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Indian Journal of Nephrology 2019Atheroembolic renal disease (AERD), a part of systemic cholesterol embolization syndrome, is caused by the occlusion of small arteries in the kidneys by cholesterol...
Atheroembolic renal disease (AERD), a part of systemic cholesterol embolization syndrome, is caused by the occlusion of small arteries in the kidneys by cholesterol crystal emboli from ulcerated atherosclerotic plaques. Kidney is commonly involved because of its proximity to the abdominal aorta and its enormous blood supply. AERD is an under diagnosed condition. We report eight cases of AERD, highlighting the variability in its clinical presentation and the importance of a renal biopsy to arrive at a definitive diagnosis.
PubMed: 31798227
DOI: 10.4103/ijn.IJN_265_18 -
Journal of Nuclear Medicine : Official... Sep 2019Thin-cap fibroatheroma (TCFA) are the unstable lesions in coronary artery disease that are prone to rupture, resulting in substantial morbidity and mortality worldwide....
Thin-cap fibroatheroma (TCFA) are the unstable lesions in coronary artery disease that are prone to rupture, resulting in substantial morbidity and mortality worldwide. However, their small size and complex morphologic and biologic features make early detection and risk assessment difficult. We tested our newly developed catheter-based ircumferential-ntravascular-adioluminescence-hotoacoustic-maging (CIRPI) system in vivo to enable detection and characterization of vulnerable plaque structure and biology in rabbit abdominal aorta. The CIRPI system includes a novel optical probe combining circumferential radioluminescence imaging and photoacoustic tomography (PAT). The probe's CaF:Eu-based scintillating imaging window captures radioluminescence images (360° view) of plaques by detecting β-particles during F-FDG decay. A tunable laser-based PAT characterizes tissue constituents of plaque at 7 different wavelengths-540 and 560 nm (calcification), 920 nm (cholesteryl ester), 1040 nm (phospholipids), 1180 nm (elastin/collagen), 1210 nm (cholesterol), and 1235 nm (triglyceride). A single B-scan is concatenated from 330 A-lines captured during a 360° rotation. The abdominal aorta was imaged in vivo in both atherosclerotic rabbits (Watanabe Heritable Hyper Lipidemic [WHHL], 13-mo-old male, = 5) and controls (New Zealand White, = 2). Rabbits were fasted for 6 h before 5.55 × 10 Bq (1.5 mCi) of F-FDG were injected 1 h before the imaging procedure. Rabbits were anesthetized, and the right or left common carotid artery was surgically exposed. An 8 French catheter sheath was inserted into the common carotid artery, and a 0.035-cm (0.014-in) guidewire was advanced to the iliac artery, guided by x-ray fluoroscopy. A bare metal stent was implanted in the dorsal abdominal aorta as a landmark, followed by the 7 French imaging catheters that were advanced up to the proximal stent edge. Our CIRPI and clinical optical coherence tomography (OCT) were performed using pullback and nonocclusive flushing techniques. After imaging with the CIRPI system, the descending aorta was flushed with contrast agent, and OCT images were obtained with a pullback speed of 20 mm/s, providing images at 100 frames/s. Results were verified with histochemical analysis. Our CIRPI system successfully detected the locations and characterized both stable and vulnerable aortic plaques in vivo among all WHHL rabbits. Calcification was detected from the stable plaque (540 and 560 nm), whereas TCFA exhibited phospholipids/cholesterol (1040 nm, 1210 nm). These findings were further verified with the clinical OCT system showing an area of low attenuation filled with lipids within TCFA. PAT images illustrated broken elastic fiber/collagen that could be verified with the histochemical analysis. All WHHL rabbits exhibited sparse to severe macrophages. Only 4 rabbits showed both moderate-to-severe level of calcifications and cholesterol clefts. However, all rabbits exhibited broken elastic fibers and collagen deposition. Control rabbits showed normal wall thickness with no presence of plaque tissue compositions. These findings were verified with OCT and histochemical analysis. Our novel multimodality hybrid system has been successfully translated to in vivo evaluation of atherosclerotic plaque structure and biology in a preclinical rabbit model. This system proposed a paradigm shift that unites molecular and pathologic imaging technologies. Therefore, the system may enhance the clinical evaluation of TCFA, as well as expand our understanding of coronary artery disease.
