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Plasma hepatocyte growth factor is a novel marker of AL cardiac amyloidosis.
Swiger KJ, Friedman EA, Brittain EL, Tomasek KA, Huang S, Su YR, Sawyer DB, Lenihan DJ
(2016) Amyloid 23: 242-248
MeSH Terms: Aged, Amyloidosis, Biomarkers, Cardiomyopathies, Cohort Studies, Diagnosis, Differential, Female, Galectin 3, Heart Failure, Systolic, Hepatocyte Growth Factor, Humans, Hypertrophy, Left Ventricular, Immunoglobulin Light Chains, Interleukin-6, Male, Middle Aged, Prealbumin, Registries, Survival Analysis, Vascular Endothelial Growth Factor A
Show Abstract · Added June 7, 2018
BACKGROUND - Cardiac amyloidosis is an infiltrative cardiomyopathy that is challenging to diagnose. We hypothesized that the novel biomarkers hepatocyte growth factor (HGF), galectin-3 (GAL-3), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) would be elevated in cardiac amyloidosis and may be able to discriminate from non-cardiac systemic amyloidosis or other cardiomyopathies with similar clinical or morphologic characteristics.
METHODS - Patients were selected from the Vanderbilt Main Heart Registry according to the following groups: (1) amyloid light-chain (AL) cardiac amyloidosis (n = 26); (2) transthyretin (ATTR) cardiac amyloidosis (n = 7); (3) left ventricular hypertrophy (LVH) (n = 45); (4) systolic heart failure (n = 42); and (5) non-cardiac systemic amyloidosis (n = 7). Biomarkers were measured in stored plasma samples. Biomarkers' discrimination performance in predicting AL cardiac amyloidosis (i.e., Concordance index) was reported. A survival analysis was used to explore the relationship between HGF levels and mortality among AL cardiac amyloidosis patients.
RESULTS - HGF levels were markedly elevated in patients with AL cardiac amyloidosis (median = 622, interquartile range (IQR): 299-1228 pg/mL) compared with the other groups, including those with non-cardiac systemic amyloidosis (median = 134, IQR: 94-163 pg/mL, p < 0.001). HGF was not a specific marker for ATTR amyloidosis. Gal-3 was elevated in all groups with amyloidosis but could not differentiate between those with and without cardiac involvement. There was no difference in IL-6 or VEGF between those with AL cardiac amyloidosis compared to other groups (p = 0.13 and 0.057, respectively).
CONCLUSIONS - HGF may be a specific marker that distinguishes AL cardiac amyloidosis from other cardiomyopathies with similar clinical or morphologic characteristics. Further studies are necessary to determine whether HGF levels predict the likelihood of survival.
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MeSH Terms
Potentiation and tolerance of toll-like receptor priming in human endothelial cells.
Koch SR, Lamb FS, Hellman J, Sherwood ER, Stark RJ
(2017) Transl Res 180: 53-67.e4
MeSH Terms: Endothelial Cells, Extracellular Signal-Regulated MAP Kinases, Human Umbilical Vein Endothelial Cells, Humans, Immune Tolerance, Interferon Regulatory Factor-7, Interferons, Interleukin-6, Lipopeptides, Lipopolysaccharides, Nuclear Pore Complex Proteins, Phosphorylation, Poly I-C, RNA-Binding Proteins, Toll-Like Receptors, Up-Regulation
Show Abstract · Added August 28, 2016
Repeated challenge of lipopolysaccharide (LPS) alters the response to subsequent LPS exposures via modulation of toll-like receptor 4 (TLR4). Whether activation of other TLRs can modulate TLR4 responses, and vice versa, remains unclear. Specifically with regards to endothelial cells, a key component of innate immunity, the impact of TLR cross-modulation is unknown. We postulated that TLR2 priming (via Pam3Csk4) would inhibit TLR4-mediated responses while TLR3 priming (via Poly I:C) would enhance subsequent TLR4-inflammatory signaling. We studied human umbilical vein endothelial cells (HUVECs) and neonatal human dermal microvascular endothelial cells (HMVECs). Cells were primed with a combination of Poly I:C (10 μg/ml), Pam3Csk4 (10 μg/ml), or LPS (100 ng/ml), then washed and allowed to rest. They were then rechallenged with either Poly I:C, Pam3Csk4 or LPS. Endothelial cells showed significant tolerance to repeated LPS challenge. Priming with Pam3Csk4 also reduced the response to secondary LPS challenge in both cell types, despite a reduced proinflammatory response to Pam3Csk4 in HMVECs compared to HUVECs. Poly I:C priming enhanced inflammatory and interferon producing signals upon Poly I:C or LPS rechallenge, respectively. Poly I:C priming induced interferon regulatory factor 7, leading to enhancement of interferon production. Finally, both Poly I:C and LPS priming induced significant changes in receptor-interacting serine/threonine-protein kinase 1 activity. Pharmacological inhibition of receptor-interacting serine/threonine-protein kinase 1 or interferon regulatory factor 7 reduced the potentiated phenotype of TLR3 priming on TLR4 rechallenge. These results demonstrate that in human endothelial cells, prior activation of TLRs can have a significant impact on subsequent exposures and may contribute to the severity of the host response.
