Hypoxia compensates cell cycle arrest with progenitor differentiation during angiogenesis.

Angiogenesis, the main mechanism that allows vascular expansion for tissue regeneration or disease progression, is often triggered by an imbalance between oxygen consumption and demand. Here, by analyzing changes in the transcriptomic profile of endothelial cells (ECs) under hypoxia we uncovered that the repression of cell cycle entry and DNA replication stand as central responses in the early adaptation of ECs to low oxygen tension. Accordingly, hypoxia imposed a restriction in S-phase in ECs that is mediated by Hypoxia-Inducible Factors. Our results indicate that the induction of angiogenesis by hypoxia in Embryoid Bodies generated from murine Stem Cells is accomplished by the compensation of decreased S-phase entry in mature ECs and differentiation of progenitor cells. This conditioning most likely allows an optimum remodeling of the vascular network. Identification of the molecular underpinnings of cell cycle arrest by hypoxia would be relevant for the design of improved strategies aimed to suppress angiogenesis in pathological contexts where hypoxia is a driver of neovascularization.

The Neutrophil Secretome as a Crucial Link between Inflammation and Thrombosis.

Cardiovascular diseases are a leading cause of death. Blood-cell interactions and endothelial dysfunction are fundamental in thrombus formation, and so further knowledge of the pathways involved in such cellular crosstalk could lead to new therapeutical approaches. Neutrophils are secretory cells that release well-known soluble inflammatory signaling mediators and other complex cellular structures whose role is not fully understood. Studies have reported that neutrophil extracellular vesicles (EVs) and neutrophil extracellular traps (NETs) contribute to thrombosis. The objective of this review is to study the role of EVs and NETs as key factors in the transition from inflammation to thrombosis. The neutrophil secretome can promote thrombosis due to the presence of different factors in the EVs bilayer that can trigger blood clotting, and to the release of soluble mediators that induce platelet activation or aggregation. On the other hand, one of the main pathways by which NETs induce thrombosis is through the creation of a scaffold to which platelets and other blood cells adhere. In this context, platelet activation has been associated with the induction of NETs release. Hence, the structure and composition of EVs and NETs, as well as the feedback mechanism between the two processes that causes pathological thrombus formation, require exhaustive analysis to clarify their role in thrombosis.

The Association Between Pain Relief Using Video Games and an Increase in Vagal Tone in Children With Cancer: Analytic Observational Study With a Quasi-Experimental Pre/Posttest Methodology.

BACKGROUND: Patients with secondary pain due to mucositis after chemotherapy require treatment with morphine. Use of electronic video games (EVGs) has been shown to be an effective method of analgesia in other clinical settings. OBJECTIVE: The main objective of this study was to assess the association between the use of EVGs and the intensity of pain caused by chemotherapy-induced mucositis in pediatric patients with cancer. The secondary objective was to assess the association between changes in pain intensity and sympathetic-parasympathetic balance in this sample of pediatric patients. METHODS: Clinical records were compared between the day prior to the use of EVGs and the day after the use of EVGs. The variables were variations in pupil size measured using the AlgiScan video pupilometer (IDMed, Marseille, France), heart rate variability measured using the Analgesia Nociception Index (ANI) monitor (Mdoloris Medical Systems, Loos, France), intensity of pain measured using the Numerical Rating Scale (score 0-10), and self-administered morphine pump parameters. RESULTS: Twenty patients (11 girls and nine boys; mean age 11.5 years, SD 4.5 years; mean weight 41.5 kg, SD 20.7 kg) who met all the inclusion criteria were recruited. EVGs were played for a mean of 2.3 (SD 1.3) hours per day, resulting in statistically significant changes. After playing EVGs, there was significantly lower daily morphine use (before vs after playing EVGs: 35.9 vs 28.6 µg/kg/day, P=.003), lower demand for additional pain relief medication (17 vs 9.6 boluses in 24 hours, P=.001), lower scores of incidental pain intensity (7.7 vs 5.4, P=.001), lower scores of resting pain (4.8 vs 3.2, P=.01), and higher basal parasympathetic tone as measured using the ANI monitor (61.8 vs 71.9, P=.009). No variation in pupil size was observed with the use of EVGs. CONCLUSIONS: The use of EVGs in pediatric patients with chemotherapy-induced mucositis has a considerable analgesic effect, which is associated physiologically with an increase in parasympathetic vagal tone despite lower consumption of morphine.