Topics: Animals; Aorta, Abdominal; Calcinosis; Carotid Arteries; Catheters; Cholesterol; Coronary Artery Disease; Coronary Vessels; Endoscopy; Image Processing, Computer-Assisted; Luminescence; Male; Multimodal Imaging; Pathology, Molecular; Photoacoustic Techniques; Plaque, Atherosclerotic; Rabbits; Refractometry; Tomography
PubMed: 30737298
DOI: 10.2967/jnumed.118.222471 -
Human Mutation Feb 2013Schnyder corneal dystrophy (SCD) is an autosomal dominant disease characterized by germline variants in UBIAD1 introducing missense alterations leading to deposition of...
Schnyder corneal dystrophy (SCD) is an autosomal dominant disease characterized by germline variants in UBIAD1 introducing missense alterations leading to deposition of cholesterol in the cornea, progressive opacification, and loss of visual acuity. UBIAD1 was recently shown to synthesize menaquinone-4 (MK-4, vitamin K(2) ), but causal mechanisms of SCD are unknown. We report a novel c.864G>A UBIAD1 mutation altering glycine 177 to glutamic acid (p.G177E) in six SCD families, including four families from Finland who share a likely founder mutation. We observed reduced MK-4 synthesis by UBIAD1 altered by SCD mutations p.N102S, p.G177R/E, and p.D112N, and molecular models showed p.G177-mutant UBIAD1 disrupted transmembrane helices and active site residues. We show UBIAD1 interacts with HMGCR and SOAT1, enzymes catalyzing cholesterol synthesis and storage, respectively, using yeast two-hybrid screening and immunoprecipitation. Docking simulations indicate cholesterol binds to UBIAD1 in the substrate-binding cleft and substrate-binding overlaps with GGPP binding, an MK-4 substrate, suggesting potential competition between these metabolites. Impaired MK-4 synthesis is a biochemical defect identified in SCD suggesting UBIAD1 links vitamin K and cholesterol metabolism through physical contact between enzymes and metabolites. Our data suggest a role for endogenous MK-4 in maintaining cornea health and visual acuity.
Topics: Aged; Aged, 80 and over; Amino Acid Sequence; Cholesterol; Cornea; Corneal Dystrophies, Hereditary; Dimethylallyltranstransferase; Female; Finland; Genetic Variation; Glutamic Acid; Glycine; Humans; Hydroxymethylglutaryl CoA Reductases; Immunoprecipitation; Japan; Lipid Metabolism; Male; Middle Aged; Models, Molecular; Molecular Sequence Data; Mutation, Missense; Pedigree; Protein Conformation; Sequence Analysis, DNA; Sterol O-Acyltransferase; Turkey; Vitamin K 2
PubMed: 23169578
DOI: 10.1002/humu.22230 -
EBioMedicine Oct 2020During atherogenesis, cholesterol precipitates into cholesterol crystals (CC) in the vessel wall, which trigger plaque inflammation by activating the NACHT, LRR and PYD...
BACKGROUND
During atherogenesis, cholesterol precipitates into cholesterol crystals (CC) in the vessel wall, which trigger plaque inflammation by activating the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome. We investigated the relationship between CC, complement and NLRP3 in patients with cardiovascular disease.
METHODS
We analysed plasma, peripheral blood mononuclear cells (PBMC) and carotid plaques from patients with advanced atherosclerosis applying ELISAs, multiplex cytokine assay, qPCR, immunohistochemistry, and gene profiling.
FINDINGS
Transcripts of interleukin (IL)-1beta(β) and NLRP3 were increased and correlated in PBMC from patients with acute coronary syndrome (ACS). Priming of these cells with complement factor 5a (C5a) and tumour necrosis factor (TNF) before incubation with CC resulted in increased IL-1β protein when compared to healthy controls. As opposed to healthy controls, systemic complement was significantly increased in patients with stable angina pectoris or ACS. In carotid plaques, complement C1q and C5b-9 complex accumulated around CC-clefts, and complement receptors C5aR1, C5aR2 and C3aR1 were higher in carotid plaques compared to control arteries. Priming human carotid plaques with C5a followed by CC incubation resulted in pronounced release of IL-1β, IL-18 and IL-1α. Additionally, mRNA profiling demonstrated that C5a and TNF priming followed by CC incubation upregulated plaque expression of NLRP3 inflammasome components.