Copyright © 2016 Elsevier Inc. All rights reserved.
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16 MeSH Terms
Association of markers of endothelial dysregulation Ang1 and Ang2 with acute kidney injury in critically ill patients.
Robinson-Cohen C, Katz R, Price BL, Harju-Baker S, Mikacenic C, Himmelfarb J, Liles WC, Wurfel MM
(2016) Crit Care 20: 207
MeSH Terms: Acute Kidney Injury, Adult, Aged, Angiopoietin-1, Angiopoietin-2, Biomarkers, Cohort Studies, Critical Illness, Female, Humans, Intensive Care Units, Interleukin-6, Male, Middle Aged, Retrospective Studies, Washington
Show Abstract · Added September 19, 2017
BACKGROUND - The role of endothelial dysregulation with acute kidney injury (AKI) in critically ill patients is unclear.
METHODS - We retrospectively assessed the associations of AKI with biomarkers of endothelial function and inflammation among 948 subjects admitted to the intensive care unit (ICU) at Harborview Medical Center (Seattle, WA, USA). From plasma obtained within 24 h of enrollment, we measured angiopoietin (Ang)-1 and Ang-2 alongside biomarkers of inflammation, including interleukin (IL)-6, IL-17 and granulocyte colony-stimulating factor. We tested for associations between standardized concentrations of biomarkers and AKI, defined by serum creatinine, from ICU admission to up to 7 days later.
RESULTS - All biomarkers of inflammation and endothelial dysfunction were associated with AKI. After adjustment for demographics, comorbidities, and IL-6 concentration, every standard deviation of Ang-1 concentration was associated with a 19 % lower risk of AKI (relative risk (RR) = 0.85, 95 % confidence interval (CI) 0.77-0.93, p < 0.001). Conversely, higher Ang-2 concentration was associated with higher risk of AKI (RR per standard deviation = 1.17, 95 % CI 1.13-1.22, p < 0.001).
CONCLUSIONS - In critically ill patients, plasma concentration of the endothelial growth factors Ang-1 and Ang-2 are associated with AKI, independently of inflammation.
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16 MeSH Terms
Interstitial renal fibrosis due to multiple cisplatin treatments is ameliorated by semicarbazide-sensitive amine oxidase inhibition.
