Structure, regulation, and physiological functions of NADPH oxidase 5 (NOX5)

NOX5 is the last member of the NADPH oxidase (NOXs) family to be identified and presents some specific characteristics differing from the rest of the NOXs. It contains four Ca2+ binding domains at the N-terminus and its activity is regulated by the intracellular concentration of Ca2+. NOX5 generates superoxide (O2•−) using NADPH as a substrate, and it modulates functions related to processes in which reactive oxygen species (ROS) are involved. Those functions appear to be detrimental or beneficial depending on the level of ROS produced. For example, the increase in NOX5 activity is related to the development of various oxidative stress-related pathologies such as cancer, cardiovascular, and renal diseases. In this context, pancreatic expression of NOX5 can negatively alter insulin action in high-fat diet-fed transgenic mice. This is consistent with the idea that the expression of NOX5 tends to increase in response to a stimulus or a stressful situation, generally causing a worsening of the pathology. On the other hand, it has also been suggested that it might have a positive role in preparing the body for metabolic stress, for example, by inducing a protective adipose tissue adaptation to the excess of nutrients supplied by a high-fat diet. In this line, its endothelial overexpression can delay lipid accumulation and insulin resistance development in obese transgenic mice by inducing the secretion of IL-6 followed by the expression of thermogenic and lipolytic genes. However, as NOX5 gene is not present in rodents and human NOX5 protein has not been crystallized, its function is still poorly characterized and further extensive research is required. (AU)

Contemporary Antiplatelet and Anticoagulant Therapies for Secondary Stroke Prevention: A Narrative Review of Current Literature and Guidelines.

PURPOSE OF REVIEW: Stroke is a leading cause of death and disability worldwide. The annual incidence of new or recurrent stroke is approximately 795,000 cases per year in the United States, of which 87% are ischemic in nature. In addition to the management of modifiable high-risk factors to reduce the risk of recurrent stroke, antithrombotic agents (antiplatelets and anticoagulants) play an important role in secondary stroke prevention. This review will discuss the published literature on the use of antiplatelets and anticoagulants in secondary prevention of acute ischemic stroke and transient ischemic attack (TIA), including their pharmacology, efficacy, and adverse effects. We will also highlight the role of dual antiplatelet therapy (DAPT) in secondary stroke prevention, along with supporting literature. RECENT FINDINGS: Single antiplatelet therapy (SAPT) with aspirin or clopidogrel reduces the risk of recurrent ischemic stroke in patients with non-cardioembolic ischemic stroke or TIA. However, as shown in recent trials, short-term DAPT with aspirin and clopidogrel or ticagrelor for 21-30 days is more effective than SAPT in patients with minor acute non-cardioembolic stroke or high-risk TIA. Although short-term DAPT is highly effective in preventing recurrent stroke, a more prolonged course can increase bleeding risks without additional benefit. DAPT for 90 days, followed by aspirin monotherapy for patients with large vessel intracranial atherosclerotic disease, is suitable for secondary stroke prevention. However, patients need to be monitored for both minor (e.g., bruising) and major (e.g., intracranial) bleeding complications. Conversely, oral warfarin and newer direct oral anticoagulant (DOACs) such as dabigatran, rivaroxaban, apixaban, and edoxaban are the agents of choice for secondary stroke prevention in patients with non-valvular cardioembolic strokes. DOACs may be preferred over warfarin due to decreased bleeding risks, including ICH, lack of need for international normalized ratio monitoring, no dietary restrictions, and limited drug-drug interactions. The choice between different antiplatelets and anticoagulants for prevention of ischemic stroke depends on the underlying stroke mechanism, cytochrome P450 2C19 polymorphisms, bleeding risk profile, compliance, drug tolerance, and drug resistance. Physicians must carefully weigh each patient's relative benefits and bleeding risks before initiating an antiplatelet/anticoagulant treatment regimen. Further studies are warranted to study the optimal duration of DAPT in symptomatic intracranial atherosclerosis since the benefit is most pronounced in the short term while the bleeding risk remains high during the extended duration of therapy.

Structure, regulation, and physiological functions of NADPH oxidase 5 (NOX5).

NOX5 is the last member of the NADPH oxidase (NOXs) family to be identified and presents some specific characteristics differing from the rest of the NOXs. It contains four Ca2+ binding domains at the N-terminus and its activity is regulated by the intracellular concentration of Ca2+. NOX5 generates superoxide (O2•-) using NADPH as a substrate, and it modulates functions related to processes in which reactive oxygen species (ROS) are involved. Those functions appear to be detrimental or beneficial depending on the level of ROS produced. For example, the increase in NOX5 activity is related to the development of various oxidative stress-related pathologies such as cancer, cardiovascular, and renal diseases. In this context, pancreatic expression of NOX5 can negatively alter insulin action in high-fat diet-fed transgenic mice. This is consistent with the idea that the expression of NOX5 tends to increase in response to a stimulus or a stressful situation, generally causing a worsening of the pathology. On the other hand, it has also been suggested that it might have a positive role in preparing the body for metabolic stress, for example, by inducing a protective adipose tissue adaptation to the excess of nutrients supplied by a high-fat diet. In this line, its endothelial overexpression can delay lipid accumulation and insulin resistance development in obese transgenic mice by inducing the secretion of IL-6 followed by the expression of thermogenic and lipolytic genes. However, as NOX5 gene is not present in rodents and human NOX5 protein has not been crystallized, its function is still poorly characterized and further extensive research is required.

