1,720,989 research outputs found
Glucocorticoids in pregnancy
Full text linkThe physiological changes that occur during pregnancy include altered regulation of the hypothalamo-pituitary-adrenal axis. The fetoplacental unit plays a major role in this, together with alteration of circulating cortisol-binding globulin levels, with a net effect to increase both total and free cortisol levels. Importantly, there are several pathological conditions that require steroid treatment or replacement during pregnancy, and optimizing therapy is clearly crucial. The potential for acute and chronic adverse effects that can impact upon both the mother and the fetus makes the decision of how and when to instigate steroid therapy particularly challenging. In this review, we describe the physio-pathological changes to the hypothalamo-pituitary-adrenal axis that occur during pregnancy, tools to assess endogenous glucocorticoid reserve as well as discuss treatment strategies and the potential for the development of adverse events
Priming metabolism with the type 5 phosphodiesterase: the role of cGMP-hydrolyzing enzymes
No full textThe cyclic guanosine monophosphate (cGMP) signaling system is one of the most prominent regulators of many physiopathological processes in humans and rodents. It has been strongly established as an accomplished cellular signal involved in the regulation of energy homeostasis and cell metabolism, and pharmacological enhancement of cGMP has shown beneficial effects in metabolic disorders models. cGMP intracellular levels are finely regulated by phosphodiesterases (PDEs). The main enzyme responsible for the degradation of cGMP is PDE5. Preclinical and clinical studies have shown that PDE5 inhibitors (PDE5i) have beneficial effects on improving insulin resistance and glucose metabolism representing a promising therapeutic strategy for the treatment of metabolic disorders. This review aims to describe the molecular basis underlying the use of PDE5i to prompt cell metabolism and summarize current clinical trials assessing the effects of PDE5i on glucose metabolism
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Late-onset hypogonadism: reductio ad absurdum of the cardiovascular risk-benefit of testosterone replacement therapy
Full text linkBackground: Low testosterone (T) level is considered a marker of poor cardiovascular health. Ten years ago, the Testosterone in Older Men with Mobility Limitations (TOM) trial was discontinued due to a higher number of adverse events in men receiving T compared with placebo. Since then, several studies have investigated the risks of T replacement therapy (TRT) in late-onset hypogonadism (LOH). Objective: To review the mechanism by which TRT could damage the cardiovascular system. Materials and methods: Comprehensive literature search of recent clinical and experimental studies. Results: The mechanisms of T-mediated coronary vasodilation were reviewed with emphasis on calcium-activated and ATP-sensitive potassium ion channels. We showed how T regulates endothelial nitric oxide synthase (eNOS) and phosphoinositide 3-kinase/protein kinase B/eNOS signaling pathways in vessel walls and its direct effects on cardiomyocytes via β1-adrenergic and ryanodine receptors and provided data on myocardial infarction and heart failure. Vascular smooth muscle senescence could be explained by the modulation of growth factors, matrix metalloproteinase-2, and angiotensin II by T. Furthermore, leukocyte trafficking, facilitated by changes in TNF-α, could explain some of the effects of T on atheromatous plaques. Conflicting data on prothrombotic risk linked to platelet aggregation inhibition via NO-triggered arachidonate synthesis or increased aggregability due to enhanced thromboxane A in human platelets provide evidence regarding the hypotheses on plaque maturation and rupture risk. The effects of T on cardiac electrophysiology and oxygen delivery were also reviewed. Discussion: The effects of TRT on the cardiovascular system are complex. Although molecular studies suggest a potential benefit, several clinical observations reveal neutral or occasionally detrimental effects, mostly due to confounding factors. Conclusions: Attempts to demonstrate that TRT damages the cardiovascular system via systematic analysis of the putative mechanisms led to the contradiction of the initial hypothesis. Current evidence indicates that TRT is safe once other comorbidities are addressed
Use of glucocorticoids in patients with adrenal insufficiency and COVID-19 infection
Full text linkIn March 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), reached pandemic level with a high global mortality rate. The initial immune response to viral load is followed by an uncontrolled cytokine storm with hyperinflammation and immunosuppression. In the patients who are critically ill, infected alveolar epithelial cells trigger the release of inflammatory cytokines, which activates fibroblasts. Subsequently, uncontrolled viral propagation induces cytotoxicity and hyperactivation of immune cells. The cytokine storm leads to increased clotting, vascular inflammation, thromboembolism, and hypotensive shock.
Glucocorticoids have both stimulating and inhibitory effects on the immune response. In the initial phases of an infection, physiological glucocorticoid concentrations help to prime the immune system. In turn, this response activates the hypothalamic–pituitary–adrenal (HPA) axis to mild immunosuppression to reduce autoimmunity and cytokine toxicity. In critical illness (eg, COVID-19 pneumonia), HPA activation might be blunted, leading to corticosteroid insufficiency related to critical illness.
