The relationship between circulating estrogen levels and cardiometabolic risk factors such as insulin resistance is unclear in postmenopausal women. High estradiol (E
) levels have been reported to ...predict increased risk of type 2 diabetes in this population. We aimed to examine associations among estrogen levels, adiposity measurements, and cardiometabolic risk variables including insulin resistance in postmenopausal women. One hundred-one healthy participants (mean ± SD: age 57 ± 4 yr, BMI 27.9 ± 4.8 kg/m
) were included in the analysis. Fifteen plasma steroids or metabolites were measured by liquid chromatography-tandem mass spectrometry. Insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp. Body composition and fat distribution were determined with hydrostatic weighing and computed tomography, respectively. Blood lipids and circulating cytokines were also measured. Circulating E
was positively correlated with all adiposity indexes ( r = 0.62 to 0.42, P < 0.0001) except waist-to-hip ratio. E
was positively correlated with VLDL-cholesterol, plasma-, VLDL-, and HDL-triglyceride levels ( r = 0.31 to 0.24, P < 0.02) as well as with hs-CRP and IL-6 ( r = 0.52 and 0.29, P < 0.005) and negatively with HDL-cholesterol, adiponectin, and insulin sensitivity ( r = -0.36 to -0.20, P < 0.02). With adjustments for percent body fat, correlations between E
and metabolic risk variables were no longer significant. Similar results were observed for circulating estrone (E
) and estrone-sulfate (E
-S) levels. In conclusion, circulating estrogen concentrations are proportional to adipose mass in postmenopausal women, although they remain in the low range. Insulin resistance as well as altered blood lipids and cytokines are observed when circulating estrogen levels are high within that range, but these differences are explained by concomitant variation in total adiposity.
This article tries to reconsider the relationship to work that one can develop to the point when it impacts the intimate sphere. To do so, it shall question the role of the sexualisation of the ...suffering between subject and object of a work/job that has become the vector of an enjoyable torment. The study will focus on the clinical case of a patient who is being treated in psychoanalytical psychotherapy (she started the therapy 5 years ago). This patient maintains a relationship to her work that could be defined as "addictive." The approach will be to use the psychodynamics of work (Dejours, 1992. "Pathologie de la communication. Situation de travail et espace public: le cas du nucléaire." In Pouvoir et légitimité, Raison pratiques, edited by A. Cotterau and P. Ladrière, vol. 3, 177-201. Paris: Éditions de l'EHESS; 2003. L'évaluation du travail à l'épreuve du réel: Critiques des fondements de l'évaluation. Paris: INRAA Editions) in perspective of Paul Denis's work on satisfaction and influence. Therefore, it will clinically illustrate the process inherent in the subversive and intimate perversion of the relationship to work: between resistance and suffering serving a satisfaction for which the relations of impulsive subordination (between means and goal) have been inverted to the benefit of a repetitive compulsion.
Mathematical models of a cellular action potential (AP) in cardiac modelling have become increasingly complex, particularly in gating kinetics, which control the opening and closing of individual ion ...channel currents. As cardiac models advance towards use in personalized medicine to inform clinical decision-making, it is critical to understand the uncertainty hidden in parameter estimates from their calibration to experimental data. This study applies approximate Bayesian computation to re-calibrate the gating kinetics of four ion channels in two existing human atrial cell models to their original datasets, providing a measure of uncertainty and indication of potential issues with selecting a single unique value given the available experimental data. Two approaches are investigated to reduce the uncertainty present: re-calibrating the models to a more complete dataset and using a less complex formulation with fewer parameters to constrain. The re-calibrated models are inserted back into the full cell model to study the overall effect on the AP. The use of more complete datasets does not eliminate uncertainty present in parameter estimates. The less complex model, particularly for the fast sodium current, gave a better fit to experimental data alongside lower parameter uncertainty and improved computational speed. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.
Severe obesity is associated with major health issues and bariatric surgery is still the only treatment to offer significant and durable weight loss. Assessment of dietary intakes is an important ...component of the bariatric surgery process. Objective: To document the dietary assessment tools that have been used with patients targeted for bariatric surgery and patients who had bariatric surgery and explore the extent to which these tools have been validated. Methods: A literature search was conducted to identify studies that used a dietary assessment tool with patients targeted for bariatric surgery or who had bariatric surgery. Results: 108 studies were included. Among all studies included, 27 used a dietary assessment tool that had been validated either as part of the study per se (n = 11) or in a previous study (n = 16). Every tool validated per se in the cited studies was validated among a bariatric population, while none of the tools validated in previous studies were validated in this population. Conclusion: Few studies in bariatric populations used a dietary assessment tool that had been validated in this population. Additional studies are needed to develop valid and robust dietary assessment tools to improve the quality of nutritional studies among bariatric patients.
