Search

Background Hyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain. Methods To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate.1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism. Results A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73 m2; 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings. Conclusions In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia. Clinical Trial r

The inertial properties, both translational and rotational, of an object subjected to motions are crucial information for understanding its dynamics during operation and also design of various practical engineering applications. In the present study, a simple low cost apparatus together with the associated techniques for measuring inertial properties of a motorcycle has been developed. The apparatus was designed to be adapted for a small motorcycle and its variants which typically having an engine capacity of 125±25 cc, a wet mass of about 100±10 kg and a wheelbase of about 1250±50 mm. The apparatus incorporates both the functionalities to determine the CG location, and also the rotational inertia, or the mass moment of inertia (MMI), of motorcycles with respect to the x-, y- and zaxis in orthogonal coordinate system in a few standardized simple steps. The underlying concept of the present designed method are based on a free hanging compound pendulum for locating the CG location of a test object, and based on the theory of periodic oscillation of a pendulum for determining the rotational inertia quantities. The general flow of operation of the measurement was presented, along with the relevant mathematical formulae for calculating the corresponding inertia quantities. Performance of the apparatus was also evaluated and the deviations were found to be within the acceptable range of 2-6%.

A surprisingly high number of shallow water sponge species (197) were recorded from extensive sampling of natural intertidal and subtidal habitats in Singapore (Southeast Asia) from May 2003 to June 2010. This is in spite of a highly modified coastline that encompasses one of the world’s largest container ports as well as extensive oil refining and bunkering industries. A total of 99 intertidal species was recorded in this study. Of these, 53 species were recorded exclusively from the intertidal zone and only 45 species were found on both intertidal and subtidal habitats, suggesting that tropical intertidal and subtidal sponge assemblages are different and distinct. Furthermore, only a third of the fouling species of sponges from a previous study was recorded in this study, thus suggesting that sponge assemblages from natural and fouling communities in the tropics are different as well. A new species, Forcepia (Forcepia) vansoesti is described from Singapore. Members of this genus possess unique spicules shaped in the form of a pair of forceps. The new species is distinguished from its congeners in having the largest forceps (nearly 300 μm in length) so far recorded

The thermal reaction norms of 4 closely related intertidal Nacellid limpets, Antarctic (Nacella concinna), New Zealand (Cellana ornata), Australia (C. tramoserica) and Singapore (C. radiata), were compared across environments with different temperature magnitude, variability and predictability, to test their relative vulnerability to different scales of climate warming. Lethal limits were measured alongside a newly developed metric of "duration tenacity", which was tested at different temperatures to calculate the thermal reaction norm of limpet adductor muscle fatigue. Except in C. tramoserica which had a wide optimum range with two break points, duration tenacity did not follow a typical aerobic capacity curve but was best described by a single break point at an optimum temperature. Thermal reaction norms were shifted to warmer temperatures in warmer environments; the optimum temperature for tenacity (T(opt)) increased from 1.0°C (N. concinna) to 14.3°C (C. ornata) to 18.0°C (an average for the optimum range of C. tramoserica) to 27.6°C (C. radiata). The temperature limits for duration tenacity of the 4 species were most consistently correlated with both maximum sea surface temperature and summer maximum in situ habitat logger temperature. Tropical C. radiata, which lives in the least variable and most predictable environment, generally had the lowest warming tolerance and thermal safety margin (WT and TSM; respectively the thermal buffer of CT(max) and T(opt) over habitat temperature). However, the two temperate species, C. ornata and C. tramoserica, which live in a variable and seasonally unpredictable microhabitat, had the lowest TSM relative to in situ logger temperature. N. concinna which lives in the most variable, but seasonally predictable microhabitat, generally had the highest TSMs. Intertidal animals live at the highly variable interface between terrestrial and marine biomes and even small changes in the magnitude and predictability of their environment

