ABSTRACT
Severe mitral regurgitation (MR) is associated with increased morbidity and mortality. Thus, the correct evaluation of the underlying etiology, pathomechanism and severity is crucial for optimal treatment. Echocardiography is the predominant diagnostic modality in the clinical routine as it enables grading of mitral regurgitation, which can frequently be achieved by readily available qualitative parameters. Additionally, echocardiography provides several methods to quantify the hemodynamic significance of MR. The effective regurgitation orifice area (EROA) is the quantitative parameter best correlated with clinical events. American and European imaging guidelines both recommend the use of quantitative parameters even though they disagree on the cut-off values for secondary MR. The evaluation of MR should always include an assessment of the adjacent heart chambers in order to be able to assess the impact of volume overload on size and function of the left ventricle and left atrium. The final interpretation of the quantitative parameters requires knowledge of left ventricular volume and ejection fraction. Newer 3D-echocardiographic approaches to quantify MR are less dependent on mathematical assumptions and have shown convincing results in several studies but still lack sufficient clinical validation. As an alternative to echocardiography, for specific indications cardiac magnetic resonance imaging (MRI) has proven to be a systematic and observer-independent method for quantification of MR.
Subject(s)
Echocardiography, Three-Dimensional , Mitral Valve Insufficiency , Echocardiography, Doppler, Color , Heart Ventricles , Humans , Mitral Valve Insufficiency/diagnostic imaging , Severity of Illness IndexABSTRACT
Stochastic Langevin dynamics has been traditionally used as a tool to describe nonequilibrium processes. When utilized in systems with collective modes, traditional Langevin dynamics relaxes all modes indiscriminately, regardless of their wavelength. We propose a generalization of Langevin dynamics that can capture a differential coupling between collective modes and the bath, by introducing spatial correlations in the random forces. This allows modeling the electronic subsystem in a metal as a generalized Langevin bath endowed with a concept of locality, greatly improving the capabilities of the two-temperature model. The specific form proposed here for the spatial correlations produces a physical wave-vector and polarization dependency of the relaxation produced by the electron-phonon coupling in a solid. We show that the resulting model can be used for describing the path to equilibration of ions and electrons and also as a thermostat to sample the equilibrium canonical ensemble. By extension, the family of models presented here can be applied in general to any dense system, solids, alloys, and dense plasmas. As an example, we apply the model to study the nonequilibrium dynamics of an electron-ion two-temperature Ni crystal.
ABSTRACT
OBJECTIVE: This study was conducted to identify cytokine profiles associated with radiographic phenotypes of knee osteoarthritis (rKOA) with a focus on early stage of the disease. METHODS: The pilot population study involved 60 middle-aged patients (mean age 50 ± 7.3y.). Standardized weight-bearing anteroposterior and axial radiographs were used to assess rKOA severity in tibiofemoral (TFJ) of patellofemoral joint (PFJ) by grading system (grades 0-3). Luminex (xMAP®) technology was used to simultaneously assess 60 biomarkers (BMs). RESULTS: Several pathways of angiogenic (CXCL10/IP-10, FGF1/2, PDGF-AA/BB, ANG1, RANTES), tissue remodeling/fibrosis (MMP1/3, TIMP2/3/4, TGFß), and fat tissue (leptin) BMs associated with rKOA severity already in very early phase (grade 1). We identified several sets of cytokines as key markers of early knee osteoarthritis (KOA) predicting radiographic features in logistic-regression models (AUC = 0.80-0.97). Marked sex-specificity of rKOA course was detected: upregulation of angiogenesis dominated in females, whereas the activation of tissue remodeling was dominant in males. Several of these shifts, e.g., decrease of CXCL10/IP-10, took place only in grade 1 KOA and disappeared or reversed in later stages. OA of different knee-joint compartments has distinct profiles of cytokines. A broad list of BMs (TIMP2/3/4, MMP1/3, TGFß1/2, vWF-A2, sE-selectin and leptin) associated with OA in the PFJ. CONCLUSION: Our results demonstrate that substantial and time-limited shifts in the angiogenic and TIMP/MMP systems occur in the early stage of KOA. Our study findings highlight the sex-, grade- and compartment-dependent shifts in above processes. The data may contribute to the individualized prevention of KOA in the future.
