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Frontiers in Immunology 2020Inflammation is central to pathogenic processes in diabetes mellitus and the metabolic syndrome and particularly implicates innate immunity in the development of... (Review)
Review
Inflammation is central to pathogenic processes in diabetes mellitus and the metabolic syndrome and particularly implicates innate immunity in the development of complications. Inflammation is a primary event in Type 1 diabetes where infectious (viral) and/or autoimmune processes initiate disease; in contrast, chronic inflammation is typical in Type 2 diabetes and is considered a sequel to increasing insulin resistance and disturbed glucose metabolism. Diabetic retinopathy (DR) is perceived as a vascular and neurodegenerative disease which occurs after some years of poorly controlled diabetes. However, many of the clinical features of DR are late events and reflect the nature of the retinal architecture and its cellular composition. Retinal microvascular disease is, in fact, an early event pathogenetically, induced by low grade, persistent leukocyte activation which causes repeated episodes of capillary occlusion and, progressive, attritional retinal ischemia. The later, overt clinical signs of DR are a consequence of the retinal ischemia. Metabolic dysregulation involving both lipid and glucose metabolism may lead to leukocyte activation. On a molecular level, we have shown that macrophage-restricted protein tyrosine phosphatase 1B (PTP1B) is a key regulator of inflammation in the metabolic syndrome involving insulin resistance and it is possible that PTP1B dysregulation may underlie retinal microvascular disease. We have also shown that adherent CCR5CD11b monocyte macrophages appear to be selectively involved in retinal microvascular occlusion. In this review, we discuss the relationship between early leukocyte activation and the later features of DR, common pathogenetic processes between diabetic microvascular disease and other vascular retinopathies, the mechanisms whereby leukocyte activation is induced in hyperglycemia and dyslipidemia, the signaling mechanisms involved in diabetic microvascular disease, and possible interventions which may prevent these retinopathies. We also address a possible role for adaptive immunity in DR. Although significant improvements in treatment of DR have been made with intravitreal anti-VEGF therapy, a sizeable proportion of patients, particularly with sight-threatening macular edema, fail to respond. Alternative therapies targeting inflammatory processes may offer an advantage.
Topics: Animals; Diabetic Retinopathy; Humans; Inflammation; Leukocytes; Macrophages; Monocytes; Retina
PubMed: 33240272
DOI: 10.3389/fimmu.2020.583687 -
Neural Regeneration Research May 2023Diabetic retinopathy, characterized as a microangiopathy and neurodegenerative disease, is the leading cause of visual impairment in diabetic patients. Many clinical... (Review)
Review
Diabetic retinopathy, characterized as a microangiopathy and neurodegenerative disease, is the leading cause of visual impairment in diabetic patients. Many clinical features observed in diabetic retinopathy, such as capillary occlusion, acellular capillaries and retinal non-perfusion, aggregate retinal ischemia and represent relatively late events in diabetic retinopathy. In fact, retinal microvascular injury is an early event in diabetic retinopathy involving multiple biochemical alterations, and is manifested by changes to the retinal neurovascular unit and its cellular components. Currently, intravitreal anti-vascular endothelial growth factor therapy is the first-line treatment for diabetic macular edema, and benefits the patient by decreasing the edema and improving visual acuity. However, a significant proportion of patients respond poorly to anti-vascular endothelial growth factor treatments, indicating that factors other than vascular endothelial growth factor are involved in the pathogenesis of diabetic macular edema. Accumulating evidence confirms that low-grade inflammation plays a critical role in the pathogenesis and development of diabetic retinopathy as multiple inflammatory factors, such as interleukin-1β, monocyte chemotactic protein-1 and tumor necrosis factor -α, are increased in the vitreous and retina of diabetic retinopathy patients. These inflammatory factors, together with growth factors such as vascular endothelial growth factor, contribute to blood-retinal barrier breakdown, vascular damage and neuroinflammation, as well as pathological angiogenesis in diabetic retinopathy, complicated by diabetic macular edema and proliferative diabetic retinopathy. In addition, retinal cell types including microglia, Müller glia, astrocytes, retinal pigment epithelial cells, and others are activated, to secrete inflammatory mediators, aggravating cell apoptosis and subsequent vascular leakage. New therapies, targeting these inflammatory molecules or related signaling pathways, have the potential to inhibit retinal inflammation and prevent diabetic retinopathy progression. Here, we review the relevant literature to date, summarize the inflammatory mechanisms underlying the pathogenesis of diabetic retinopathy, and propose inflammation-based treatments for diabetic retinopathy and diabetic macular edema.
