Accumulation Of Lipid-laden Macrophages Research Articles

Xanthogranulomatous pyelonephritis: A focus on histopathological findings

ABSTRACT Xanthogranulomatous pyelonephritis (XGP) is a rare chronic renal condition with an incidence rate of 0.6 to 1%, characterized by the accumulation of lipid-laden macrophages, known as Xanthoma cells, in the renal parenchyma. This often leads to renal tissue destruction. The aim of this study is to present a case of XGP in a right non-functional kidney. A 50-year-old male patient underwent right nephrectomy, and the specimen received measured 12 × 9 × 7.6 cm, showing bosselation and hemorrhage on the outer surface. The tissue was processed and stained with H and E. Histopathological examination revealed the replacement of renal parenchyma by sheets of foamy histiocytes and dense mononuclear chronic inflammatory infiltrates. Large areas of focal glomerular sclerosis and dilated, congested tubules with necrosis were observed, confirming the diagnosis of XGP. In conclusion, XGP in its focal form is a rare benign kidney disease, usually diagnosed histologically after surgical treatment. The management approach typically involves conservative treatment, including partial or total nephrectomy.

A Systematic Review and Meta-Analysis on the Role of Bempedoic Acid in Cardiovascular Outcomes for Patients With Statin Intolerance.

Atherosclerosis, a multifaceted pathogenic process affecting the arteries and aorta, poses a significant threat because of its potential to impede or entirely obstruct blood flow by narrowing blood vessels. This intricate progression involves various factors such as dyslipidemia, immunological responses, inflammation, and endothelial dysfunction. The initial phase manifests as the formation of fatty streaks, considered a pivotal hallmark in the inception of atherosclerotic plaques, a process that can commence as early as childhood. Over time, this process evolves, characterized by the thickening of the arterial inner layer (intima) and accumulation of lipid-laden macrophages, commonly known as foam cells, along with the buildup of the extracellular matrix. Subsequent stages witness the proliferation and aggregation of smooth muscle cells, culminating in the formation of atheroma plaques. As these lesions progress, apoptosis can occur in the deeper layers, further recruiting macrophages, which may undergo calcification and transform into atherosclerotic plaques. Notably, mechanisms such as arterial remodeling and intraplaque hemorrhage also contribute significantly to the progression of atherosclerotic cardiovascular disease, although these facets fall beyond the scope of this article. This study aimed to systematically review and conduct a meta-analysis of randomized controlled trials investigating the efficacy and safety of bempedoic acid in statin-intolerant patients with hyperlipidemia and to provide conclusions and recommendations accordingly. A systematic search of databases, such as PubMed, Web of Science, and Embase, will be performed. Only randomized trials will be included comparing bempedoic acid with placebo in statin-intolerant patients. This study aimed to provide a comprehensive understanding of the role of bempedoic acid in managing hyperlipidemia in statin-intolerant patients. In primary prevention, for patients unable to tolerate recommended statins, bempedoic acid was associated with a significant reduction in major adverse cardiovascular events (MACE) as the primary endpoint.

Unusual effects of PCSK9 E670G (rs505151) variation in patients with in-stent restenosis: Variable effects on restenosis risk according to concomitant chronic conditions

Recent reports showing that neo-atherosclerosis formation in stented coronary artery is characterized by the accumulation of lipid-laden macrophages within the neointima has strengthened the possibility that elevated low-density lipoprotein (LDL)-cholesterol may be a risk factor for in-stent restenosis (ISR). Protein Convertase Subtilisin/Kexin-9 (PCSK9) protein plays an important role in cholesterol metabolism by degrading of LDL receptors. The gain-of-function E670G (rs505151) mutation of the PCSK9 gene is a well-known genetic risk factor for hypercholesterolemia. This study evaluated for the first time the association of the E670G variation with the serum lipids, PCSK9 levels and concomitant diseases on the ISR risk. The study included 109 ISR, and 82 Non-ISR patients, based on the results of coronary angiography. Genotypes were determined using the real-time PCR and serum PCSK9 levels were measured by ELISA technique. The rare G allele of PCSK9 E670G (p < 0.05), hyperlipidemia (HL) (p < 0.001), and type 2 diabetes (T2DM) (p < 0.01) were associated with increased risk for ISR. In hyperlipidemic conditions, the E670G-G allele was associated with hypercholesterolemia and a higher risk of ISR (p < 0.001), while the E670G-AA genotype has been associated with a high prevalence of T2DM and hypertension. In addition, diabetic ISRs had higher serum PCSK9 levels (p < 0.05) and the E670G-AA genotype was associated with increased levels of diabetes markers. Our results indicated that the unusual effects of both G allele and AA genotype of the PCSK9 E670G variation may be involved in the risk of ISR in association with concomitant metabolic diseases.

