Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients

International audienceINTRODUCTION: Septic shock remains a major health care problem worldwide. Sepsis-induced immune alterations are thought to play a major role in patients' mortality and susceptibility to nosocomial infections. Programmed death-1 (PD-1) receptor system constitutes a newly described immunoregulatory pathway that negatively controls immune responses. It has recently been shown that PD-1 knock-out mice exhibited a lower mortality in response to experimental sepsis. The objective of the present study was to investigate PD-1-related molecule expressions in septic shock patients. METHODS: This prospective and observational study included 64 septic shock patients, 13 trauma patients and 49 healthy individuals. PD-1-related-molecule expressions were measured by flow cytometry on circulating leukocytes. Plasmatic interleukin (IL)-10 concentration as well as ex vivo mitogen-induced lymphocyte proliferation were assessed. RESULTS: We observed that septic shock patients displayed increased PD-1, PD-Ligand1 (PD-L1) and PD-L2 monocyte expressions and enhanced PD-1 and PD-L1 CD4+ T lymphocyte expressions at day 1-2 and 3-5 after the onset of shock in comparison with patients with trauma and healthy volunteers. Importantly, increased expressions were associated with increased occurrence of secondary nosocomial infections and mortality after septic shock as well as with decreased mitogen-induced lymphocyte proliferation and increased circulating IL-10 concentration. CONCLUSIONS: These findings indicate that PD-1-related molecules may constitute a novel immunoregulatory system involved in sepsis-induced immune alterations. Results should be confirmed in a larger cohort of patients. This may offer innovative therapeutic perspectives on the treatment of this hitherto deadly disease

Diverse aging rates in ectothermic tetrapods provide insights for the evolution of aging and longevity

Comparative studies of mortality in the wild are necessary to understand the evolution of aging; yet, ectothermic tetrapods are underrepresented in this comparative landscape, despite their suitability for testing evolutionary hypotheses. We present a study of aging rates and longevity across wild tetrapod ectotherms, using data from 107 populations (77 species) of nonavian reptiles and amphibians. We test hypotheses of how thermoregulatory mode, environmental temperature, protective phenotypes, and pace of life history contribute to demographic aging. Controlling for phylogeny and body size, ectotherms display a higher diversity of aging rates compared with endotherms and include phylogenetically widespread evidence of negligible aging. Protective phenotypes and life-history strategies further explain macroevolutionary patterns of aging. Analyzing ectothermic tetrapods in a comparative context enhances our understanding of the evolution of aging.Animal science

Chronic infusion of low-dose angiotensin II potentiates the adrenergic response in vivo

Objective: The aim of this study was to investigate the role of angiotensin ll-induced potentiation of the α1-adrenergic contractile response in the aetiology of low-dose angiotensin ll-induced hypertension. Methods: Wistar rats (250 g) received angiotensin II (120ng/kg per min) from subcutaneous minipumps for 21 days. The responses of vaso-active properties of second-order mesenteric arteries (200 µm) to potassium, phenylephrine, angiotensin II and acetylcholine were assessed. The acute amplification effects of angiotensin II on the response to phenylephrine were examined. Results: Angiotensin II induced a progressive hypertension, which reached a plateau after approximately 5 days. The responses to potassium, angiotensin II and acetylcholine were not significantly modified in rats treated chronically with angiotensin II. The major finding of this study is that the response to phenylephrine (1-3 µmol/l) was potentiated (sevenfold at 1.75µmol/l) after chronic treatment with angiotensin II. In control vessels acute addition of angiotensin II (10-10mol/l) produced no contraction but induced potentiation of the phenylephrine response (1-3 µmol/l). No further potentiation of the phenylephrine response was observed in the rats treated chronically with angiotensin II. Conclusions: Thus, although the direct contractile responses to potassium and angiotensin II remain unaffected following chronic angiotensin II treatment, the α1-adrenergic contractile response to phenylephrine is significantly potentiated by angiotensin II in this model of hypertension. We suggest that this potentiation contributes to the hypertension observed in response to infusion of low-dose angiotensin II

Effects of chronic losartan treatment on vascular reactivity in normotensive rats

