ABSTRACT
Osteomyelitis (OM) is a major challenge in orthopedic surgery. The diagnosis of OM is based on imaging and laboratory tests, but it still presents some limitations. Therefore, a deeper comprehension of the pathogenetic mechanisms could enhance diagnostic and treatment approaches. OM pathogenesis is based on an inflammatory response to pathogen infection, leading to bone loss. The present study aims to investigate the potential diagnostic role of a panel of osteoimmunological serum biomarkers in the clinical approach to OM. The focus is on the emerging infection biomarker sCD14-ST, along with osteoimmunological and inflammatory serum biomarkers, to define a comprehensive biomarker panel for a multifaced approach to OM. The results, to our knowledge, demonstrate for the first time the diagnostic and early prognostic role of sCD14-ST in OM patients, suggesting that this biomarker could address the limitations of current laboratory tests, such as traditional inflammatory markers, in diagnosing OM. In addition, the study highlights a relevant diagnostic role of SuPAR, the chemokine CCL2, the anti-inflammatory cytokine IL-10, the Wnt inhibitors DKK-1 and Sclerostin, and the RANKL/OPG ratio. Moreover, CCL2 and SuPAR also exhibited early prognostic value.
ABSTRACT
Lipidome perturbation occurring during meta-inflammation is associated to left ventricle (LV) remodeling though the activation of the NLRP3 inflammasome, a key regulator of chronic inflammation in obesity-related disorders. Little is known about phosphatidylcholine (PC) and phosphatidylethanolamine (PE) as DAMP-induced NLRP3 inflammasome. Our study is aimed to evaluate if a systemic reduction of PC/PE molar ratio can affect NLRP3 plasma levels in cardiovascular disease (CVD) patients with insulin resistance (IR) risk. Forty patients from IRCCS Policlinico San Donato were enrolled, and their blood samples were drawn before heart surgery. LV geometry measurements were evaluated by echocardiography and clinical data associated to IR risk were collected. PC and PE were quantified by ESI-MS/MS. Circulating NLRP3 was quantified by an ELISA assay. Our results have shown that CVD patients with IR risk presented systemic lipid impairment of PC and PE species and their ratio in plasma was inversely associated to NLRP3 levels. Interestingly, CVD patients with IR risk presented LV changes directly associated to increased levels of NLRP3 and a decrease in PC/PE ratio in plasma, highlighting the systemic effect of meta-inflammation in cardiac response. In summary, PC and PE can be considered bioactive mediators associated to both the NLRP3 and LV changes in CVD patients with IR risk.
Subject(s)
Cardiovascular Diseases , Inflammasomes , Insulin Resistance , NLR Family, Pyrin Domain-Containing 3 Protein , Phosphatidylcholines , Phosphatidylethanolamines , Ventricular Remodeling , Humans , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Phosphatidylcholines/blood , Inflammasomes/metabolism , Male , Female , Middle Aged , Phosphatidylethanolamines/blood , Phosphatidylethanolamines/metabolism , Cardiovascular Diseases/blood , Cardiovascular Diseases/pathology , AgedABSTRACT
BACKGROUND: Chronic kidney disease (CKD) is characterized by an overproduction and accumulation of advanced glycation end products (AGEs). Because AGEs may play a role in the development of malnutrition and sarcopenia, two essential components of frailty, we evaluated whether they may also contribute to the onset of frailty in CKD patients. METHODS: We performed a cross-sectional analysis of 117 patients. AGEs were quantified using a fluorescence spectrophotometer and soluble receptor for AGE (sRAGE) isoforms by ELISA. We defined frailty according to the frailty phenotype (FP) proposed by Fried. RESULTS: The average age of patients was 80 ± 11 years, 70% were male, and the mean eGFR was 25 + 11 mL/min/1.73m2. Frailty was diagnosed in 51 patients, and 40 patients were classified as pre-frail. AGEs and RAGE isoforms seem not to correlate with overall frailty. Instead, AGEs were associated with specific frailty domains, inversely associated with BMI (R = -0.22, p = 0.016) and directly associated with gait test time (R = 0.17, p = 0.049). AGEs were also associated with involuntary weight loss (OR 1.84 p = 0.027), independent of age and sex. CONCLUSIONS: AGEs are associated with some pivotal components of the frailty phenotype, although they are not associated with frailty overall.