Secondary vs. primary pituitary xanthogranulomas: which yellow is more mellow?

Pituitary xanthogranulomatomas (XG) are a rare pathological entity caused by accumulation of lipid laden macrophages and reactive granuloma formation usually triggered by cystic fluid leakage or hemorrhage. Our aim was to compare clinical characteristics and presenting features of patients with secondary etiology of XG and those with no identifiable founding lesion (primary -"pure" XG) in order to gain new insights into this rare pituitary pathology. In a retrospective review of 714 patients operated for sellar masses, at tertiary center, we identified 16 (2.24%) with histologically confirmed diagnosis of pituitary XG over the period of 7 years (2015-2021). Patients were further analyzed according to XG etiology: "pure"- XG (n = 8) with no identifiable founding lesion were compared to those with histological elements of pituitary tumor or cyst - secondary XG (n = 8). We identified 16 patients (11 male), mean age 44.8 ± 22.3 years, diagnosed with pituitary XG. Secondary forms were associated with Ratke's cleft cyst (RCC, n = 2) and pituitary adenoma (PA, n = 6). The most common presenting features in both groups were hypopituitarism (75%), headache (68.5%) and visual disturbances (37.5%). Predominance of male sex was noted (males 68.75%, females 31.25%), especially in patients with primary forms. Patients with primary pituitary XG were all males (p = 0.0256) and more frequently affected by panhypopituitarism (87.5% vs. 25%, p = 0.0406) compared to patients with secondary causes. Hyperprolactinemia was noted in pituitary tumor group with secondary etiology only (p = 0.0769). Majority of lesions were solid on magnetic resonance imaging - MRI (81.25%). Distinct clinical phenotype was observed dependent on the etiology of XG.

Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation

Accumulation of lipid-laden macrophages within the arterial neointima is a critical step in atherosclerotic plaque formation. Here, we show that reduced levels of the cellular plasticity factor ZEB1 in macrophages increase atherosclerotic plaque formation and the chance of cardiovascular events. Compared to control counterparts (Zeb1WT/ApoeKO), male mice with Zeb1 ablation in their myeloid cells (Zeb1∆M/ApoeKO) have larger atherosclerotic plaques and higher lipid accumulation in their macrophages due to delayed lipid traffic and deficient cholesterol efflux. Zeb1∆M/ApoeKO mice display more pronounced systemic metabolic alterations than Zeb1WT/ApoeKO mice, with higher serum levels of low-density lipoproteins and inflammatory cytokines and larger ectopic fat deposits. Higher lipid accumulation in Zeb1∆M macrophages is reverted by the exogenous expression of Zeb1 through macrophage-targeted nanoparticles. In vivo administration of these nanoparticles reduces atherosclerotic plaque formation in Zeb1∆M/ApoeKO mice. Finally, low ZEB1 expression in human endarterectomies is associated with plaque rupture and cardiovascular events. These results set ZEB1 in macrophages as a potential target in the treatment of atherosclerosis.