Subject(s)
Cytokines/physiology , Intercellular Signaling Peptides and Proteins/physiology , Neovascularization, Pathologic/pathology , Osteoarthritis, Knee/pathology , Biomarkers/metabolism , Chemokine CXCL10/metabolism , Chemokine CXCL10/physiology , Cytokines/metabolism , Disease Progression , Fibroblast Growth Factor 1/metabolism , Fibroblast Growth Factor 1/physiology , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase 1/physiology , Middle Aged , Neovascularization, Pathologic/metabolism , Osteoarthritis, Knee/metabolism , Pilot Projects , Platelet-Derived Growth Factor/metabolism , Platelet-Derived Growth Factor/physiology , Sex Factors , Tissue Inhibitor of Metalloproteinase-2/metabolism , Tissue Inhibitor of Metalloproteinase-2/physiology , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/physiologyABSTRACT
INTRODUCTION: Endogenous immunoglobulins (Igs) are of fundamental importance in the host defense after microbial infections. However, the therapeutic administration of intravenous IgG (IVIgG) has not yet been shown to improve clinical outcomes in patients suffering from sepsis, and in the case of IgM-containing preparations (IVIgGMA) the positive evidence is only weak. Recently published studies implicate that Ig levels on admission could have an impact on the patient's response to IVIg treatment and on outcomes of critically ill patients. METHODS: In this noninterventional study, the serum levels of IgG, IgM, and IgA were determined in 340 medical patients on ICU admission, and clinical outcomes were prospectively recorded (ICU mortality, need for renal replacement therapy (RRT), need for mechanical ventilation, substitution of coagulation factors, and amount of red cell transfusions). Patients were prospectively grouped according to their main reason for ICU admission (sepsis, respiratory failure, cardiovascular diseases, acute renal failure, postoperative condition, state after cardiopulmonal resuscitation, gastrointestinal diseases, and others). RESULTS AND DISCUSSION: There was no correlation between the Ig levels on admission and ICU mortality neither in the total cohort of medical ICU patients nor in any prespecified subgroup. However, in a logistic regression model that was adjusted for APACHE II score on admission, an increase in serum IgG was associated with a reduced need for mechanical ventilation in patients suffering from cardiovascular disease. On the other hand, in patients suffering from sepsis, an increased level of IgM was linked to an increased administration of coagulation factors. CONCLUSION: Our data do not support the hypothesis that serum levels of immunoglobulins are linked to mortality in medical ICU patients.
Subject(s)
Critical Care , Critical Illness/therapy , Immunoglobulins/blood , Treatment Outcome , Aged , Aged, 80 and over , Critical Illness/mortality , Female , Humans , Immunization, Passive , Male , Middle Aged , Prospective Studies , Statistics as Topic , Survival AnalysisABSTRACT
Primary radiation damage formation in solid materials typically involves collisions between atoms that have up to a few hundred keV of kinetic energy. During these collisions, the distance between two colliding atoms can approach 0.05 nm. At such small atomic separations, force fields fitted to equilibrium properties tend to significantly underestimate the potential energy of the colliding dimer. To enable molecular dynamics simulations of high-energy collisions, it is common practice to use a screened Coulomb force field to describe the interactions and to smoothly join this to the equilibrium force field at a suitable interatomic spacing. However, there is no accepted standard method for choosing the parameters used in the joining process, and our results prove that defect production is sensitive to how the force fields are linked. A new procedure is presented that involves the use of ab initio calculations to determine the magnitude and spatial dependence of the pair interactions at intermediate distances, along with systematic criteria for choosing the joining parameters. Results are presented for the case of nickel, which demonstrate the use and validity of the procedure.