Subject(s)
Frailty , Renal Insufficiency, Chronic , Male , Female , Humans , Receptor for Advanced Glycation End Products/genetics , Glycation End Products, Advanced , Cohort Studies , Cross-Sectional Studies , Protein IsoformsABSTRACT
Accurate studies on the dynamics of Pfizer-Biontech BNT162b2-induced antibodies are crucial to better tailor booster dose administration depending on age, comorbidities, and previous natural infection with SARS-CoV-2. To date, little is known about the durability and kinetics of antibody titers months after receiving a booster dose. In this work, we studied the dynamic of anti-Trimeric Spike (anti-TrimericS) IgG titer in the healthcare worker population of a large academic hospital in Northern Italy, in those who had received two vaccine doses plus a booster dose. Blood samples were collected on the day of dose 1, dose 2, then 1 month, 3 months, and 6 months after dose 2, the day of the administration of the booster dose, then 1 month and 3 months after the booster dose. The vaccination immunogenicity was evaluated by dosing anti-TrimericS IgG titer, which was further studied in relation to SARS-CoV-2 infection status, age, and sex. Our results suggest that after the booster dose, the anti-TrimericS IgG production was higher in the subjects that were infected only after the completion of the vaccination cycle, compared to those that were infected both before and after the vaccination campaign. Moreover, the booster dose administration exerts a leveling effect, mitigating the differences in the immunogenicity dependent on sex and age.
ABSTRACT
BACKGROUND: In patients with chronic kidney disease (CKD), there is an overproduction and accumulation of advanced glycation end-products (AGEs). Since AGEs may have detrimental effects on muscular trophism and performance, we evaluated whether they may contribute to the onset of sarcopenia in CKD patients. METHODS: We enrolled 117 patients. The AGEs were quantified by fluorescence intensity using a fluorescence spectrophotometer and soluble receptor for AGE (sRAGE) isoforms by ELISA. As for the sarcopenia definition, we used the European Working Group on Sarcopenia in Older People (EWGSOP2) criteria. RESULTS: The average age was 80 ± 11 years, 70% were males, and the mean eGFR was 25 + 11 mL/min/1.73 m2. Sarcopenia was diagnosed in 26 patients (with a prevalence of 22%). The sarcopenic patients had higher levels of circulating AGEs (3405 ± 951 vs. 2912 ± 722 A.U., p = 0.005). AGEs were higher in subjects with a lower midarm muscle circumference (MAMC) (3322 ± 919 vs. 2883 ± 700 A.U., respectively; p = 0.005) and were directly correlated with the gait test time (r = 0.180, p = 0.049). The total sRAGE and its different isoforms (esRAGE and cRAGE) did not differ in patients with or without sarcopenia. CONCLUSIONS: In older CKD patients, AGEs, but not sRAGE, are associated with the presence of sarcopenia. Therefore, AGEs may contribute to the complex pathophysiology leading to the development of sarcopenia in CKD patients.
ABSTRACT
Since no definitive cure for COVID-19 is available so far, one of the challenges against the disease is understanding the clinical features and the laboratory inflammatory markers that can differentiate among different severity grades of the disease. The aim of the present study is a comprehensive and longitudinal evaluation of SCD14-ST and other new inflammatory markers, as well as cytokine storm molecules and current inflammatory parameters, in order to define a panel of biomarkers that could be useful for a better prognostic prediction of COVID-19 mortality. SCD14-ST, as well as the inflammatory markers IL-6, IL-10, SuPAR and sRAGE, were measured in plasma-EDTA of ICU COVID-19 positive patients. In this longitudinal study, SCD14-ST resulted significantly higher in patients who eventually died compared to those who were discharged from the ICU. The results suggest that the new infection biomarker SCD14-ST, in addition to new generation inflammatory biomarkers, such as SuPAR, sRAGE and the cytokines IL-6 and IL-10, can be a useful prognostic tool associated with canonical inflammatory parameters, such as CRP, to predict SARS-CoV-2 outcome in ICU patients.