Patients with adrenal insufficiency have an increased risk of infection due to their depleted innate immunity, characterised by increased monocytes and decreased cytotoxic natural killer cells,which could facilitate the worsening of a SARS-CoV-2 infection into severe acute respiratory distress syndrome. Given the role of the HPA axis in stress priming the immune response, patients with adrenal insufficiency are intuitively at high risk of infection, especially as corticosteroid therapy during infection is still largely tailored empirically, often disregarding timing and dosage. The rationale of the more the better avoids risking inadequate concentrations of corticosteroids.
In summary, tailoring of glucocorticoid stress regimens in COVID-19 requires a more evidence-based approach. The pathophysiology of immune response and the systemic complications associated with a SARS-CoV-2 infection set the pace, and the protocol should be adapted to the patient's clinical stage
Quantitative assessment of diffuse myocardial fibrosis in II-type diabetes mellitus patients using T1 mapping technique: preliminary data
Full text linkIn diabetic cardiomyopathy (DCM), ventricular remodelling consists in a progressive impairment of myocardial contraction (evolving from diastolic to combined diastolic-systolic dysfunction) occurring regardless of ischemic heart disease, hypertension or other macrovascular complications, which ultimately leads to heart failure. Early stages of DCM are asymptomatic and characterised by initial contractile disfunction and various degree of myocardial fibrosis, that may not be recognised by traditional cardiology tests. Our purpose was to detect myocardial fibrotic infiltration in DM-II patients by using T1-mapping technique with extracellular volume fraction (ECV) measurement
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Everything you ever wanted to know about phosphodiesterase 5 inhibitors and the heart (but never dared ask). how do they work
No full textIntroduction: Phosphodiesterase 5 inhibitors (PDE5i) were developed while investigating novel treatments for coronary artery disease, but their andrological side effects shifted their indication toward the management of erectile dysfunction. Although PDE5i are now also indicated for pulmonary arterial hypertension and there are mounting preclinical and clinical evidences about their potentially beneficial cardiac effects, their use remains controversial and the involved mechanisms remain unclear.
Materials and methods: This review aimed to analyze the effects of PDE5i administration in various animal and humans models of cardiovascular diseases.
Results: Animal studies have shown that PDE5i have protective effects in several models of cardiac disease. In humans, some studies showed that PDE5i improves microvascular and endothelial dysfunction and exerts positive effects in different samples of cardiovascular (CV) impairment. In contrast, other studies found no benefit (and no harm) in heart failure with preserved ejection fraction. The discrepancies in these findings are likely related to the fact that the mechanisms targeted by PDE5i in human disease are still poorly understood and the target population not yet identified. The mechanisms of actions herein reviewed suggest that hypertrophy, microvascular impairment, and inflammation, should be variably present for PDE5i to work. All these conditions frequently coexist in diabetes. A gender responsiveness has also been recently proposed.
Conclusions: Continuous PDE5 inhibition may exert cardioprotective effects, improving endothelial function and counteracting cardiac remodeling in some but not all conditions. A better patient selection could help to clarify the controversies on PDE5i use for CV disorders
Novel nanoarchitectures based on lignin nanoparticles for electrochemical eco‐friendly biosensing development
Full text linkNovel nanoarchitectures based on lignin nanoparticles (LNPs) were designed and realized for electrochemical eco‐friendly biosensing development. Two types of lignin nanoparticles were utilized for the modification of a gold bare electrode, namely organosolv (OLNPs) and kraft lignin (KLNPs) nanoparticles, synthetized from a sulfur‐free and a sulfur lignin, respectively. The electrochemical behavior of LNP‐modified electrodes was studied using two electrochemical techniques, cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Compared to the gold bare electrode, an evident decrease in the faradaic current and increase of the ΔEp were observed in cyclic voltammograms. In addition, larger semicircles were registered in Nyquist plots. These results suggest a strong inhibition effect of the electron transfer reaction by LNPs layer, especially in the case of KLNPs. The modified electrodes, properly assembled with concanavalin A (ConA) and glucose oxidase (GOx), were successively tested as biosensing platforms for glucose, showing a sensitivity of (4.53 ± 0.467) and (13.74 ± 1.84) μA mM−1 cm2 for Au/SAMCys/OLNPs/ConA/GOx and Au/KLNPs/ConA/GOx biosensors, respectively. Finally, different layers of the KNLPs/ConA/GOx‐modified Au electrode were tested, and the three‐layered Au(KNLPs/ConA/GOx)3 showed the best analytical performance
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