ABSTRACT
SUMMARY: Rhythmic gymnastics as high-impact bone loading sport has positive effects on bone mineralization in prepubertal years. Sclerostin and preadipocyte factor-1 (Pref-1) are hormones that inhibit bone formation. The present study demonstrates that these hormones are higher in gymnasts, and gymnasts present higher bone mineral density (BMD) as compared to controls. INTRODUCTION: Rhythmic gymnasts (RG) start their heavy trainings already in prepuberty and despite of low body fat mass (FM) and hypoleptinemia, their BMD is higher than in non-trained normal girls. The specific role of sclerostin and Pref-1, which are the inhibitors of bone formation, in bone development is not well understood. The impact of sclerostin and Pref-1 levels on BMD, body composition, and adipocytokine values was studied in prepubertal RG and untrained controls (UC). METHODS: Sixty-four 9-10-year-old girls were divided into RG (n = 32) and UC (n = 32) groups. Bone mineral and body composition values were measured by dual-energy X-ray absorptiometry and bone age by X-ray. Sclerostin, Pref-1, leptin, and adiponectin levels were measured from fasting blood samples. RESULTS: Sclerostin (RG 19.8 ± 6.3 pmol/l; UC 15.8 ± 5.4 pmol/l) and Pref-1 (RG 1.6 ± 1.0 ng/ml; UC 1.1 ± 0.5 ng/ml) were higher (p < 0.05) in RG compared with UC. Sclerostin was related to adiponectin (r = 0.41; p < 0.05) in UC. No relationship was found between sclerostin and Pref-1 with BMD values in prepubertal RG and age-matched UC groups. CONCLUSIONS: Sclerostin and Pref-1 levels are higher in RG compared to UC girls. Specific physical activity pattern seen in prepubertal RG has a beneficial effect on bone mineralization despite increased levels of hormones that inhibit bone formation.
Subject(s)
Body Composition/physiology , Bone Density/physiology , Bone Morphogenetic Proteins/blood , Gymnastics/physiology , Intercellular Signaling Peptides and Proteins/blood , Membrane Proteins/blood , Absorptiometry, Photon/methods , Adaptor Proteins, Signal Transducing , Adipokines/blood , Biomarkers/blood , Calcium-Binding Proteins , Case-Control Studies , Child , Female , Genetic Markers , Humans , Puberty/bloodABSTRACT
OBJECTIVE: To detect connections between parameters of ventilation and outcomes of cardiac intensive care patients. DESIGN AND SETTING: Noninterventional study. Between 05/11 and 05/12 all patients with acute heart failure and post cardiopulmonary resuscitation were registered. Lung protective ventilation was defined as peak inspiratory pressure (PIP) < 30 mmHg and tidal volume (Vt) < = 6 ml/kg. RESULTS: In total, 129 patients were included in the study, 68.2 % male, age 67.9 ± 13.4 years, weight 71.4 ± 37.2 kg, predictive body weight 66.9 ± 8.8 kg, mortality 47.3 %. Lung protective ventilated patients at day 1: 17.3 % with a significant difference between surviving and nonsurviving patients (24.1 % vs. 9.6 %; p < 0.05). Logistic regression models showed a strong connection between PIP and survival (odds ratio 1.13; p < 0.05). Vt showed no significant influence on survival. CONCLUSION: Our data recommends a strict observance of a low PIP for cardiac intensive care patients, whereas Vt seems to be of secondary importance.
