Serum Uric Acid Levels, but Not rs7442295 Polymorphism of SCL2A9 Gene, Predict Mortality in Clinically Stable Coronary Artery Disease.

Serum uric acid (SUA) has been associated with cardiovascular disease, but up to now whether SUA is an independent cardiovascular risk factor or merely a disease-related epiphenomenon remains still controversial. within the framework of the Verona Heart Study, we prospectively followed 703 subjects with angiographically demonstrated and clinically stable coronary artery disease between May 1996 and March 2007. At baseline, SUA levels were measured in all the patients. Genotype data of SCL2A9 rs7442295 polymorphism, which has been associated with SUA by genome-wide association studies, were available for 686 subjects (97.6%). After a median follow-up of 57 months, 116 patients (16.5%) had died, 83 (11.8%) because of cardiovascular causes. Patients with hyperuricemia, defined by SUA levels above the 75th percentile (≥0.41 mmol/L), had an increased total and cardiovascular mortality rate than those with SUA below this threshold level (23.3% vs 14.1%, P = 0.048 and 19.4% vs 9.2%, P = 0.001, respectively, by Kaplan-Meier with Log-Rank test). These associations were confirmed by Cox regression after adjustment for sex, age, other predictors of mortality, coronary revascularization, and drug therapies at discharge (hazard ratio for total mortality 1.87 [1.05-3.34], P = 0.033; hazard ratio for cardiovascular mortality 2.09 [1.03-4.25], P = 0.041). Although associated with SUA levels, rs7442295 polymorphism did not predict total or cardiovascular mortality. our data support that SUA may be a prognostic cardiovascular biomarker, predicting total and cardiovascular mortality in the setting of secondary prevention of coronary artery disease. On the other hand, SCL2A9 gene polymorphism, notwithstanding a clear influence on SUA levels, was not associated with mortality.

Basophil Blood Cell Count Is Associated With Enhanced Factor II Plasma Coagulant Activity and Increased Risk of Mortality in Patients With Stable Coronary Artery Disease: Not Only Neutrophils as Prognostic Marker in Ischemic Heart Disease.

Background White blood cell count, which is inexpensive and widely available in clinical practice, has been proposed to provide prognostic information in coronary artery disease (CAD). Elevated levels of white blood cell subtypes may play different roles in atherothrombosis and predict cardiovascular outcomes. Methods and Results The association between white blood cell counts and mortality was evaluated in 823 subjects with angiographically demonstrated and clinically stable CAD in an observational-longitudinal study. The correlation among white blood cell counts and factor II plasma coagulant activity was analyzed in 750 subjects (554 CAD and 196 CAD-free) not taking anticoagulant drugs. Subjects with overt leukocytosis or leukopenia were excluded. In the longitudinal study after a median follow-up of 61 months, 160 (19.4%) subjects died, 107 (13.0%) of whom from cardiovascular causes. High levels of neutrophils, monocytes, eosinophils, and basophils were associated with an increased mortality rate. In multiadjusted Cox regression models, only neutrophils and basophils remained predictors of total and cardiovascular mortality. The associations remained significant after adjustment for traditional cardiovascular risk factors and by including D-dimer and the chemokine CXCL12 in the regression models. Neutrophils and basophils were also significant predictors of factor II plasma coagulant activity variability after adjustment for blood cell counts, age, sex, inflammatory markers, CAD diagnosis, and prothrombin G20210A polymorphism. Factor II plasma coagulant activity was similarly increased in subjects with high neutrophil and basophil counts and in carriers of the prothrombin 20210A allele. Conclusions Both high neutrophil and basophil blood counts may predict mortality in patients with clinically stable CAD and are associated with enhanced factor II plasma coagulant activity, thereby suggesting underlying prothrombotic mechanisms.

High Plasma Concentration of Apolipoprotein C-III Confers an Increased Risk of Cerebral Ischemic Events on Cardiovascular Patients Anticoagulated With Warfarin.