Dietary Insights in Neurological Diseases.

PURPOSE OF REVIEW: Dietary interventions may play a role in the pathophysiology of common neurological disorders such as Alzheimer's disease, Parkinson's disease, stroke, migraines, multiple sclerosis, and epilepsy. This article describes the most common and impactful dietary regimens for commonly encountered neurological disorders. RECENT FINDINGS: Plant-based, low-fat, high-fiber diets, rich in antioxidants and other lifestyle interventions may reduce the burden and disability of common neurological disorders. The ketogenic diet, the diet of choice for the treatment of refractory epilepsy, is such an example. Diverse neurological disorders demonstrate several common pathophysiological mechanisms including increased oxidative stress, neuroinflammation, and disrupted metabolism. Dietary interventions can potentially influence these pathophysiological processes and thus favorably alter clinical outcomes. Adequate dietary choices should be considered as part of a continuum of healthy lifestyle choices.

Safer Stroke-Dx Instrument: Identifying Stroke Misdiagnosis in the Emergency Department.

BACKGROUND: Missed or delayed diagnosis of acute stroke, or false-negative stroke (FNS), at initial emergency department (ED) presentation occurs in ≈9% of confirmed stroke patients. Failure to rapidly diagnose stroke can preclude time-sensitive treatments, resulting in higher risks of severe sequelae and disability. In this study, we developed and tested a modified version of a structured medical record review tool, the Safer Dx Instrument, to identify FNS in a subgroup of hospitalized patients with stroke to gain insight into sources of ED stroke misdiagnosis. METHODS: We conducted a retrospective cohort study at 2 unaffiliated comprehensive stroke centers. In the development and confirmatory cohorts, we applied the Safer Stroke-Dx Instrument to report the prevalence and documented sources of ED diagnostic error in FNS cases among confirmed stroke patients upon whom an acute stroke was suspected by the inpatient team, as evidenced by stroke code activation or urgent neurological consultation, but not by the ED team. Inter-rater reliability and agreement were assessed using interclass coefficient and kappa values (κ). RESULTS: Among 183 cases in the development cohort, the prevalence of FNS was 20.2% (95% CI, 15.0-26.7). Too narrow a differential diagnosis and limited neurological examination were common potential sources of error. The interclass coefficient for the Safer Stroke-Dx Instrument items ranged from 0.42 to 0.91, and items were highly correlated with each other. The κ for diagnostic error identification was 0.90 (95% CI, 0.821-0.978) using the Safer Stroke-Dx Instrument. In the confirmatory cohort of 99 cases, the prevalence of FNS was 21.2% (95% CI, 14.2-30.3) with similar sources of diagnostic error identified. CONCLUSIONS: Hospitalized patients identified by stroke codes and requests for urgent neurological consultation represent an enriched population for the study of diagnostic error in the ED. The Safer Stroke-Dx Instrument is a reliable tool for identifying FNS and sources of diagnostic error.

Management dilemmas in acute ischemic stroke and concomitant acute pulmonary embolism: Case series and literature review.

BACKGROUND: Pulmonary embolism (PE) and acute ischemic stroke (AIS) are common disorders with high morbidity and mortality, rarely presenting simultaneously. There is a paucity of data regarding the management of this uncommon presentation. The treatment of these two entities is complex in the acute phase due to the concomitant need for thrombolysis in AIS and anticoagulation for PE. METHODS: We retrospectively reviewed confirmed ischemic stroke cases to identify patients presented with simultaneous PE from June 2018 to May 2019. Additionally, a literature review was performed. Two reviewers assessed the manuscripts' quality, and relevant data regarding clinical course and management was extracted. RESULTS: We reviewed 439 patient charts, identifying two cases of concomitant AIS and PE. Additionally, twelve articles (n = 15 subjects) fulfilled our literature review criteria for a total of 17 cases, including ours. Intravenous anticoagulation (70.5%) was the most frequent intervention targeting both disorders. Therapies such as intravenous thrombolysis (23.53% (n = 4)) and mechanical thrombectomy (23.53% (n = 4)) were specific in AIS. Catheter-directed thrombolysis (5.88%) was used for PE. Clinical outcomes were favorable (asymptomatic or mild disable symptoms) in 47.05% (N = 8) of patients, while 41.17% had poor outcomes (severe disable symptoms or death). CONCLUSIONS: AIS and PE stand for a challenge when they present simultaneously. The evaluation of risks and benefits of therapies such as intravenous thrombolysis, mechanical thrombectomy, and catheter-directed-thrombolysis in the clinical context is essential. According to our review, the ischemic stroke burden guides systemic anticoagulation decisions over interventional procedures when the hemodynamic status remains unaffected.