PubMed: 36254977
DOI: 10.4103/1673-5374.355743 -
Cells Oct 2020Up to 18% of patients with acute myeloid leukemia (AML) present with a white blood cell (WBC) count of greater than 100,000/µL, a condition that is frequently referred... (Review)
Review
Up to 18% of patients with acute myeloid leukemia (AML) present with a white blood cell (WBC) count of greater than 100,000/µL, a condition that is frequently referred to as hyperleukocytosis. Hyperleukocytosis has been associated with an adverse prognosis and a higher incidence of life-threatening complications such as leukostasis, disseminated intravascular coagulation (DIC), and tumor lysis syndrome (TLS). The molecular processes underlying hyperleukocytosis have not been fully elucidated yet. However, the interactions between leukemic blasts and endothelial cells leading to leukostasis and DIC as well as the processes in the bone marrow microenvironment leading to the massive entry of leukemic blasts into the peripheral blood are becoming increasingly understood. Leukemic blasts interact with endothelial cells via cell adhesion molecules such as various members of the selectin family which are upregulated via inflammatory cytokines released by leukemic blasts. Besides their role in the development of leukostasis, cell adhesion molecules have also been implicated in leukemic stem cell survival and chemotherapy resistance and can be therapeutically targeted with specific inhibitors such as plerixafor or GMI-1271 (uproleselan). However, in the absence of approved targeted therapies supportive treatment with the uric acid lowering agents allopurinol and rasburicase as well as aggressive intravenous fluid hydration for the treatment and prophylaxis of TLS, transfusion of blood products for the management of DIC, and cytoreduction with intensive chemotherapy, leukapheresis, or hydroxyurea remain the mainstay of therapy for AML patients with hyperleukocytosis.
Topics: Animals; Bone Marrow; Cell Communication; Cell Transformation, Neoplastic; Humans; Leukemia, Myeloid, Acute; Leukostasis; Molecular Targeted Therapy
PubMed: 33080779
DOI: 10.3390/cells9102310 -
Proceedings of the National Academy of... Nov 2022In ischemic retinopathy, overactivated retinal myeloid cells are a crucial driving force of pathological angiogenesis and inflammation. The cyclic GMP-AMP synthase...
In ischemic retinopathy, overactivated retinal myeloid cells are a crucial driving force of pathological angiogenesis and inflammation. The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) signaling are key regulators of inflammation. This study aims to investigate the association of cGAS-STING signaling with ischemic retinopathy and the regulation of its activation. We found that protein levels of cGAS and STING were markedly up-regulated in retinal myeloid cells isolated from mice with oxygen-induced retinopathy (OIR). Knockout of and pharmacological inhibition of STING both alleviated retinal neovascularization (NV) and reduced retinal vascular leakage in OIR. Further, knockout and STING inhibitor also alleviated leukocyte adhesion to retinal vasculature and infiltration into the retina as well as microglial activation in OIR. These results suggest that cGAS-STING signaling played a pathogenic role in retinal myeloid cell activation and NV in ischemic retinopathy. To identify the regulation of cGAS-STING signaling in OIR, we evaluated the role of transcription factor peroxisome proliferator-activated receptor α (PPARα). The results demonstrated that PPARα was down-regulated in OIR retinas, primarily in myeloid cells. Furthermore, knockout significantly up-regulated cGAS and STING levels in retinal CD11b cells, while PPARα agonist inhibited cGAS-STING signaling and cytosolic mitochondrial DNA (mtDNA) release, a causative feature for cGAS activation. Knockout of ameliorated retinal NV, hyperpermeability, and leukostasis in mice with OIR. These observations suggest that PPARα regulates cGAS-STING signaling, likely through mtDNA release, and thus, is a potential therapeutic target for ischemic retinopathy.