Subject(s)
Critical Care , Respiration, Artificial , Respiratory Distress Syndrome , Tidal Volume , Aged , Female , Humans , Lung , Male , Middle Aged , Positive-Pressure RespirationABSTRACT
BACKGROUND AND PURPOSE: Although blood pressure reduction has been postulated to result in a fall in cerebral perfusion pressure in patients with intracerebral hemorrhage, the latter is rarely measured. We assessed regional cerebral perfusion pressure in patients with intracerebral hemorrhage by using CT perfusion source data. MATERIALS AND METHODS: Patients with acute primary intracerebral hemorrhage were randomized to target systolic blood pressures of <150 mm Hg (n = 37) or <180 mm Hg (n = 36). Regional maps of cerebral blood flow, cerebral perfusion pressure, and cerebrovascular resistance were generated by using CT perfusion source data, obtained 2 hours after randomization. RESULTS: Perihematoma cerebral blood flow (38.7 ± 11.9 mL/100 g/min) was reduced relative to contralateral regions (44.1 ± 11.1 mL/100 g/min, P = .001), but cerebral perfusion pressure was not (14.4 ± 4.6 minutes(-1) versus 14.3 ± 4.8 minutes(-1), P = .93). Perihematoma cerebrovascular resistance (0.34 ± 0.11 g/mL) was higher than that in the contralateral region (0.30 ± 0.10 g/mL, P < .001). Ipsilateral and contralateral cerebral perfusion pressure in the external (15.0 ± 4.6 versus 15.6 ± 5.3 minutes(-1), P = .15) and internal (15.0 ± 4.8 versus 15.0 ± 4.8 minutes(-1), P = .90) borderzone regions were all similar. Borderzone cerebral perfusion pressure was similar to mean global cerebral perfusion pressure (14.7 ± 4.7 minutes(-1), P ≥ .29). Perihematoma cerebral perfusion pressure did not differ between blood pressure treatment groups (13.9 ± 5.5 minutes(-1) versus 14.8 ± 3.4 minutes(-1), P = .38) or vary with mean arterial pressure (r = -0.08, [-0.10, 0.05]). CONCLUSIONS: Perihematoma cerebral perfusion pressure is maintained despite increased cerebrovascular resistance and reduced cerebral blood flow. Aggressive antihypertensive therapy does not affect perihematoma or borderzone cerebral perfusion pressure. Maintenance of cerebral perfusion pressure provides physiologic support for the safety of blood pressure reduction in intracerebral hemorrhage.
Subject(s)
Cerebral Hemorrhage/physiopathology , Cerebrovascular Circulation/physiology , Intracranial Pressure/physiology , Acute Disease , Aged , Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , Cerebral Hemorrhage/diagnostic imaging , Female , Humans , Intracranial Pressure/drug effects , Male , Middle Aged , Tomography, X-Ray ComputedABSTRACT
Most of the atomistic modeling of semicoherent metal-metal interfaces has so far been based on the use of semiempirical interatomic potentials. We show that key conclusions drawn from previous studies are in contradiction with more precise ab-initio calculations. In particular we find that single point defects do not delocalize, but remain compact near the interfacial plane in Cu-Nb multilayers. We give a simple qualitative explanation for this difference on the basis of the well known limited transferability of empirical potentials.
ABSTRACT
OBJECTIVE: To determine the value of bone markers in early-stage progressive knee osteoarthritis (OA), a population-based cohort of middle-aged subjects with chronic knee complaints was followed over 6 years (two consecutive two 3-year periods). METHODS: Tibiofemoral (TF) and patellofemoral (PF) radiographs were graded in 128 subjects (mean age at baseline 45 ± 6.2 years) in 2002, 2005 and 2008. Bone formation was assessed by the serum concentration of procollagen type I amino-terminal propeptide (sPINP); bone resorption by the level of the C-terminal cross-linked telopeptides of type I collagen (sCTx-I); and bone mineralization by the values of osteocalcin (sOC) by electrochemiluminescence immunoassay. A novel marker of bone resorption, urinary osteocalcin midfragments (uMidOC), was assayed using enzyme linked immunosorbent assay (ELISA). RESULTS: Several diagnostic associations were found between the bone markers (PINP, OC, MidOC) and progressive OA expressed by TF osteophytosis. The increasing output of MidOC demonstrated several-fold higher risk for progressive TF osteophytosis [odds ratio (OR) 5.32; 95% confidence interval (CI) 1.41-20.06, P = 0.014] than other bone markers. The values of PINP had prognostic value for subsequent more severely expressed knee OA progression [r(s) = 0.460, P = 0.005]. CONCLUSIONS: Bone metabolism is activated in early-stage knee OA. OA progression was preceded by the enhanced bone formation (by PINP) and accompanied by the activation of bone formation (by PINP), non-collagenous bone resorption (by MidOC), as well as by changes in mineralization (by OC). All three bone markers had diagnostic value, and one of them, PINP, had also a predictive value for knee OA progression, especially for progressive osteophytosis.