Subject(s)
COVID-19 , Lipopolysaccharide Receptors , Biomarkers , COVID-19/diagnosis , Humans , Interleukin-10 , Interleukin-6 , Longitudinal Studies , Receptors, Urokinase Plasminogen Activator , SARS-CoV-2ABSTRACT
BACKGROUND: To investigate the presence of genetic material of viral agents and the serum level of inflammatory cytokines in patients submitted to carotid endarterectomy having vulnerable versus stable atherosclerotic plaques. METHODS: Data of patients consecutively submitted to carotid endarterectomy for a significant stenosis from July 2019 to December 2019 were prospectively collected. The genetic material of Epstein-Barr (EBV), CitoMegalo (CMV), Herpes Simplex (HSV), Varicella-Zoster (VZV) and Influenza (IV) Viruses was searched in the patient's plaques, both in the "mid" of the plaque and in an adjacent lateral portion of no-plaque area. The serum levels of TNF-α, IL-1ß, IL-6, IL10 and CCL5 were determined. The obtained results were then correlated to the histologic vulnerability of the removed carotid plaque. P values < 0.05 were considered statistically significant. RESULTS: Data of 50 patients were analyzed. A vulnerable plaque was found in 31 patients (62%). The genome of CMV, HSV, VZV and IV was not found in any of the vascular samples, while the EBV genome was found in the "mid" of 2 vulnerable plaques, but not in their respective control area. Eighty-two percent of patients who did not receive anti-IV vaccination (23/28) had vulnerable carotid plaque, compared with 36% of vaccinated patients (8/22, P = 0.001). Serum levels of TNF-α and IL-6 were higher in patients with a vulnerable plaque compared to patients with a stable plaque (73.6 ± 238.2 vs. 3.9 ± 13.1 pg/ml, P= 0.01, and 45.9 ± 103.6 vs. 10.1 ± 25.3 pg/ml, P= 0.01, respectively), independent of comorbidities, viral exposure or flu vaccination. CONCLUSIONS: The EBV genome was found in the "core" of 2 vulnerable carotid plaques, but not in their respective adjacent control. Influenza vaccination was associated with a lower incidence of carotid plaque vulnerability. Serum levels of TNF-α and IL-6 were higher in patients with a vulnerable plaque compared to patients with a stable plaque.
Subject(s)
Carotid Stenosis , Cytokines , Cytomegalovirus Infections , Endarterectomy, Carotid , Interleukin-6 , Plaque, Atherosclerotic , Tumor Necrosis Factor-alpha , Carotid Stenosis/diagnostic imaging , Cytokines/blood , Cytomegalovirus Infections/diagnosis , Cytomegalovirus Infections/genetics , Endarterectomy, Carotid/adverse effects , Epstein-Barr Virus Infections/diagnosis , Epstein-Barr Virus Infections/genetics , Humans , Inflammation/diagnosis , Influenza, Human/diagnosis , Influenza, Human/genetics , Interleukin-6/blood , Plaque, Atherosclerotic/genetics , Treatment Outcome , Tumor Necrosis Factor-alpha/bloodABSTRACT
Sarcopenia is common in chronic kidney disease (CKD), and it is independently associated with morbidity and mortality. Advanced glycation end products (AGE) are mainly known as aging products. In CKD, AGE accumulate due to increased production and reduced kidney excretion. The imbalance between oxidant/antioxidant capacities in CKD patients is one of the main factors leading to AGE synthesis. AGE can, in turn, promote CKD progression and CKD-related complications by increasing reactive oxygen species generation, inducing inflammation, and promoting fibrosis. All these derangements can further increase AGE and uremic toxin accumulation and promote loss of muscle mass and function. Since the link between AGE and sarcopenia in CKD is far from being fully understood, we revised hereby the data supporting the potential contribution of AGE as mediators of oxidative stress in the pathogenesis of sarcopenia. Understanding how AGE and oxidative stress impact the onset of sarcopenia in CKD may help to identify new potential markers of disease progression and/or therapeutic targets.