THU468 Finding An Effective Treatment For Osteoporosis In Gaucher Disease

Abstract Disclosure: C. Lesniak: None. M.S. Akula: None. Background: Gaucher disease is a rare autosomal recessive disorder, leading to a deficiency of the enzyme glucocerebrosidase and accumulation of lipid-laden macrophages and dysfunction of multiple organs. The skeletal system is commonly affected resulting in reduced bone mineral density (BMD), marrow infiltration and bone infarction. Enzyme replacement therapy (ERT) has been a mainstay of treatment, and bisphosphonate therapy has been used to help treat osteoporosis, but newer agents are not well studied in this population. Case Description: The patient is a 62 year old female with a history of Gaucher disease Type 1 (GD1) and osteoporosis, treated with alendronate. She was diagnosed with GD1 in childhood and treated with glucocerebrosidase as ERT. She was diagnosed with osteoporosis in 2018 and started on bisphosphonates after a DXA scan showed a T-score at the lumbar spine of −3.2 and -1.4 at the left hip. She denied bone or back pain and has no history of any osteolytic lesions or osteonecrosis. Workup for secondary causes of osteoporosis was negative. She was taking alendronate 70 mg weekly, calcium 1800 mg daily, and vitamin D 4000 IU daily. Labs showed calcium 9.1 mg/dL, TSH 1.530 uIU/mL, PTH 34 pg/mL, and 25-hydroxy vitamin D 38.7 ng/mL. Repeat DXA scan showed worsening osteoporosis with a T-score at the lumbar spine of −3.4 and left hip of −2.5. As her BMD worsened while on alendronate for 3 years, teriparatide was offered as an alternative treatment. Discussion: Gaucher disease is a rare lysosomal storage disorder affecting multiple organs. Up to 90% of patients with GD1 have bone involvement of some kind. DXA scan should be done soon after diagnosis. Reduced BMD in GD1 is common and is associated with increased fracture risk. ERT has been the main management option to treat bone manifestations with improvement in BMD shown after 3-5 years. After 8 years of treatment with ERT, patients have been shown to reach the BMD of the age and sex matched population. In addition to ERT, calcium and vitamin D3 are recommended to increase BMD. There is no standard of treatment for osteoporosis in Gaucher patients, although bisphosphonates have been shown to improve BMD. Had our patient had early DXA scans, treatment may have been initiated sooner. A single case report showed improvement in BMD with the use of teriparatide after bisphosphonate failure. The efficacy of alternative agents, such as teriparatide and romosumab, in treating osteoporosis in patients with Gaucher disease needs to be further investigated. Presentation: Thursday, June 15, 2023

Xanthogranulomatous Cholecystitis Mimicking Gall Bladder Cancer: a Diagnostic Dilemma and Review of Literature.

Xanthogranulomatous cholecystitis (XGC) is one of the rare variants of chronic cholecystitis which is characterized by inflammation of gall bladder along with infiltration by acute and chronic inflammatory cells. Intramural accumulation of lipid laden macrophages in GB wall is the hallmark of the disease. XGC results in dense adhesion of gall bladder (GB) to surrounding structures, like duodenum, colon, and stomach. The intense GB inflammation results in gall bladder perforation and development of fistulous communication between gall bladder and surrounding structures. This may also lead to formation of inflammatory mass which closely mimic gall bladder malignancy. Often differentiation from carcinoma of GB (Ca GB) on the basis of clinical presentation and even on intra-operative and radiological findings is difficult, and the issue could only be resolved on final Histopathology (HPE). We review presentation and investigation of a patient, discuss our approach in managing dilemma in treating such cases of XGC, and review the literature.

Cardiorespiratory and Immunologic Effects of Electronic Cigarettes.

