-dimer (3,360 ng/mL [1668-7575]), factor V (166 IU/dL [136-195]) and factor VIII activities (294 IU/dL [223-362]). We evidenced significant discrepant protein C anticoagulant and chromogenic activities, combined with slightly decreased protein S activity. Plasma D-dimer >3,300 ng/mL predicted VTE presence with 78% (95%-confidence interval (95% CI), 62-89) sensitivity, 69% (95% CI, 55-81) specificity, 66% (95% CI, 51-79) positive predictive value and 80% (95% CI, 65-90) negative predictive value [area under the ROC curve, 0.779 (95%CI, 0.681-0.859), p=0.0001]. CONCLUSIONS: Mechanically ventilated COVID-19 patients present with an imbalance between markedly increased factor V/VIII activity and overwhelmed protein C/S pathway. Plasma D-dimer may be a useful biomarker at the bedside for suspicion of VTE.

Roux-en-Y gastric bypass, but not sleeve gastrectomy, decreases plasma PCSK9 levels in morbidly obese patients.

AIM: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a master regulator of low-density lipoprotein cholesterol (LDL-C) metabolism, acting as an endogenous inhibitor of the LDL receptor. While it has been shown that bariatric surgery differentially affects plasma LDL-C levels, little is known of its effects on plasma PCSK9 concentrations. Therefore, the present study aimed to: (i) investigate the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on plasma PCSK9 concentrations; and (ii) correlate baseline or postoperative plasma PCSK9 concentration variations with anthropometric and metabolic parameters. METHODS: Fasting plasma PCSK9 levels were measured by ELISA in morbidly obese patients before and 6 months after bariatric surgery. Patients were recruited from three prospective cohorts (in Nantes and Colombes in France, and Antwerp in Belgium). RESULTS: A total of 156 patients (34SG, 122RYGB) were included. Plasma PCSK9, LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) levels were significantly reduced after RYGB (-19.6%, -16.6% and -19.5%, respectively; P<0.0001), but not after SG. In all patients, postoperative PCSK9 change was positively correlated with fasting plasma glucose (FPG; r=0.22, P=0.007), HOMA-IR (r=0.24, P=0.005), total cholesterol (r=0.17, P=0.037) and non-HDL-C (r=0.17, P=0.038) variations, but not LDL-C. In contrast to what was observed for glucose parameters (FPG, HOMA-IR), correlation between PCSK9 and non-HDL-C changes after RYGB was independent of total weight loss. CONCLUSION: RYGB, but not SG, promotes a significant reduction in plasma PCSK9 levels, and such changes in circulating PCSK9 levels after RYGB appear to be more associated with glucose improvement than with lipid homoeostasis parameters.

ADAMTS-13 and von Willebrand factor predict venous thromboembolism in patients with cancer.

UNLABELLED: ESSENTIALS: Cancer patients are at high risk of venous thromboembolism (VTE). In this study, cases and controls were cancer patients who did or did not develop VTE. von Willebrand factor (VWF) levels were higher if compared with controls and correlated with cancer stage. VWF and ADAMTS-13 are associated with the occurrence of VTE in cancer. BACKGROUND: Patients with cancer are at high risk of venous thromboembolism (VTE). ADAMTS-13 regulates von Willebrand factor (VWF) activity, which plays a role in the development of cancer and in VTE. OBJECTIVES: The aim of this study was to search for an association between the levels of VWF and ADAMTS-13 and VTE in patients with cancer and to compare current scoring systems for prediction of VTE before and after addition of these parameters. PATIENTS/METHODS: In a case-control study, in which patients with recently diagnosed cancer were followed-up for 6 months, we compared 20 patients who developed VTE (cases) and 140 patients with cancer without VTE (controls), matched for sex, age, and type and stage of cancer. We measured VWF, ADAMTS-13 (activity and antigen), P-selectin, D-dimer and F1 + 2 levels at baseline, and calculated both the Khorana score and the Khorana score expanded after addition of P-selectin and D-dimer levels. RESULTS: VWF levels were significantly higher in cases when compared with controls (326 ± 185% vs. 242 ± 158%) and correlated with advanced stage of cancer: localized, 185 [142; 222]; locally advanced, 240 [146; 257]; metastatic, 267 [153; 324] (mean [interquartile range]). The addition of two biomarkers, ADAMTS-13 activity and F1 + 2 levels, to the Khorana score improved receiver operating curves. CONCLUSIONS: von Willebrand factor and ADAMTS-13 are associated with the occurrence of VTE in patients with cancer. Moreover, addition of ADAMTS-13 and F1 + 2 levels to the Khorana score considerably increases the predictive value for VTE.

[Telemedicine in thrombotic microangiopathies: A way forward in rare diseases requiring emergency care]. / L'activité de télémédecine dans les microangiopathies thrombotiques : un progrès dans les maladies rares nécessitant une prise en charge en urgence.

