Hémostase et Dynamique Cellulaire Vasculaire

Escaping the cage: Retinoic acid (RA), a crucial signaling molecule for the embryogenesis of vertebrates, can be photoreleased from a simple caged derivative (cRA) upon illumination. In zebrafish embryos, cRA causes RA-induced phenotypes with one- and two-photon excitation (see picture), which opens a route to the noninvasive generation of controlled RA concentration patterns in vivo. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2008/z800037_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Mammalian cells accumulate Ca2+ into agonist-sensitive acidic organelles, vesicles that possess a vacuolar proton-ATPase. Acidic Ca2+ stores include secretory granules and lysosome-related organelles. Current evidence clearly indicates that acidic Ca2+ stores participate in cell signaling and function, including the activation of store-operated Ca2+ entry in human platelets upon depletion of the acidic stores, although the mechanism underlying the activation of store-operated Ca2+ entry controlled by the acidic stores remains unclear. STIM1 has been presented as the endoplasmic reticulum Ca2+ sensor, but its role sensing intraluminal Ca2+ concentration in the acidic stores has not been investigated. Here we report that STIM1 and STIM2 are expressed in the lysosome-related organelles and dense granules in human platelets isolated by immunomagnetic sorting. Depletion of the acidic Ca2+ stores using the specific vacuolar proton-ATPase inhibitor, bafilomycin A1, enhanced the association between STIM1 and STIM2 as well as between these proteins and the plasma membrane channel Orai1. Depletion of the acidic Ca2+ stores also induces time-dependent co-immunoprecipitation of STIM1 with the TRPC proteins hTRPC1 and hTRPC6, as well as between Orai1 and both TRPC proteins. In addition, bafilomycin A1 enhanced the association between STIM2 and SERCA3. These findings demonstrate the location of STIM1 and STIM2 in the acidic Ca2+ stores and their association with Ca2+ channels and ATPases upon acidic stores discharge.

Cardiogenic shock (CS) is characterized by low cardiac output and sustained tissue hypoperfusion that may result in end-organ dysfunction and death. CS is associated with high short-term mortality, and its management remains challenging despite recent advances in therapeutic options. Timely diagnosis and multidisciplinary team-based management have demonstrated favourable effects on outcomes. We aimed to review evidence-based practices for managing patients with ischemic and non-ischemic CS, detailing the multi-organ supports needed in this critically ill patient population.

Excess soluble fms-like tyrosine kinase 1 (sFlt-1), a soluble inhibitor of vascular endothelial growth factor pathway, has been demonstrated to promote endothelial dysfunction. Here, we demonstrate that sFlt-1 plasma levels correlate with respiratory symptom severity, expression of endothelial dysfunction biomarker, and incidence of organ failure in coronavirus disease 2019 patients. Clinical Trials Registration: NCT04394195.

Auf freien Fuß gesetzt: Retinsäure (RA), ein entscheidender molekularer Signalgeber für der Embryogenese von Vertebraten, kann photochemisch aus einem einfachen Derivat (cRA) freigesetzt werden. Nach Ein- und Zweiphotonanregung von cRA in Zebrafischembryos entstehen RA-induzierte Phänotypen (siehe Bild). Auf diesem Weg lassen sich gewünschte RA-Konzentrationsmuster nichtinvasiv in vivo erzeugen. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2008/z800037_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Potential under- or overdose of antibiotics may occur in intensive care units due to high variability in plasma concentrations. The risk is either treatment failure or toxicity. Thus, therapeutic drug monitoring of antibiotics may guide dosing adjustment, maximising antibacterial efficacy and minimising toxicity. The aim of this study was to develop and validate a method for the analysis of 15 antibiotics including beta-lactams, linezolid, fluoroquinolones, daptomycin, and clindamycin to have a complete panel in the management of infections. We proposed to develop a fast, sensitive, and quantitative method for the analysis of 15 antibiotics using ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometer (UPLC-MS/MS) technology. this method required only 100 µL of plasma and consisted of a rapid liquid-liquid deproteinisation using methanol. Calibration curves ranged from 0.078 to 500 mg/L depending on the molecules, and were defined according to a therapeutic range. Inter- and intra-assay precisions values were less than 15%. This work described the development and the full validation of a precise, sensitive and accurate assay using UPLC-MS/MS technology. After validation, this new assay was successfully applied to routine therapeutic drug monitoring.

Immunotherapies are now considered as a pillar of non-small-cell lung cancer treatment. The main targets of immune-checkpoint inhibitors (ICI) are programmed cell death 1/programmed cell death ligand 1 and cytotoxic T-lymphocyte antigen 4, aiming at restoring antitumor immunity. Despite durable responses observed in some patients, all patients do not benefit from the treatment and almost all responders ultimately relapse after some time. In this review, we discuss the biomarkers that could be used to predict response to ICI, the current indications of ICI in non-small-cell lung cancer, the mechanisms inducing tumor-cell intrinsic or extrinsic resistance to ICI and finally, the potential treatment response monitoring.

