Controlled-Release of Tegretol-XR for Treatment of Epileptic Seizures

Fifty million people around the world are currently affected by epilepsy. Fortunately, the disease responds to treatment 70% of the time, but many of the medications prescribed require multiple dosages per day. To ensure patient compliance, prevent adverse consequences due to missed dosing, and to enhance medicative convenience for the patient, Tegretol has engineered as extended-release pill, Tegretol-XR, which delivers carbamazepine at a nearly constant rate for a twelve hour time period. The design of these tablets involves a drug infused matrix surrounded by an insoluble shell, with a small orifice to allow drug release. When water diffuses through the orifice, the interior pill matrix saturates, and carbamazepine begins to elute out of the orifice until depletion, a process that is designed to take twelve hours. Using COMSOL, a Tegretol-XR tablet was modeled as a 2D rectangular, axisymmetrical slab. Researched diffusivity constants were found to precisely model the water and drug flow into and out of the pills. The diffusion of the drug is coupled with the concentration of water, and as the water infuses into the pill, the diffusivity of the drug is altered, ultimately leading to a sustained release of carbamazepine over the allotted twelve hours. Results from our model indicate that drug release closely follows ideal release kinetics and keeps an ample amount of drug in the bloodstream at all times. It was found that altering the orifice size by 5% resulted in changes of up to 16% in final average drug concentration, implicating that this is the most sensitive variable analyzed. Variables like water diffusivity were much less influential to the final solution. Our model of Tegretol-XR gives epileptic patients the option of taking only two pills a day, and thus, significantly lowers the risk of a missed dose

Permeability and Mechanotransduction in Aging Endothelial Cells

<p>Complications from cardiovascular disease, such as a heart attack or a stroke, represent the leading cause of death in the United States and many developed and developing countries. Atherosclerosis is the primary pathology underlying cardiovascular disease. It is caused by an increase in endothelial cell (EC) permeability, leading to the buildup of cholesterol and lipids which form the atherosclerotic plaque. Accelerated aging in regions of atherosclerosis contribute to the development and progression of the disease. The global hypothesis that motivated this research was that activation of deacetylase antioxidant regulator, Sirtuin1 (SIRT1), improved function in senescent endothelial cells ECs by increasing the integrity of cell-cell junctions. In turn, this led to elevated EC permeability, a decline in the response to shear stress, and elevated traction forces.</p><p>Aging of hCB-ECs significantly increased permeability due to changes in tight junction protein localization and phosphorylation. Activation of SIRT1 significantly reduced permeability in aged hCB-ECs and restored junction integrity. ECs under flow also exhibited changes in cell junctions with increasing age. Aged hCB-ECs were less responsive to shear stress, exhibiting lower levels of atheroprotective genes, KLF2 and eNOS. Activation of SIRT1 in aged hCB-ECs restored the response to shear stress by altering localization and phosphorylation of adherens junction protein, VE-cadherin. The endothelial glycocalyx is a layer of proteoglycans and glycoproteins on the surface of ECs that is important in maintaining EC barrier function. In aging ECs, the glycocalyx was thinner and less dense. However, activation of SIRT1 restored the structure of the glycocalyx, suggesting that the positive effect of SIRT1 on elevated permeability in aged hCB-ECs may also be due to restoration of the glycocalyx. Aged hCB-ECs also exhibited elevated traction forces for measurements done with single cells, cell clusters (2 to 3 cells), and cell monolayers (20 to 30 cells). The elevated traction forces correlated with altered actin localization and increased actin filament thickness. Activation of SIRT1 reduced traction forces and decreased actin stress fiber thickness in aged hCB-ECs, suggesting that the effects of SIRT1 on cell-cell junctions alters binding of junction proteins to the actin cytoskeleton and generation of cell traction forces. Together, these results implicate an important role for SIRT1 in regulating permeability and mechanotransduction in aging endothelium.</p>Dissertatio

The lift industry in Hong Kong : regulatory action and capacity building

published_or_final_versionPolitics and Public AdministrationMasterMaster of Public Administratio

Put a limit on it:The protective effects of scarcity heuristics when self-control is low

Low self-control is a state in which consumers are assumed to be vulnerable to making impulsive choices that hurt long-term goals. Rather than increasing self-control, the current research exploits the tendency for heuristic-based thinking in low self-control by employing scarcity heuristics to promote better consumption choices. Results indicate that consumers low in self-control especially benefited and selected more healthy choices when marketed as “scarce” (Study 1), and that a demand (vs supply) scarcity heuristic was most effective in promoting utilitarian products (Study 2) suggests low self-control involves both an enhanced reward orientation and increased tendency to conform to descriptive norms

Clinical outcomes after upgrading from pacemakers to cardiac resynchronization therapy