Topics: Animals; Mice; Disease Models, Animal; DNA, Mitochondrial; Inflammation; Ischemia; Membrane Proteins; Mice, Knockout; Neovascularization, Pathologic; Nucleotidyltransferases; PPAR alpha; Retinal Diseases
PubMed: 36409895
DOI: 10.1073/pnas.2208934119 -
Asia-Pacific Journal of Ophthalmology... 2018Fenofibrate is a safe and inexpensive orally administered fibric acid derivative conventionally used to treat dyslipidemia. Two large randomized clinical trials, the... (Review)
Review
Fenofibrate is a safe and inexpensive orally administered fibric acid derivative conventionally used to treat dyslipidemia. Two large randomized clinical trials, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies, demonstrated the benefit of oral fenofibrate in the treatment of patients with type 2 diabetes and diabetic retinopathy (DR), including reduced disease progression and need for laser treatment for diabetic macular edema and proliferative diabetic retinopathy. These findings are supported by results of experimental studies, which have demonstrated beneficial effects of fenofibrate ameliorating retinal vascular leakage and leukostasis, downregulating vascular endothelial growth factor, and reducing endothelial cell and pericyte loss, among others; all of these are characteristic features of DR. In spite of this evidence, fenofibrate is not prescribed routinely for treating patients with diabetes and DR. In FIELD and ACCORD studies, retinopathy was not the primary outcome and this may explain, at least partly, its lack of use for this indication. New trials are now underway to specifically address the effects of fenofibrate in DR; these trials will provide additional and robust data that may support current evidence favoring the use of fenofibrate in this common microvascular complication of diabetes.
Topics: Diabetes Mellitus, Type 2; Diabetic Retinopathy; Dyslipidemias; Fenofibrate; Humans; Hypolipidemic Agents; Randomized Controlled Trials as Topic
PubMed: 30058790
DOI: 10.22608/APO.2018288 -
Journal of Education & Teaching in... Apr 2020This scenario was developed to educate emergency medicine residents on the diagnosis and management of blast crisis.
AUDIENCE
This scenario was developed to educate emergency medicine residents on the diagnosis and management of blast crisis.
INTRODUCTION
Chronic myeloid leukemia (CML) makes up 15% of diagnosed adult leukemias with the median age of diagnosis being 67 years old. Chronic myeloid leukemia consists of three phases: chronic, accelerated, and blast phases. Most patients are initially diagnosed while in the chronic phase.1 Of those diagnosed in the chronic phase and being treated with a tyrosine kinase inhibitor (TKI), about 1% -1.5% of CML patients per year will subsequently transform into an advanced phase or blast crisis.2 While rare, blast crisis is considered an oncologic emergency, with increased mortality occurring primarily from subsequent infections or bleeding. Therefore, emergency physicians must be familiar with its clinical presentation and subsequent management.
EDUCATIONAL OBJECTIVES
By the end of this simulation, the participant will be able to: 1) create a thorough differential for the undifferentiated febrile, altered patient, 2) identify the signs and symptoms of blast crisis, 3) describe proper resuscitation of a patient in blast crisis, and 4) describe the indications, steps, and contraindications of performing a lumbar puncture.
EDUCATIONAL METHODS
This session was conducted using high-fidelity simulation, followed by a debriefing session and lecture on the diagnosis, differential diagnosis, and management of blast crisis. Debriefing methods may be left to the discretion of participants, but the authors have used advocacy-inquiry techniques. This scenario may also be run as an oral boards case.
RESEARCH METHODS
Our simulation center's feedback form is based on the Center of Medical Simulation's Debriefing Assessment for Simulation in Healthcare (DASH) Student Version Short Form, with the inclusion of required qualitative feedback if an element was scored less than a 6 or 7.
RESULTS
This session received all 6 or 7 scores (consistently effective/very good or extremely effective/outstanding). During the debriefing session, feedback from the residents was largely positive. They appreciated reviewing the broad differential of altered mental status and oncologic emergencies. While many groups anchored on the diagnosis of encephalitis, they also expressed that after this experience, blast crisis would be added to their differential for patients with CML.
DISCUSSION
This is a cost-effective method for reviewing blast crisis. Learners were able to identify more common causes of altered mental status in their differentials, but without further prompting, they were unable to ultimately come up with the diagnosis of blast crisis. Our main take-away is to continue reviewing oncologic emergencies as a part of our residency curriculum.
