Pathogenesis and Treatment of Thrombohemorrhagic Diathesis in Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a distinct subtype of myeloid leukemia characterized by t(15;17) chromosomal translocation, which involves the retinoic acid receptor-alpha (RAR-alpha). APL typically presents with a life-threatening hemorrhagic diathesis. Before the introduction of all-trans retinoic acid (ATRA) for the cure of APL, fatal hemorrhages due, at least in part, to the APL-associated coagulopathy, were a major cause of induction remission failure. The laboratory abnormalities of blood coagulation found in these patients indicate the occurrence of a hypercoagulable state. Major determinants of the coagulopathy of APL are endogenous factors expressed by the leukemic cells, including procoagulant factors, fibrinolytic proteins, and non-specific proteolytic enzymes. In addition, these cells have an increased capacity to adhere to the vascular endothelium, and to secrete inflammatory cytokines [i.e. interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF-alpha)], which in turn stimulate the expression of prothrombotic activities by endothelial cells and leukocytes. ATRA can interfere with each of the principal hemostatic properties of the leukemic cell, thus reducing the APL cell procoagulant potential, in parallel to the induction of cellular differentiation. This effect occurs in vivo, in the bone marrow of APL patients receiving ATRA, and is associated with the improvement of the bleeding symptoms. Therapy with arsenic trioxide (ATO) also beneficially affects coagulation in APL. However, early deaths from bleeding still remain a major problem in APL and further research is required in this field. In this review, we will summarize our current knowledge of the pathogenesis of the APL-associated coagulopathy and will overview the therapeutic approaches for the management of this complication

The Association of HLA-DQ2 with Celiac Disease

DQ2 is a surface receptor of class II MHC exposed on APC immune-competent cells. Its function is to recognize non-self-antigens and present them to CD4+ T-helper lymphocytes, which activate cytokine production and control antibody production and cell response. The activation of T lymphocytes by peptides derived from gluten proteins and the production of antibodies directed against tTG in tissues where it is localized is the basis of the etiopathogenesis of celiac disease (CD). CD is frequently associated with the presence of specific HLA system genes encoding heterodimers DQ2 and DQ8, identifiable by the DQA1*0501/DQB1*0201 or DQA1*0501/DQB1*0202 and DQB1*0302 alleles. DQ2 is also associated with genetic, endocrinological and neurological diseases such as: type 1 diabetes, thyroiditis, pancreatitis and multiple sclerosis. Interactions between DQ2 and T lymphoma have also been demonstrated. The correlation between autoimmune diseases in patients with CD and therefore DQ2 is much more frequent than in healthy subjects

The identification of a novel Sulfolobus islandicus CAMP-like peptide points to archaeal microorganisms as cell factories for the production of antimicrobial molecules

Background: Pathogenic bacteria easily develop resistance to conventional antibiotics so that even relatively new molecules are quickly losing efficacy. This strongly encourages the quest of new antimicrobials especially for the treatment of chronic infections. Cationic antimicrobial peptides (CAMPs) are small positively charged peptides with an amphipathic structure, active against Gram-positive and Gram-negative bacteria, fungi, as well as protozoa.Results: A novel (CAMP)-like peptide (VLL-28) was identified in the primary structure of a transcription factor, Stf76, encoded by pSSVx, a hybrid plasmid-virus from the archaeon Sulfolobus islandicus. VLL-28 displays chemical, physical and functional properties typical of CAMPs. Indeed, it has a broad-spectrum antibacterial activity and acquires a defined structure in the presence of membrane mimetics. Furthermore, it exhibits selective leakage and fusogenic capability on vesicles with a lipid composition similar to that of bacterial membranes. VLL-28 localizes not only on the cell membrane but also in the cytoplasm of Escherichia coli and retains the ability to bind nucleic acids. These findings suggest that this CAMP-like peptide could exert its antimicrobial activity both on membrane and intra cellular targets.Conclusions: VLL-28 is the first CAMP-like peptide identified in the archaeal kingdom, thus pointing to archaeal microorganisms as cell factories to produce antimicrobial molecules of biotechnological interest. Furthermore, results from this work show that DNA/RNA-binding proteins could be used as sources of CAMPs

Understanding developments in Participatory Governance: a report on findings from a scoping review of the literature and expert interviews