Background and Aims: Right ventricular pacing may lead to heart failure (HF). Upgrades from pacemakers to cardiac resynchronization therapy (CRT) were excluded from most randomized, controlled trials. We sought to determine the long-term outcomes of upgrading from pacemakers to CRT with (CRT-D) or without (CRT-P) defibrillation in patients with no history of sustained ventricular arrhythmias. Methods and Results: In this observational study, clinical events were quantified in relation to the type of implant (de novo or upgrade) and device type at upgrade (CRT-P or CRT-D). Patients underwent CRT implantation (n = 1,545; 1,314 [85%] de novo implants and 231 [15%] upgrades) over a median of 4.6 years [interquartile range: 2.4 - 7.0]). In analyses of crude event rates, upgrades had a higher total mortality (adjusted hazard ratio [aHR]: 1.33; 95% confidence interval [CI] 0.10-1.61), a higher total mortality or HF hospitalization (aHR: 1.26; 95% CI 1.05-1.51), but similar mortality or hospitalization for major adverse cardiac events (MACEs, aHR: 1.15; 95% CI 0.96-1.38). No group differences emerged in any of these endpoints after propensity score matching. After inverse probability weighting in upgrades, total mortality (HR: 0.55; 95% CI 0.36-0.73), total mortality or HF hospitalization (HR: 0.56; 95% CI 0.34-0.79) and total mortality or hospitalization for MACEs (HR: 0.61; 95% CI 0.40-0.82) were lower after CRT-D than after CRT-P. Conclusion: Upgrading from pacemakers to CRT was associated with a similar long-term risk of mortality and morbidity to de novo CRT. After upgrade, CRT-D was CRT-D was associated with lower mortality than CRT-

High redshift X-ray cooling-core cluster associated with the luminous radio loud quasar 3C186

We present the first results from a new, deep (200ks) Chandra observation of the X-ray luminous galaxy cluster surrounding the powerful (L ~10^47 erg/s), high-redshift (z=1.067), compact-steep-spectrum radio-loud quasar 3C186. The diffuse X-ray emission from the cluster has a roughly ellipsoidal shape and extends out to radii of at least ~60 arcsec (~500 kpc). The centroid of the diffuse X-ray emission is offset by 0.68(+/-0.11) arcsec (5.5+/-0.9 kpc) from the position of the quasar. We measure a cluster mass within the radius at which the mean enclosed density is 2500 times the critical density, r_2500=283(+18/-13)kpc, of 1.02 (+0.21/-0.14)x10^14 M_sun. The gas mass fraction within this radius is f_gas=0.129(+0.015/-0.016). This value is consistent with measurements at lower redshifts and implies minimal evolution in the f_gas(z) relation for hot, massive clusters at 0<z<1.1. The measured metal abundance of 0.42(+0.08/-0.07) Solar is consistent with the abundance observed in other massive, high redshift clusters. The spatially-resolved temperature profile for the cluster shows a drop in temperature, from kT~8 keV to kT~3 keV, in its central regions that is characteristic of cooling core clusters. This is the first spectroscopic identification of a cooling core cluster at z>1. We measure cooling times for the X-ray emitting gas at radii of 50 kpc and 25 kpc of 1.7(+/-0.2)x10^9 years and 7.5(+/-2.6)x 10^8 years, as well as a nominal cooling rate (in the absence of heating) of 400(+/-190)M_sun/year within the central 100 kpc. In principle, the cooling gas can supply enough fuel to support the growth of the supermassive black hole and to power the luminous quasar. The radiative power of the quasar exceeds by a factor of 10 the kinematic power of the central radio source, suggesting that radiative heating may be important at intermittent intervals in cluster cores.Comment: 15 pages, 9 figures, ApJ in pres

Massive amplitudes on the Coulomb branch of N=4 SYM

We initiate a systematic study of amplitudes with massive external particles on the Coulomb-branch of N=4 super Yang Mills theory: 1) We propose that (multi-)soft-scalar limits of massless amplitudes at the origin of moduli space can be used to determine Coulomb-branch amplitudes to leading order in the mass. This is demonstrated in numerous examples. 2) We find compact explicit expressions for several towers of tree-level amplitudes, including scattering of two massive W-bosons with any number of positive helicity gluons, valid for all values of the mass. 3) We present the general structure of superamplitudes on the Coulomb branch. For example, the n-point "MHV-band" superamplitude is proportional to a Grassmann polynomial of mixed degree 4 to 12, which is uniquely determined by supersymmetry. We find explicit tree-level superamplitudes for this MHV band and for other simple sectors of the theory. 4) Dual conformal generators are constructed, and we explore the dual conformal properties of the simplest massive amplitudes. Our compact expressions for amplitudes and superamplitudes should be of both theoretical and phenomenological interest; in particular the tree-level results carry over to truncations of the theory with less supersymmetry.Comment: 29 pages, 1 figur

A Cross-Sectional Characterization of Insulin Resistance by Phenotype and Insulin Clamp in East Asian Americans with Type 1 and Type 2 Diabetes