INTERPRETATION
We demonstrate that CC are important local- and systemic complement activators, and we reveal that the interaction between CC and complement could exert its effect by activating the NLRP3 inflammasome, thus promoting the progression of atherosclerosis.
Topics: Carotid Artery Diseases; Cholesterol; Complement C5a; Complement System Proteins; Computational Biology; Coronary Artery Disease; Cytokines; Disease Susceptibility; Gene Expression Profiling; Humans; Inflammasomes; Inflammation Mediators; Leukocytes, Mononuclear; Liquid Crystals; NLR Family, Pyrin Domain-Containing 3 Protein; Plaque, Atherosclerotic; Signal Transduction
PubMed: 32927275
DOI: 10.1016/j.ebiom.2020.102985 -
Proceedings of the National Academy of... Mar 2015Atherosclerosis, the build-up of occlusive, lipid-rich plaques in arterial walls, is a focal trigger of chronic coronary, intracranial, and peripheral arterial diseases,...
Atherosclerosis, the build-up of occlusive, lipid-rich plaques in arterial walls, is a focal trigger of chronic coronary, intracranial, and peripheral arterial diseases, which together account for the leading causes of death worldwide. Although the directed treatment of atherosclerotic plaques remains elusive, macrophages are a natural target for new interventions because they are recruited to lipid-rich lesions, actively internalize modified lipids, and convert to foam cells with diseased phenotypes. In this work, we present a nanomedicine platform to counteract plaque development based on two building blocks: first, at the single macrophage level, sugar-based amphiphilic macromolecules (AMs) were designed to competitively block oxidized lipid uptake via scavenger receptors on macrophages; second, for sustained lesion-level intervention, AMs were fabricated into serum-stable core/shell nanoparticles (NPs) to rapidly associate with plaques and inhibit disease progression in vivo. An AM library was designed and fabricated into NP compositions that showed high binding and down-regulation of both MSR1 and CD36 scavenger receptors, yielding minimal accumulation of oxidized lipids. When intravenously administered to a mouse model of cardiovascular disease, these AM NPs showed a pronounced increase in lesion association compared with the control nanoparticles, causing a significant reduction in neointimal hyperplasia, lipid burden, cholesterol clefts, and overall plaque occlusion. Thus, synthetic macromolecules configured as NPs are not only effectively mobilized to lipid-rich lesions but can also be deployed to counteract atheroinflammatory vascular diseases, highlighting the promise of nanomedicines for hyperlipidemic and metabolic syndromes.
Topics: Animals; Atherosclerosis; CD36 Antigens; Carbohydrates; Humans; Hyperplasia; Lipids; Macrophages; Mice; Mice, Knockout; Nanoparticles; Neointima; Oxidation-Reduction; Plaque, Atherosclerotic; Scavenger Receptors, Class A
PubMed: 25691739
DOI: 10.1073/pnas.1424594112 -
Nature Communications Nov 2019Killer T cells (cytotoxic T lymphocytes, CTLs) maintain immune homoeostasis by eliminating virus-infected and cancerous cells. CTLs achieve this by forming an...
Killer T cells (cytotoxic T lymphocytes, CTLs) maintain immune homoeostasis by eliminating virus-infected and cancerous cells. CTLs achieve this by forming an immunological synapse with their targets and secreting a pore-forming protein (perforin) and pro-apoptotic serine proteases (granzymes) into the synaptic cleft. Although the CTL and the target cell are both exposed to perforin within the synapse, only the target cell membrane is disrupted, while the CTL is invariably spared. How CTLs escape unscathed remains a mystery. Here, we report that CTLs achieve this via two protective properties of their plasma membrane within the synapse: high lipid order repels perforin and, in addition, exposed phosphatidylserine sequesters and inactivates perforin. The resulting resistance of CTLs to perforin explains their ability to kill target cells in rapid succession and to survive these encounters. Furthermore, these mechanisms imply an unsuspected role for plasma membrane organization in protecting cells from immune attack.
