The application of adaptive step-size control in the numerical simulation of calcium release in vascular smooth muscle

An algorithm for the adaptive control of numerical integration step-size is developed and implemented for the simulation of a three compartment model for Vascular Smooth Muscle. The three compartment model accounts for the simultaneous diffusion of Ca, 45Ca, EGTA, Ca-EGTA, and 45Ca-EGTA, and is an extension of a two compartment model by Diecke for the simultaneous diffusion of Ca, EGTA, and Ca-EGTA. The addition of the third compartment is to account for the presence of the Sarcoplasmic Reticulum which stores the calcium needed for contraction and is the primary regulator of calcium in the VSM cell. The SR has been implicated as the slow component in calcium release, as measured by Stout and Diecke in saponin skinned VSM. The compartmental model is developed from mass-balance equations and is solved numerically with a Runge-Kutta-Gill algorithm. Step-size is controlled with an adaptive algorithm which adjusts the integration interval (step-size) for the transient and steady-state phases of the simulation. The implementation of the various programs is designed to accommodate automated execution and analysis of a high volume of simulation runs. Some introduction into the methodology of modeling and simulation, as well as the complex physiology of the SR is discussed and the complete process of modeling, simulation, and analysis is illustrated for a simple model of a two-compartment leaky tank. A more comprehensive introduction into numerical integration is included to provide sufficient background for the development of the adaptive algorithm. The adaptive algorithm allows a complex simulation to be executed in one-fifth the time required for constant step (non-adaptive) numerical integration without incurring significant error. This reduction in the amount of computer time required permits more aggressive protocols for the determination of parameters and model responses by allowing more simulation runs to be processed in the course of a study. The simulation of calcium release from VSM revealed that the response of the system is not a multiple of the increase in rate but is instead related via a linear function representative of the buffering capacity of the model. Results from a similar two-compartment model suggest that the EGTA buffer system has a significant impact of the perceived rates of release

Optical scattering and backscattering by organic and inorganic particulates in U.S. coastal waters

We present the results of a study of optical scattering and backscattering of particulates for three coastal sites that represent a wide range of optical properties that are found in U.S. near-shore waters. The 6000 scattering and backscattering spectra collected for this study can be well approximated by a power-law function of wavelength. The power-law exponent for particulate scattering changes dramatically from site to site (and within each site) compared with particulate backscattering where all the spectra, except possibly the very clearest waters, cluster around a single wavelength power-law exponent of −0.94 . The particulate backscattering-to-scattering ratio (the backscattering ratio) displays a wide range in wavelength dependence. This result is not consistent with scattering models that describe the bulk composition of water as a uniform mix of homogeneous spherical particles with a Junge-like power-law distribution over all particle sizes. Simultaneous particulate organic matter (POM) and particulate inorganic matter (PIM) measurements are available for some of our optical measurements, and site-averaged POM and PIM mass-specific cross sections for scattering and backscattering can be derived. Cross sections for organic and inorganic material differ at each site, and the relative contribution of organic and inorganic material to scattering and backscattering depends differently at each site on the relative amount of material that is present

Safety of intravenous ferric carboxymaltose versus oral iron in patients with nondialysis-dependent CKD: an analysis of the 1-year FIND-CKD trial.

Background: The evidence base regarding the safety of intravenous (IV) iron therapy in patients with chronic kidney disease (CKD) is incomplete and largely based on small studies of relatively short duration. Methods: FIND-CKD (ClinicalTrials.gov number NCT00994318) was a 1-year, open-label, multicenter, prospective study of patients with nondialysis-dependent CKD, anemia and iron deficiency randomized (1:1:2) to IV ferric carboxymaltose (FCM), targeting higher (400-600 µg/L) or lower (100-200 µg/L) ferritin, or oral iron. A post hoc analysis of adverse event rates per 100 patient-years was performed to assess the safety of FCM versus oral iron over an extended period. Results: The safety population included 616 patients. The incidence of one or more adverse events was 91.0, 100.0 and 105.0 per 100 patient-years in the high ferritin FCM, low ferritin FCM and oral iron groups, respectively. The incidence of adverse events with a suspected relation to study drug was 15.9, 17.8 and 36.7 per 100 patient-years in the three groups; for serious adverse events, the incidence was 28.2, 27.9 and 24.3 per 100 patient-years. The incidence of cardiac disorders and infections was similar between groups. At least one ferritin level ≥800 µg/L occurred in 26.6% of high ferritin FCM patients, with no associated increase in adverse events. No patient with ferritin ≥800 µg/L discontinued the study drug due to adverse events. Estimated glomerular filtration rate remained the stable in all groups. Conclusions: These results further support the conclusion that correction of iron deficiency anemia with IV FCM is safe in patients with nondialysis-dependent CKD

Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia

BACKGROUND Patients with elevated triglyceride levels are at increased risk for ischemic events. Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride levels, but data are needed to determine its effects on ischemic events. METHODS We performed a multicenter, randomized, double-blind, placebo-controlled trial involving patients with established cardiovascular disease or with diabetes and other risk factors, who had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg per deciliter (1.52 to 5.63 mmol per liter) and a low-density lipoprotein cholesterol level of 41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter). The patients were randomly assigned to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS A total of 8179 patients were enrolled (70.7% for secondary prevention of cardiovascular events) and were followed for a median of 4.9 years. A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001); the corresponding rates of the key secondary end point were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P<0.001). The rates of additional ischemic end points, as assessed according to a prespecified hierarchical schema, were significantly lower in the icosapent ethyl group than in the placebo group, including the rate of cardiovascular death (4.3% vs. 5.2%; hazard ratio, 0.80; 95% CI, 0.66 to 0.98; P=0.03). A larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation or flutter (3.1% vs. 2.1%, P=0.004). Serious bleeding events occurred in 2.7% of the patients in the icosapent ethyl group and in 2.1% in the placebo group (P=0.06). CONCLUSIONS Among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower among those who received 2 g of icosapent ethyl twice daily than among those who received placebo. (Funded by Amarin Pharma; REDUCE-IT ClinicalTrials.gov number, NCT01492361

APM Best Practices: Realizing Application Performance Management

The objective of APM Best Practices: Realizing Application Performance Management is to establish reliable application performance management (APM) practices - to demonstrate value, to do it quickly, and to adapt to the client circumstances. It's important to balance long-term goals with short-term deliverables, but without compromising usefulness or correctness. The successful strategy is to establish a few reasonable goals, achieve them quickly, and then iterate over the same topics two more times, with each successive iteration expanding the skills and capabilities of the APM team. This st

PPP1R35 is a novel centrosomal protein that regulates centriole length in concert with the microcephaly protein RTTN

Centrosome structure, function, and number are finely regulated at the cellular level to ensure normal mammalian development. Here, we characterize PPP1R35 as a novel bona fide centrosomal protein and demonstrate that it is critical for centriole elongation. Using quantitative super-resolution microscopy mapping and live-cell imaging we show that PPP1R35 is a resident centrosomal protein located in the proximal lumen above the cartwheel, a region of the centriole that has eluded detailed characterization. Loss of PPP1R35 function results in decreased centrosome number and shortened centrioles that lack centriolar distal and microtubule wall associated proteins required for centriole elongation. We further demonstrate that PPP1R35 acts downstream of, and forms a complex with, RTTN, a microcephaly protein required for distal centriole elongation. Altogether, our study identifies a novel step in the centriole elongation pathway centered on PPP1R35 and elucidates downstream partners of the microcephaly protein RTTN.</p