INTRODUCTION: Apolipoprotein C-III (Apo CIII) is a crucial regulator of triglyceride-rich lipoproteins (TRLs) and influences the risk of cardiovascular diseases. High levels of Apo CIII have been also associated with cerebrovascular events and earlier works showed procoagulant effects of Apo CIII. The main aim was to assess whether the plasma concentration of Apo CIII could confer an increased risk of cerebral ischemic events in anticoagulated patients at high-risk of cardioembolism. METHODS: We systematically checked medical records and quantified cerebral ischemic events in a selected cohort of 118 subjects [median age 68 with interquartile range (IQR) 59-75 years, 66.9% males, 52.5% with coronary artery disease (CAD)], taking anticoagulant therapy with warfarin because of atrial fibrillation (AF) and/or mechanical prosthetic heart valves. All the subjects, enrolled between May 1999 and December 2006, were prospectively followed until death or July 31, 2018. Assessments of complete plasma lipid and apolipoprotein profiles, including Apo A-I, B, CIII, and E, were available for all subjects at enrollment. RESULTS: After a median follow-up of 109 months (IQR, 58-187), 24 subjects (20.3%) had cerebral ischemic events: stroke (n = 15) and TIA (n = 9). Subjects with plasma concentration of Apo CIII above the median value (10.3 mg/dL) had an about three-fold increased risk of stroke/TIA than those with lower levels of Apo C-III [hazard ratio 3.08 (95%CI, 1.22-7.77)]. This result was confirmed in multiple Cox regression models adjusted for gender, age, CAD, AF, diabetes, hypertension, plasma lipids, and CHA2DS2-VASc score. By stratifying the sample on the basis of Apo CIII level and CHA2DS2-VASc score, an additive effect was observed with the highest risk in subjects with both high Apo C-III concentration and CHA2DS2-VASc score. CONCLUSION: High Apo CIII plasma levels may be associated with an increased risk of ischemic stroke/TIA in high-risk cardiovascular patients anticoagulated with warfarin.

Development of Algorithm for Clinical Management of Sickle Cell Bone Disease: Evidence for a Role of Vertebral Fractures in Patient Follow-up.

Sickle-cell disease (SCD) is a worldwide distributed hemoglobinopathy, characterized by hemolytic anemia associated with vaso-occlusive events. These result in acute and chronic multiorgan damage. Bone is early involved, leading to long-term disability, chronic pain and fractures. Here, we carried out a retrospective study to evaluate sickle bone disease (SBD) in a cohort of adults with SCD. We assessed bone density, metabolism and turnover. We also evaluated the presence of fractures and the correlation between SCD severity and skeletal manifestations. A total of 71 patients with SCD were analyzed. The mean age of population was 39 ± 10 years, 56% of which were females. We found osteoporosis in a range between 7% and 18% with a high incidence of vertebral fractures. LDH and AST were predictive for the severity of vertebral fractures, while bone density was not. Noteworthy, we identified -1.4 Standard Deviations T-score as the cutoff for detecting the presence of fractures in patients with SCD. Collectively our data allowed us to develop an algorithm for the management of SBD, which may be useful in daily clinical practice to early intersect and treat SBD.

Aptamer-modified FXa generation assays to investigate hypercoagulability in plasma from patients with ischemic heart disease.

BACKGROUND: High plasma levels of activated Factor VII-Antithrombin complex (FVIIa-AT) have been associated with an increased risk of cardiovascular mortality in patients with stable coronary artery disease (CAD). OBJECTIVES: To investigate if FVIIa-AT levels are associated with activated factor X generation (FXaG) in modified assays. PATIENTS/METHODS: Forty CAD patients were characterized for FVIIa-AT levels by ELISA and for FXaG in plasma. Novel fluorogenic FXaG assays, based on aptamers inhibiting thrombin and/or tissue factor pathway inhibitor (TFPI), were set up. RESULTS: FXaG correlated with FVIIa-AT levels (RAUC = 0.393, P = 0.012). The combination of thrombin inhibition and FXaG potentiation by using anti-thrombin and anti-TFPI aptamers, respectively, favors the study of time parameters. The progressive decrease in lag time from the lowest to the highest FVIIa-AT quartile was magnified by combining TFPI and thrombin inhibitory aptamers, thus supporting increased FXaG activity in the coagulation initiation phase. By exploring FXaG rates across FVIIa-AT quartiles, the largest relative differences were detectable at the early times (the highest versus the lowest quartile; 5.0-fold, P = 0.005 at 45 s; 3.5-fold, P = 0.001 at 55 s), and progressively decreased over time (2.3-fold, P = 0.002 at 75 s; 1.8-fold, P = 0.008 at 95 s; 1.6-fold, P = 0.022 at 115 s). Association between high FVIIa-AT levels and increased FXaG was independent of F7 -323 A1/A2 polymorphism influencing FVIIa-AT levels. CONCLUSIONS: High FVIIa-AT plasma levels were associated with increased FXaG. Hypercoagulability features were specifically detectable in the coagulation initiation phase, which may have implications for cardiovascular risk prediction by either FVIIa-AT complex measurement or modified FXaG assays.