Recent evidences suggest that the activity of glycogen synthase kinase-3 (GSK3) contributes to the tumorigenic potential of pancreatic cancer cells through modulation of cell proliferation and ...survival. However, further investigations are needed to identify GSK3-dependent mechanisms involved in the control of pancreatic cancer cell proliferation and survival. This study was undertaken to provide further support for a role of GSK3 in pancreatic cancer cell growth as well as to identify new cellular and molecular mechanisms involved. Herein, we demonstrate that prolonged inhibition of GSK3 triggers an apoptotic response only in human pancreatic cancer cells but not in human non-transformed pancreatic epithelial cells. We show that prolonged inhibition of GSK3 activity increases Bim messenger RNA and protein expressions. Moreover, we provide evidence that activation of the c-jun N-terminal kinase (JNK) pathway is necessary for the GSK3 inhibition-mediated increase in Bim expression and apoptotic response. Finally, we demonstrate that concomitant inhibition of GSK3 potentiates the death ligand-induced apoptotic response in pancreatic cancer cells but not in non-transformed pancreatic epithelial cells and that this effect also requires JNK activity. Considering that different approaches leading to stimulation of death receptor signaling are under clinical trials for treatment of unresectable or metastatic pancreatic cancer, inhibition of GSK3 could represent an attractive new avenue to improve their effectiveness.
Ca/calmodulin-dependent protein kinase II (CaMKII) was shown to increase diastolic sarcoplasmic reticulum (SR) Ca leak, which can result in delayed afterdepolarizations and triggered arrhythmias. ...Since increased CaMKII expression and activity has been mechanistically linked to arrhythmias in human heart failure (HF) and atrial fibrillation (AF), specific strategies aimed at CaMKII inhibition may have therapeutic potential.
We tested the antiarrhythmic and inotropic effects of a novel selective and ATP-competitive CaMKII inhibitor (GS-680).
Trabeculae were isolated from right atrial appendage biopsies of patients undergoing cardiac surgery. Premature atrial contractions (PACs) were induced by stimulation with isoproterenol (ISO, 100 nM) at increased Cao (3.5 mM). Interestingly, compared to vehicle, PACs were significantly inhibited by exposure to GS-680 (at 100 and 300 nM). GS-680 also significantly decreased early and delayed afterdepolarizations in isolated human atrial myocytes. Moreover, GS-680 (at 100 or 300 nM) significantly inhibited diastolic SR Ca leak, measured as frequency of spontaneous SR Ca release events (Ca sparks) in isolated human atrial myocytes (Fluo-4 loaded) similar to the well-established peptide CaMKII inhibitor AIP. In accordance, GS-680 significantly reduced CaMKII autophosphorylation (Western blot) but enhanced developed tension after 10 or 30 s pause of electrical stimulation (post-rest behavior). Surprisingly, we found a strong negative inotropic effect of GS-680 in atrial trabeculae at 1 Hz stimulation rate, which was not observed at 4 Hz and abolished by beta-adrenergic stimulation. In contrast, GS-680 did not impair systolic force of isolated ventricular trabeculae from explanted hearts of heart transplant recipients at 1 Hz, blunted the negative force-frequency relationship (1–3 Hz) and significantly increased the Ca transient amplitude.
The novel ATP-competitive and selective CaMKII inhibitor GS-680 inhibits pro-arrhythmic activity in human atrium and improves contractility in failing human ventricle, which may have therapeutic implications.
Display omitted
•The novel CaMKII inhibitor GS-680 inhibits pro-arrhythmic activity in human atrial trabeculae and myocytes•GS-680 potently reduces diastolic SR Ca leak in human cardiomyocytes•GS-680 blunts the negative force-frequency relationship of failing human ventricular trabeculae•GS-680 increases Ca transient amplitude in failing human ventricular myocytes
Oscillation properties are usually measured by fitting symmetric Lorentzian profiles to the power spectra of Sun-like stars. However, the line profiles of solar oscillations have been observed to be ...asymmetrical for the Sun. The physical origin of this line asymmetry is not fully understood; though, it should depend on the depth dependence of the source of wave excitation (convective turbulence) and details of the observable (velocity or intensity). For oscillations of the Sun, it has been shown that neglecting the asymmetry leads to systematic errors in the frequency determination. This could subsequently affect the results of seismic inferences of the solar internal structure. Using light curves from the Kepler spacecraft, we have measured mode asymmetries in 43 stars. We confirm that neglecting the asymmetry leads to systematic errors that can exceed the 1 confidence intervals for seismic observations longer than one year. Therefore, the application of an asymmetric Lorentzian profile should be favored to improve the accuracy of the internal stellar structure and stellar fundamental parameters. We also show that the asymmetry changes sign between cool Sun-like stars and hotter stars. This provides the best constraints to date on the location of the excitation sources across the Hertzsprung-Russel diagram.
•SIMS and TEM techniques were combined to compare the thermal behaviour of Cs and Xe in UO2.•Both elements form bubbles with different growth kinetics.•At 1600 °C, caesium is found to be highly ...mobile in the UO2 matrix while Xe distribution does not evolve.