ABSTRACT
BACKGROUND AND AIMS: Recently, it has been hypothesized that Tri-Ponderal Mass Index (TMI) may be a valid alternative to Body Mass Index (BMI) when measuring body fat in adolescents. We aimed to verify whether TMI has better accuracy than BMI in discriminating central obesity and hypertension in adolescents with overweight. METHODS AND RESULTS: This monocentric and retrospective cross-sectional study included 3749 pupils, 1889 males and 1860 females, aged 12-13. BMI (kg/m2) was calculated and expressed as percentiles and as z-scores. TMI (kg/m3) was calculated, and we used pre-defined cut-off previously proposed by Peterson et al.. For central obesity we adopted the Waist-to-Height Ratio (WHtR) discriminatory value of 0.5. Hypertension was defined as blood pressure ≥95th percentile of age- sex-, and height-specific references recommended by NHBPEP Working Group. The discriminant ability of TMI, BMI and BMI z-score, with respect to central obesity and hypertension, was investigated using non-parametric receiver operating characteristic analysis. The overall misclassification rate for central obesity was 8.88% for TMI vs 14.10% for BMI percentiles and vs 14.92% for BMI z-scores (P < 0.001). The overall misclassification rate for hypertension was 7.50% for TMI vs 22.03% for BMI percentiles and vs 25.19% for BMI z-scores (P < 0.001). CONCLUSION: TMI is a superior body fat index and it could discriminate body fat distribution more accurately than BMI. This supports the use of TMI, in association with WHtR, to characterize adolescents with overweight and high cardio-metabolic risk. Our analysis needs to be extended to other ethnic groups and replicated in a wider age range and in longitudinal studies.
Subject(s)
Adiposity , Blood Pressure , Body Mass Index , Hypertension/diagnosis , Obesity, Abdominal/diagnosis , Pediatric Obesity/diagnosis , Adolescent , Age Factors , Cardiometabolic Risk Factors , Child , Cross-Sectional Studies , Diagnosis, Differential , Female , Humans , Hypertension/epidemiology , Hypertension/physiopathology , Italy/epidemiology , Male , Obesity, Abdominal/epidemiology , Obesity, Abdominal/physiopathology , Pediatric Obesity/epidemiology , Pediatric Obesity/physiopathology , Predictive Value of Tests , Prevalence , Reproducibility of Results , Retrospective Studies , Risk Assessment , Waist-Hip RatioABSTRACT
Advanced glycation end-products (AGE) can promote chronic kidney disease (CKD) progression and CKD-related morbidities. The soluble receptor for AGE (sRAGE) is a potential biomarker of inflammation and oxidative stress. Here, we explored the role of AGE, glycated albumin, sRAGE and its different forms, cRAGE and esRAGE, as prognostic factors for mortality in 111 advanced CKD patients. The median follow-up time was 39 months. AGE were quantified by fluorescence, sRAGE and its forms by ELISA. Malnutrition was screened by the Malnutrition Inflammation Score (MIS). The Cox proportional hazards regression model was used to assess the association of variables with all-cause mortality. Mean levels of sRAGE, esRAGE and cRAGE were 2318 ± 1224, 649 ± 454 and 1669 ± 901 pg/mL. The mean value of cRAGE/esRAGE was 2.82 ± 0.96. AGE were 3026 ± 766 AU and MIS 6.0 ± 4.7. eGFR correlated negatively with AGE, sRAGE, esRAGE and cRAGE, but not with cRAGE/esRAGE. Twenty-eight patients died. No difference was observed between diabetic and non-diabetic patients. Starting dialysis was not associated with enhanced risk of death. AGE, esRAGE and cRAGE/esRAGE were independently associated with all-cause mortality. AGE, esRAGE and cRAGE/esRAGE may help to stratify overall mortality risk. Implementing the clinical evaluation of CKD patients by quantifying these biomarkers can help to improve patient outcomes.
