Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets.

BACKGROUND: PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is a circulating protein that promotes hypercholesterolemia by decreasing hepatic LDL receptor protein. Under non interventional conditions, its expression is driven by sterol response element binding protein 2 (SREBP2) and follows a diurnal rhythm synchronous with cholesterol synthesis. Plasma PCSK9 is associated to LDL-C and to a lesser extent plasma triglycerides and insulin resistance. We aimed to verify the effect on plasma PCSK9 concentrations of dietary interventions that affect these parameters. METHODS: We performed nutritional interventions in young healthy male volunteers and offspring of type 2 diabetic (OffT2D) patients that are more prone to develop insulin resistance, including: i) acute post-prandial hyperlipidemic challenge (n=10), ii) 4 days of high-fat (HF) or high-fat/high-protein (HFHP) (n=10), iii) 7 (HFruc1, n=16) or 6 (HFruc2, n=9) days of hypercaloric high-fructose diets. An acute oral fat load was also performed in two patients bearing the R104C-V114A loss-of-function (LOF) PCSK9 mutation. Plasma PCSK9 concentrations were measured by ELISA. For the HFruc1 study, intrahepatocellular (IHCL) and intramyocellular lipids were measured by 1H magnetic resonance spectroscopy. Hepatic and whole-body insulin sensitivity was assessed with a two-step hyperinsulinemic-euglycemic clamp (0.3 and 1.0 mU.kg-1.min-1). FINDINGS: HF and HFHP short-term diets, as well as an acute hyperlipidemic oral load, did not significantly change PCSK9 concentrations. In addition, post-prandial plasma triglyceride excursion was not altered in two carriers of PCSK9 LOF mutation compared with non carriers. In contrast, hypercaloric 7-day HFruc1 diet increased plasma PCSK9 concentrations by 28% (p=0.05) in healthy volunteers and by 34% (p=0.001) in OffT2D patients. In another independent study, 6-day HFruc2 diet increased plasma PCSK9 levels by 93% (p<0.0001) in young healthy male volunteers. Spearman's correlations revealed that plasma PCSK9 concentrations upon 7-day HFruc1 diet were positively associated with plasma triglycerides (r=0.54, p=0.01) and IHCL (r=0.56, p=0.001), and inversely correlated with hepatic (r=0.54, p=0.014) and whole-body (r=-0.59, p=0.0065) insulin sensitivity. CONCLUSIONS: Plasma PCSK9 concentrations vary minimally in response to a short term high-fat diet and they are not accompanied with changes in cholesterolemia upon high-fructose diet. Short-term high-fructose intake increased plasma PCSK9 levels, independent on cholesterol synthesis, suggesting a regulation independent of SREBP-2. Upon this diet, PCSK9 is associated with insulin resistance, hepatic steatosis and plasma triglycerides.

Development of Preliminary Load and Resistance Factor Design of Drilled Shafts in Iowa, RB03-012, 2014

The Federal Highway Administration (FHWA) mandated utilizing the Load and Resistance Factor Design (LRFD) approach for all new bridges initiated in the United States after October 1, 2007. To achieve part of this goal, a database for Drilled Shaft Foundation Testing (DSHAFT) was developed and reported on by Garder, Ng, Sritharan, and Roling in 2012. DSHAFT is aimed at assimilating high-quality drilled shaft test data from Iowa and the surrounding regions. DSHAFT is currently housed on a project website (http://srg.cce.iastate.edu/dshaft) and contains data for 41 drilled shaft tests. The objective of this research was to utilize the DSHAFT database and develop a regional LRFD procedure for drilled shafts in Iowa with preliminary resistance factors using a probability-based reliability theory. This was done by examining current design and construction practices used by the Iowa Department of Transportation (DOT) as well as recommendations given in the American Association of State Highway and Transportation Officials (AASHTO) LRFD Bridge Design Specifications and the FHWA drilled shaft guidelines. Various analytical methods were used to estimate side resistance and end bearing of drilled shafts in clay, sand, intermediate geomaterial (IGM), and rock. Since most of the load test results obtained from O-cell do not pass the 1-in. top displacement criterion used by the Iowa DOT and the 5% of shaft diameter for top displacement criterion recommended by AASHTO, three improved procedures are proposed to generate and extend equivalent top load-displacement curves that enable the quantification of measured resistances corresponding to the displacement criteria. Using the estimated and measured resistances, regional resistance factors were calibrated following the AASHTO LRFD framework and adjusted to resolve any anomalies observed among the factors. To illustrate the potential and successful use of drilled shafts in Iowa, the design procedures of drilled shaft foundations were demonstrated and the advantages of drilled shafts over driven piles were addressed in two case studies.