TOPICS
Medical simulation, chronic myeloid leukemia, blast crisis, leukostasis, emergency medicine, oncologic emergencies, hematologic emergencies.
PubMed: 37465412
DOI: 10.21980/J8W35K -
EJHaem May 2023
PubMed: 37206295
DOI: 10.1002/jha2.666 -
International Journal of General... 2021Hyperleukocytosis is a hematologic crisis caused by excessive proliferation of leukemic cells and has a relatively high early mortality due to a series of severe... (Review)
Review
Hyperleukocytosis is a hematologic crisis caused by excessive proliferation of leukemic cells and has a relatively high early mortality due to a series of severe complications. Therefore, prompt and effective intervention is required. Leukapheresis performed using apheresis equipment to separate leukocytes from peripheral blood, at the same time returns autologous plasma, platelets and erythrocytes to the patient, is applied clinically for the treatment of hyperleukocytosis. Leukapheresis not only removes excessive leukocytes rapidly and corrects metabolic abnormalities but also alleviates the symptoms of leukostasis. In addition, the procedure of leukapheresis is generally well tolerated. Leukapheresis has become one of the most imperative adjuvant therapies to treat hyperleukocytosis, especially in the patient who was not inappropriate to cytoreduce with Ara-C or hydroxyurea. In this review, we present the background of leukapheresis development and highlight its clinical application in hyperleukocytic leukemia patients.
PubMed: 34285568
DOI: 10.2147/IJGM.S321787 -
Cureus Jan 2023The prevalence of cancer continues to grow globally every year. With therapeutic advances over the recent decades, the prevalence of individuals living with cancer... (Review)
Review
The prevalence of cancer continues to grow globally every year. With therapeutic advances over the recent decades, the prevalence of individuals living with cancer continues to increase. Internal medicine residents can see patients admitted to the hospital for cancer-related emergencies. Early identification and appropriate management of these emergencies have been shown to improve mortality and morbidity. In this article, we aim to review the recent updates in the management of commonly encountered oncologic emergencies in the practice of internal medicine residents. This review will cover spinal cord compression, superior vena cava syndrome, tumor lysis syndrome, hypercalcemia, pericardial tamponade, hypoglycemia, hyponatremia, bowel obstruction, increased intracranial pressure, leukostasis, hyperviscosity syndrome, neutropenic fever, and hypersensitivity reactions.
PubMed: 36779153
DOI: 10.7759/cureus.33563 -
Investigative Ophthalmology & Visual... Dec 2013Hyperglycemia has toxic effects on almost all cells in the body. Ophthalmic complications of hyperglycemia are most profound in cornea and retina. Seventy percent of... (Review)
Review
Hyperglycemia has toxic effects on almost all cells in the body. Ophthalmic complications of hyperglycemia are most profound in cornea and retina. Seventy percent of diabetics suffer from corneal complications, collectively called diabetic keratopathy, which includes include recurrent erosions, delayed wound healing, ulcers, and edema. Confocal microscopy has permitted in vivo imaging of corneal nerves, which are also affected in diabetic subjects. Gene therapies upregulating MNNG HOS transforming gene (cMet) and/or downregulating MMP10 and cathepsin S are potential future therapies for diabetic keratopathy. Diabetic retinopathy (DR) is the most common cause of blindness in people over the age of 50. There is accumulating evidence that DR is an inflammatory disease. The initial events in animal models of DR are increased vascular permeability and leukostasis. This binding of leukocytes to the endothelium results from an increase in intracellular adhesion molecule-1 (ICAM-1) on the retinal capillary endothelium (EC) and expression of CD11/CD18 on the surface of the activated leukocyte. We have observed polymorphonuclear leukocytes (PMNs) at sites of EC vascular dysfunction in diabetic retinas as well as choroid. Anti-inflammatory drugs like etanercept, aspirin, or meloxicam reduce leukostasis and EC death. Future therapies may include repopulation of the acellular capillaries after EC and pericyte death with vascular progenitors made from the patient's own blood cells.
Topics: Animals; Blood Glucose; Diabetes Complications; Disease Management; Eye Diseases; Global Health; Humans; Incidence; Insulin Resistance
PubMed: 24335073
DOI: 10.1167/iovs.13-12979