This study was carried out to compare the surface morphological changes and cell-to-cell attachment with different concentrations of gentamicin-coated hydroxyapatite (HA) on the osteoblast cell lines. Osteoblast cell lines were cultured and maintained in complete medium, 1:1 HAM’s F12 Medium Dulbecco's modified Eagle's medium without phenol red (DMEM) and incubated at 37oC in 5% CO2. The cell lines were treated with gentamicin-coated HA and undergone the 3-(4,5-di-methylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) assay. After 72 hours treatment, the gentamicin-coated HA was processed for viewing the morphological changes by using scanning electron microscopy. The MTT assay results indicated that varying concentrations of gentamicin coated hydroxyapatite do not significantly affect viability of osteoblast. The osteoblast-like cells attached and spread well on the surface of hydroxyapatite and grew into the pores. In conclusion, the gentamicin-coated HA is biocompatible towards osteoblast.

A two-step process with an intermediate annealing was used in an attempt to improve the critical current density (Jc) through a core densification of in situ MgB2/Fe wires. MgB2/Fe wires were first drawn to an outer diameter of 1.9mm, and heat-treated at 600º for 0.5, 1, 2 and 4 h in flowing Ar gas as an intermediate annealing (IA) step. In the cases of the wires heat-treated at 600ºC for 0.5-2h, un-reacted Mg and MgB2 phases coexisted. The sample heat-treated for 4 h showed a full MgB2 formation through a solid state reaction. The intermediate-annealed wires were then further drawn to an outer diameter of 1.42 mm as an attempt to reduce the porosity. This second mechanical deformation crushed the super-conducting grains into smaller pieces and mixed preformed MgB2 phase with un-reacted Mg and B powders. And then, the second heat-treatment was performed at 650ºC for 0.5 h. The Jc values of the MgB2 wires prepared with an intermediate annealing step were notably lower, over a wide range of magnetic fields, when compared to the reference sample heat-treated once at 650ºC for 0.5 h. The decrease in Jc is probably due to the introduction of a large amount of weak links between the grains.

The influence of heating rates and annealing temperatures on the transition temperatures (Tc) and critical current densities (Jc) of pure MgB2, carbon nanotube- and nano-SiC-doped in situ monofilamentary MgB2/Fe wires was investigated. It was found that higher Jc was obtained for pure MgB2 samples when heat treated with slower heating rates. SiC-doped samples also have higher Jc with slower heating rates, but the Jc is less sensitive to annealing temperatures. However, the Jc of the carbon nanotube-doped wire was found to be insensitive to heating rates. The variation in Tc and Jc with heating rate, and the different behaviors of differently doped MgB2/Fe wires, make it essential to carefully select the optimum heating rates for heat treatment.

Dasatinib treatment leads to excellent molecular responses in chronic phase chronic myeloid leukemia (CP-CML). Pleural effusions, an adverse event related dasatinib treatment, may lead to intolerance and drug discontinuations. Strategies aimed at minimising this may improve outcomes. In the Phase III Dasision study, pleural effusion affected ~22% of patients after 4 years of dasatinib treatment at 100mg/d (Cortes et al, 2016 JCO 34(20) 2333-40). The elderly are at particular risk (Latagliata et al 2013 Hem Onc 31(2) 103-9), and there is suggestion that higher dasatinib trough (Cmin) levels may increase the risk of pleural effusions. The randomised OPTIM study (EHA 2014 abstract 5678) has previously reported that patients with Cmin >3nM benefited from dose reductions with preservation of molecular responses. The CML12 (DIRECT) study, run by the Australasian Leukaemia & Lymphoma Group (ALLG) with financial support from BMS, is a single arm phase II study with the aim of minimizing dasatinib related toxicity whilst preserving efficacy using a similar treatment schema to the OPTIM study. Here, we report results of a per-protocol interim analysis based on early molecular response (EMR; BCR-ABL1 <=10% at 3 months) and MMR (BCR-ABL1 <=0.1%) at 12 months, both key secondary endpoints of the study. The primary endpoint of the study- the cumulative incidence of pleural effusion at 24 months - is not yet evaluable. DIRECT initially only enrolled patients >60 years old, predicted to derive the greatest potential benefit from a reduction in toxicity. The protocol was amended after 34 pts were accrued to include patients >18 years old at the recommendation of the trial management committee. All patients started treatment with dasatinib 100mg/day. Dasatinib Cmin was taken at 7, 28 and 56 days after treatment commencement. All Cmin directed dose adjustments were made prior to assessment of BCR-ABL1 at 3 months. Patients sequentially dose reduced to 70mg/day, then to 50mg/day, for C