Endothelial Nox5 Expression Modulates Glucose Uptake and Lipid Accumulation in Mice Fed a High-Fat Diet and 3T3-L1 Adipocytes Treated with Glucose and Palmitic Acid.

Obesity is a global health issue associated with insulin resistance and altered lipid homeostasis. It has been described that reactive oxygen species (ROS) derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity are involved in the development of these pathologies. The present study describes the role of endothelial NOX5 expression over adipose tissue by using two experimental systems: NOX5 conditional knock-in mice fed with a high-fat diet and 3T3-L1 adipocytes cultured with conditioned media of NOX5-expressing endothelial cells previously treated with glucose and palmitic acid. Animals expressing NOX5 presented lower body weight gain and less mesenteric and epididymal adipose mass compared to control mice fed with the same diet. NOX5-expressing mice also showed significantly lower glycaemia and improved insulin-induced glucose uptake. In addition, Glut4 and Caveolin 1 (Cav1) expression were significantly increased in the adipose tissue of these animals. Likewise, 3T3-L1 adipocytes treated with conditioned media from NOX5-expressing endothelial cells, incubated with high glucose and palmitic acid, presented a reduction in lipid accumulation and an increase in glucose uptake. Moreover, a significant increase in the expression of Glut4 and Cav1 was also detected in these cells. Taken together, all these data support that, in response to a highly caloric diet, NOX5 endothelial activity may regulate glucose sensitivity and lipid homeostasis in the adipose tissue.

Neurologic complications of implantable devices.

Technologies for repairing cardiac structures or sustaining cardiac function with implantable devices have helped patients with an ever-expanding array of cardiac conditions. Patients are surviving and thriving with cardiac conditions that would formerly have been disabling or fatal. With the implantation of devices in the heart, however, comes the inevitable risk of neurological complications. This chapter focuses on devices implanted in the chambers or valves of the heart itself, including prosthetic heart valves, closure devices for patent foramen ovale, atrial appendage occluder devices, short-term implantable circulatory assist devices, and long-term ventricular assist devices, but excluding coronary artery stents or extracardiac devices. Further, it considers the procedural and postprocedural risks of the devices, leaving the discussion of clinical effectiveness of the devices to other chapters of this book.

Immune-Mediated Disorders Affecting the Spinal Cord and the Spine.

PURPOSE OF REVIEW: To review the most recent advances and provide a description of the most common autoimmune diseases causing myelitis and selective spine disorders. The ultimate goal of this article is to facilitate the prompt recognition of these diseases. RECENT FINDINGS: The recent discovery of biomarkers such as aquaporin 4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies has changed our understanding of autoimmune diseases affecting the spinal cord as well as their treatment and outcomes. Autoimmune neurology is an increasingly evolving field that encompasses a broad spectrum of autoimmune-inflammatory diseases of the central nervous system (CNS) and peripheral nervous system (PNS). Autoimmune disorders of the spinal cord are a heterogeneous group of myelopathies with a broad differential diagnosis and many of them have been recently identified. Prompt recognition of these myelopathies is important as some of them are treatable, which could improve patient outcomes and prevent disability.

Endothelial NOX5 Expression Modulates Thermogenesis and Lipolysis in Mice Fed with a High-Fat Diet and 3T3-L1 Adipocytes through an Interleukin-6 Dependent Mechanism.

Obesity is a global health issue associated with the development of metabolic syndrome, which correlates with insulin resistance, altered lipid homeostasis, and other pathologies. One of the mechanisms involved in the development of these pathologies is the increased production of reactive oxygen species (ROS). One of the main producers of ROS is the family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, among which NOX5 is the most recently discovered member. The aim of the present work is to describe the effect of endothelial NOX5 expression on neighboring adipose tissue in obesity conditions by using two systems. An in vivo model based on NOX5 conditional knock-in mice fed with a high-fat diet and an in vitro model developed with 3T3-L1 adipocytes cultured with conditioned media of endothelial NOX5-expressing bEnd.3 cells, previously treated with glucose and palmitic acid. Endothelial NOX5 expression promoted the expression and activation of specific markers of thermogenesis and lipolysis in the mesenteric and epididymal fat of those mice fed with a high-fat diet. Additionally, the activation of these processes was derived from an increase in IL-6 production as a result of NOX5 activity. Accordingly, 3T3-L1 adipocytes treated with conditioned media of endothelial NOX5-expressing cells, presented higher expression of thermogenic and lipolytic genes. Moreover, endothelial NOX5-expressing bEnd.3 cells previously treated with glucose and palmitic acid also showed interleukin (IL-6) production. Finally, it seems that the increase in IL-6 stimulated the activation of markers of thermogenesis and lipolysis through phosphorylation of STAT3 and AMPK, respectively. In conclusion, in response to obesogenic conditions, endothelial NOX5 activity could promote thermogenesis and lipolysis in the adipose tissue by regulating IL-6 production.