ABSTRACT
The receptor for advanced glycation end products (RAGE), a well-known player of diabetes mellitus (DM)-related morbidities, was supposed to be involved in coronavirus disease-19 (COVID-19), but no data exist about COVID-19, DM, and the soluble RAGE (sRAGE) forms. We quantified total sRAGE and its forms, the endogenously secretory esRAGE and the membrane-cleaved cRAGE, in COVID-19 patients with and without DM and in healthy individuals to explore how COVID-19 may affect these molecules and their potential role as biomarkers. Circulating sRAGE and esRAGE were quantified by enzyme-linked-immunosorbent assays. cRAGE was obtained by subtracting esRAGE from total sRAGE. sRAGE, esRAGE, cRAGE, and the cRAGE/esRAGE ratio did not differ between DM and non-DM patients and had the same trend when compared to healthy individuals. Levels of total sRAGE, cRAGE, and cRAGE/esRAGE ratio were upregulated, while esRAGE was downregulated. The lack of difference between DM and non-DM COVID-19 patients in the levels of sRAGE and its forms supports the hypothesis that in COVID-19 the RAGE system is modulated regardless of glycemic control. Identifying how sRAGE and its forms associate to COVID-19 prognosis and the potential of RAGE as a therapeutic target to control inflammatory burden seem of relevance to help treatment of COVID-19.
ABSTRACT
Epicardial adipose tissue (EAT) has the unique property to release mediators that nourish the heart in healthy conditions, an effect that becomes detrimental when volume expands and proinflammatory cytokines start to be produced. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a proinflammatory mediator involved in atherosclerosis, is also produced by visceral fat. Due to the correlation of inflammation with PCSK9 and EAT enlargement, we evaluated whether PCSK9 was expressed in EAT and associated with EAT inflammation and volume. EAT samples were isolated during surgery. EAT thickness was measured by echocardiography. A microarray was used to explore EAT transcriptoma. The PCSK9 protein levels were measured by Western Blot in EAT and ELISA in plasma. PCSK9 was expressed at both the gene and protein levels in EAT. We found a positive association with EAT thickness and local proinflammatory mediators, in particular, chemokines for monocytes and lymphocytes. No association was found with the circulating PCSK9 level. The expression of PCSK9 in EAT argues that PCSK9 is part of the EAT secretome and EAT inflammation is associated with local PCSK9 expression, regardless of circulating PCSK9 levels. Whether reducing EAT inflammation or PCSK9 local levels may have beneficial effects on EAT metabolism and cardiovascular risk needs further investigations.
Subject(s)
Adipose Tissue/metabolism , Inflammation/metabolism , Pericardium/metabolism , Proprotein Convertase 9/metabolism , Aged , Anthropometry , Body Mass Index , Case-Control Studies , Chemokines/metabolism , Coronary Artery Disease/complications , Female , Heart Valve Diseases/complications , Humans , Lymphocytes/metabolism , Male , Middle Aged , Monocytes/metabolism , Protein Array Analysis , RiskABSTRACT
Bone and the immune system are closely linked: bone regulates the hematopoietic stem cells, which are precursors of immune cells, and several immunoregulatory cytokines influence the differentiation of bone cells, thus defining the osteoimmunological system. Cytokines and growth factors produced by immune and bone cells promote tumors in bone, supporting the vicious cycle of bone metastasis. Therefore osteoimmunological molecules linking the immune and bone systems could have diagnostic and prognostic potential for bone metastases. The osteoimmunologic Wnt pathway has been recently described as an important pathway with a vital role in bone carcinogenesis and metastatic progression. We examined the Wnt inhibitor DKK-1, sclerostin and several other osteoimmunological biomarkers involved in bone metastatic progression: RANKL, OPG, OPN, matrix metalloproteinase MMP-3 and the Receptor of Advanced Glycosylated End-products sRAGE. OPN and sclerostin proved good biomarkers of metastatic bone progression; the RANKL/OPG ratio was a good indicator of bone erosion in the metastatic process, while sRAGE had a protective role against metastatic progression in bone. These results serve to define a panel of new osteoimmunological biomarkers that could be useful in assessing the progress of osteolytic bone metastases.