Katagiri D, Hamasaki Y, Doi K, Negishi K, Sugaya T, Nangaku M, Noiri E
(2016) Kidney Int 89: 374-85
MeSH Terms: Actins, Acute Kidney Injury, Allylamine, Amine Oxidase (Copper-Containing), Animals, Antineoplastic Agents, Benzamides, Chemokine CCL2, Cisplatin, Drug Evaluation, Preclinical, Fatty Acid-Binding Proteins, Fibrosis, Interleukin-6, Kidney, Male, Mice, Inbred C57BL, Mice, Transgenic, Transforming Growth Factor beta, Tumor Necrosis Factor-alpha, Vascular Endothelial Growth Factor A
Show Abstract · Added February 11, 2016
Elucidation of acute kidney diseases and disorders (AKD), including acute kidney injury (AKI), is important to prevent their progression to chronic kidney disease. Current animal AKI models are often too severe for use in evaluating human AKI. Therefore, new animal models of mild kidney injury are needed. Here a new clinically relevant animal model using multiple low doses of cisplatin (CP) was used to evaluate AKD. When 10 mg/kg CP was administered intraperitoneally once weekly for three times to L-type fatty acid-binding protein (L-FABP) transgenic mice, moderate renal interstitial fibrosis and tubule dilatation occurred, accompanied by brush-border loss. Urinary L-FABP, a promising biomarker of AKI, changed more drastically than blood urea nitrogen or creatinine. Preventing fibrosis in organs was also studied. Oral administration of a recently reported selective semicarbazide-sensitive amine oxidase inhibitor, PXS-4728A, for 1 week attenuated kidney injury and interstitial fibrosis compared with vehicle. Inhibition of renal lipid accumulation in semicarbazide-sensitive amine oxidase inhibitor-treated mice, together with reduced oxidative stress and L-FABP suppression in proximal tubules, suggested an antifibrotic effect of semicarbazide-sensitive amine oxidase inhibition in this CP-AKD model, a representative onco-nephrology. Thus, semicarbazide-sensitive amine oxidase inhibitors may be promising candidates for the prevention of chronic kidney disease in patients using CP to treat malignancy.
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20 MeSH Terms
The effects of omega-3 polyunsaturated fatty acids and genetic variants on methylation levels of the interleukin-6 gene promoter.
Ma Y, Smith CE, Lai CQ, Irvin MR, Parnell LD, Lee YC, Pham LD, Aslibekyan S, Claas SA, Tsai MY, Borecki IB, Kabagambe EK, Ordovás JM, Absher DM, Arnett DK
(2016) Mol Nutr Food Res 60: 410-9
MeSH Terms: Adult, CpG Islands, DNA Methylation, Fatty Acids, Omega-3, Female, Humans, Interleukin-6, Male, Middle Aged, Polymorphism, Single Nucleotide, Promoter Regions, Genetic
Show Abstract · Added February 18, 2016
SCOPE - Omega-3 PUFAs (n-3 PUFAs) reduce IL-6 gene expression, but their effects on transcription regulatory mechanisms are unknown. We aimed to conduct an integrated analysis with both population and in vitro studies to systematically explore the relationships among n-3 PUFA, DNA methylation, single nucleotide polymorphisms (SNPs), gene expression, and protein concentration of IL6.
METHODS AND RESULTS - Using data in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study and the Encyclopedia of DNA Elements (ENCODE) consortium, we found that higher methylation of IL6 promoter cg01770232 was associated with higher IL-6 plasma concentration (p = 0.03) and greater IL6 gene expression (p = 0.0005). Higher circulating total n-3 PUFA was associated with lower cg01770232 methylation (p = 0.007) and lower IL-6 concentration (p = 0.02). Moreover, an allele of IL6 rs2961298 was associated with higher cg01770232 methylation (p = 2.55 × 10(-7) ). The association between n-3 PUFA and cg01770232 methylation was dependent on rs2961298 genotype (p = 0.02), but higher total n-3 PUFA was associated with lower cg01770232 methylation in the heterozygotes (p = 0.04) not in the homozygotes.
CONCLUSION - Higher n-3 PUFA is associated with lower methylation at IL6 promoter, which may be modified by IL6 SNPs.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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11 MeSH Terms
Thrombin induced by the extrinsic pathway and PAR-1 regulated inflammation at the site of fracture repair.