Apolipoprotein C-III Strongly Correlates with Activated Factor VII-Anti-Thrombin Complex: An Additional Link between Plasma Lipids and Coagulation.

Activated factor VII-anti-thrombin (FVIIa-AT) complex is a potential biomarker of pro-thrombotic diathesis reflecting FVIIa-tissue factor (TF) interaction and has been associated with mortality in patients with coronary artery disease (CAD). Previous data indicated plasma lipids as predictors of FVIIa-AT variability, and plasma lipoproteins as potential stimulators of the coagulation cascade. Our aim was to evaluate the relationships between FVIIa-AT plasma concentration and a broad apolipoprotein profile (including ApoA-I, ApoB, ApoC-III and ApoE). Within the framework of the observational Verona Heart Study, we selected 666 subjects (131 CAD-free and 535 CAD, 75.4% males, mean age: 61.1 ± 10.9 years) not taking anticoagulant drugs and for whom plasma samples were available for both FVIIa-AT assay and a complete lipid profile. Plasma concentration of FVIIa-AT levels significantly and directly correlated with total and high-density lipoprotein cholesterol, triglycerides, ApoA-I, ApoC-III and ApoE levels. ApoC-III showed the strongest correlation (R = 0.235, p = 7.7 × 10-10), confirmed in all the sub-group analyses (males/females and CAD/CAD-free). Only ApoC-III remained associated with FVIIa-AT plasma concentration, even after adjustment for sex, age, CAD diagnosis, body mass index, renal function, smoking status, lipid-lowering therapies and FVIIa levels. The APOC3 gene locus-tagging polymorphism rs964184, previously linked with cardiovascular risk and plasma lipids by genome-wide association studies, was associated with both ApoC-III and FVIIa-AT plasma concentration. Our results indicate a strong association between ApoC-III and FVIIa-AT levels, thereby suggesting that an increased ApoC-III concentration may identify subjects with a pro-thrombotic diathesis characterized by an enhanced TF-FVIIa interaction and activity.

Increased plasma thrombin potential is associated with stable coronary artery disease: An angiographically-controlled study.

INTRODUCTION: Coagulation plays a crucial role in coronary artery disease (CAD) contributing to both atherosclerotic plaque development and acute thrombotic complications, like myocardial infarction (MI). Coagulation biomarkers have been linked with ischemic heart disease, but results are still controversial. MATERIALS AND METHODS: D-dimer and thrombin generation, two "overall" coagulation assays, were evaluated in 775 subjects with or without angiographically-proven CAD (170 CAD-free and 605 CAD, 355 of whom with history of previous MI). Subjects taking anticoagulant drugs or with any acute illness were excluded. D-dimer plasma concentration was determined by an immuno-turbidimetric assay. Thrombin generation was assessed as the ability of plasma to generate thrombin triggered by the addition of tissue factor ex-vivo by means of a chromogenic method. RESULTS: Both D-dimer and thrombin generation parameters were associated with several traditional cardiovascular risk factors. Lag-time, time-to-peak, peak height, and Endogenous Thrombin Potential (ETP), as well as D-dimer levels, were higher in CAD patients than in CAD-free subjects. After adjustment for all the traditional risk factors, only ETP levels remained significantly associated with CAD (the highest versus the lowest tertile: OR 2.61 with 95%CI 1.14-5.99), but without improvement of C-statistic. The association of D-dimer vanished after adjustment for inflammatory markers. No difference of either D-dimer or thrombin generation parameters was found between CAD patients with or without previous MI history. CONCLUSIONS: Our results suggest that an increased plasma thrombin potential is characteristic in patients with clinically stable CAD, irrespective of previous MI history and independent of traditional cardiovascular risk factors.