Subject(s)
Biomarkers/blood , Bone Neoplasms/blood , Bone Neoplasms/secondary , Immunologic Factors/blood , Wnt Proteins/antagonists & inhibitors , Aged , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/pathology , Female , Humans , Immunomodulation/drug effects , Longitudinal Studies , Male , Middle Aged , Osteolysis , ROC CurveABSTRACT
BACKGROUND: Epicardial adipose tissue (EAT) is a risk factor for cardiovascular diseases. Glucagon-like peptide 1 analogs (GLP-1A) may have beneficial cardiovascular effects and reduce EAT, possibly throughout targeting GLP-1 receptor (GLP-1R). Nevertheless, the role of EAT GLP-1R, GLP-2R and their interplay with EAT genes involved in adipogenesis and fatty acid (FA) metabolism are unknown. We analyzed whether EAT transcriptome is related to GLP-1R/GLP-2R gene expression, and GLP-1/GLP-2 plasma levels in coronary artery disease patients (CAD). METHODS: EAT was collected from 17 CAD patients undergoing CABG for microarray analysis of GLP-1R, GLP-2R and genes involved in FA metabolism and adipogenesis. EAT thickness was measured by echocardiography. GLP-1 and GLP-2 levels were quantified by ELISA in CAD and healthy subjects (CTR). RESULTS: EAT GLP-1R was directly correlated with genes promoting beta-oxidation and white-to-brown adipocyte differentiation, and inversely with pro-adipogenic genes. GLP-2R was positively correlated with genes involved in adipogenesis and lipid synthesis, and inversely with genes promoting beta-oxidation. GLP-1 and GLP-2 levels were higher in CAD than CTR and in patients with greater EAT thickness. CONCLUSIONS: GLP-1 analogs may target EAT GLP-1R and therefore reduce local adipogenesis, improve fat utilization and induce brown fat differentiation. As EAT lies in direct contiguity to myocardium and coronary arteries, the beneficial effects of GLP-1 activation may extent to the heart. The increased levels of circulating GLP-1 and GLP-2 and EAT GLP-2R may be compensatory mechanisms related to CAD and also EAT expansion, but the meaning of these observations needs to be further investigated.