Purpose of ReviewAlthough e-cigarettes have become popular, especially among youth, the health effects associated with e-cigarette use remain unclear. This review discusses current evidence relating to the cardiovascular, pulmonary, and immunological effects of e-cigarettes.Recent FindingsThe use of e-cigarettes by healthy adults has been shown to increase blood pressure, heart rate, and arterial stiffness, as well as resistance to air flow in lungs. Inhalation of e-cigarette aerosol has been shown to elicit immune responses and increase the production of immunomodulatory cytokines in young tobacco-naïve individuals. In animal models, long-term exposure to e-cigarettes leads to marked changes in lung architecture, dysregulation of immune genes, and low-grade inflammation. Exposure to e-cigarette aerosols in mice has been shown to induce DNA damage, inhibit DNA repair, and promote carcinogenesis. Chronic exposure to e-cigarettes has also been reported to result in the accumulation of lipid-laden macrophages in the lung and dysregulation of lipid metabolism and transport in mice. Although, the genotoxic and inflammatory effects of e-cigarettes are milder than those of combustible cigarettes, some of the cardiorespiratory effects of the two insults are comparable. The toxicity of e-cigarettes has been variably linked to nicotine, as well as other e-cigarette constituents, operating conditions, and use patterns.SummaryThe use of e-cigarettes in humans is associated with significant adverse cardiorespiratory and immunological changes. Data from animal models and in vitro studies support the notion that long-term use of e-cigarettes may pose significant health risks.

LncRNA-modulated autophagy in plaque cells: a new paradigm of gene regulation in atherosclerosis?

The development of atherosclerosis is accompanied by the functional deterioration of plaque cells, which leads to the escalation of endothelial inflammation, abnormal vascular smooth muscle cell phenotype switching and the accumulation of lipid-laden macrophages within vascular walls. Autophagy, a highly conserved homeostatic mechanism, is critical for the delivery of cytoplasmic substrates to lysosomes for degradation. Moderate levels of autophagy prevent atherosclerosis by safeguarding plaque cells against apoptosis, preventing inflammation, and limiting the lipid burden, whereas excessive autophagy exacerbates cell damage and inflammation and thereby accelerates the formation of atherosclerotic plaques. Increasing lines of evidence suggest that long noncoding RNAs can be either beneficial or detrimental to atherosclerosis development by regulating the autophagy level. This review summarizes the research progress related to 1) the significant role of autophagy in atherosclerosis and 2) the effects of the lncRNA-mediated modulation of autophagy on the plaque cell fate, inflammation levels, proliferative capacity, and cholesterol metabolism and subsequently on atherogenesis.

Cardiovascular Protection Mediated by the Chemokine CXCL5

One out of every four deaths in the United States can be attributed to heart disease. Atherosclerosis is a prevalent form of cardiovascular disease that describes the narrowing of arteries, leading to the restriction of blood flow. Atherosclerosis is caused in part by the accumulation of lipid‐laden macrophages (foam cells) in the walls of arteries. Determining mechanisms that influence lipid metabolism in macrophages may uncover new approaches to modify the disease process and decrease the disease burden. Recently, our lab identified a genetic link between the expression of the chemokine CXCL5 and atherosclerosis in patients that is consistent with a cardioprotective role for CXCL5. One effect of CXCL5 appears to be in the regulation of reverse cholesterol transporters. We found that exposure to CXCL5 decreases foam cell forming macrophages, suggesting CXCL5 may directly impact lipid metabolism. What is not known is how CXCL5 modifies the pathophysiological response to conditions that contribute to atherosclerosis, such as a high fat diet (HFD). We hypothesized that CXCL5 mediates cardioprotection by altering the physiological response to a HFD, such that, lower levels of CXCL5 will lead to altered lipid handling and predisposition to more severe atherosclerosis. We challenged wild‐type (WT) and CXCL5−/− mice with either a HFD (0.2% cholesterol, 42% calories from fat, N = 17 per genotype), or normal chow (NC, 0% cholesterol, 16% calories from fat, N = 15 per genotype) for 16 w. To determine the effect of the diet on circulating lipid levels, we performed blood lipid analysis after the feeding regimen. Interestingly, HFD did not increase cholesterol levels to the same extent in CXCL5−/− mice as compared to WT mice. Specifically, we found that WT mice had a robust, diet‐dependent increase in both high‐density lipoprotein and low‐density lipoprotein levels (LDL: 59.6 mg/dl vs 11.3 mg/dl and HDL: 118.7 mg/dl vs 68.1 mg/dl in HFD vs NC, respectively), whereas in CXCL5−/− mice, this response was diminished (LDL: 20.6 mg/dl vs 8.8 mg/dl and HDL: 82.6 mg/dl vs 56.8 mg/dl in HFD vs NC, respectively). These results suggest that the genetic depletion of CXCL5 alters lipid handling in vivo. Additionally, white blood cell analysis identified that WT mice responded to the HFD with an increase in the number of lymphocytes (10.3e3 cells/μl vs 5.2e3 cells/μl in HFD WT vs NC WT, p = 0.0224) and basophils (20 cells/μl vs 4.0 cells/μl, p = 0.0038), an effect that was attenuated in KO mice in response to the HFD (p &gt; 0.05). These findings suggest that CXCL5 may modify a specific component in the chronic inflammatory response to the HFD. Unexpectedly, HFD led to a modest decrease in cardiac function in KO mice after 16 w of the HFD compared to WT mice (74% vs 82% ejection fraction in CXCL5−/− vs WT mice, respectively, p = 0.0058). These preliminary findings suggest that CXCL5 plays a multifaceted role in the cardiovascular system’s response to an atherogenic diet. Currently, studies are underway using athero‐prone mice to study the effect of CXCL5 on plaque formation, using the ApoE−/− model. Future directions include treating mice with CXCL5 to study the effects on both the progression and regression of atherosclerosis. If successful, our studies would bring light to a new therapeutic target that could be used to combat cardiovascular disease.