Subject(s)
Collagen Type I/blood , Osteoarthritis, Knee/metabolism , Osteocalcin/metabolism , Peptide Fragments/blood , Peptides/blood , Procollagen/blood , Adult , Biomarkers/metabolism , Bone Resorption/metabolism , Disease Progression , Enzyme-Linked Immunosorbent Assay , Follow-Up Studies , Humans , Middle Aged , Osteogenesis/physiologyABSTRACT
ADAM12 (A disintegrin and metalloprotease) is one of the candidate genes demonstrating susceptibility to osteoarthritis. The purpose of this study was to investigate the relationship between ADAM12-S protein and radiographic knee osteoarthritis (KOA) and its correlation to several bone and cartilage biomarkers. The ADAM12-S protein was measured in 276 subjects (60% women, aged 32-60 years), including 181 individuals with and 95 without radiographic KOA features. The radiographs were obtained from both tibiofemoral (TF) and patellofemoral (PF) joints. The serum levels of ADAM12-S protein were measured by DELFIA1/AutoDELFIA research kit. The ADAM12-S protein was found in detectable ranges in 43 subjects (16 men), without statistical difference between the two genders. In the whole group, the ADAM12-S was related to radiographic KOA grades in TF (P = 0.004) as well in PF joint (P = 0.003). We also found a correlation between ADAM12-S protein and osteophytes in TF and/or PF joints (P = 0.003). No correlations were found between serum levels of S-CTx-I (C-terminal cross-linked telopeptides of type I collagen) or S-PINP (type I procollagen N-terminal propeptide) and ADAM12-S. Similarly, in the whole group, the ADAM12-S protein was not correlated with U-CTx-II (urinary C-telopeptide fragments of type II collagen); however, in the female group, trend to positive correlation between the investigated biomarkers (P = 0.019) was observed. The ADAM12-S protein could be elevated in some KOA cases, and this elevation correlates with the grades of the disease, mostly owning to development of osteophytes. This finding suggests the possible involvement of the ADAM12-S protein in the pathogenesis of KOA.
Subject(s)
ADAM Proteins/metabolism , Cartilage, Articular/diagnostic imaging , Cartilage, Articular/metabolism , Membrane Proteins/metabolism , Osteoarthritis, Knee/diagnostic imaging , Osteoarthritis, Knee/metabolism , ADAM12 Protein , Adult , Arthrography , Biomarkers/metabolism , Cartilage, Articular/pathology , Female , Humans , Male , Middle Aged , Osteoarthritis, Knee/pathologyABSTRACT
OBJECTIVE: To clarify the role of common genetic variation in the Interleukin-1ß (IL1B) and Interleukin-1R antagonist (IL1RN) genes on risk of knee and hip osteoarthritis (OA) and severity of knee OA by means of large-scale meta-analyses. METHODS: We searched PubMed for articles assessing the role of IL1B and IL1RN polymorphisms/haplotypes on the risk of hip and/or knee OA. Novel data were included from eight unpublished studies. Meta-analyses were performed using fixed- and random-effects models with a total of 3595 hip OA and 5013 knee OA cases, and 6559 and 9132 controls respectively. The role of ILRN haplotypes on radiographic severity of knee OA was tested in 1918 cases with Kellgren-Lawrence (K/L) 1 or 2 compared to 199 cases with K/L 3 or 4. RESULTS: The meta-analysis of six published studies retrieved from the literature search and eight unpublished studies showed no evidence of association between common genetic variation in the IL1B or IL1RN genes and risk of hip OA or knee OA (P>0.05 for rs16944, rs1143634, rs419598 and haplotype C-G-C (rs1143634, rs16944 and rs419598) previously implicated in risk of hip OA). The C-T-A haplotype formed by rs419598, rs315952 and rs9005, previously implicated in radiographic severity of knee OA, was associated with reduced severity of knee OA (odds ratio (OR)=0.71 95%CI 0.56-0.91; P=0.006, I(2)=74%), and achieved borderline statistical significance in a random-effects model (OR=0.61 95%CI 0.35-1.06 P=0.08). CONCLUSION: Common genetic variation in the Interleukin-1 region is not associated with prevalence of hip or knee OA but our data suggest that IL1RN might have a role in severity of knee OA.