Thrombotic microangiopathies (TMA) represent rare diseases requiring a high skill for their management that deserved in France the identification of a dedicated National reference center. TMA are short-term life-threatening diseases; however, with an adapted management, their prognosis can be excellent. It is therefore mandatory to recognize and treat them rapidly according to standard guidelines. Telemedicine is a specialized hub consisting of highly skilled staff trained in a specific domain of medicine. The telemedicine activity of a reference center is an important representative indicator of its expertise and recourse ability. It requires to be accurately evaluated and promoted. In this work, we report the French reference center for TMA telemedicine activity since its setting-up. TMA represent an interesting model of diseases that required a specific organization of telemedicine activity to adapt to clinicians demand, which includes particularly the need to answer resorts in real time 24/7.

[Morphological changes in brain tissues of rat with local permanent ischemia model under the action of 2-methyl-6-ethyl-3-hydroxypyridine hemisuccinate].

The influence of 2-methyl-6-ethyl-3-hydroxypiridine hemisuccinate on the morphological state of rat brain tissue after the occlusion of left middle cerebral artery has been studied. It was found that 6- and 12-day treatment with 2-methyl-6-ethyl-3-hydroxypyridine hemisuccinate at a dose of 100 mg/kg (intraperitoneal) led to regenerative processes in ischemic brain tissue. The latter treatment duration was most effective.

[The effect of 5-hydroxyadamantan-2-one on morphological status of rats' brain tissues in local permanent ischemia conditions].

The effect of 5-hydroxyadamantane-2-one was studied on morphological state of brain tissue of rats after the occlusion of left middle cerebral artery. It was shown that intraperitoneal administration of 5-hydroxyadamantane-2-on at dose 100mg/kg, in 30 minutes after occlusion and once daily for the following 6 and 12 days leads to significant regenerative processes in brain tissue. These processes were more profound after the 12-day treatment with 5-hydroxyadamanta-ne-2-one.

[Surgery of the diaphragm in the planned thoracic surgery].

122 patients with different diseases of the diaphragm were operated on during 1963-2011 yy. The majority of patients - 76 (62.3%) - had hernias of the weak phrenic zones. 14 (11.5%) and 17 (14.0%) patients had posttraumatic hernia and phrenic relaxation, respectively. The majority of patients had no complaints and the disease was diagnosed on the X-ray examination. Rarely, the compression syndrome, caused by the translocation of the bowel into the thoracic cavity, was registered. That clinically emerged as short breath, heaviness sensation and cardiac rhythm disorders. The worked out reconstructive operations allow to cure such patients with minimal risk.

[Electrophysiological and morphohistochemical study of adrenalectomy on the hippocampal neurons].

Chronic insufficiency of adrenal hormones is a pathology leading to brain dysfunction. In electrophysiological studies, by extracellular recording of spike activity of single hippocampal neurons (HN) caused by high-frequency stimulation of the entorhinal cortex (EC) in rats with unilateral removal of adrenal (adrenalectomy - AE), we analyzed mechanisms of adaptation of neural networks to chronic hormonal deprivation. The balance of excitatory and inhibitory responses, recorded in HN of intact rats was submitted to characteristic changes in dynamics of development of neurodegeneration: the dominating in norm inhibitory responses were decreased at all AE terms (from 42 % to 25 % by the 18th week). On the contrary, the minimal in norm percent of excitatory responses sharply increased (from 17 % to 60 %) at the 25-27th day after AE, which indicates a possible increase of cholinergic neurotransmission. There was recorded a high level of the mean frequency of peristimulus spiking from the 25-27th day to the 18th week after AE, which indicates the high glutamate level or pronounced activation of NMDA receptors. On the whole, the ratio of excitatory/inhibitory HN responses indicates discoordinated activity of neuronal chains of EC-HN under conditions of AE. Histochemical analysis revealed an increased sensitivity to AE in neurons of the CA1 fields. After disturbance of neuronal structure by the 5th day, 25-27 days after AE, there was observed proliferation cell elements in the CA1 field; as a result, by the 10th week, there is observed the complete filling of "devastated" areas of hippocampus and a sharp rise of phosphatase activity in nuclei of dentate gyrus. 18 weeks after AE, the majority of the CA1 field neurons are submitted to chromatolysis, and the phosphatase activity falls. The presented data make certain contribution to understanding of mechanisms of control of cognitive brain functions and plasticity in interconnection with the hormonal factor.

[Dinitrosyl iron complexes with glutathione recover rats with experimental endometriosis].