Cyclodextrin conjugated ferritin nanocages reduce intracellular cholesterol level in foam cells

Accumulation of lipid-laden macrophages (foam cells) is characteristic of atherosclerosis development in the arterial walls. Ferritin nanocages have been found to passively accumulate in the atherosclerotic plaque. Ferritin has been actively investigated as a carrier for contrast agents in atherosclerosis diagnosis. We demonstrate the potential of ferritin as a carrier for therapeutic molecules to mediate cholesterol reduction from foam cells. Cyclodextrin molecules are chemically conjugated to the ferritin nanocages surface or encapsulated within the nanocages using metal co-loading methods. The cyclodextrin-conjugated ferritin has nanomolar affinity to cholesterol molecules. Treatment of foam cells with the conjugates shows decreased levels of intracellular accumulated cholesterol. The preferential localization of ferritin to foam cells is due to transferrin receptor-mediated endocytosis process. These findings show that ferritin nanocages as carriers localize cyclodextrin molecules to foam cells which mediate intracellular cholesterol reduction, thus highlighting its potential use as a therapeutic agent.

Antigen-presenting dendritic cells in atherosclerosis

Atherosclerosis is characterized by lipid accumulation and chronic inflammation of the arterial wall, involving both innate and adaptive immune responses. Accumulation of lipid-laden macrophages is a key event in atherosclerosis. However, also other immune cells, such as dendritic cells (DC) and T cells, are found within lesions. DCs are classified as a separate lineage of mononuclear phagocytes that arise from progenitors distinct from precursors of monocytes/macrophages. Although a clear attribution of the effects of antigen-presenting cells (APCs) to monocytes/macrophages and DCs is hampered by the use of promiscuous surface markers, recent research has approached to resolve the contribution of bona fide DCs and their subsets, and of plasmacytoidDCs (pDCs) to atherosclerosis. We here discuss the pathogenic and protective mechanisms engaged by APCs in atherosclerosis and highlight current concepts to further address their role in atherosclerosis.

Xanthogranulomatous cholecystitis: Is an initial laparoscopic approach feasible?