Classic features of type 1 and type 2 diabetes may not apply in Asian Americans, due to shared absence of common HLA DR-DQ genotype, low prevalence of positive anti-islet antibodies and low BMI in both types of diabetes. Our objective was to characterize diabetic phenotypes in Asian Americans by clamp and clinical features.This was a cross-sectional study conducted in a referral center. Thirty East young Asian American adult volunteers (27.6±5.5 years) with type 1, type 2 diabetes or controls underwent hyperinsulinemic euglycemic clamp to assess insulin resistance and DEXA to assess adiposity.Gender, BMI, waist/hip ratio, leptin, LDL, anti-GAD, anti-IA2 antibodies and C-reactive protein were similar among three groups. Serum C-peptide, adiponectin, free fatty acid, HDL concentrations and truncal fat by DEXA, were different between diabetic groups. Glucose disposal rate by clamp was lowest in type 2 diabetes, followed by type 1 diabetes and controls (5.43±2.70, 7.62±2.59, 8.61±2.37 mg/min/kg, respectively, p = 0.001). Free fatty acid concentration universally plummeted during steady state of the clamp procedure regardless of diabetes types in all three groups. Adipocyte fatty acid binding protein in the entire cohort (r = -0.625, p = 0.04) and controls (r = -0.869, p = 0.046) correlated best with insulin resistance, independent of BMI.Type 2 diabetes in Asian Americans was associated with insulin resistance despite having low BMI as type 1 diabetes, suggesting a potential role for targeting insulin resistance apart from weight loss. Adipocyte fatty acid binding protein, strongly associated with insulin resistance, independent of adiposity in the young Asian American population, may potentially serve as a biomarker to identify at-risk individuals. Larger studies are needed to confirm this finding

Evaluation of the combined use of adiponectin and C-reactive protein levels as biomarkers for predicting the deterioration in glycaemia after a median of 5.4 years

Aims/hypothesis: Hypoadiponectinaemia and raised C-reactive protein (CRP) level are obesity-related biomarkers associated with glucose dysregulation. We evaluated the combined use of these two biomarkers in predicting the deterioration of glycaemia in a prospective study after a median of 5.4 years. Methods: In total 1,288 non-diabetic participants from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2, with high-sensitivity CRP (hsCRP) and total adiponectin levels measured were included. OGTT was performed in all participants. Two hundred and six participants had deterioration of glycaemia at follow-up, whereas 1,082 participants did not. Results: Baseline age, hsCRP and adiponectin levels were significant independent predictors of the deterioration of glycaemia in a Cox regression analysis after adjusting for baseline age, sex, BMI, hypertension, triacylglycerols, 2 h post-OGTT glucose and homeostasis model assessment of insulin resistance index (all p < 0.01). The introduction of hsCRP or adiponectin level to a regression model including the other biomarker improved the prediction of glycaemic progression significantly in all participants, especially in women (all p < 0.01). The combined inclusion of the two biomarkers resulted in a modest improvement in model discrimination, compared with the inclusion of either one alone. Among participants with impaired fasting glucose/impaired glucose tolerance (IFG/IGT) at baseline, hsCRP and adiponectin levels were not predictive of progression or improvement of glycaemic status. Conclusions/interpretation: Adiponectin and hsCRP levels are independent factors in predicting the deterioration of glycaemia, supporting the role of adiposity-related inflammation in the development of type 2 diabetes. Their combined use as predictive biomarkers is especially useful in women, but not in participants with IFG/IGT. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201

A population of gamma-ray emitting globular clusters seen with the Fermi Large Area Telescope

Globular clusters with their large populations of millisecond pulsars (MSPs) are believed to be potential emitters of high-energy gamma-ray emission. Our goal is to constrain the millisecond pulsar populations in globular clusters from analysis of gamma-ray observations. We use 546 days of continuous sky-survey observations obtained with the Large Area Telescope aboard the Fermi Gamma-ray Space Telescope to study the gamma-ray emission towards 13 globular clusters. Steady point-like high-energy gamma-ray emission has been significantly detected towards 8 globular clusters. Five of them (47 Tucanae, Omega Cen, NGC 6388, Terzan 5, and M 28) show hard spectral power indices $(0.7 < \Gamma <1.4)$ and clear evidence for an exponential cut-off in the range 1.0-2.6 GeV, which is the characteristic signature of magnetospheric emission from MSPs. Three of them (M 62, NGC 6440 and NGC 6652) also show hard spectral indices $(1.0 < \Gamma < 1.7)$, however the presence of an exponential cut-off can not be unambiguously established. Three of them (Omega Cen, NGC 6388, NGC 6652) have no known radio or X-ray MSPs yet still exhibit MSP spectral properties. From the observed gamma-ray luminosities, we estimate the total number of MSPs that is expected to be present in these globular clusters. We show that our estimates of the MSP population correlate with the stellar encounter rate and we estimate 2600-4700 MSPs in Galactic globular clusters, commensurate with previous estimates. The observation of high-energy gamma-ray emission from a globular cluster thus provides a reliable independent method to assess their millisecond pulsar populations that can be used to make constraints on the original neutron star X-ray binary population, essential for understanding the importance of binary systems in slowing the inevitable core collapse of globular clusters.Comment: Accepted for publication in A&A. Corresponding authors: J. Kn\"odlseder, N. Webb, B. Pancraz