Subject(s)
3-Hydroxyacyl CoA Dehydrogenases/metabolism , Acetyl-CoA C-Acyltransferase/metabolism , Adipose Tissue, Brown/metabolism , Adipose Tissue, White/metabolism , Carbon-Carbon Double Bond Isomerases/metabolism , Cardiovascular Diseases/blood , Enoyl-CoA Hydratase/metabolism , Glucagon-Like Peptide-1 Receptor/blood , Pericardium/metabolism , Racemases and Epimerases/metabolism , 3-Hydroxyacyl CoA Dehydrogenases/genetics , Acetyl-CoA C-Acyltransferase/genetics , Adipose Tissue, Brown/diagnostic imaging , Adipose Tissue, White/diagnostic imaging , Adult , Aged , Anthropometry/methods , Carbon-Carbon Double Bond Isomerases/genetics , Cardiovascular Diseases/diagnostic imaging , Cardiovascular Diseases/genetics , Enoyl-CoA Hydratase/genetics , Female , Glucagon-Like Peptide-1 Receptor/genetics , Humans , Male , Middle Aged , Pericardium/diagnostic imaging , Racemases and Epimerases/genetics , Risk FactorsABSTRACT
Most of the obesity-related complications are due to ectopic fat accumulation. Recently, the activation of the cell-surface receptor for advanced glycation end products (RAGE) has been associated with lipid accumulation in different organs. Nevertheless, the role of RAGE and sRAGE, the soluble form that prevents ligands to activate RAGE, in intramyocardial lipid accumulation is presently unknown. To this aim, we analyzed whether, in obesity, intramyocardial lipid accumulation and lipid metabolism-related transcriptome are related to RAGE and sRAGE. Heart and serum samples were collected from 10 lean (L) and 10 obese (OB) Zucker rats. Oil red staining was used to detect lipids on frozen heart sections. The lipid metabolism-related transcriptome (84 genes) was analyzed by a specific PCR array. Heart RAGE expression was explored by real-time RT-PCR and Western blot analyses. Serum levels of sRAGE (total and endogenous secretory form (esRAGE)) were quantified by ELISA. Genes promoting fatty acid transport, activation, and oxidation in mitochondria/peroxisomes were upregulated in OB hearts. Intramyocardial lipid content did not differ between OB and L rats, as well as RAGE expression. A slight increase in epicardial adipose tissue was observed in OB hearts. Total sRAGE and esRAGE concentrations were significantly higher in OB rats. sRAGE may protect against obesity-induced intramyocardial lipid accumulation by preventing RAGE hyperexpression, therefore allowing lipids to be metabolized. EAT also played a protective role by working as a buffering system that protects the myocardium against exposure to excessively high levels of fatty acids. These observations reinforce the potential role of RAGE pathway as an interesting therapeutic target for obesity-related complications, at least at the cardiovascular level.
Subject(s)
Glycation End Products, Advanced/metabolism , Lipid Metabolism/physiology , Myocardium/metabolism , Obesity/metabolism , Receptor for Advanced Glycation End Products/metabolism , Animals , Biomarkers , Blotting, Western , Enzyme-Linked Immunosorbent Assay , Lipids , Male , Obesity/blood , Rats , Rats, Zucker , Real-Time Polymerase Chain ReactionABSTRACT
Aseptic loosening is a major cause of premature failure of total knee replacement (TKR). Variations in periprosthetic bone mineral density (BMD) and osteoimmunological biomarkers levels could help to quantify prosthesis osteointegration and predict early aseptic loosening. The gene expression of 5 selected osteoimmunological biomarkers was evaluated in tibial plateau bone biopsies by real-time polymerase chain reaction and changes in their serum levels after TKR were prospectively evaluated with enzyme-linked immunosorbent assay for 1 yr after surgery. These variations were correlated to changes in periprosthetic BMD. Sixteen patients were evaluated. A statistically significant decrease in serum levels of Sclerostin (pâ¯=â¯0.0135) was observed immediately after surgery. A specular pattern was observed between dickkopf-related protein 1 and osteoprotegerin expression. No statistically significant changes were detectable in the other study biomarkers. Periprosthetic BMD did not change significantly across the duration of the follow-up. Prosthetic knee surgery has an impact on bone remodeling, in particular on sclerostin expression. Although not showing statistically significant changes, in the patterns of dickkopf-related protein 1, osteoprotegerin, and the ligand of the receptor activator of nuclear factor kappa-B symmetries and correspondences related to the biological activities of these proteins could be identified. Variation in osteoimmunological biomarkers after TKR surgery can help in quantifying prosthesis osteointegration.