Xanthogranulomatous cholecystitis is an inflammatory disease with pathologically distinct characteristics such as accumulation of lipid-laden macrophages, fibrous tissue, and acute and chronic inflammatory cells. It often involves adjacent organs and mimics gallbladder cancer. The purpose of this study was to review the clinical findings of xanthogranulomatous cholecystitis and to determine the appropriate treatment plan. We retrospectively analyzed clinical demographics, operation records, and postoperative results of 31 patients with a pathological diagnosis of xanthogranulomatous cholecystitis who underwent surgery between January 2010 and 2015 at two university hospitals. Xanthogranulomatous cholecystitis was found in 0.81% (31/3820) of cholecystectomy patients in our hospital over 5years. The most frequently observed clinical symptom was abdominal pain (21 patients, 67.7%). Preoperative radiological studies showed cholelithiasis in 23 patients (74.2%), thickening of the gallbladder wall in 23 patients (74.2%), and suspicious cancer in 2 patients (6.5%), but there were no cases of gallbladder cancer accompanying xanthogranulomatous cholecystitis. Laparoscopic cholecystectomy was planned in all patients and was converted to open cholecystectomy in five patients. T-tube choledocholithotomy was needed in one patient due to common bile duct injury. Mean operation time was 149.2min, and estimated blood loss was 270.1mL. There were two patients with complications greater than Clavien-Dindo Classification grade III (CBD injury, pleural effusion). An initial laparoscopic approach is possible for xanthogranulomatous cholecystitis. However, it is troublesome and challenging, with significantly higher conversion and complication rates compared to standard laparoscopic cholecystectomy.

Pulmonary Involvement in Niemann-Pick Disease: A State-of-the-Art Review.

Niemann-Pick disease is a rare autosomal recessive lysosomal storage disease with three subtypes. Types A and B result from a deficiency of acid sphingomyelinase activity, associated with the accumulation of lipid-laden macrophages (so-called Niemann-Pick cells) in various tissues, especially the liver and spleen. Type A is a fatal neurodegenerative disorder of infancy. Type B Niemann-Pick disease is a less severe form with milder neurological involvement, characterized by hepatosplenomegaly, hyperlipidemia, and pulmonary involvement; most patients live into adulthood. Type C Niemann-Pick disease is a complex lipid storage disorder caused by defects in cholesterol trafficking, resulting in a clinical presentation dominated by neurological involvement. Pulmonary involvement occurs in all three types of Niemann-Pick disease, but most frequently in type B. Respiratory manifestations range from a lack of symptoms to respiratory failure. Progression of respiratory disease is slow, but inexorable, due to the accumulation of Niemann-Pick cells in the alveolar septa, bronchial walls, and pleura, potentially leading to a progressively worsening restrictive pattern on pulmonary function testing. Bronchoalveolar lavage has important diagnostic value because it shows the presence of characteristic Niemann-Pick cells. Radiographic findings consist of a reticular or reticulonodular pattern and, eventually, honeycombing, involving mainly the lower lung zones. The most common changes identified by high-resolution computed tomography are ground-glass opacities, mild smooth interlobular septal thickening, and intralobular lines. The aim of this review is to describe the main clinical, imaging, and pathological aspects of Niemann-Pick disease, with a focus on pulmonary involvement.

RAGE Against the ABCs.

Diabetes is an insidious disease that significantly contributes to the development of atherosclerotic cardiovascular disease (CVD). One of the major factors contributing to atherosclerosis is the accumulation of lipid-laden macrophages in the vascular wall (1). Removal of cholesterol from macrophages is essential for the regression of atherosclerotic lesions. This can be achieved by cholesterol-lowering drugs (i.e., statins) or by enhancing the reverse cholesterol transport pathway (i.e., raising HDL). Unfortunately, in the setting of diabetes, cholesterol-lowering drugs such as statins can be less effective (2), and preclinical models have revealed a major defect in lesion regression even when cholesterol levels are normalized (3–5). This suggests that a major defect in cholesterol metabolism occurs in the setting of diabetes. The Hedrick and Oram laboratories originally discovered that diabetes causes a downregulation of the ATP binding cassette transporters ABCG1 (6) and ABCA1 (7) in macrophages, promoting foam cell formation. ABCA1 and ABCG1 provide the dominant pathway of cholesterol removal from a number of cells in the body. Yvan-Charvet et al. (8) made the seminal discovery that codeletion of ABCA1/G1 results in a dramatic increase in atherosclerosis. Extensive research on the antiatherogenic role of these transporters has revealed their importance in removing cholesterol from plaque macrophages (9). However, recent discoveries have shown that ABCA1 and ABCG1 regulate the proliferation of hematopoietic stem and progenitor cells to control the abundance of blood monocytes (10). Along with promoting cholesterol efflux from macrophages, suppressing monocyte levels can directly inhibit the progression of atherosclerotic lesions, promote lesion regression, and provide beneficial outcomes after …