BACKGROUND AND PURPOSE: In acute ischemic stroke, the negative susceptibility vessel sign on T2*-weighted images traditionally highlights fibrin-rich clots, which are particularly challenging to remove. In vitro, fast stent retrieval improves fibrin-rich clot extraction. We aimed to evaluate whether the speed of stent retrieval influences the recanalization and clinical outcome of patients presenting with the negative susceptibility vessel sign. MATERIALS AND METHODS: Patients were identified from a registry of patients with ischemic stroke receiving mechanical thrombectomy between January 2016 and January 2020. Inclusion criteria were the following: 1) acute ischemic stroke caused by an isolated occlusion of the anterior circulation involving the MCA (Internal Carotid Artery-L, M1, M2) within 8 hours of symptom onset; 2) a negative susceptibility vessel sign on prethrombectomy T2*-weighted images; and 3) treatment with a combined technique (stent retriever + contact aspiration). Patients were dichotomized according to retrieval speed (fast versus slow). The primary outcome was the first-pass recanalization rate. RESULTS: Of 68 patients who met inclusion criteria, 31 (45.6%) were treated with fast retrieval. Patients receiving a fast retrieval had greater odds of first-pass complete (relative risk and 95% confidence interval [RR 95% CI], 4.30 [1.80-10.24]), near-complete (RR 95% CI, 3.24 [1.57-6.68]), and successful (RR 95% CI, 2.60 [1.53-4.43]) recanalization as well as greater odds of final complete (RR 95% CI, 4.18 [1.93-9.04]), near-complete (RR 95% CI, 2.75 [1.55-4.85]), and successful (RR 95% CI, 1.52 [1.14-2.03]) recanalization. No significant statistical differences in procedure-related serious adverse events, distal embolization, or symptomatic intracranial hemorrhage were reported. No differences were noted in terms of functional independence (RR 95% CI, 1.01 [0.53-1.93]) and all-cause mortality (RR 95% CI, 0.90 [0.35-2.30]) at 90 days. CONCLUSIONS: A fast stent retrieval during mechanical thrombectomy is safe and improves the retrieval of clots with the negative susceptibility vessel sign.

OBJECTIVES: To report our experience with a case of a child with bilateral testicular micro-lithiasis (TML) who developed bilateral metachronous testicular germ cell tumor (TGCT) and determine the most appropriate follow-up and care management in children with testicular micro calcifications in regards to the theoretical risk of testicular cancer. CASE REPORT: A 12 year-old boy was diagnosed with TGCT and TML. Ten years after complete remission, he presented with a recurrence on the contralateral testis. Genetic screening was performed on both resected and the patient's karyotype was analyzed. RESULTS: Blood karyotype was normal. Aberrations were found in the tumor karyotype. CGH array showed alterations in chromosome arm 12p. DISCUSSION: TML is frequently associated with testicular malignancy in adults: in 16.9% of cases the normal contralateral testicle develops TML in TGCT. Recent works of literature find no relationship between TML and cancer in general, but in patients with additional risks, the relationship becomes stronger. Some authors suggest that environmental components and genetics are determinant factors. This is highly suspected in our reported case. It would seem that TML is not a precancerous lesion per se, but rather a marker of an at-risk situation. Long term evolution is uncertain and regular self-palpation that starts before puberty is the only way to ensure proper screening and monitoring. CONCLUSION: TML have been suspected to be a sign of testicular dysgenesis syndrome, which yields a risk of developing TGCT in case of noxious associations. In patients with a history of TGCT contralateral TML is alarming and aggressive surgical management should be discussed. Therapeutic education of these patients on self-palpation is the best way to ensure proper follow-up.

Abstract Management of left-sided accessory pathways (APs) is based on catheter ablation through an antegrade or retrograde approach. Both are safe and effective but are associated with exposure to x-rays; however, recipients of ablation are generally young. We sought to evaluate the impact of the approach chosen on dose–area product (DAP). A total of 95 patients who underwent radiofrequency ablation of a left-sided AP between January 2011 and January 2020 were included. The primary endpoint was the radiation dose received by the patient. Secondary endpoints were procedural success and complication and recurrence rates. The mean age of the study population was 34.3 ± 16.6 years. The antegrade transseptal approach was used in 63.5% of cases. By multivariate analysis, the antegrade transseptal approach was associated with a 53% reduction in DAP ( p < 0.001). The radiation dose received was also significantly associated with body mass index and total fluoroscopy time ( p < 0.001). There was no significant difference in other secondary endpoints between approaches. The use of an antegrade transseptal approach is associated with a significant reduction in DAP compared with the retrograde approach, and procedural success and complication and recurrence rates are similar.

The electronic cigarette has been suggested as a safer alternative to the conventional tobacco cigarette. However, some vaping products have been shown to have cardiovascular effects, although this remains controversial. Several clinical studies have identified a possible alteration of endothelial function due to exposure to e-cigarette aerosols. However, the underlying biological mechanisms responsible for this observation in humans are still unclear. Thus, the development of preclinical mechanistic studies seems necessary. The aim of this review is, therefore, to provide a comprehensive overview of preclinical studies addressing the question of how e-cigarettes may cause endothelial dysfunction, a predictive marker of cardiovascular events. 53 papers were included in the analysis. We analyzed these papers qualitatively and quantitatively and discussed their limitations. We found that while 30% of in vitro studies showed no effect of e-cigarette aerosols on endothelial cells 26% showed variable effects, and 44% showed a significant adverse effect on endothelial function. In vivo studies were more consistent, with the vast majority (96%) reporting negative effects of e-cigarettes on endothelial function. We concluded that e-cigarettes should not be considered harmless in terms of cardiovascular effects, as they may impair endothelial function through various mechanisms such as oxidative stress and inflammation. However, more studies with standardized and optimized designs are still needed to distinguish the role of nicotine, which is known to affect the cardiovascular system, from that of other components in e-cigarette aerosol.