Objective: To investigate the vasoactive properties of large (aorta) and small (mesenteric) arteries in vitro after chronic losartan treatment of normotensive rats, hence providing information on the role played by angiotensin II in vascular tone. Methods: Wistar rats were treated with 10 mg/kg per day losartan for 3 weeks. Ring segments of thoracic aorta and mesenteric resistance arteries (200 μm diameter) were mounted in myographs and wall force measured isometrically. Results: The mean carotid blood pressure was reduced significantly after chronic losartan treatment (108 ± 3 mmHg, n = 17 versus 116 ± 2 mmHg, n = 16 in control rats, P < 0.05). In the mesenteric resistance artery the contractile response to 125 mmol/l K+, phenylephrine and angiotensin II was not affected significantly by losartan treatment. A subcontractile concentration of angiotensin II (0.1 nmol/l) induced a significant potentiation of the response to 0.03–100 μmol/l phenylephrine (450 ± 180 to 150 ± 20% of the previous response to phenylephrine in control rats). This potentiation was attenuated significantly in the losartan group (240 ± 80 to 100 ± 15% of the previous response, P < 0.01 versus control rats). In the aorta, the response to 125 mmol/l K+ was not affected by chronic losartan treatment. The concentration required for the half-maximal effect for phenylephrine was increased significantly in the losartan group (0.51 ± 0.11 μmol/l versus 0.17 ± 0.03 μmol/l in controls rats; no change in maximum response) and the maximum response to angiotensin II was reduced significanatly (0.7 ± 0.08 mN/mg tissue versus 1.9 ± 0.2 mN/mg tissue in control rats; the concentration for the half-maximal effect was not affected). Potentiation of phenylephrine-induced tone by 0.1 nmol/l angiotensin II (273 ± 55 to 122 ± 12% of the previous response in control rats) was attenuated significantly by losartan treatment (91 ± 46 to 95 ± 23% of the previous response, P < 0.01 versus control) Conclusions: Chronic administration of losartan could act on resistance arteries in normotensive rats by blocking the potentiation by angiotensin II of the agonist-induced tone

Critical limb ischemia: thrombogenic evaluation of two autologous cell therapy products and biologic profile in treated patients

International audienceBackground: Cell therapy has been proposed as a salvage limb procedure in critical limb ischemia (CLI). Autologous cell therapy products (CTP) are obtained from patients with advanced peripheral arterial disease to be injected at the site of ischemia. Thrombogenicity of CTPs has not yet been assessed. The objectives were: 1) to assess thrombotic risk in candidates for cell therapy, 2) to evaluate two different CTPs in terms of thrombogenic potential, and 3) to evaluate clinical thrombotic events.Study design and methods: In this ancillary study of a Phase I and II clinical trial, bone marrow (BM)-CTPs (n = 20) and CTPs obtained by cytapheresis (peripheral blood [PB]-CTPs; n = 20) were compared. Inflammatory and coagulation markers were measured at baseline and 24 hours after CTP implantation. CTP cell content and tissue factor (TF) expression (mRNA and protein) were analyzed. Thrombin generation assessed CTP-related thrombogenicity.Results: All patients presented cardiovascular risk factors. At baseline, the patients' biologic profile was characterized by high levels of fibrinogen, C-reactive protein (CRP), D-dimer, interleukin (IL)-6, and plasmatic TF, whereas IL-10 was low. Although different in terms of cell composition, both BM- and PB-CTPs support low thrombin generation. Twenty-four hours after implantation, biologic markers remained stable in the PB-CTP group, except for IL-6. In the BM-CTP group, a significant increase of IL-6 but also of CRP and D-dimer was observed. Clinically, one single patient developed deep vein thrombosis 24 hours after the implantation of autologous PB-CTP.Conclusion: CTPs supported low thrombin generation and were well tolerated after calf implantation

Low-field NMR water proton longitudinal relaxation in ultrahighly diluted aqueous solutions of silica-lactose prepared in glass material for pharmaceutical use

Low-field (0.02-4 MHz) proton nuclear magnetic resonance (NMR) longitudinal relaxometry was applied to ultrahighly diluted aqueous solutions in order to detect physical modifications induced in the solvent by the dilution process. A mixture of silica-lactose (1.67·10-5 M silica, 2.92·10-2 M lactose) was initially solubilized in water or in saline, then submitted to eighteen iterative centesimal dilutions in water or in saline under vigorous vortex agitation and rigorously controlled atmospheric conditions, and compared to similarly treated pure water and saline as controls. Several independent series of samples were measured according to a blind protocol (total of 140 code-labelled samples). A slight frequency dispersion (about 4%) was found within the 0.02-4 MHz range, centered around 0.55 MHz, and ascribed to combined effects of silica and trace paramagnetic contaminants, both concentrated and in a reduced motion at the borosilicate wall tube interface. The iterative dilution-agitation process in pure water and saline induced no significant effect on relaxivity. Slightly increased relaxivity compared to solvent was found in the initial silica-lactose dilution (especially in saline, about 4%), which vanished unexpectedly slowly upon dilution, as adjusted to an arbitrary log-linear model. Statistical analysis was applied to succeed in discriminating solutions from their solvents beyond the 10-12 level of dilution. No clear explanation emerged, but post-experiment chemical analysis revealed high amounts (6 ppm) of released silica from the glass material used, with excess in silica-lactose samples, and lower amounts of trace paramagnetic contaminants in highly diluted silica-lactose samples, which could provide a clue.SCOPUS: ar.jinfo:eu-repo/semantics/publishe