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Cell May 2020Swelling of the brain or spinal cord (CNS edema) affects millions of people every year. All potential pharmacological interventions have failed in clinical trials,...
Swelling of the brain or spinal cord (CNS edema) affects millions of people every year. All potential pharmacological interventions have failed in clinical trials, meaning that symptom management is the only treatment option. The water channel protein aquaporin-4 (AQP4) is expressed in astrocytes and mediates water flux across the blood-brain and blood-spinal cord barriers. Here we show that AQP4 cell-surface abundance increases in response to hypoxia-induced cell swelling in a calmodulin-dependent manner. Calmodulin directly binds the AQP4 carboxyl terminus, causing a specific conformational change and driving AQP4 cell-surface localization. Inhibition of calmodulin in a rat spinal cord injury model with the licensed drug trifluoperazine inhibited AQP4 localization to the blood-spinal cord barrier, ablated CNS edema, and led to accelerated functional recovery compared with untreated animals. We propose that targeting the mechanism of calmodulin-mediated cell-surface localization of AQP4 is a viable strategy for development of CNS edema therapies.
Topics: Animals; Aquaporin 4; Astrocytes; Brain; Brain Edema; Calmodulin; Central Nervous System; Edema; Male; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries; Trifluoperazine
PubMed: 32413299
DOI: 10.1016/j.cell.2020.03.037 -
Current Diabetes Reports Sep 2021This review highlights indications and evidence on laser therapy in the management of diabetic retinopathy and diabetic macular edema. Particular focus is placed upon... (Review)
Review
PURPOSE OF REVIEW
This review highlights indications and evidence on laser therapy in the management of diabetic retinopathy and diabetic macular edema. Particular focus is placed upon the benefits and limitations of conventional laser photocoagulation versus more modern laser photocoagulation techniques, as well as the role of laser photocoagulation in treatment of diabetic retinopathy and diabetic macular edema with the frequent utilization of pharmacologic, including anti-vascular endothelial growth factor (VEGF), therapy.
RECENT FINDINGS
Laser photocoagulation remains the gold-standard therapy for the effective, definitive treatment of PDR, and also is highly effective in the management of DME. However, numerous recent studies have demonstrated the clinical efficacy and improved functional and anatomic outcomes of combination therapy with pharmacologic treatment. Continuing innovations in laser technology and improved understanding of laser-retinal interactions and pathophysiology demonstrate that laser therapy will continue to play a critical role in the treatment of diabetic retinopathy and diabetic macular edema for many years to come.
Topics: Angiogenesis Inhibitors; Diabetes Mellitus; Diabetic Retinopathy; Humans; Laser Coagulation; Laser Therapy; Macular Edema
PubMed: 34487257
DOI: 10.1007/s11892-021-01403-6 -
Frontiers in Cardiovascular Medicine 2022Myocarditis is an inflammatory disease of the myocardium with focal or diffuse involvement. Viral infections are the most common cause of myocarditis, especially in... (Review)
Review
Myocarditis is an inflammatory disease of the myocardium with focal or diffuse involvement. Viral infections are the most common cause of myocarditis, especially in Western countries. A recent viral illness with gastroenteric or upper respiratory symptoms often precedes myocarditis. The absence of specific pathognomonic features in conjunction with the wide spectrum of clinical manifestations that range from subclinical cases to sudden cardiac death (SCD) makes myocarditis diagnosis particularly challenging. Moreover, myocarditis might represent a cause of initially unexplained dilated cardiomyopathy (DCM) and heart failure (HF), especially among children and young adults. Cardiac magnetic resonance imaging (CMR) is crucial for myocarditis diagnosis, because of its ability to detect interstitial edema during acute inflammation. Assessment of subepicardial or mid-myocardial fibrosis by late gadolinium enhancement (LGE) is typical for myocarditis. Cardiac arrhythmias are frequent events that may arise especially in more severe myocarditis cases. The most common form of arrhythmia is atrial fibrillation, followed by ventricular tachycardia. Documented arrhythmias have been reported more commonly with HIV myocarditis than other more common infections such as Adenovirus, Parvovirus B19, human Herpes virus 6, and Enterovirus. The mechanisms of arrhythmogenesis in myocardial inflammation are not fully understood; in the acute phase, the spectrum of arrhythmogenesis ranges from a direct effect on cardiomyocytes that leads to electrical instability and ion channel impairment to ischemia from coronary macro- or microvascular disease. In chronic myocarditis, instead, myocardial replacement with fibrosis promotes scar-mediated re-entrant ventricular arrhythmias. Observational data suggested the important role of CMR, with LGE being the strongest independent predictor of SCD, cardiac, and all-cause mortality. In acute myocarditis, the most common localization of subepicardial LGE dwells in the lateral wall. Patients with myocarditis that develop HF and arrhythmias usually show a larger LGE distribution involving several myocardial segments. Moreover, a mid-layer LGE in the interventricular septum is more frequent in acute myocarditis than in acute coronary syndromes cases. The risk of SCD in patients with wide areas of LGE is significant, and a shared decision-making approach is warranted. Nevertheless, there is no formal consensus about the extension of LGE to justify implantable cardioverter defibrillator (ICD) implantation in primary prevention.