Experimental and numeric stress analysis of titanium and zirconia one-piece dental implants.

PURPOSE: To compare the stress in bone around zirconia and titanium implants under loading. MATERIALS AND METHODS: A one-piece zirconia implant and a replica of the same implant made of commercially pure titanium were embedded in two self-curing acrylic resin blocks. To measure strain, a strain gauge was applied on the surface of the two samples. Loads of 50, 100, and 150 N, with orientations of 30, 45, and 60 degrees with respect to the implant axis were applied on the implant. Strain under all loading conditions on both samples was measured. Three-dimensional virtual replicas of both the implants were reproduced using the finite element method and inserted into a virtual acrylic resin block. All the materials were considered isotropic, linear, and elastic. The same geometry and loading conditions of the experimental setup were used to realize two new models, with the implants embedded within a virtual bone block. RESULTS: Very close values of strain in the two implants embedded in acrylic resin were obtained both experimentally and numerically. The stress states generated by the implants embedded in virtual bone were also very similar, even if the two implants moved differently. Moreover, the stress levels were higher on cortical bone than on trabecular bone. CONCLUSIONS: The stress levels in bone, generated by the two implants, appeared to be very similar. From a mechanical point of view, zirconia is a feasible substitute for titanium.

The effect of temperature on the mechanical behavior of nickel-titanium orthodontic initial archwires.

OBJECTIVES: To investigate and compare the characteristics of commonly used types of traditional and heat-activated initial archwires at different temperatures by plotting their load/deflection graphs and quantifying three parameters describing the discharge plateau phase. MATERIALS AND METHODS: Forty-eight archwires of cross-sectional diameters ranging from 0.010 inches to 0.016 inches were obtained from seven different manufacturers. A modified three-point wire-bending test was performed on three analogous samples of each type of archwire at 55°C and 5°C, simulating an inserted archwire that is subjected to cold or hot drinks during a meal. For each resulting load/deflection curve the plateau section was isolated and the mean value of each parameter for each type of wire was obtained. RESULTS: Permanent strain was exhibited by all wires tested at 55°C. Statistically significant differences were found between almost all wires for the three considered parameters when tested at 55°C and 5°C. Loads were greater at 55°C than at 5°C. Differences were also found between traditional and heat-activated archwires, the latter of which generated longer plateaus at 55°C, shorter plateaus at 5°C, and lighter mean forces at both temperatures. The increase in average force seen with increasing diameter tended to be rather stable at both temperatures. CONCLUSIONS: All nickel-titanium wires tested showed a significant change related to temperature in terms of behavior and force for both traditional and heat-activated wires. Stress under high temperatures can induce permanent strain, whereas the residual strain detected at low temperatures can be recovered from as temperature increases.

Three-dimensional finite-element analysis of a central lower incisor under labial and lingual loads.

INTRODUCTION: The aim was to evaluate the differences between labial and lingual application of an orthodontic force. This was achieved using a three-dimensional CAD design software model of a real lower incisor surrounded by a prismatic representation of the mandibular bone. This model was subjected to various loading conditions, with finite-element analysis. MATERIALS AND METHODS: Cone-beam computed tomography scanning was used to create a three-dimensional geometric model of a lower incisor, together with its simulated periodontal ligament. This model was then meshed and analysed with commercial finite-element code. Various single and combined forces and moments were applied to each side of the simulated lower incisor at the centre of the clinical crown. To evaluate the effects of the various forces considered, the instantaneous displacement and stress generated in the bone and the periodontal ligament were measured, as a comparison of the labial and lingual loading sites. RESULTS: Dental movement was only influenced by the side of the force application when an intrusive component was present. The simulations showed larger displacement when a vertical force was present at the lingual surface. In general, this movement was of the tipping type when the combined forces were applied, while there was greater intrusion upon application of combined forces and an anticlockwise moment to the labial surface. CONCLUSIONS: Application of an intrusive lingual force to a lower incisor appears to generate bodily movement, while the same intrusive labial force appears to lead to labial tipping. Subject to further study, this should be taken into consideration when devising treatment plans for fixed appliances.