Subject(s)
Interleukin 1 Receptor Antagonist Protein/antagonists & inhibitors , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin-1beta/genetics , Osteoarthritis, Hip/genetics , Osteoarthritis, Knee/genetics , Polymorphism, Genetic , Adult , Aged , Aged, 80 and over , Female , Genetic Markers , Genetic Predisposition to Disease , Haplotypes , Humans , Male , Middle Aged , Osteoarthritis, Hip/diagnostic imaging , Osteoarthritis, Knee/diagnostic imaging , Radiography , Severity of Illness IndexABSTRACT
OBJECTIVE: To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes. METHODS: Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. We investigated whether different OA definitions result in different association results by creating various hip OA definitions in one large population based cohort (the Rotterdam Study I (RSI)) and testing those for association with gender, age and body mass index using one-way ANOVA. For ROA, we standardized the hip-, knee- and hand ROA definitions and calculated prevalence's of ROA before and after standardization in nine cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment. RESULTS: In this consortium, all studies with SOA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee-, hip- and hand ROA five, four and seven different definitions were used, respectively. Different hip ROA definitions do lead to different association results. For example, we showed in the RSI that hip OA defined as "at least definite joint space narrowing (JSN) and one definite osteophyte" was not associated with gender (P =0.22), but defined as "at least one definite osteophyte" was significantly associated with gender (P=3×10(-9)). Therefore, a standardization process was undertaken for ROA definitions. Before standardization a wide range of ROA prevalence's was observed in the nine cohorts studied. After standardization the range in prevalence of knee- and hip ROA was small. CONCLUSION: Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies.
Subject(s)
Osteoarthritis/diagnosis , Analysis of Variance , Case-Control Studies , Cohort Studies , Female , Humans , Male , Osteoarthritis/epidemiology , Osteoarthritis/genetics , Phenotype , Prevalence , Reference StandardsABSTRACT
OBJECTIVE: Interleukin-6 is a pro-inflammatory cytokine involved in the pathogenesis of osteoarthritis (OA). We investigated the role of two single nucleotide polymorphisms (SNPs) mapping to the promoter of the IL-6 gene on genetic susceptibility to hip and knee OA. METHODS: The -174G/C (rs1800795) and -597G/A (rs1800797) SNPs, implicated in the literature in risk of hip and hand OA, were genotyped in 2511 controls, 1101 hip OA cases and 1904 knee OA cases from four cohorts from the UK and Estonia. Data were analysed in conjuntion with published data on rs1800797 from the Genetics of OA and Lifestyle study (UK) on 791 controls, 1034 knee and 997 hip OA cases and rs1800795 data on 75 hip OA cases and 96 controls from Italy. Cases included both radiographic OA only and radiographic and symptomatic OA. Fixed and random-effects meta-analysis models were tested. RESULTS: No significant association was found with hip OA or knee OA with either SNP nor with the haplotypes formed by them. For individual SNPs the smallest P-value for hip OA was observed using a random-effects model for rs1800795 OR(Gallele)=1.066 (95% CI 0.89-1.28) P<0.49, and significant heterogeneity between cohorts (I(2)=65%, P<0.034) was detected. For knee OA the smallest P-value was seen for rs1800797 OR(Aallele)=1.055 (95%CI 0.98-1.12) P<0.18, no significant heterogeneity was observed (I(2)=0%, P<0.68). CONCLUSIONS: Our data do not support a role for the -174 and -597 IL-6 promoter polymorphisms in genetic susceptibility to knee or hip OA in Caucasian populations.