Sato N, Ichikawa J, Wako M, Ohba T, Saito M, Sato H, Koyama K, Hagino T, Schoenecker JG, Ando T, Haro H
(2016) Bone 83: 23-34
MeSH Terms: Animals, Cell Movement, Chemokine CCL2, Disease Models, Animal, Fracture Healing, Humans, Inflammation, Interleukin-6, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Models, Biological, Osteoblasts, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, RAW 264.7 Cells, Receptor, PAR-1, Thrombin, Thromboplastin
Show Abstract · Added February 22, 2016
Thrombin (coagulation factor IIa) is a serine protease encoded by the F2 gene. Pro-thrombin (coagulation factor II) is cut to generate thrombin in the coagulation cascade that results in a reduction of blood loss. Procoagulant states that lead to activation of thrombin are common in bone fracture sites. However, its physiological roles and relationship with osteoblasts in bone fractures are largely unknown. We herein report various effects of thrombin on mouse osteoblastic MC3T3-E1 cells. MC3T3-E1 cells expressed proteinase-activated receptor 1 (PAR1), also known as the coagulation factor II receptor. They also produced monocyte chemoattractant protein (MCP-1), tissue factor (TF), MCSF and IL-6 upon thrombin stimulation through the PI3K-Akt and MEK-Erk1/2 pathways. Furthermore, MCP-1 obtained from thrombin-stimulated MC3T3-E1 cells induced migration by macrophage RAW264 cells. All these effects of thrombin on MC3T3-E1 cells were abolished by the selective non-peptide thrombin receptor inhibitor SCH79797. We also found that thrombin, PAR-1, MCP-1, TF as well as phosphorylated AKT and p42/44 were significantly expressed at the fracture site of mouse femoral bone. Collectively, thrombin/PAR-1 interaction regulated MCP-1, TF, MCSF and IL-6 production by MC3T3-E1 cells. Furthermore, MCP-1 induced RAW264 cell migration. Thrombin may thus be a novel cytokine that regulates several aspects of osteoblast function and fracture healing.
Copyright © 2015 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Uric acid correlates to oxidation and inflammation in opposite directions in women.
Wu SH, Shu XO, Milne G, Xiang YB, Zhang X, Cai Q, Fazio S, Linton MF, Chen H, Purdue M, Rothman N, Gao YT, Zheng W, Yang G
(2015) Biomarkers 20: 225-31
MeSH Terms: Aged, Biomarkers, C-Reactive Protein, Case-Control Studies, Chromatography, Liquid, F2-Isoprostanes, Female, Gas Chromatography-Mass Spectrometry, Humans, Inflammation, Inflammation Mediators, Interleukin-6, Middle Aged, Oxidation-Reduction, Tandem Mass Spectrometry, Tumor Necrosis Factor-alpha, Uric Acid
Show Abstract · Added March 10, 2016
OBJECTIVE - To evaluate the association of uric acid (UA) levels with a panel of markers of oxidative stress and inflammation.
METHODS - Plasma UA levels, along with a panel of oxidative stress and inflammatory markers, were measured in 755 Chinese women.
RESULTS - Plasma UA levels were inversely associated with urinary levels of the oxidative stress marker F2-isoprostanes and positively correlated to levels of inflammatory markers, such as C-reactive protein and some proinflammatory cytokines (tumor necrosis factor-α and interleukin-6) in blood as well as prostaglandin E2 metabolites in urine.
CONCLUSIONS - Plasma UA levels correlate to oxidation and inflammation biomarkers in opposite directions in women.
1 Communities
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17 MeSH Terms
Glycoprotein130 (Gp130)/interleukin-6 (IL-6) signalling in osteoclasts promotes bone formation in periosteal and trabecular bone.