The following report presents findings from a scoping review of the literature and a series of expert interviews carried out between April and December 2021. The purpose of both the scoping review and the interviews was to gain an overview of recent practice in participatory governance, looking at initiatives across Europe over the past decade. By participatory governance, we refer to participatory forms of political decision-making used to improve the quality of democracy (Geißel 2009, cited in Heinelt 2019). More specifically, we were interested in understanding whether and how efforts at institutionalisation and rapid digitalisation are facilitating deeper embedding of participatory governance within politics and policymaking, by identifying and analysing innovations, new insights, and persistent barriers. Furthermore, we examined what efforts are being made to include disempowered people within analogue and digital spaces, how certain groups continue to be excluded, and which strategies are being adopted to deepen inclusion.info:eu-repo/semantics/publishedVersio

Synthesis of Chitosan-Coated Silver Nanoparticle Bioconjugates and Their Antimicrobial Activity against Multidrug-Resistant Bacteria

The increase in multidrug-resistant bacteria represents a true challenge in the pharmaceutical and biomedical fields. For this reason, research on the development of new potential antibacterial strategies is essential. Here, we describe the development of a green system for the synthesis of silver nanoparticles (AgNPs) bioconjugated with chitosan. We optimized a Prunus cerasus leaf extract as a source of silver and its conversion to chitosan–silver bioconjugates (CH-AgNPs). The AgNPs and CH-AgNPs were characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FT-IR), ultraviolet–visible spectroscopy (UV–Vis), and zeta potential measurement (Z-potential). The cytotoxic activity of AgNPs and CH-AgNPs was assessed on Vero cells using the 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyltetrazolium bromide (MTT) cell proliferation assay. The antibacterial activity of AgNPs and CH-AgNPs synthesized using the green system was determined using the broth microdilution method. We evaluated the antimicrobial activity against standard ATCC and clinically isolated multisensitive (MS) and multidrug-resistant bacteria (MDR) Escherichia coli (E. coli), Enterococcus faecalis (E. faecalis), Klebsiella pneumonia (K. pneumoniae), and Staphylococcus aureus (S. aureus), using minimum inhibitory concentration (MIC) assays and the broth dilution method. The results of the antibacterial studies demonstrate that the silver chitosan bioconjugates were able to inhibit the growth of MDR strains more effectively than silver nanoparticles alone, with reduced cellular toxicity. These nanoparticles were stable in solution and had wide-spectrum antibacterial activity. The synthesis of silver and silver chitosan bioconjugates from Prunus cerasus leaf extracts may therefore serve as a simple, ecofriendly, noncytotoxic, economical, reliable, and safe method to produce antimicrobial compounds with low cytotoxicity

The Swift capture of a long X-ray burst from XTE J1701-407

XTE J1701-407 is a new transient X-ray source discovered on June 8th, 2008. More than one month later it showed a rare type of thermonuclear explosion: a long type I X-ray burst. We report herein the results of our study of the spectral and flux evolution during this burst, as well as the analysis of the outburst in which it took place. We find an upper limit on the distance to the source of 6.1 kpc by considering the maximum luminosity reached by the burst. We measure a total fluence of 3.5*10^{-6} erg/cm^2 throughout the ~20 minutes burst duration and a fluence of 2.6*10^{-3} erg/cm^2 during the first two months of the outburst. We show that the flux decay is best fitted by a power law (index ~1.6) along the tail of the burst. Finally, we discuss the implications of the long burst properties, and the presence of a second and shorter burst detected by Swift ten days later, for the composition of the accreted material and the heating of the burning layer.Comment: MNRAS-Letters, accepted. Minor changes according to referee's report. 5 pages, 3 figure

The Luminosity and Energy Dependence of Pulse Phase Lags in the Accretion-Powered Millisecond Pulsar Sax J1808.4-3658

Soft phase lags, in which X-ray pulses in lower energy bands arrive later than pulses in higher energy bands, have been observed in nearly all accretion-powered millisecond pulsars, but their origin remains an open question. In a study of the 2.5 ms accretion-powered pulsar SAX J1808.4–3658, we report that the magnitude of these lags is strongly dependent on the accretion rate. During the brightest stage of the outbursts from this source, the lags increase in magnitude as the accretion rate drops; when the outbursts enter their dimmer flaring-tail stage, the relationship reverses. We evaluate this complex dependence in the context of two theoretical models for the lags, one relying on the scattering of photons by the accretion disk and the other invoking a two-component model for the photon emission. In both cases, the turnover suggests that we are observing the source transitioning into the "propeller" accretion regime.United States. National Aeronautics and Space Administration. RXTE Guest Observer Progra