The effect of binuclear dinitrosyl iron complexes (DNIC) with glutathione on endometrioid tumors in rats with experimental endometriosis has been studied. The latter was induced by an autotransplantation model, where two fragments of endometrium with myometrium (2 x 2 mm) from the left uterine horn was grafted to the inner surface of the anterior abdominal wall. The test animals received intraperitoneal injections of 0.5 ml DNIC-glutathione at the dose of 12.5 micromole per kg daily for 12 days 28 days after operation. The injections resulted in more than a 2-fold decrease in the total volume of both large tumors formed from grafts and small additive tumors formed nearby grafts. The disappearance of the additive tumors was also observed in test animals. The EPR signal with g(av) = 2.03 characteristic of protein bound DNIC with thiol-containing ligands was recorded in livers, graft and additive tumors of test and control animals pointing out intensive generation of nitric oxide in rats with experimental endometriosis. Ribonucleotide reductase activation discovered by doublet the EPR signal at g = 2.0 with 2.3 mT hyperfine structure splitting was found in small tumors. The cytotoxic effect of DNIC-glutathione on endometrioid tumors was suggested to be due to DNIC degradation nearby the tumors induced by iron chelating compounds released from the tumors. The degradation resulted in release of a high amount of nitric oxide molecules and nitrosonium ions from DNICs affecting the tumors by way of the cytotoxic effect.

[Gender differences of dynamic changes of anterior cortical activity under negative emotional strain].

Dynamic changes of anterior cortical areas activity under negative emotional strain at male and female teenage examinees were investigated. Dependence of anterior cortical activity changes on gender and initial conflictness level of examinees is determined, which is also confirmed by detected shifts in phychoemotional sphere.

[Autonomic cardiac rhythm regulation in adolescents during simulation of conflict-inducing medium].

Autonomic balance shifts were studied from the parameters of cardiac rhythm variability in subjects of both sexes with a varying conflict potential under the influence of a conflict-inducing factor. There was autonomic balance displacement towards a reduced sympathotonus in conflict subjects irrespective of gender and in non-conflict girls during simulation of a conflict-inducing medium, which suggests their favorable response to presented loads. The sympathetic part of the autonomic nervous system was found to play an increased role in the regulation of cardiac performance in examined non-conflict boys during simulation of a conflict-inducing medium, suggesting the development of psychogenic emotional tension by the negative psychosomatic type.

[Gender differences of the influence of an "aggressive" computer game on the variability of the heart rhythm].

The influence of virtual aggressogenic environment on psychoemotional sphere of male and female teenagers with different levels of personal aggression was studied by characteristics of the heart rate. The exposure to the aggressogenic factors produced a change of the centralized control for the autonomic control in female and male teenagers with the high level of aggression and females with the low level of aggression. Male teenagers with the low level of aggression displayed the prevalence of the centralized control. Thus, the influence of exposure of teenagers to the virtual aggressogenic environment was shown to be ambiguous depending on the level of the level of personal aggression and gender.

[Stress index as an indicator of autonomic regulation while working on a computer].

Cardiac rhythm variability was studied in examinees of both sexes with varying aggressiveness during simulation of the virtual aggressogenic environment. Central regulation showed a shift towards autonomic one in highly aggressive examinees of both sexes and in lowly aggressive girls and there was a preponderance of central regulation in lowly aggressive boys under the influence of an aggressogenic factor. There was an association of the intensity of responses to an aggressogenic factor with gender.

The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes.

AIMS/HYPOTHESIS: Obesity is associated with adipose tissue inflammation. The CD40 molecule, TNF receptor superfamily member 5 (CD40)/CD40 ligand (CD40L) pathway plays a role in the onset and maintenance of the inflammatory reaction, but has not been studied in human adipose tissue. Our aim was to examine CD40 expression by human adipocytes and its participation in adipose tissue inflammation. METHODS: CD40 expression was investigated in human whole adipose tissue and during adipocyte differentiation by real-time PCR, Western blot and immunohistochemistry. The CD40/CD40L pathway was studied using recombinant CD40L (rCD40L) in adipocyte culture and neutralising antibodies in lymphocyte/adipocyte co-culture. RESULTS: CD40 mRNA levels in subcutaneous adipose tissue were higher in the adipocyte than in the stromal-vascular fraction. CD40 expression was upregulated during adipocyte differentiation. Addition of rCD40L to adipocytes induced mitogen activated protein kinase (MAPK) activation, stimulated inflammatory adipocytokine production, and decreased insulin-induced glucose transport in parallel with a downregulation of IRS1 and GLUT4 (also known as SCL2A4). rCD40L decreased the expression of lipogenic genes and increased lipolysis. CD40 mRNA levels were significantly higher in subcutaneous adipose tissue than in visceral adipose tissue of obese patients and were positively correlated with BMI, and with IL6 and leptin mRNA levels. Lymphocyte/adipocyte co-culture led to an upregulation of proinflammatory adipocytokines and a downregulation of leptin and adiponectin. Physical separation of the two cell types attenuated these effects, suggesting the involvement of a cell-cell contact. Blocking the CD40/CD40L interaction with neutralising antibodies reduced IL-6 secretion from adipocytes. CONCLUSIONS/INTERPRETATION: Adipocyte CD40 may contribute to obesity-related inflammation and insulin resistance. T lymphocytes regulate adipocytokine production through both the release of soluble factor(s) and heterotypic contact with adipocytes involving CD40.