PubMed: 35795363
DOI: 10.3389/fcvm.2022.908663 -
Cells Jun 2022Diabetic macular edema (DME) is a major ocular complication of diabetes mellitus (DM), leading to significant visual impairment. DME's pathogenesis is multifactorial.... (Review)
Review
Diabetic macular edema (DME) is a major ocular complication of diabetes mellitus (DM), leading to significant visual impairment. DME's pathogenesis is multifactorial. Focal edema tends to occur when primary metabolic abnormalities lead to a persistent hyperglycemic state, causing the development of microaneurysms, often with extravascular lipoprotein in a circinate pattern around the focal leakage. On the other hand, diffusion edema is due to a generalized breakdown of the inner blood-retinal barrier, leading to profuse early leakage from the entire capillary bed of the posterior pole with the subsequent extravasation of fluid into the extracellular space. The pathogenesis of DME occurs through the interaction of multiple molecular mediators, including the overexpression of several growth factors, including vascular endothelial growth factor (VEGF), insulin-like growth factor-1, angiopoietin-1, and -2, stromal-derived factor-1, fibroblast growth factor-2, and tumor necrosis factor. Synergistically, these growth factors mediate angiogenesis, protease production, endothelial cell proliferation, and migration. Treatment for DME generally involves primary management of DM, laser photocoagulation, and pharmacotherapeutics targeting mediators, namely, the anti-VEGF pathway. The emergence of anti-VEGF therapies has resulted in significant clinical improvements compared to laser therapy alone. However, multiple factors influencing the visual outcome after anti-VEGF treatment and the presence of anti-VEGF non-responders have necessitated the development of new pharmacotherapies. In this review, we explore the pathophysiology of DME and current management strategies. In addition, we provide a comprehensive analysis of emerging therapeutic approaches to the treatment of DME.