Grip and load force coordination in cyclical isometric manipulation task is not affected by the feedback type

Background: The relationship between normal and tangential force components (grip force - GF and load force - LF, respectively) acting on the digits-object interface during object manipulation reveals neural mechanisms involved in movement control. Here, we examined whether the feedback type provided to the participants during exertion of LF would influence GF-LF coordination and task performance. Methods. Sixteen young (24.7 ±3.8 years-old) volunteers isometrically exerted continuously sinusoidal FZ (vertical component of LF) by pulling a fixed instrumented handle up and relaxing under two feedback conditions: targeting and tracking. In targeting condition, FZ exertion range was determined by horizontal lines representing the upper (10 N) and lower (1 N) targets, with frequency (0.77 or 1.53 Hz) dictated by a metronome. In tracking condition, a sinusoidal template set at similar frequencies and range was presented and should be superposed by the participants' exerted FZ. Task performance was assessed by absolute errors at peaks (AEPeak) and valleys (AEValley) and GF-LF coordination by GF-LF ratios, maximum cross-correlation coefficients (r max), and time lags. Results: The results revealed no effect of feedback and no feedback by frequency interaction on any variable. AE Peak and GF-LF ratio were higher and rmax lower at 1.53 Hz than at 0.77 Hz. Conclusion: These findings indicate that the type of feedback does not influence task performance and GF-LF coordination. Therefore, we recommend the use of tracking tasks when assessing GF-LF coordination during isometric LF exertion in externally fixed instrumented handles because they are easier to understand and provide additional indices (e.g., RMSE) of voluntary force control. © 2013 Pedão et al.; licensee BioMed Central Ltd.

Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets

Background PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is a circulating protein that promotes hypercholesterolemia by decreasing hepatic LDL receptor protein. Under non interventional conditions, its expression is driven by sterol response element binding protein 2 (SREBP2) and follows a diurnal rhythm synchronous with cholesterol synthesis. Plasma PCSK9 is associated to LDL-C and to a lesser extent plasma triglycerides and insulin resistance. We aimed to verify the effect on plasma PCSK9 concentrations of dietary interventions that affect these parameters. Methods We performed nutritional interventions in young healthy male volunteers and offspring of type 2 diabetic (OffT2D) patients that are more prone to develop insulin resistance, including: i) acute post-prandial hyperlipidemic challenge (n=10), ii) 4 days of high-fat (HF) or high-fat/high-protein (HFHP) (n=10), iii) 7 (HFruc1, n=16) or 6 (HFruc2, n=9) days of hypercaloric high-fructose diets. An acute oral fat load was also performed in two patients bearing the R104C-V114A loss-of-function (LOF) PCSK9 mutation. Plasma PCSK9 concentrations were measured by ELISA. For the HFruc1 study, intrahepatocellular (IHCL) and intramyocellular lipids were measured by 1H magnetic resonance spectroscopy. Hepatic and whole-body insulin sensitivity was assessed with a two-step hyperinsulinemic-euglycemic clamp (0.3 and 1.0 mU.kg-1.min-1). Findings HF and HFHP short-term diets, as well as an acute hyperlipidemic oral load, did not significantly change PCSK9 concentrations. In addition, post-prandial plasma triglyceride excursion was not altered in two carriers of PCSK9 LOF mutation compared with non carriers. In contrast, hypercaloric 7-day HFruc1 diet increased plasma PCSK9 concentrations by 28% (p=0.05) in healthy volunteers and by 34% (p=0.001) in OffT2D patients. In another independent study, 6-day HFruc2 diet increased plasma PCSK9 levels by 93% (p<0.0001) in young healthy male volunteers. Spearman’s correlations revealed that plasma PCSK9 concentrations upon 7-day HFruc1 diet were positively associated with plasma triglycerides (r=0.54, p=0.01) and IHCL (r=0.56, p=0.001), and inversely correlated with hepatic (r=0.54, p=0.014) and whole-body (r=−0.59, p=0.0065) insulin sensitivity. Conclusions Plasma PCSK9 concentrations vary minimally in response to a short term high-fat diet and they are not accompanied with changes in cholesterolemia upon high-fructose diet. Short-term high-fructose intake increased plasma PCSK9 levels, independent on cholesterol synthesis, suggesting a regulation independent of SREBP-2. Upon this diet, PCSK9 is associated with insulin resistance, hepatic steatosis and plasma triglycerides.

Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress.