Practical Recommendations for Optimal Thromboprophylaxis in Patients with COVID-19:A Consensus Statement Based on Available Clinical Trials

Coronavirus disease 2019 (COVID-19) has been shown to be strongly associated with increased risk for venous thromboembolism events (VTE) mainly in the inpatient but also in the outpatient setting. Pharmacologic thromboprophylaxis has been shown to offer significant benefits in terms of reducing not only VTE events but also mortality, especially in acutely ill patients with COVID-19. Although the main source of evidence is derived from observational studies with several limitations, thromboprophylaxis is currently recommended for all hospitalized patients with acceptable bleeding risk by all national and international guidelines. Recently, high quality data from randomized controlled trials (RCTs) further support the role of thromboprophylaxis and provide insights into the optimal thromboprophylaxis strategy. The aim of this statement is to systematically review all the available evidence derived from RCTs regarding thromboprophylaxis strategies in patients with COVID-19 in different settings (either inpatient or outpatient) and provide evidence-based guidance to practical questions in everyday clinical practice. Clinical questions accompanied by practical recommendations are provided based on data derived from 20 RCTs that were identified and included in the present study. Overall, the main conclusions are: (i) thromboprophylaxis should be administered in all hospitalized patients with COVID-19, (ii) an optimal dose of inpatient thromboprophylaxis is dependent upon the severity of COVID-19, (iii) thromboprophylaxis should be administered on an individualized basis in post-discharge patients with COVID-19 with high thrombotic risk, and (iv) thromboprophylaxis should not be routinely administered in outpatients. Changes regarding the dominant SARS-CoV-2 variants, the wide immunization status (increasing rates of vaccination and reinfections), and the availability of antiviral therapies and monoclonal antibodies might affect the characteristics of patients with COVID-19; thus, future studies will inform us about the thrombotic risk and the optimal therapeutic strategies for these patients

Antithrombotic Treatment in Patients With Hemophilia: an EHA-ISTH-EAHAD-ESO Clinical Practice Guidance

Cardiovascular disease is an emerging medical issue in patients with hemophilia (PWH) and its prevalence is increasing up to 15% in PWH in the United States. Atrial fibrillation, acute and chronic coronary syndromes, venous thromboembolism, and cerebral thrombosis are frequent thrombotic or prothrombotic situations, which require a careful approach to fine-tune the delicate balance between thrombosis and hemostasis in PWH when using both procoagulant and anticoagulant treatments. Generally, PWH could be considered as being naturally anticoagulated when clotting factors are 20 IU/dL in need for any form of antithrombotic therapy, usually treatment without additional clotting factor prophylaxis could be used, but careful monitoring for bleeding is recommended. For antiplatelet treatment, this threshold could be lower with single-antiplatelet agent, but again factor level should be at least 20 IU/dL for dual antiplatelet treatment. In this complex growing scenario, the European Hematology Association in collaboration with the International Society on Thrombosis and Haemostasis, the European Association for Hemophilia and Allied Disorders, the European Stroke Organization, and a representative of the European Society of Cardiology Working Group on Thrombosis has produced this current guidance document to provide clinical practice recommendations for health care providers who care for PWH

Coherence of burst oscillations and accretion-powered pulsations in the accreting millisecond pulsar XTE J1814-338

X-ray timing of the accretion-powered pulsations during the 2003 outburst of the accreting millisecond pulsar XTE J1814-338 has revealed variation in the pulse time of arrival residuals. These can be interpreted in several ways, including spin-down and wandering of the fuel impact point around the magnetic pole. In this Letter we show that the burst oscillations of this source are coherent with the persistent pulsations, to the level where they track all of the observed fluctuations. Only one burst, which occurs at the lowest accretion rates, shows a significant phase offset. We discuss what might lead to such rigid phase-locking between the modulations in the accretion and thermonuclear burst emission, and consider the implications for spin variation and the burst oscillation mechanism. Wandering of the fuel impact hot spot around a fixed magnetic pole seems the most likely cause for the accretion-powered pulse phase variations. This means that the burst asymmetry is coupled to the hot spot, not the magnetic pole. If premature ignition at this point (due to higher local temperatures) triggers a burning front that stalls before spreading over the entire surface, the resulting localized nuclear hot spot may explain the unusual burst and burst oscillation properties of this source.Comment: Improvements throughout, accepted for publication in ApJ Letter