Xenon and caesium are among the most impacting fission products when studying the nuclear fuel: xenon for its role on the fuel rod thermomechanical behaviour during reactor operation and caesium in the case of atmospheric radioactive release during an accident in a nuclear power plant. This paper focuses on the comparison of caesium and xenon thermal behaviour in polycrystalline uranium dioxide (UO2) pellets. Caesium-133 or xenon-136 stable isotopes were introduced in depleted UO2 samples by ion implantation at a maximum concentration of 0.08 at% at a depth of around 140 nm below the sample surface. Annealing under reducing atmosphere (Ar/H2 5 %) was performed at 1000 °C or 1600 °C, which corresponds respectively to a representative temperature during nuclear reactor operation (at the centre of the fuel pellets) and during an accident. The caesium migration in UO2 was investigated by Secondary Ion Mass Spectrometry and compared to the thermal behaviour of xenon in UO2 at 1600 °C. Transmission Electron Microscopy was performed in order to characterise UO2 microstructure before and after annealing. The results indicate that caesium has a different behaviour than xenon with which it is often compared for its release from the nuclear fuel. In particular, we highlight a difference between the growth kinetics of caesium and of xenon bubbles at 1600 °C which can be correlated to the availability of thermal vacancies in UO2 and to the different ability of Xe and Cs atoms for thermal resolution.
Purpose
Although half of women and one-quarter of men aged 50 and older will sustain an acute low-trauma fracture, less than a quarter receive appropriate secondary fracture prevention. The goal of ...this quality improvement demonstration project was to implement a Fracture Liaison Service (FLS) focused on secondary prevention of an osteoporotic fracture in three open health care systems aided by a cloud-based tool.
Methods
The pre–post study design examined the proportion of men and women over age 50 who received appropriate assessment (bone mineral density, vitamin D levels) and treatment (calcium/vitamin D, pharmacologic therapy) in the six months following a recently diagnosed fracture. The pre-study (Pre FLS) included a retrospective chart review for baseline data (
N
= 344 patients) within each health care system. In the post-evaluation (Post FLS,
N
= 148 patients), the FLS coordinator from each health care system examined these parameters following enrollment and for 6 months following the recently diagnosed fracture. Data were managed in the cloud-based FLS application tool.
Results
Ninety-three participants completed the program. The FLS program increased the percentage of patients receiving bone mineral density testing from 21% at baseline to 93% (
p
< 0.001) Post FLS implementation. Assessments of vitamin D levels increased from 25 to 84% (
p
< 0.001). Patients prescribed calcium/vitamin D increased from 36% at baseline to 93% (
p
< 0.001) and those prescribed pharmacologic treatment for osteoporosis increased on average from 20 to 54% (
p
< 0.001) Post FLS.
Conclusions
We conclude that the FLS model of care in an open health care system, assisted by a cloud-based tool, significantly improved assessment and/or treatment of patients with a recently diagnosed osteoporotic fracture. Future studies are necessary to determine if this model of care is scalable and if such programs result in prevention of fractures. Mini-Abstract: The goal was to implement a Fracture Liaison Service (FLS) focused on secondary prevention of an osteoporotic fracture in open health care systems aided by a cloud-based tool. This model significantly improved assessment and/or treatment of patients with a recently diagnosed fracture.
The learning curve has been established for robotic-assisted total knee arthroplasty (RATKA) during the first month of use; however, there have been no studies evaluating this on a longer term. ...Therefore, the purpose of this study was to compare operative times for three cohorts during the first year following adoption of RATKA (initial, 6 months, and 1 year) and a prior cohort of manual TKA. We investigated both mean operative times and the variability of operative time in each cohort. This is a learning curve study comparing a single surgeon's experience using RAKTA. The study groups were made up of two cohorts of 60 cementless RATKAs performed at ∼6 months and 1 year of use. A learning curve was created based on the mean operative times and individual operative times were stratified into different cohorts for comparison. Study groups were compared with the surgeon's initial group of 20 cemented RATKAs and 60 cementless manual cases. Descriptive numbers were compiled and mean operative times were compared using Student's
-tests for significant differences with a
-value of < 0.05. The mean surgical times continued to decrease after 6 months of RATKA. In 1 year, the surgeon was performing 88% of the RATKA between 50 and 69 minutes. The initial cohort and 1-year robotic-assisted mean operative times were 81 and 62 minutes, respectively (
< 0.00001). Mean 6-month robotic-assisted operative times were similar to manual times (
= 0.12). A significant lower time was found between the mean operative times for the 1-year robotic-assisted and manual (
= 0.008) TKAs. The data show continued improvement of operative times at 6 months and 1 year when using this new technology. The results of this study are important because they demonstrate how the complexity of a technology which initially increases operative time can be overcome and become more time-effective than conventional techniques.
PDF