PDGFR is an important target for novel anticancer therapeutics because it is overexpressed in a wide variety of malignancies. Recently, however, several anticancer drugs that inhibit PDGFR signaling have been associated with clinical heart failure. Understanding this effect of PDGFR inhibitors has been difficult because the role of PDGFR signaling in the heart remains largely unexplored. As described herein, we have found that PDGFR-beta expression and activation increase dramatically in the hearts of mice exposed to load-induced cardiac stress. In mice in which Pdgfrb was knocked out in the heart in development or in adulthood, exposure to load-induced stress resulted in cardiac dysfunction and heart failure. Mechanistically, we showed that cardiomyocyte PDGFR-beta signaling plays a vital role in stress-induced cardiac angiogenesis. Specifically, we demonstrated that cardiomyocyte PDGFR-beta was an essential upstream regulator of the stress-induced paracrine angiogenic capacity (the angiogenic potential) of cardiomyocytes. These results demonstrate that cardiomyocyte PDGFR-beta is a regulator of the compensatory cardiac response to pressure overload-induced stress. Furthermore, our findings may provide insights into the mechanism of cardiotoxicity due to anticancer PDGFR inhibitors.

Sports after Busy Work: Work-Related Cognitive Failure Corresponds to Risk Bearing Behaviors and Athletic Injury

Although employees are encouraged to take exercise after work to keep physically fit, they should not suffer injury. Some sports injuries that occur after work appear to be work-related and preventable. This study investigated whether cognitive failure mediates the influence of mental work demands and conscientiousness on risk-taking and risky and unaware behaviour during after-work sports activities. Participants were 129 employees (36% female) who regularly took part in team sports after work. A structural equation model showed that work-related cognitive failure significantly mediated the influence of mental work demands on risky behaviour during sports (p < .05) and also mediated the directional link between conscientiousness and risky behaviour during sports (p < .05). A path from risky behaviour during sports to sports injuries in the last four weeks was also significant (p < .05). Performance constraints, time pressure, and task uncertainty are likely to increase cognitive load and thereby boost cognitive failures both during work and sports activities after work. Some sports injuries after work could be prevented by addressing the issue of work redesign.

Analytical bearing capacity of strip footing in weightless materials with power-law failure criteria

Sokolovskii’s method of characteristics is extended to provide analytical solutions for the ultimate load at the moment of plastic failure under plane-strain conditions of shallow strip foundations on weightless rigid-plastic media with a noncohesive power-law failure envelope. The formulation is made parametrically in terms of the instantaneous friction angle, and the key idea to obtain the bearing capacity is that information can be transmitted from the free surface (where external loads are known) to the contact plane of the foundation. The methodology can consider foundations adjacent to a slope, external surcharges at the free surface, and inclined loads (both on the slope and on the foundation). Sensitivity analyses illustrate the influence on bearing capacity of changes in the different geometrical parameters involved. An application example is presented and design plots are provided, and model predictions are compared with results of bearing capacity tests under low gravity.

The steady performance of a porous and compliant aerostatic thrust bearing

Recent developments in aerostatic thrust bearings have included: (a) the porous aerostatic thrust bearing containing a porous pad and (b) the inherently compensated compliant surface aerostatic thrust bearing containing a thin elastomer layer. Both these developments have been reported to improve the bearing load capacity compared to conventional aerostatic thrust bearings with rigid surfaces. This development is carried one stage further in a porous and compliant aerostatic thrust bearing incorporating both a porous pad and an opposing compliant surface. The thin elastomer layer forming the compliant surface is bonded to a rigid backing and is of a soft rubber like material. Such a bearing is studied experimentally and theoretically under steady state operating conditions. A mathematical model is presented to predict the bearing performance. In this model is a simplified solution to the elasticity equations for deflections of the compliant surface. Account is also taken of deflections in the porous pad due to the pressure difference across its thickness. The lubrication equations for flow in the porous pad and bearing clearance are solved by numerical finite difference methods. An iteration procedure is used to couple deflections of the compliant surface and porous pad with solutions to the lubrication equations. Comparisons between experimental results and theoretically predicted bearing performance are in good agreement. However these results show that the porous and compliant aerostatic thrust bearing performance is lower than that of a porous aerostatic thrust bearing with a rigid surface in place of the compliant surface. This discovery is accounted to the recess formed in the bearing clearance by deflections of the compliant surface and its effect on flow through the porous pad.