Authorship Correction: The Association Between Pain Relief Using Video Games and an Increase in Vagal Tone in Children With Cancer: Analytic Observational Study With a Quasi-Experimental Pre/Posttest Methodology.

[This corrects the article DOI: 10.2196/16013.].

Structural and Functional Basis for Understanding the Biological Significance of P2X7 Receptor.

The P2X7 receptor (P2X7R) possesses a unique structure associated to an as yet not fully understood mechanism of action that facilitates cell permeability to large ionic molecules through the receptor itself and/or nearby membrane proteins. High extracellular adenosine triphosphate (ATP) levels-inexistent in physiological conditions-are required for the receptor to be triggered and contribute to its role in cell damage signaling. The inconsistent data on its activation pathways and the few studies performed in natively expressed human P2X7R have led us to review the structure, activation pathways, and specific cellular location of P2X7R in order to analyze its biological relevance. The ATP-gated P2X7R is a homo-trimeric receptor channel that is occasionally hetero-trimeric and highly polymorphic, with at least nine human splice variants. It is localized predominantly in the cellular membrane and has a characteristic plasticity due to an extended C-termini, which confers it the capacity of interacting with membrane structural compounds and/or intracellular signaling messengers to mediate flexible transduction pathways. Diverse drugs and a few endogenous molecules have been highlighted as extracellular allosteric modulators of P2X7R. Therefore, studies in human cells that constitutively express P2X7R need to investigate the precise endogenous mediator located nearby the activation/modulation domains of the receptor. Such research could help us understand the possible physiological ATP-mediated P2X7R homeostasis signaling.

Degree of dyspnoea at admission and discharge in patients with heart failure and respiratory diseases.

BACKGROUND: Dyspnoea is a disabling symptom in patients admitted with heart failure (HF) and respiratory diseases (RD). The main aim of this study is to evaluate its intensity at admission and discharge and the relation with quality of life. We also describe its management, intensity, and evolution in HF and RD. METHODS: In this descriptive, cross-sectional study, we included prospectively all patients admitted with decompensated HF and chronic obstructive pulmonary disease (COPD)/pulmonary fibrosis during 4 months. Surveys quantifying dyspnoea (Numerical Rating Scale 1-10) and quality of life (EuroQoL 5d) were administered at discharge. RESULTS: A total of 258 patients were included: 190 (73.6%) with HF and 68 (26.4%) with RD (62 COPD and 6 pulmonary fibrosis). Mean age was 74.0±1.2 years, and 157 (60.6%) were men. Dyspnoea before admission was 7.5±0.1. Patients with RD showed greater dyspnoea than those with HF both before admission (8.1±0.2 vs. 7.3±0.2, p=0.01) and at discharge (3.2±0.3 vs. 2.0±0.2, p=0.0001). They also presented a higher rate of severe dyspnoea (≥5) at discharge (23 [34.3%] vs. 36 [19.1%], p=0.02). Opioids were used in 41 (15.9%), mean dose 8.7±0.8 mg Morphine Equivalent Daily Dose. HF patients had worse EuroQoL 5d scores than those with RD, due to mobility problems (118 [62.1%] vs. 28 [41.8%], p=0.004), and lower punctuation in Visual Analogue Scale (57.9±1.6 vs. 65.6±1.0, p=0.006). CONCLUSIONS: About a quarter of patients admitted with HF or RD persist with severe dyspnoea at discharge. Opioids are probably underused. HF patients have less dyspnoea than patients with RD but present worse quality of life.

Abacavir causes leukocyte/platelet crosstalk by activating neutrophil P2X7 receptors thus releasing soluble lectin-like oxidized low-density lipoprotein receptor-1.