Topics: Angiogenesis Inhibitors; Blood-Retinal Barrier; Diabetes Mellitus; Diabetic Retinopathy; Humans; Macular Edema; Vascular Endothelial Growth Factor A
PubMed: 35741079
DOI: 10.3390/cells11121950 -
ESC Heart Failure Oct 2020The presence of chronic heart failure (CHF) results in a significant risk of leg oedema. Medical compression (MC) treatment is one of the basic methods of leg oedema... (Review)
Review
The presence of chronic heart failure (CHF) results in a significant risk of leg oedema. Medical compression (MC) treatment is one of the basic methods of leg oedema elimination in patients with chronic venous disease and lymphedema, but it is not routinely considered in subjects with CHF-related swelling. In the study, an overview of the current knowledge related to the benefits and risk of using MC in the supportive treatment of leg oedema in CHF patients is presented. The available studies dedicated the comprehensive management of leg swelling using MC in CHF patients published in the English language literature till December 2019 were evaluated in term of the treatment efficacy and safety. In studies performed on CHF populations, manual lymphatic drainage, MC stocking, multilayer bandaged, as well as intermittent pneumatic compression or electric calf stimulations were used. The current evidence is based on non-randomized studies, small study cohorts, as well as very heterogenous populations. The use of the intermittent pneumatic compression in CHF patients significantly increases the right auricular pressure and mean pulmonary artery pressures as well as decreases systemic vascular resistance in most patients without the clinical worsening. The transient and rapid increase in the human atrial natriuretic peptide, after an application of the MC stocking in New York Heart Association (NYHA) class II patients was observed without clinical exacerbation. An application of the multilayer bandages in NYHA classes III and IV patients lead a significant increase in the right arterial pressure and lead to transient deterioration of the right and the left ventricular functions. In the manual lymphatic drainage study, aside from expected leg circumference reduction, no clinical worsening was observed. In a pilot study performed in a small cohort of CHF patients, electrical calf stimulation use resulted in a reduction in the lean mass of the legs without cardiac function worsening. The use of local leg compression can be considered stable CHF patients without decompensated heart function for both CHF-related oedema treatment and for treatment of the concomitant diseases leading to leg swelling occurrence. The use of MC in more severe classes of CHF (NYHA III and IV) should be the subject of future clinical studies to select the safest and most efficient compression method as well as to select the patients who benefit most from this kind of treatment.
Topics: Edema; Heart Failure; Humans; Leg; Pilot Projects; Pressure
PubMed: 32710511
DOI: 10.1002/ehf2.12848 -
International Journal of Emergency... Jul 2021A 14-year-old African American female presented to the emergency department with spontaneous, sudden-onset lip swelling for 1 h. On examination, there was significant...
A 14-year-old African American female presented to the emergency department with spontaneous, sudden-onset lip swelling for 1 h. On examination, there was significant water-bag edema of the upper lip extending to the philtrum and premaxilla. Nasopharyngeal laryngoscopy revealed a patent airway without edema. She was initiated on intravenous dexamethasone, famotidine, and diphenhydramine, after which her edema improved but did not resolve. She was subsequently transferred to a local pediatric hospital and upon further testing she was found to have a C1 esterase inhibitor de novo gene mutation. Angioedema causes localized, non-pitting edema of the dermis, subcutaneous and submucosal tissue, and often manifests in the lips, face, mouth, and throat. Signs of laryngeal involvement include change in voice, stridor, dysphagia, and dyspnea. When laryngeal edema is present, it may necessitate definitive airway management and patients should be monitored in the intensive care unit.
PubMed: 34325646
DOI: 10.1186/s12245-021-00364-7 -
The Journal of Experimental Medicine Dec 2020Perihematomal edema (PHE) occurs within hours after intracerebral hemorrhage (ICH), leading to secondary injury manifested by impaired blood-brain barrier (BBB)...
Perihematomal edema (PHE) occurs within hours after intracerebral hemorrhage (ICH), leading to secondary injury manifested by impaired blood-brain barrier (BBB) integrity and destruction of adjacent tissue. To dissect the mechanisms underlying PHE formation, we profiled human and mouse perihematomal tissues and identified natural killer (NK) cells as the predominant immune cell subset that outnumbers other infiltrating immune cell types during early stages of ICH. Unbiased clustering of single-cell transcriptional profiles revealed two major NK cell subsets that respectively possess high cytotoxicity or robust chemokine production features in the brain after ICH, distinguishing them from NK cells of the periphery. NK cells exacerbate BBB disruption and brain edema after ICH via cytotoxicity toward cerebral endothelial cells and recruitment of neutrophils that augment focal inflammation. Thus, brain-bound NK cells acquire new features that contribute to PHE formation and neurological deterioration following ICH.
Topics: Animals; Antibodies, Monoclonal; Blood-Brain Barrier; Brain; Brain Edema; Cerebral Hemorrhage; Chemokine CXCL2; Disease Models, Animal; Disease Progression; Endothelial Cells; Female; Humans; Inflammation; Killer Cells, Natural; Male; Mice, Inbred C57BL; Poly I-C; Transcriptome
PubMed: 32870258
DOI: 10.1084/jem.20200213