Brush plating of bearing alloys on aluminium alloy shells

The turbocharging of diesel engines has led to increase in temperature, load and corrosive attack of plain bearings. To meet these requirements, overlay plated aluminium alloys are now preferred. Currently, lead-tin alloys are deposited using a zincate layer and nickel strike, as intermediate stages in the process. The nickel has undesirable seizure characteristics and the zincate can given rise to corrosion problems. Consequently, brush plating allows the possible elimination of these stages and a decrease in process together with greater automation. The effect of mode application, on the formation of zincate films, using film growth weight measurements, potential-time studies, peel adhesion testing and Scanning Electron Microscopy was studied, for both SIC and AS15 aluminium alloys. The direct plating of aluminium was also successfully achieved. The results obtained indicate that generally, although lower adhesion resulted when a brush technique was used, satisfactory adhesion for fatigue testing was achieved. Both lead-tin and tin-cobalt overlays were examined and a study of the parameters governing brush plating were carried out using various electrolytes. An experimentally developed small scale rig, was used to produce overlay plated bearings that were fatigue tested until failure. The bearings were then examined and an analysis of the failure mechanisms undertaken. The results indicated that both alloy systems are of the regular codeposition type. Tin-cobalt overlays were superior to conventional lead-tin overlays and remained in good condition, although the lining (substrate) failed. Brush plated lead-tin was unsatisfactory. Sufficient understanding has now been gained, to enable a larger scale automated plant to be produced. This will allow a further study of the technique to be carried out, on equipment that more closely resembles that of a full scale production process.

Rolling bearing vibrations: the effects of varying compliance, manufacturing tolerances and wear

In this study some common types of Rolling Bearing vibrations are analysed in depth both theoretically and experimentally. The study is restricted to vibrations in the radial direction of bearings having pure radial load and a positive radial clearance. The general vibrational behaviour of such bearings has been investigated with respect to the effects of varying compliance, manufacturing tolerances and the interaction between the bearing and the machine structure into which it is fitted. The equations of motion for a rotor supported by a bearing in which the stiffness varies with cage position has been set up and examples of solutions,obtained by digital simulation. is given. A method to calculate amplitudes and frequencies of vibration components due to out of roundness of the inner ring and varying roller diameters has been developed. The results from these investigations have been combined with a theory for bearing/machine frame interaction using mechanical impedance technique, thereby facilitating prediction of the vibrational behaviour of the whole set up. Finally. the effects of bearing fatigue and wear have been studied with particular emphasis on the use of vibration analysis for condition monitoring purposes. A number of monitoring methods have been tried and their effectiveness discussed. The experimental investigation was carried out using two purpose built rigs. For the purpose of analysis of the experimental measurements a digital mini computer was adapted for signal processing and a suite of programs was written. The program package performs several of the commonly used signal analysis processes and :include all necessary input and output functions.

Two near-optimal layouts for trusslike bridge structures bearing uniform weight between supports

Although the primary objective on designing a structure is to support the external loads, the achievement of an optimal layout that reduces all costs associated with the structure is an aspect of increasing interest. The problem of finding the optimal layout for bridgelike structures subjected to a uniform load is considered. The problem is formulated following a theory on economy of frame structures, using the stress volume as the objective function and including the selection of appropriate values for statically indeterminate reactions. It is solved in a function space of finite dimension instead of using a general variational approach, obtaining near-optimal solutions. The results obtained with this profitable strategy are very close to the best layouts known to date, with differences of less than 2% for the stress volume, but with a simpler layout that can be recognized in some real bridges. This strategy could be a guide to preliminary design of bridges subject to a wide class of costs.

Kinesiographic Study Of Masticatory Movements In Denture Wearers With Normal And Resorbed Denture-bearing Areas.

An unfavorable denture-bearing area could compromise denture retention and stability, limit mastication, and possibly alter masticatory motion. The purpose of this study was to evaluate the masticatory movements of denture wearers with normal and resorbed denture-bearing areas. Completely edentulous participants who received new complete dentures were selected and divided into 2 groups (n=15) according to the condition of their denture-bearing areas as classified by the Kapur method: a normal group (control) (mean age, 65.9 ± 7.8 years) and a resorbed group (mean age, 70.2 ± 7.6 years). Masticatory motion was recorded and analyzed with a kinesiographic device. The patients masticated peanuts and Optocal. The masticatory movements evaluated were the durations of opening, closing, and occlusion; duration of the masticatory cycle; maximum velocities and angles of opening and closing; total masticatory area; and amplitudes of the masticatory cycle. The data were analyzed by 2-way ANOVA and the Tukey honestly significant difference post hoc test (α=.05). The group with a resorbed denture-bearing area had a smaller total masticatory area in the frontal plane and shorter horizontal masticatory amplitude than the group with normal denture-bearing area (P<.05). Denture wearers with resorbed denture-bearing areas showed reduced jaw motion during mastication.