Topics: Animals; CD8-Positive T-Lymphocytes; Cell Death; Cell Line; Cell Membrane; Cholesterol; Membrane Lipids; Mice, Transgenic; Natural Killer T-Cells; Perforin; Phosphatidylserines; T-Lymphocytes, Cytotoxic
PubMed: 31776337
DOI: 10.1038/s41467-019-13385-x -
The Journal of Medical Investigation :... 2023Epidermoid cysts in intrapancreatic accessory spleen (ECIPAS) are a rare lesion. Its pathogenesis, including the origin of cystic epithelium, is not well established. We...
BACKGROUND
Epidermoid cysts in intrapancreatic accessory spleen (ECIPAS) are a rare lesion. Its pathogenesis, including the origin of cystic epithelium, is not well established. We aimed to elucidate new aspects of the pathological features of ECIPAS to clarify its pathogenesis.
METHODS
Six cases of ECIPAS were included in this study. As well as histopathological analysis, to elucidate the features and nature of cystic epithelial cells, immunohistochemical analysis including Pbx1 and Tlx1 and imaging mass spectrometry was performed.
RESULTS
Histologically, the cysts were covered by either monolayered or multilayered epithelium. Immunohistochemistry revealed that the epithelial cells in multilayered epithelium exhibited different attributes between the basal and superficial layers. Few epithelial cells had abundant clear cytoplasm and were immunohistochemically positive for adipophilin, suggesting lipid-excreting function. The intracystic fluid contained cholesterol clefts and foamy macrophages, and imaging mass spectrometry revealed the accumulation of lipids. Immunohistochemical analysis indicated that the epithelial cells were positive for Pbx1 in some cases.
CONCLUSION
Novel histological features of epithelial cells of ECIPAS were indicated. Although more cases need to be evaluated, we propose that the cause of ECIPAS may be different from that of pancreatic ductal origin. J. Med. Invest. 70 : 251-259, February, 2023.
Topics: Humans; Epidermal Cyst; Spleen; Pancreatic Diseases; Epithelial Cells; Immunohistochemistry
PubMed: 37164730
DOI: 10.2152/jmi.70.251 -
EuroIntervention : Journal of EuroPCR... Aug 2020The aim of this study was to determine the ability of optical frequency domain imaging (OFDI)/optical coherence tomography (OCT) imaging systems to visualise the...
AIMS
The aim of this study was to determine the ability of optical frequency domain imaging (OFDI)/optical coherence tomography (OCT) imaging systems to visualise the presence of cholesterol crystals (CCR) in human atherosclerotic coronary arteries.
METHODS AND RESULTS
We performed ex vivo imaging of human coronary arteries by OFDI/OCT. A total of 559 cross-sectional images from 45 autopsy cases were co-registered with histology; 117 histologic sections showed presence of necrotic core with cholesterol clefts (CC). We modified a previously used OFDI/OCT definition for identification of CCRs which we now define as a linear and discrete high-intensity signal (bright area) within the plaque with sharp borders between it and adjacent low-/intermediate-intensity tissue. Additionally, the high-intensity signal is not a spot but a well-defined area distinguishing it from macrophages which lack sharp borders. OFDI/OCT imaging identified the presence of CCR in 30 of the 117 histologic sections. The sensitivity and specificity of OFDI/OCT for detection of CCR was 25.6% and 100.0%, respectively. By multivariate analysis, significant predictors to visualise CCR by OCT/OFDI were 1) an overlying fibrous plaque, and 2) the presence of stacked CC, defined as CC arranged one on top of another with >3 layers of CC. The prevalence of complicated plaques (i.e., plaque haemorrhage and late necrotic core) was significantly higher in detectable CCR by OFDI/OCT as compared to undetectable CCR.
CONCLUSIONS
The presence of stacked CCs is required to detect CCR by OFDI/OCT. Detection of CCR by OCT/OFDI may help us to identify the late stages of atherosclerotic coronary plaque progression and improve risk stratification.