Johnson RW, McGregor NE, Brennan HJ, Crimeen-Irwin B, Poulton IJ, Martin TJ, Sims NA
(2015) Bone 81: 343-351
MeSH Terms: Animals, Bone Marrow, Bone Marrow Cells, Bone and Bones, Cartilage, Cathepsin K, Cytokine Receptor gp130, Female, Femur, Gene Deletion, Interleukin-6, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteoclasts, Osteogenesis, Real-Time Polymerase Chain Reaction, Receptors, Interleukin-11, Receptors, Interleukin-6, Sex Factors, Signal Transduction, X-Ray Microtomography
Show Abstract · Added March 26, 2019
Interleukin-6 (IL-6) and interleukin-11 (IL-11) receptors (IL-6R and IL-11R, respectively) are both expressed in osteoclasts and transduce signal via the glycoprotein130 (gp130) co-receptor, but the physiological role of this pathway is unclear. To determine the critical roles of gp130 signalling in the osteoclast, we generated mice using cathepsin K Cre (CtskCre) to disrupt gp130 signalling in osteoclasts. Bone marrow macrophages from CtskCre.gp130(f/f) mice generated more osteoclasts in vitro than cells from CtskCre.gp130(w/w) mice; these osteoclasts were also larger and had more nuclei than controls. While no increase in osteoclast numbers was observed in vivo, osteoclasts on trabecular bone surfaces of CtskCre.gp130(f/f) mice were more spread out than in control mice, but had no functional defect detectable by serum CTX1 levels or trabecular bone cartilage remnants. However, trabecular osteoblast number and mineralising surfaces were significantly lower in male CtskCre.gp130(f/f) mice compared to controls, and this was associated with a significantly lower trabecular bone volume at 12 weeks of age. Furthermore, CtskCre.gp130(f/f) mice exhibited greatly suppressed periosteal bone formation at this age, indicated by significant reductions in both double-labelled surface and mineral apposition rate. By 26 weeks of age, CtskCre.gp130(f/f) mice exhibited narrower femora, with lower periosteal and endocortical perimeters than CtskCre.gp130(w/w) controls. Since IL-6 and IL-11R global knockout mice exhibited a similar reduction in femoral width, we also assessed periosteal bone formation in those strains, and found bone forming surfaces were also reduced in male IL-6 null mice. These data suggest that IL-6/gp130 signalling in the osteoclast is not essential for normal bone resorption in vivo, but maintains both trabecular and periosteal bone formation in male mice by promoting osteoblast activity through the stimulation of osteoclast-derived "coupling factors" and "osteotransmitters", respectively.
Copyright © 2015 Elsevier Inc. All rights reserved.
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Association of plasma F2-isoprostanes and isofurans concentrations with erythropoiesis-stimulating agent resistance in maintenance hemodialysis patients.
Rivara MB, Ikizler TA, Ellis CD, Mehrotra R, Himmelfarb J
(2015) BMC Nephrol 16: 79
MeSH Terms: Adult, Aged, Anemia, C-Reactive Protein, Drug Resistance, F2-Isoprostanes, Female, Furans, Hematinics, Humans, Inflammation, Interleukin-6, Iron, Kidney Failure, Chronic, Linear Models, Male, Middle Aged, Oxidative Stress, Prospective Studies, Renal Dialysis
Show Abstract · Added August 5, 2015
BACKGROUND - In patients undergoing maintenance hemodialysis (HD), hyporesponsiveness to erythropoiesis stimulating agents (ESAs) is associated with adverse clinical outcomes. Systemic inflammation is highly prevalent in HD patients and is associated with ESA hyporesponsiveness. Oxidative stress is also highly prevalent in HD patients, but no previous study has determined its association with ESA response. This study assessed the association of plasma markers of oxidative stress and inflammation with ESA resistance in patients undergoing maintenance HD.
METHODS - We analyzed data from 165 patients enrolled in the Provision of Antioxidant Therapy in Hemodialysis study, a randomized controlled trial evaluating antioxidant therapy in prevalent HD patients. Linear and mixed-effects regression were used to assess the association of baseline and time-averaged high sensitivity F2-isoprostanes, isofurans, C-reactive protein (hsCRP), and interleukin-6 (IL-6) with ESA resistance index (ERI), defined as the weekly weight-adjusted ESA dose divided by blood hemoglobin level. Unadjusted models as well as models adjusted for potential confounders were examined. Predicted changes in ERI per month over study follow-up among baseline biomarker quartiles were also assessed.