Effect of cyclic load on vertical misfit of prefabricated and cast implant single abutment

OBJECTIVES: The purpose of this in vitro study was to evaluate misfit alterations at the implant/abutment interface of external and internal connection implant systems when subjected to cyclic loading. MATERIAL AND METHODS: Standard metal crowns were fabricated for 5 groups (n=10) of implant/abutment assemblies: Group 1, external hexagon implant and UCLA cast-on premachined abutment; Group 2, internal hexagon implant and premachined abutment; Group 3, internal octagon implant and prefabricated abutment; Group 4, external hexagon implant and UCLA cast-on premachined abutment; and Group 5, external hexagon implant and Ceraone abutment. For groups 1, 2, 3 and 5, the crowns were cemented on the abutments and in group 4 crowns were screwed directly on the implant. The specimens were subjected to 500,000 cycles at 19.1 Hz of frequency and non-axial load of 133 N in a MTS 810 machine. The vertical misfit (μm) at the implant/abutment interface was evaluated before (B) and after (A) application of the cyclic loading. Data were analyzed statistically by using two-away ANOVA and Tukey's post-hoc test (p<0.05). RESULTS: Before loading values showed no difference among groups 2 (4.33±3.13), 3 (4.79±3.43) and 5 (3.86±4.60); between groups 1 (12.88±6.43) and 4 (9.67±3.08), and among groups 2, 3 and 4. However, groups 1 and 4 were significantly different from groups 2, 3 and 5. After loading values of groups 1 (17.28±8.77) and 4 (17.78±10.99) were significantly different from those of groups 2 (4.83±4.50), 3 (8.07±4.31) and 5 (3.81±4.84). There was a significant increase in misfit values of groups 1, 3 and 4 after cyclic loading, but not for groups 2 and 5. CONCLUSIONS: The cyclic loading and type of implant/abutment connection may develop a role on the vertical misfit at the implant/abutment interface.

Load Ratio Estimation Through Striation Height and Spacing Analysis of an Aerospace Al Alloy 7475-T7351

It is well known that striation spacing may be related to the crack growth rate, da/dN, through Paris equation, as well as the maximum and minimum loads under service loading conditions. These loads define the load ratio, R, and are considered impossible to be evaluated from the inter-spacing striations analysis. In this way, this study discusses the methodology proposed by Furukawa to evaluate the maximum and minimum loads based on the experimental fact that the relative height of a striation, H, and the striation spacing, s, are strongly influenced by the load ratio, R. Fatigue tests in C(T) specimens were conducted on SAE 7475-T7351 Al alloy plates at room temperature and the results showed a straightforward correlation between the parameters H, s, and R. Measurements of striation height, H, were performed using scanning electron microscopy and field emission gun (FEG) after sectioning the specimen at a large inclined angle to amplify the height of the striations. The results showed that for increasing R the values of H/s tend to increase. Striation height, striation spacing, and load ratio correlations were obtained, which allows one to estimate service loadings from fatigue fracture surface survey.

The frequency of CD127(low) expressing CD4(+)CD25(high) T regulatory cells is inversely correlated with human T lymphotrophic virus type-1 (HTLV-1) proviral load in HTLV-1-infection and HTLV-1-associated myelopathy/tropical spastic paraparesis

Background: CD4(+)CD25(high) regulatory T (T(Reg)) cells modulate antigen-specific T cell responses, and can suppress anti-viral immunity. In HTLV-1 infection, a selective decrease in the function of T(Reg) cell mediated HTLV-1-tax inhibition of FOXP3 expression has been described. The purpose of this study was to assess the frequency and phenotype of T(Reg) cells in HTLV-1 asymptomatic carriers and in HTLV-1-associated neurological disease (HAM/TSP) patients, and to correlate with measures of T cell activation. Results: We were able to confirm that HTLV-1 drives activation, spontaneous IFN gamma production, and proliferation of CD4+ T cells. We also observed a significantly lower proportion of CTLA-4(+) T(Reg) cells (CD4(+)CD25(high) T cells) in subjects with HAM/TSP patients compared to healthy controls. Ki-67 expression was negatively correlated to the frequency of CTLA-4(+) T(Reg) cells in HAM/TSP only, although Ki-67 expression was inversely correlated with the percentage of CD127(low) T(Reg) cells in healthy control subjects. Finally, the proportion of CD127(low) T(Reg) cells correlated inversely with HTLV-1 proviral load. Conclusion: Taken together, the results suggest that T(Reg) cells may be subverted in HAM/TSP patients, which could explain the marked cellular activation, spontaneous cytokine production, and proliferation of CD4(+) T cells, in particular those expressing the CD25(high)CD127(low) phenotype. T(Reg) cells represent a potential target for therapeutic intervention for patients with HTLV-1-related neurological diseases.