Topics: Cholesterol; Coronary Artery Disease; Coronary Vessels; Cross-Sectional Studies; Humans; Plaque, Atherosclerotic; Tomography, Optical Coherence
PubMed: 32310132
DOI: 10.4244/EIJ-D-20-00202 -
Molecular and Clinical Oncology Mar 2018Xanthogranuloma, also referred to as cholesterol granuloma or xanthogranulomatous reaction, is a granulomatous lesion that is infrequently found in the sellar and...
Xanthogranuloma, also referred to as cholesterol granuloma or xanthogranulomatous reaction, is a granulomatous lesion that is infrequently found in the sellar and parasellar regions. Xanthogranulomatous pituitary adenoma is relatively rare and, thus, the etiology, diagnosis, management and prognosis of this condition remain incompletely understood. We herein report the case of a 56-year-old female patient who presented to our institution with intermittent headache, vomiting and distending pain in the bilateral orbital regions. Brain magnetic resonance imaging revealed a sellar mass with a heterogeneous signal. The mass was subtotally resected, and histopathological examination confirmed the diagnosis of xanthogranulomatous pituitary adenoma. Although the patient's symptoms were relieved following surgical treatment, intractable hyponatremia and diabetes insipidus developed and she received hormone replacement therapy. At the last follow-up (November 2016), the patient remained recurrence-free. A total of 14 cases of pituitary adenoma with concomitant xanthogranuloma were identified in the literature, and the clinical and radiological manifestations are discussed. Sellar xanthogranuloma is usually associated with craniopharyngioma or Rathke's cleft cyst; however, it may also occur in isolation. Xanthogranulomatous pituitary adenomas are infrequent, making their diagnosis challenging. Surgical resection is the preferred treatment, and attention should be paid to postoperative hypopituitarism and development of diabetes insipidus.
PubMed: 29456852
DOI: 10.3892/mco.2018.1547 -
The New England Journal of Medicine Dec 2003Intraplaque hemorrhage is common in advanced coronary atherosclerotic lesions. The relation between hemorrhage and the vulnerability of plaque to disruption may involve...
BACKGROUND
Intraplaque hemorrhage is common in advanced coronary atherosclerotic lesions. The relation between hemorrhage and the vulnerability of plaque to disruption may involve the accumulation of free cholesterol from erythrocyte membranes.
METHODS
We stained multiple coronary lesions from 24 randomly selected patients who had died suddenly of coronary causes with an antibody against glycophorin A (a protein specific to erythrocytes that facilitates anion exchange) and Mallory's stain for iron (hemosiderin), markers of previous intraplaque hemorrhage. Coronary lesions were classified as lesions with pathologic intimal thickening, fibrous-cap atheromas with cores in an early or late stage of necrosis, or thin-cap fibrous atheromas (vulnerable plaques). The arterial response to plaque hemorrhage was further defined in a rabbit model of atherosclerosis.
RESULTS
Only traces of glycophorin A and iron were found in lesions with pathologic intimal thickening or fibrous-cap atheromas with cores in an early stage of necrosis. In contrast, fibroatheromas with cores in a late stage of necrosis or thin caps had a marked increase in glycophorin A in regions of cholesterol clefts surrounded by iron deposits. Larger amounts of both glycophorin A and iron were associated with larger necrotic cores and greater macrophage infiltration. Rabbit lesions with induced intramural hemorrhage consistently showed cholesterol crystals with erythrocyte fragments, foam cells, and iron deposits. In contrast, control lesions from the same animals had a marked reduction in macrophages and lipid content.
CONCLUSIONS
By contributing to the deposition of free cholesterol, macrophage infiltration, and enlargement of the necrotic core, the accumulation of erythrocyte membranes within an atherosclerotic plaque may represent a potent atherogenic stimulus. These factors may increase the risk of plaque destabilization.
Topics: Animals; Antibodies; Cholesterol; Coronary Artery Disease; Coronary Vessels; Disease Models, Animal; Disease Progression; Erythrocyte Membrane; Glycophorins; Hemorrhage; Hemosiderin; Humans; Macrophages; Rabbits; Rupture, Spontaneous
PubMed: 14668457
DOI: 10.1056/NEJMoa035655