BACKGROUND AND PURPOSE: Abacavir, an antiretroviral drug used in HIV therapy associated with myocardial infarction, promotes thrombosis through P2X7 receptors. The role of platelets as pro-thrombotic cells is acknowledged whereas that of neutrophils-due to their secretory capacity-is gaining recognition. This study analyses the role of neutrophils-specifically the secretome of abacavir-treated neutrophils (SNABC )-in platelet activation that precedes thrombosis. EXPERIMENTAL APPROACH: Effects of abacavir or SNABC on platelet activation and platelet-leukocyte interactions and expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) were analysed by flow cytometry. The secretome was analysed by proteomics. The role of leukocytes in the actions of abacavir was evaluated in a mouse model of thrombosis. KEY RESULTS: Abacavir induced platelet-leukocyte interactions, not directly via effects of abacavir on platelets, but via activation of neutrophils, which triggered interactions between platelet P-selectin and neutrophil P-selectin glycoprotein ligand-1 (PSGL-1). SNABC stimulated platelet activation and platelet-leukocyte interactions through a process that was dependent on LOX-1, neutrophil P2X7 and platelet P2Y1, P2Y12 and P2X1 receptors. Abacavir induced the expression of LOX-1 on neutrophils and of the soluble form of LOX-1 (sLOX-1) in SNABC . Neutrophils, LOX-1, P2X7, P2Y1, P2Y12 and P2X1 receptors were required for the pro-thrombotic actions of abacavir in vivo. CONCLUSION AND IMPLICATIONS: Neutrophils are target cells in abacavir-induced thrombosis. Abacavir released sLOX-1 from neutrophils via activation of their P2X7 receptors, which in turn activated platelets. Hence, sLOX-1 could be the missing link in the cardiovascular risk associated with abacavir.

Pediatric Infective Endocarditis: A Literature Review.

Infective endocarditis in children is a rare entity that poses multiple challenges. A history of congenital heart disease is the most common risk factor, although in recent years, other emerging predisposing conditions have gained relevance, such as central venous catheters carriers or children with chronic debilitating conditions; cases in previously healthy children with no medical history are also seen. Diagnosis is complex, although it has improved with the use of multimodal imaging techniques. Antibiotic treatment should be started early, according to causative microorganism and risk factors. Complications are frequent and continue to cause significant morbidity. Most studies have been conducted in adults and have been generalized to the pediatric population, with subsequent limitations. Our manuscript presents a comprehensive review of pediatric infective endocarditis, including recent advances in diagnosis and management.

Role of Neutrophil Extracellular Traps in COVID-19 Progression: An Insight for Effective Treatment.

The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has resulted in a pandemic with over 270 million confirmed cases and 5.3 million deaths worldwide. In some cases, the infection leads to acute respiratory distress syndrome (ARDS), which is triggered by a cytokine storm and multiple organ failure. Clinical hematological, biochemical, coagulation, and inflammatory markers, such as interleukins, are associated with COVID-19 disease progression. In this regard, neutrophilia, neutrophil-to-lymphocyte ratio (NLR), and neutrophil-to-albumin ratio (NAR), have emerged as promising biomarkers of disease severity and progression. In the pathophysiology of ARDS, the inflammatory environment induces neutrophil influx and activation in the lungs, promoting the release of cytokines, proteases, reactive oxygen species (ROS), and, eventually, neutrophil extracellular traps (NETs). NETs components, such as DNA, histones, myeloperoxidase, and elastase, may exert cytotoxic activity and alveolar damage. Thus, NETs have also been described as potential biomarkers of COVID-19 prognosis. Several studies have demonstrated that NETs are induced in COVID-19 patients, and that the highest levels of NETs are found in critical ones, therefore highlighting a correlation between NETs and severity of the disease. Knowledge of NETs signaling pathways, and the targeting of points of NETs release, could help to develop an effective treatment for COVID-19, and specifically for severe cases, which would help to manage the pandemic.

[Position document of the spanish association of paediatrics group for the study of paediatric pain on the recording of pain as fifth vital sign]. / Documento de posicionamiento del Grupo Español para el Estudio del Dolor Pediátrico (GEEDP) de la Asociación Española de Pediatría sobre el registro del dolor como quinta constante.

