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Rivaroxaban’s Vascular Dose for the Neurovascular Clinician
No full textRivaroxaban, a direct oral anticoagulant, has proven efficacy and safety at its standard dose in the treatment and prevention of various vascular conditions. These include the treatment of venous thromboembolism and stroke prevention in non-valvular atrial fibrillation. A “very low” vascular dose of rivaroxaban, when combined with low-dose aspirin, has been demonstrated to reduce major adverse cardiovascular events, including stroke, in both acute and chronic coronary syndrome. The combination of rivaroxaban and low-dose aspirin could potentially offer an additional strategy for stroke prevention in selected non-atrial fibrillation patients who are at a high risk of stroke
The Evolving Role of Disproportionality Analysis in Pharmacovigilance
No full textIntroduction: From 2009 to 2015, the IMI PROTECT conducted rigorous studies addressing questions about optimal implementation and significance of disproportionality analyses, leading to the development of Good Signal Detection Practices. The ensuing period witnessed the independent exploration of research paths proposed by IMI PROTECT, accumulating valuable experience and insights that have yet to be seamlessly integrated. Areas covered: This state-of-the-art review integrates IMI PROTECT recommendations with recent acquisitions and evolving challenges. It deals with defining the object of study, disproportionality methods, subgrouping, masking, drug-drug interaction, duplication, expectedness, the debated use of disproportionality results as risk measures, integration with other types of data. Expert opinion: Despite the ongoing skepticism regarding the usefulness of disproportionality analyses and individual case safety reports, their ability to timely detect safety signals regarding rare and unpredictable adverse reactions remains unparalleled. Moreover, recent exploration into their potential for characterizing safety signals revealed valuable insights concerning potential risk factors and the patient’s perspective. To fully realize their potential beyond hypothesis generation and achieve a comprehensive evidence synthesis with other kinds of data and studies, each with their unique limitations and contributions, we need to investigate methods for more transparently communicating disproportionality results and mapping and addressing pharmacovigilance biases
Mtor Pathway Inhibition Alters Proliferation as Well as Differentiation of Neural Stem Cells
No full textIntroduction: Neural stem cells (NSCs) are essential for both embryonic development and adult neurogenesis, and their dysregulation causes a number of neurodevelopmental disorders, such as epilepsy and autism spectrum disorders. NSC proliferation and differentiation in the developing brain is a complex process controlled by various intrinsic and extrinsic stimuli. The mammalian target of rapamycin (mTOR) regulates proliferation and differentiation, among other cellular functions, and disruption in the mTOR pathway can lead to severe nervous system development deficits. In this study, we investigated the effect of inhibition of the mTOR pathway by rapamycin (Rapa) on NSC proliferation and differentiation. Methods: The NSC cultures were treated with Rapa for 1, 2, 6, 24, and 48 h. The effect on cellular functions was assessed by immunofluorescence staining, western blotting, and proliferation/metabolic assays. Results: mTOR inhibition suppressed NSC proliferation/metabolic activity as well as S-Phase entry by as early as 1 h of Rapa treatment and this effect persisted up to 48 h of Rapa treatment. In a separate experiment, NSCs were differentiated for 2 weeks after treatment with Rapa for 24 or 48 h. Regarding the effect on neuronal and glial differentiation (2 weeks post-treatment), this was suppressed in NSCs deficient in mTOR signaling, as evidenced by downregulated expression of NeuN, MAP2, and GFAP. We assume that the prolonged effect of mTOR inhibition is realized due to the effect on cytoskeletal proteins. Discussion: Here, we demonstrate for the first time that the mTOR pathway not only regulates NSC proliferation but also plays an important role in NSC differentiation into both neuronal and glial lineages
Phosphorylation of Cardiac Sodium Channel at Ser571 Anticipates Manifestations of the Aging Myopathy
No full textDiastolic dysfunction and delayed ventricular repolarization are typically observed in the elderly, but whether these defects are intimately associated with the progressive manifestation of the aging myopathy remains to be determined. In this regard, aging in experimental animals is coupled with increased late Na current (INa,L) in cardiomyocytes, raising the possibility that INa,L conditions the modality of electrical recovery and myocardial relaxation of the aged heart. For this purpose, aging male and female wild-type (WT) C57Bl/6 mice were studied together with genetically engineered mice with phosphomimetic (gain of function, GoF) or ablated (loss of function, LoF) mutations of the sodium channel Nav1.5 at Ser571 associated with, respectively, increased and stabilized INa,L. At ∼18 mo of age, WT mice developed prolonged duration of the QT interval of the electrocardiogram and impaired diastolic left ventricular (LV) filling, defects that were reversed by INa,L inhibition. Prolonged repolarization and impaired LV filling occurred prematurely in adult (∼5 mo) GoF mutant mice, whereas these alterations were largely attenuated in aging LoF mutant animals. Ca2 transient decay and kinetics of myocyte shortening/relengthening were delayed in aged (∼24 mo) WT myocytes, with respect to adult cells. In contrast, delayed Ca2 transients and contractile dynamics occurred at adult stage in GoF myocytes and further deteriorated in old age. Conversely, myocyte mechanics were minimally affected in aging LoF cells. Collectively, these results document that Nav1.5 phosphorylation at Ser571 and the late Na current modulate the modality of myocyte relaxation, constituting the mechanism linking delayed ventricular repolarization and diastolic dysfunction