Abstract 568: ApoE-/- Mice Lacking Hemopexin Develop Aggravated Atherosclerosis via Mechanisms That Include Altered High Density Lipoprotein Inflammatory Properties and Macrophage Function

Introduction: The etiology of atherosclerosis is multi-faceted. Atherosclerotic plaques are characterized by the accumulation of lipid-laden macrophages, reactive oxygen species (ROS) and pro-inflammatory lipoproteins. Recent studies suggest that the anti- or pro-inflammatory nature of high density lipoprotein (HDL) may be a more sensitive indicator of atherosclerosis than HDL-cholesterol (HDL-C) levels alone. Our laboratory previously reported that hemopexin (Hx) is significantly increased and associated with pro-inflammatory HDL under atherogenic conditions. Hx is a heme scavenging protein which together with macrophages, plays a role in mitigating heme and ROS mediated oxidative damage. However, the role of Hx in atherosclerosis is not known. Hypothesis: We hypothesized that absence of Hx plays an important role in the accumulation of pro-inflammatory HDL, macrophage function, and the development of atherosclerosis. Methods: We crossed Hx -/- mice onto the apoE -/- background (HxE -/- mice). Chow diet fed HxE -/- and apoE -/- mice (n=10-15) were analyzed for lipoprotein inflammatory properties, macrophage gene expression, and atherosclerosis. Results: Serum ROS and heme (p&lt;0.05) were significantly higher in the HxE -/- mice. Livers of HxE -/- mice showed increased lipid peroxides (p&lt;0.001), and ex vivo monocyte chemotactic assays indicated that HDL from HxE -/- mice was more pro-inflammatory (p&lt;0.002). Expression of macrophage cholesterol efflux genes: ATP-binding cassette transporter, subfamily A, member 1 (ABCA1) and its transcriptional regulator liver X receptor-alpha (LXRα), were significantly reduced (p&lt;0.05) whereas expression of the classical M1 macrophage cell-surface receptor CCR2 was significantly increased (p=0.005) in the HxE -/- mice. Atherosclerotic plaque area and macrophage infiltration was significantly higher in the aortic sinus (p&lt;0.004), and atherosclerotic lesions in the aortas were significantly higher in the HxE -/- mice (p&lt;0.05). Conclusion: Our results suggest for the first time that Hx plays a protective role in the inflammatory properties of HDL, macrophage function and in the development of atherosclerosis in apoE-/- mice. We conclude that Hx is a novel target for the treatment of atherosclerosis.

MicroRNA-mediated mechanisms of the cellular stress response in atherosclerosis.

Atherosclerosis is characterised by the accumulation of lipid-laden macrophages in atherosclerotic lesions and occurs preferentially at arterial branching points, which are prone to inflammation during hyperlipidaemic stress. The increased susceptibility at branching sites of arteries is attributable to poor adaptation of arterial endothelial cells to disturbed blood flow. In the past 5 years, several studies have provided mechanistic insights into the regulatory roles of microRNAs (miRNAs) in inflammatory activation, proliferation, and regeneration of endothelial cells during this maladaptive process. The intercellular transfer of vesicle-bound miRNAs contributes to arterial homeostasis, and the combinatorial effect of multiple miRNAs controls the unresolved inflammation orchestrated by macrophages in atherosclerotic lesions. In this Review, we highlight the miRNA-dependent regulation of the endothelial phenotype and the proliferative reserve that occurs in response to altered haemodynamic conditions as a prerequisite for atherogenic inflammation. In particular, we discuss the regulation of transcriptional modules by miRNAs and the protective role of complementary strand pairs, which encompasses remote miRNA signalling. In addition, we review the roles of miRNA tandems and describe the relevance of RNA target selection and competition to the behaviour of lesional macrophages. Elucidating miRNA-mediated regulatory mechanisms can aid the development of novel diagnostic and therapeutic strategies for atherosclerosis.