The Spanish Group for Children's Pain Study was created in 2017 in an aim to prevent, remove or reduce pain in neonates, infants, children, and adolescents. Along with a diagnosis of pain, a paediatric patient may suffer from acute or chronic pain, neuropathic, nociceptive, or mixed pain, as well as pain from procedures, and post-surgical pain. Pain suffering is too often ignored and not diagnosed. As a result of this, pain prevention and pain treatment fails. Acute pain prevalence in scientific literature is estimated to be between 22% (procedures pain) and 77% (pain on patients in emergency departments and in hospital wards). Furthermore, up to 30% of children could suffer from chronic pain during their childhood. Among the barriers detected in pain management are: difficult assesment caused by a lack of unity in pain registry, difficuties due to the choice of an assessment pain scale (according to age and type of pain), and the absence of training in the management and interpretation of these pain scales. Additionally, in some health areas there is a high workload pressure and generally there are communication difficulties between professionals, and between them and families. From this AEP working group our clear positioning is expressed in the recommendation of the systematic assessment and recording of pain in all children treated in the health system, thus considering pain as the fifth constant to be determined after the other vital signs.

Documento de posicionamiento del Grupo Español para el Estudio del Dolor Pediátrico (GEEDP) de la Asociación Española de Pediatría sobre el registro del dolor como quinta constante / Position document of the spanish association of paediatrics group for the study of paediatric pain on the recording of pain as fifth vital sign

El Grupo Español para el Estudio del Dolor Pediátrico (GEEDP) se forma en 2017 con el objetivo de ayudar a reducir o eliminar el dolor de los neonatos, lactantes, niños y adolescentes. Ante un mismo diagnóstico de dolor, los pacientes pueden padecer dolores agudos, crónicos, por procedimientos, postoperatorio, nociceptivos, neuropáticos o mixtos. Sin una adecuada valoración clínica basada en la edad, la enfermedad de base y el tipo de dolor sospechado, este sufrimiento pasa desapercibido con demasiada frecuencia y como consecuencia es infratratado y poco prevenido. La prevalencia del dolor agudo en Pediatría es difícil de estimar y según la evidencia científica actual, podemos determinar que varía entre un 22% (dolor por procedimientos) y un 77% (dolor en los pacientes de urgencias y en las plantas de hospitalización); con relación al dolor crónico, hasta un 30% de los niños pueden padecerlo en algún momento de su vida. Entre las barreras detectadas en el diagnóstico de dolor se encuentran: la dificultad para su valoración por falta de unidad en su registro, existencia de diversas escalas de valoración (según edad y tipo de dolor) y por la ausencia de formación en manejo e interpretación de estas. A esto se puede sumar, en según qué ámbitos sanitarios, la elevada presión asistencial y las dificultades de comunicación entre profesionales y entre estos con las familias. Desde nuestro grupo de trabajo de la AEP deseamos manifestar nuestro claro posicionamiento en la recomendación de la valoración y registro del dolor de forma sistemática en todos los niños atendidos en el sistema sanitario, considerando así el dolor como la quinta constante a determinar después de las constantes vitales

The Spanish Group for Children's Pain Study was created in 2017 in an aim to prevent, remove or reduce pain in neonates, infants, children, and adolescents. Along with a diagnosis of pain, a paediatric patient may suffer from acute or chronic pain, neuropathic, nociceptive, or mixed pain, as well as pain from procedures, and post-surgical pain. Pain suffering is too often ignored and not diagnosed. As a result of this, pain prevention and pain treatment fails. Acute pain prevalence in scientific literature is estimated to be between 22% (procedures pain) and 77% (pain on patients in emergency departments and in hospital wards). Furthermore, up to 30% of children could suffer from chronic pain during their childhood. Among the barriers detected in pain management are: difficult assesment caused by a lack of unity in pain registry, difficuties due to the choice of an assessment pain scale (according to age and type of pain), and the absence of training in the management and interpretation of these pain scales. Additionally, in some health areas there is a high workload pressure and generally there are communication difficulties between professionals, and between them and families. From this AEP working group our clear positioning is expressed in the recommendation of the systematic assessment and recording of pain in all children treated in the health system, thus considering pain as the fifth constant to be determined after the other vital signs