Adherence to Adhesive Patch Electrocardiographic Monitoring Among Adults With Disabilities
No full textBackground: Individuals with developmental and/or intellectual disabilities (I/DD) are at a greater risk for atrial fibrillation (AF), the most common type of cardiac arrhythmia. AF is associated with heart failure, stroke, poor mental health, and reduced quality of life. Management and treatment decisions are based on the ability to detect AF; however, noninvasive, remote cardiac monitoring may not be tolerated by individuals with I/DD. Objective: To examine adherence to the placement of an ambulatory cardiac rhythm monitoring patch device by adult patients with I/DD. Methods: Investigators extracted chart data from a consecutive series of adult patients (18 years+) who received the patch device as part of standard treatment at an adult health center between November 1, 2015 and October 31, 2019. Results: A total of 95 patients were included in data analysis. Average age of subjects was 53.8 ± 13.9 years (range: 20.2–88.5); 66.7% were male. All subjects had intellectual disabilities as follows: mild, 37.9%; moderate, 29.5%; severe, 21.0%; and, profound, 11.6%. With a prescribed duration of 14 days, subjects wore the device a median (interquartile range [IQR]) of 12.2 days (4.1–14.0); total analysis time was a median of 9.5 days (3.4–13.5). A total of 29 subjects (30.5%) received cardiac diagnoses not previously identified (median = 1 new diagnosis; range: 1–5). Conclusions: This pilot study suggests the possible utility of an ambulatory monitoring patch device in an adult population with I/DD. Investigators recommend larger studies to confirm such preliminary findings to ultimately improve clinical management and patient quality of life
Knowledge of Memory Reconsolidation Can Improve Psychodynamic Technique
No full textThe gold standard of scientific medicine is using knowledge of underlying processes to shape treatment. This has previously not been possible for psychotherapy, but with the science of memory reconsolidation, requirements for change can be more precisely defined and can improve psychotherapeutic technique by focusing on three areas: the activation of maladaptive implicit learning, the provision of disconfirming information, and attention to transmission between consciousness and limbic memory. Overall, better understanding of processes helps liberate psychotherapy from rigidities dictated by set methods
Permissive Role of Vascular Endothelium in Fibrosis: Focus on the Kidney
No full textFibrosis, the morphologic end-result of a plethora of chronic conditions and the scorch for organ function, has been thoroughly investigated. One aspect of its development and progression, namely the permissive role of vascular endothelium, has been overshadowed by studies into (myo)fibroblasts and TGF-b; thus, it is the subject of the present review. It has been established that tensile forces of the extracellular matrix acting on cells are a prerequisite for mechanochemical coupling, leading to liberation of TGF-b and formation of myofibroblasts. Increased tensile forces are prompted by elevated vascular permeability in response to diverse stressors, resulting in the exudation of fibronectin, fibrinogen/fibrin, and other proteins, all stiffening the extracellular matrix. These processes lead to the development of endothelial cells dysfunction, endothelial-to-mesenchymal transition, premature senescence of endothelial cells, perturbation of blood flow, and gradual obliteration of microvasculature, leaving behind “string” vessels. The resulting microvascular rarefaction is not only a constant companion of fibrosis but also an adjunct mechanism of its progression. The deepening knowledge of the above chain of pathogenetic events involving endothelial cells, namely increased permeability–stiffening of the matrix–endothelial dysfunction–microvascular rarefaction–tissue fibrosis, may provide a roadmap for therapeutic interventions deemed to curtail and reverse fibrosis
Spatial and Temporal Aspects of Neuronal Calcium and Sodium Signals Measured With Low-Affinity Fluorescent Indicators
No full textLow-affinity fluorescent indicators for Ca2+ or Na+ allow measuring the dynamics of intracellular concentration of these ions with little perturbation from physiological conditions because they are weak buffers. When using synthetic indicators, which are small molecules with fast kinetics, it is also possible to extract spatial and temporal information on the sources of ion transients, their localization, and their disposition. This review examines these important aspects from the biophysical point of view, and how they have been recently exploited in neurophysiological studies. We first analyze the environment where Ca2+ and Na+ indicators are inserted, highlighting the interpretation of the two different signals. Then, we address the information that can be obtained by analyzing the rising phase and the falling phase of the Ca2+ and Na+ transients evoked by different stimuli, focusing on the kinetics of ionic currents and on the spatial interpretation of these measurements, especially on events in axons and dendritic spines. Finally, we suggest how Ca2+ or Na+ imaging using low-affinity synthetic fluorescent indicators can be exploited in future fundamental or applied research