Dasatinib treatment leads to excellent molecular responses in chronic phase chronic myeloid leukemia (CP-CML). Pleural effusions, an adverse event related dasatinib treatment, may lead to intolerance and drug discontinuations. Strategies aimed at minimising this may improve outcomes. In the Phase III Dasision study, pleural effusion affected ~22% of patients after 4 years of dasatinib treatment at 100mg/d (Cortes et al, 2016 JCO 34(20) 2333-40). The elderly are at particular risk (Latagliata et al 2013 Hem Onc 31(2) 103-9), and there is suggestion that higher dasatinib trough (Cmin) levels may increase the risk of pleural effusions. The randomised OPTIM study (EHA 2014 abstract 5678) has previously reported that patients with Cmin >3nM benefited from dose reductions with preservation of molecular responses. The CML12 (DIRECT) study, run by the Australasian Leukaemia & Lymphoma Group (ALLG) with financial support from BMS, is a single arm phase II study with the aim of minimizing dasatinib related toxicity whilst preserving efficacy using a similar treatment schema to the OPTIM study. Here, we report results of a per-protocol interim analysis based on early molecular response (EMR; BCR-ABL1 <=10% at 3 months) and MMR (BCR-ABL1 <=0.1%) at 12 months, both key secondary endpoints of the study. The primary endpoint of the study- the cumulative incidence of pleural effusion at 24 months - is not yet evaluable. DIRECT initially only enrolled patients >60 years old, predicted to derive the greatest potential benefit from a reduction in toxicity. The protocol was amended after 34 pts were accrued to include patients >18 years old at the recommendation of the trial management committee. All patients started treatment with dasatinib 100mg/day. Dasatinib Cmin was taken at 7, 28 and 56 days after treatment commencement. All Cmin directed dose adjustments were made prior to assessment of BCR-ABL1 at 3 months. Patients sequentially dose reduced to 70mg/day, then to 50mg/day, for C

Several recent discoveries of the hallmark features of programmed cell death (PCD) in Plasmodium falciparum have presented the possibility of revealing novel targets for antimalarial therapy. Using a combination of cell-based assays, flow cytometry and fluorescence microscopy, we detected features including mitochondrial dysregulation, activation of cysteine proteases and in situ DNA fragmentation in parasites induced with chloroquine (CQ) and staurosporine (ST). The use of the pan-caspase inhibitor, z-Val-Ala-Asp-fmk (zVAD), and the mitochondria outer membrane permeabilization (MOMP) inhibitor, 4-hydroxytamoxifen, enabled the characterization of a novel CQ-induced pathway linking cysteine protease activation to downstream mitochondrial dysregulation, amplified protease activity and DNA fragmentation. The PCD features were observed only at high (lM) concentrations of CQ. The use of a new synthetic coumarin-labeled chloroquine (CM-CQ) showed that these features may be associated with concentration-dependent differences in drug localization. By further using cysteine protease inhibitors z-Asp-Glu-Val-Asp-fmk (zDEVD), z-Phe-Ala-fmk (zFA), z-Phe-Phe-fmk (zFF), z-Leu-Leu-Leu-fmk (zLLL), E64d and CA-074, we were able to implicate clan CA cysteine proteases in CQ-mediated PCD. Finally, CQ induction of two CQ-resistant parasite strains, 7G8 and K1, reveals the existence of PCD features in these parasites, the extent of which was less than 3D7. The use of the chemoreversal agent verapamil implicates the parasite digestive vacuole in mediating CQ-induced PCD.