Load deflection characteristics and force level of nickel titanium initial archwires.

OBJECTIVES: To investigate and compare the characteristics of commonly used types of traditional and heat-activated initial archwire by plotting their load/deflection graphs and quantifying three suitable parameters describing the discharge plateau phase. MATERIALS AND METHODS: Forty-eight archwires (22 nickel titanium [NiTi] and 26 heat-activated) of cross-sectional diameter ranging from 0.010 to 0.016 inch were obtained from seven different manufacturers. A modified three-point wire-bending test was performed on three analogous samples of each type of archwire at a constant temperature (37.0°C). For each resulting load/deflection curve, the plateau section was isolated, along with the mean value of the average plateau force, the plateau length, and the plateau slope for each type of wire obtained. RESULTS: Statistically significant differences were found between almost all wires for the three parameters considered. Statistically significant differences were also found between traditional and heat-activated archwires, the latter of which generated longer plateaus and lighter average forces. The increase in average force seen with increasing diameter tended to be rather stable, although some differences were noted between traditional and heat-activated wires. CONCLUSIONS: Although great variation was seen in the plateau behavior, heat-activated versions appear to generate lighter forces over greater deflection plateaus. On average, the increase in plateau force was roughly 50% when the diameter was increased by 0.002 inch (from 0.012 to 0.014 and from 0.014 to 0.016 inch) and about 150% when the diameter was increased by 0.004 inch (from 0.012 to 0.016), with differences between traditional and heat-activated wires noted in this case.

A numerical model for durotaxis.

Cell migration is a phenomenon that is involved in several physiological processes. In the absence of external guiding factors it shares analogies with Brownian motion. The presence of biochemical or biophysical cues, on the other hand, can influence cell migration transforming it in a biased random movement. Recent studies have shown that different cell types are able to recognise the mechanical properties of the substratum over which they move and that these properties direct the motion through a process called durotaxis. In this work a 2D mathematical model for the description of this phenomenon is presented. The model is based on the Langevin equation that has been modified to take into account the local mechanical properties of the substratum perceived by the cells. Numerical simulations of the model provide individual cell tracks, whose characteristics can be compared with experimental observations directly. The present model is solved for two important cases: an isotropic substratum, to check that random motility is recovered as a subcase, and a biphasic substratum, to investigate durotaxis. The degree of agreement is satisfactory in both cases. The model can be a useful tool for quantifying relevant parameters of cell migration as a function of the substratum mechanical properties.

Optimal palatal configuration for miniscrew applications.

OBJECTIVE: To test the hypothesis that palatal bone is not able to support titanium miniscrews (11 mm in length and 2 mm in diameter) when subjected to forces normally generated during orthodontic treatment. MATERIALS AND METHODS: The miniscrew-palatal bone system was modeled and analyzed using the commercial finite element method software ANSYS Multiphysics 10.0; tests were done in both a state of total osseointegration and in the absence of it. Calculations were carried out in both cases in configurations where the miniscrew was inserted into two different palatal regions: in the first it was anchored in one layer of cortical bone and in the underlying trabecular bone; in the second, two layers of cortical bone and the trabecular bone in between were involved. Two different loads were taken into account, 240 gf and 480 gf, both of which are within the normal range for orthodontic treatment, and applied to the miniscrew heads. RESULTS: The results demonstrated that the miniscrew inserted into the palate can be anchored to bone and loaded within normal orthodontic force range without exceeding the stress levels that lead to bone fracture. The osseointegrated system was characterized by a lower level of stress than the nonosseointegrated one, but anchorage within the second layer of cortical bone markedly reduced the stress on the trabecular bone, thereby improving the stability of the implant, also in the absence of osseointegration. CONCLUSIONS: The hypothesis is rejected. Miniscrews loaded within the normal orthodontic force range do not exceed the stress levels that lead to bone fracture.