Subject(s)
Arthroplasty, Replacement, Knee/adverse effects , Intercellular Signaling Peptides and Proteins/genetics , Osteoprotegerin/genetics , Prosthesis Failure , RANK Ligand/genetics , Adaptor Proteins, Signal Transducing/blood , Adaptor Proteins, Signal Transducing/genetics , Aged , Biomarkers/metabolism , Bone Density , Female , Femur/metabolism , Gene Expression , Humans , Interleukin-6/genetics , Knee Prosthesis , Male , Middle Aged , Osseointegration , Prospective Studies , RNA, Messenger/metabolism , Receptor Activator of Nuclear Factor-kappa B/genetics , Tibia/metabolismSubject(s)
Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Blood Coagulation Tests/methods , Administration, Oral , Antithrombins/pharmacology , Blood Coagulation/drug effects , Dabigatran/pharmacology , Humans , Platelet Membrane Glycoproteins/pharmacology , Pyrazoles/pharmacology , Pyridones/pharmacology , Rivaroxaban/pharmacologyABSTRACT
End-stage renal disease patients on dialysis (CKD-G5D) have a high mortality rate due to cardiovascular diseases (CVD). In these patients, inflammation, oxidative stress, and uremia increase the production of glycation products (AGEs) which in turn accelerate CVD onset and progression. Recently, attention has been given to the soluble receptor for AGEs (sRAGE) as a marker of inflammation, oxidative stress, atherosclerosis, and heart failure in CKD-G5D. However, its association with patient outcomes is still under debate. Our aim is to explore whether sRAGE may be a predictor of mortality in CKD-G5D. We studied 123 CKD-G5D for 24 months. Of these patients, 56 were on hemodialysis (HD) and 67 on peritoneal dialysis (PD). Demographic, anthropometric, biochemical, and clinical data were recorded. sRAGE was quantified by enzyme-linked immunosorbent assay. sRAGE was a predictor of mortality at 2-year follow-up. Each increase of 100 pg/mL in sRAGE levels was associated with an approximately 7% increased risk of mortality. Furthermore, in the entire study group, as well as in PD and HD patient subgroups, sRAGE was positively correlated with brain natriuretic peptide (BNP) levels. Mortality rates as well as sRAGE levels in patients who died did not differ between PD and HD patients. In conclusion, the positive association observed with BNP levels suggests a role for sRAGE as a prognostic factor for mortality in CKD-G5D patients displaying an active process of cardiac remodeling.
Subject(s)
Cardiovascular Diseases/metabolism , Kidney Failure, Chronic/metabolism , Peritoneal Dialysis , Receptor for Advanced Glycation End Products/metabolism , Renal Dialysis , Aged , Biomarkers/metabolism , Cardiovascular Diseases/mortality , Cardiovascular Diseases/therapy , Female , Humans , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/therapy , Middle Aged , Natriuretic Peptide, Brain/metabolism , Prospective StudiesABSTRACT
UHMWPE doped with vitamin E was introduced to provide oxidation resistance upon sterilization, without affecting UHMWPE's mechanical properties. Particle-induced macrophage activation leads to periprosthetic bone resorption, requiring total joint replacements. During osteolysis, osteoblasts produce osteoimmunological factors such as RANKL and OPG, and the inhibitors of the Wnt pathway DKK-1 and Sclerostin. This study investigated in vitro how vitamin E-blended-UHMWPE wear debris might affect osteoblast-mediated osteolysis and the production of RANKL, OPG, Sclerostin and DKK-1, compared to conventional UHMWPE wear debris. Human osteoblastic SaOS2 cells were incubated with wear particles from Vitamin E doped and conventional UHMWPE and the gene expression and protein production of IL-6, RANKL, OPG, DKK-1, and Sclerostin was evaluated, RANKL, a bone erosion marker, was reduced, while OPG, a bone protective marker, were increased by the vitamin E-blended UHMWPE compared to conventional UHMWPE. Vitamin E doped UHMWPE reduced Sclerostin level, and partially affected DKK-1 production, thereby protecting against bone erosion. In conclusion, Vitamin E-blended UHMWPE induced an osteoimmunological response in bone cells that had positive effects on the osteolysis induced by wear debris, reducing aseptic loosening of the implants. In conclusion, this is the first study showing that Vitamin E-blended UHMWPE induced an osteoimmunological response in bone cells that positively affect the osteolysis induced by wear debris, thereby reducing the aseptic loosening of the implants.