Subject(s)
Genetic Predisposition to Disease/genetics , Interleukin-6/genetics , Osteoarthritis, Hip/genetics , Osteoarthritis, Knee/genetics , Polymorphism, Single Nucleotide , Cohort Studies , Gene Frequency , Genetic Linkage , Genotype , Humans , Promoter Regions, Genetic , Risk FactorsABSTRACT
OBJECTIVE: One of the recognized candidate genes of osteoarthritis (OA) is the ADAM metallopeptidase domain 12 (meltrin alpha) gene. We investigated the potential role of two single nucleotide polymorphisms (SNP) of the ADAM12 gene in susceptibility to radiographic knee OA and its progression in an Estonian cohort. METHODS: The rs3740199 and rs1871054 polymorphisms were genotyped according to restriction fragment polymorphism in a population-based cohort consisting of 189 subjects selected from the age group 32-55 years. The radiological features of OA were measured in the tibio- and patellofemoral joints (PFJ). The X-ray investigation was repeated 3 years later for estimation of OA progression. RESULTS: We found statistically significant association between rs3740199 polymorphism and patellofemoral OA in male patients (P=0.014), genetic risk was mostly related to CC homozygosity. The same SNP also affected the presence of advanced grade (II+III) osteophytes in the whole group (P=0.042) and the occurrence of osteophytes on the patellar margins in the PFJ (P=0.046). In OA progression the most significant association was found between joint space narrowing of the tibiofemoral joint and rs3740199 SNP in women (P=0.018). The rs1871054 polymorphism was not related to OA susceptibility or to progression traits. In our study the haplotype GC (rs3740199/rs1871054) was associated with reduced risk for development of osteophytes in the PFJ (P=0.041). CONCLUSIONS: We conclude that rs3740199 polymorphism may affect occurrence of knee OA and its progression. We also hypothesize that the genetic contribution of ADAM12 to OA is remarkably gender-dependent and anatomical site-specific.
Subject(s)
ADAM Proteins/genetics , Membrane Proteins/genetics , Mutation, Missense/genetics , Osteoarthritis, Knee/genetics , ADAM12 Protein , Adult , Disease Progression , Estonia , Female , Genetic Predisposition to Disease , Genotype , Humans , Knee Joint/diagnostic imaging , Male , Middle Aged , Osteoarthritis, Knee/diagnostic imaging , Pilot Projects , Polymorphism, Single Nucleotide , RadiographySubject(s)
Extracellular Matrix Proteins/blood , Glycoproteins/blood , Knee Joint/diagnostic imaging , Osteoarthritis, Knee/diagnosis , Adult , Biomarkers/blood , Cartilage Oligomeric Matrix Protein , Cartilage, Articular/diagnostic imaging , Cohort Studies , Female , Humans , Male , Matrilin Proteins , Middle Aged , Osteoarthritis, Knee/diagnostic imaging , Sex Factors , Statistics, Nonparametric , Synovial Membrane/diagnostic imaging , UltrasonographyABSTRACT
Virtually all renal diseases progress to terminal renal failure relatively independently of the initial disease. Arresting the rate of the deterioration of kidney failure has a great impact on reducing the number of patients reaching the stage of expensive renal replacement therapy. Understanding the mechanisms of the progression of kidney disease has greatly been improved during recent years. The nature of the progressive renal damage with various etiologies includes various well-known factors where hemodynamics, renin-angiotensin system (RAS) and progressive proteinuria play the central roles. Proteinuria has to be shown as an independent risk factor for renal disease progression. Also, disturbances in lipid metabolism as well as the later structural lesions contribute to the progression. Various modalities have been used for the prevention of progressive renal disease, e.g. low-protein diet, antihypertensive therapy, antifibrotic therapy. Many recent experimental and clinical studies have shown that besides the systemic blood pressure lowering effect, RAS blocking agents provide renal protective effects via direct, hemodynamic, and indirect, non-hemodynamic, pathways: (1) lowering intraglomerular capillary hydraulic pressure, and increasing the glomerular ultrafiltration coefficient; (2) lowering proteinuria; (3) lowering hyperlipidemia; (4) diminishing kidney growth; (5) diminishing infiltration of macrophages; (6) downregulation of proinflammatory cytokines. Therefore, RAS blocking agents are widely prescribed not only for antihypertensive but also for renoprotective purposes in diabetic and non-diabetic nephropathies.