A Case of Xanthogranulomatous Cholecystitis Decreased in Size after Steroid Treatment and Avoided Extended Resection

Xanthogranulomatous cholecystitis is an uncommon destructive inflammatory disease with accumulation of lipid-laden macrophages, fibrous tissue, and inflammatory cells. It is often mistaken for gallbladder cancer due to diffuse wall thickening of gallbladder and infiltration into neighboring organs. And it is usually difficult to distinguish xanthogranulomatous cholecystitis from gallbladder cancer based on clinical, radiographic, or laboratory testing. Patients with xanthogranulomatous cholecystitis often undergo cholecystectomy to confirm the diagnosis, and to exclude gallbladder cancers. We report a case of 69-year-old woman with xanthogranulomatous cholecystitis who had been treated with steroid and avoided extended resection. Korean J Pancreatobiliary 2015;20(1):37-41

Reduced muscle fiber force production and disrupted myofibril architecture in patients with chronic rotator cuff tears

A persistent atrophy of muscle fibers and an accumulation of fat, collectively referred to as fatty degeneration, commonly occur in patients with chronic rotator cuff tears. The etiology of fatty degeneration and function of the residual rotator cuff musculature have not been well characterized in humans. We hypothesized that muscles from patients with chronic rotator cuff tears have reduced muscle fiber force production, disordered myofibrils, and an accumulation of fat vacuoles. The contractility of muscle fibers from biopsy specimens of supraspinatus muscles of 13 patients with chronic full-thickness posterosuperior rotator cuff tears was measured and compared with data from healthy vastus lateralis muscle fibers. Correlations between muscle fiber contractility, American Shoulder and Elbow Surgeons (ASES) scores, and tear size were analyzed. Histology and electron microscopy were also performed. Torn supraspinatus muscles had a 30% reduction in maximum isometric force production and a 29% reduction in normalized force compared with controls. Normalized supraspinatus fiber force positively correlated with ASES score and negatively correlated with tear size. Disordered sarcomeres were noted, along with an accumulation of lipid-laden macrophages in the extracellular matrix surrounding supraspinatus muscle fibers. Patients with chronic supraspinatus tears have significant reductions in muscle fiber force production. Force production also correlates with ASES scores and tear size. The structural and functional muscle dysfunction of the residual muscle fibers is independent of the additional area taken up by fibrotic tissue. This work may help establish future therapies to restore muscle function after the repair of chronically torn rotator cuff muscles.

A rare finding during a common procedure: xanthogranulomatous cholecystitis.

Xanthogranulomatous cholecystitis is a rare variant of chronic cholecystitis characterized by severe proliferative fibrosis and accumulation of lipid-laden macrophages in regions of destructive inflammation. Xanthogranulomatous cholecystitis clinically and radiologically mimics early-stage gallbladder cancer, with wall thickening on computed tomography. The study included 14 xanthogranulomatous cholecystitis patients that were identified following retrospective analysis of the records of 1248 patients that underwent cholecystectomy between 2005 and 2011. Mean age of the 5 male and 9 female patients was 56.7 years. All 14 patients had gallbladder stones; 10 had a history of acute cholecystitis, 1 had cholangitis, and 2 presented with obstructive jaundice. A right-upper quadrant mass was palpable in 2 patients. All patients underwent cholecystectomy. Open surgery was planned and performed in 6 of the 14 patients, and laparoscopic cholecystectomy was planned in 8 patients, but was converted to open surgery in 1 case. In total, 1 patient developed wound infection, 1 patient had postoperative pneumonia, and 1 patient developed intraabdominal hematoma. None of the patients in the series died. Xanthogranulomatous cholecystitis is difficult to diagnose, both preoperatively and intraoperatively, and definitive diagnosis depends exclusively on pathological examination. Xanthogranulomatous cholecystitis should be a consideration in all difficult cholecystectomy cases.