RESULTS - Patients with time-averaged isofurans in the highest quartile had higher adjusted mean ERI compared with patients in the lowest quartile (β = 14.9 ng/ml; 95% CI 7.70, 22.2; reference group <0.26 ng/ml). The highest quartiles of hsCRP and IL-6 were also associated with higher adjusted mean ERI (β = 10.8 mg/l; 95% CI 3.52, 18.1 for hsCRP; β = 10.2 pg/ml; 95% CI 2.98, 17.5 for IL-6). No significant association of F2-isoprostanes concentrations with ERI was observed. Analyses restricted to baseline exposures and ERI showed similar results. Baseline hsCRP, IL-6, and isofurans concentrations in the highest quartiles were associated with greater predicted change in ERI over study follow-up compared to the lowest quartiles (P = 0.008, P = 0.004, and P = 0.04, respectively). There was no association between baseline F2-isoprostanes quartile and change in ERI.
CONCLUSIONS - In conclusion, higher concentrations of isofurans, hsCRP and IL-6, but not F2-isoprostanes, were associated with greater resistance to ESAs in prevalent HD patients. Further research is needed to test whether interventions that successfully decrease oxidative stress and inflammation in patients undergoing maintenance HD improve ESA responsiveness.
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20 MeSH Terms
Tissue inflammation and nitric oxide-mediated alterations in cardiovascular function are major determinants of endotoxin-induced insulin resistance.
House LM, Morris RT, Barnes TM, Lantier L, Cyphert TJ, McGuinness OP, Otero YF
(2015) Cardiovasc Diabetol 14: 56
MeSH Terms: Animals, Arterial Pressure, Cardiac Output, Chemokine CCL2, Echocardiography, Endothelium-Dependent Relaxing Factors, Gene Expression, Glucose, Glucose Clamp Technique, Heart, Inflammation, Insulin Resistance, Interleukin-6, Lipopolysaccharides, Mice, Mice, Knockout, Microspheres, Muscle Cells, Muscle, Skeletal, Nitric Oxide, Nitric Oxide Synthase Type II, RNA, Messenger, Regional Blood Flow, Serpin E2, Tumor Necrosis Factor-alpha
Show Abstract · Added July 30, 2015
BACKGROUND - Endotoxin (i.e. LPS) administration induces a robust inflammatory response with accompanying cardiovascular dysfunction and insulin resistance. Overabundance of nitric oxide (NO) contributes to the vascular dysfunction. However, inflammation itself also induces insulin resistance in skeletal muscle. We sought to investigate whether the cardiovascular dysfunction induced by increased NO availability without inflammatory stress can promote insulin resistance. Additionally, we examined the role of inducible nitric oxide synthase (iNOS or NOS2), the source of the increase in NO availability, in modulating LPS-induced decrease in insulin-stimulated muscle glucose uptake (MGU).
METHODS - The impact of NO donor infusion on insulin-stimulated whole-body and muscle glucose uptake (hyperinsulinemic-euglycemic clamps), and the cardiovascular system was assessed in chronically catheterized, conscious mice wild-type (WT) mice. The impact of LPS on insulin action and the cardiovascular system were assessed in WT and global iNOS knockout (KO) mice. Tissue blood flow and cardiac function were assessed using microspheres and echocardiography, respectively. Insulin signaling activity, and gene expression of pro-inflammatory markers were also measured.
RESULTS - NO donor infusion decreased mean arterial blood pressure, whole-body glucose requirements, and MGU in the absence of changes in skeletal muscle blood flow. LPS lowered mean arterial blood pressure and glucose requirements in WT mice, but not in iNOS KO mice. Lastly, despite an intact inflammatory response, iNOS KO mice were protected from LPS-mediated deficits in cardiac output. LPS impaired MGU in vivo, regardless of the presence of iNOS. However, ex vivo, insulin action in muscle obtained from LPS treated iNOS KO animals was protected.
CONCLUSION - Nitric oxide excess and LPS impairs glycemic control by diminishing MGU. LPS impairs MGU by both the direct effect of inflammation on the myocyte, as well as by the indirect NO-driven cardiovascular dysfunction.
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25 MeSH Terms