Subject(s)
Kidney Diseases/physiopathology , Angiotensins/antagonists & inhibitors , Chronic Disease , Humans , Kidney Diseases/diagnosis , Kidney Diseases/prevention & control , Kidney Diseases/urine , Renin/antagonists & inhibitorsABSTRACT
IgG immune complexes are of central importance in the humoral immune system and strongly implicated in the pathogenesis of hematologic and rheumatic autoimmune disorders. Cross-linking of receptors for the Fc domain of IgG antibodies (FcgammaRs) triggers a wide variety of effector functions including phagocytosis, antibody-dependent cellular cytotoxicity, and release of inflammatory mediators, as well as immune complex clearance and regulation of antibody production. In this way, FcgammaR provide an essential feedback between the humoral and cellular immune response. In the past, significant advances have been made in the molecular dissection of FcgammaR function using cellular transfection systems. Current approaches designed to target and change individual FcgammaR genes in mice have given further insight into their specific contributions to systemic processes, also indicating them to be important immunoregulatory receptors involved in various disease states of allergy, autoimmunity, and inflammation. Future work on targeting FcgammaR binding sites in combination with humanized FcgammaR mouse models will lead to novel therapeutic strategies in the treatment of IgG-mediated human disease in which FcgammaR activation plays an integral part.
Subject(s)
Autoimmune Diseases/immunology , Hypersensitivity/immunology , Receptors, IgG/physiology , Anemia, Hemolytic/immunology , Animals , Antigens, CD/chemistry , Antigens, CD/genetics , Antigens, CD/immunology , Antigens, CD/physiology , Glomerulonephritis/immunology , Humans , Immunity, Cellular , Immunoglobulin G/immunology , Mice , Mice, Knockout , Models, Molecular , Receptors, IgG/chemistry , Receptors, IgG/genetics , Receptors, IgG/immunology , Vasculitis/immunologyABSTRACT
The structure for the three human Fc gamma receptors classes Fc gamma RI (CD64), Fc gamma RII (CD32) and Fc gamma RIII (CD16) has been well characterized. Here the IgG binding sites on Fc gamma RII and Fc gamma RII with their responsive FG, BC and C'/E loops on the membrane proximal domains are described in detail. For Fc gamma RI the second extracellular domain is suggested as a key structure of IgG binding. The lower hinge regions of human and murine IgG binding to these Fc receptors and their structural relationship in Fc gamma R-IgG interactions are discussed. The potential of inhibiting the pathophysiological effects of Fc gamma receptors by blocking studies are considered for future therapeutic modalities.
Subject(s)
Binding Sites, Antibody/physiology , Immunoglobulin G/metabolism , Receptors, IgG/physiology , HumansABSTRACT
Numerous mAbs have been generated against Fc gamma RIII (CD16), the low-affinity receptor for the Fc part of IgG. Most of the mAbs recognize both the receptor isoforms, transmembranous Fc gamma RIIIA, and glycosylphosphatidylinositol-linked Fc gamma RIIIB. Binding epitopes of some of the mAbs that differentiate between the two neutrophil Ag (NA) alleles of Fc gamma RIIIB (CLB-Gran11 against NA1; GRM1, BL-LGL/1 against NA2 allele) have been mapped on the first, membrane-distal domain of CD16. We demonstrate that mAbs 3G8, B88-9, CLB-Gran1, MEM-154, and LNK16 almost completely block the receptor's interaction with IgG. Using chimeric Fc gamma RIIIB/Fc epsilon RI receptors and molecular modeling, we localized the epitopes of 3G8 and B88-9 on the putative FG loop of the membrane-proximal Ig-like domain, which we have previously identified as the major binding site for IgG. The epitopes of CLB-Gran1 and MEM-154 are shown to reside in proximity to the FG loop (probably BC or C'E loop). The blocking mAb LNK16 was detected to be directed against the putative C' beta-sheet of the membrane-proximal domain, suggesting that additional residues may be involved in IgG binding of Fc gamma RIII.