A preliminary assessment of the effects of ATI-2042 in subjects with paroxysmal atrial fibrillation using implanted pacemaker methodology

Aims ATI-2042 (budiodarone) is a chemical analogue of amiodarone with a half life of 7 h. It is electrophysiologically similar to amiodarone, but may not have metabolic and interaction side effects. The sophisticated electrocardiograph logs of advanced DDDRP pacemakers were used to monitor the efficacy of ATI-2042. The aim of this study was to determine the preliminary efficacy and safety of ATI-2042 in patients with paroxsymal atrial fibrillation (PAF) and pacemakers. Methods and results Six women with AF burden (AFB) between 1 and 50% underwent six sequential 2-week study periods. Patients received 200 mg bid of ATI-2042 during Period 2 (p2), 400 mg bid during p3, 600 mg bid during p4, 800 mg bid during p5, and no drug during baseline and washout (p1 and p6). Pacemaker data for the primary outcome measure AFB were downloaded during each period. Mean AFB decreased between baseline and all doses: AFB at baseline (SD) was 20.3 ± 14.6% and mean AFB at 200 mg bid was 5.2 ± 4.2%, at 400 mg bid 5.2 ± 5.2%, at 600 mg bid 2.8 ± 3.4%, and at 800 mg bid 1.5 ± 0.5%. The mean reductions in AFB at all doses of ATI-2042 were statistically significant (P < 0.005). Atrial fibrillation burden increased in washout. Atrial fibrillation episodes tended to increase with ATI-2042, but this was offset by substantial decreases in episode duration. ATI-2042 was generally well tolerated. Conclusion ATI-2042 effectively reduced AFB over all doses studied by reducing mean episode duration. A large-scale study will be required to confirm this effect

Mixed methods, materialism and the micropolitics of the research-assemblage

We assess the potential for mixing social research methods, based upon a materialist and micropolitical analysis of the research-assemblage and of what individual research techniques and methods do in practice. Applying a DeleuzoGuattarian toolkit of assemblages, affects and capacities, we document what happens when research methods and techniques interact with the events they wish to study. Micropolitically, many of these techniques and methods have unintended effects of specifying and aggregating events, with the consequently that the knowledge produced by social inquiry is invested with these specifications and aggregations. We argue that rather than abandoning these social research tools, we may use the micropolitical analysis to assess precisely how each method affects knowledge production, and engineer the research designs we use accordingly. This forms the justification for mixing methods that are highly aggregative or specifying with those that are less so, effectively rehabilitating methods that have often been rejected by social researchers, including surveys and experiments

Development and validation of stability indicating method for determination of sertraline following ICH guidlines and its determination in pharmaceuticals and biological fluids

<p>Abstract</p> <p>Background</p> <p>Sertraline is a well known antidepressant drug which belongs to a class called selective serotonin reuptake inhibitor. Most published methods do not enable studying the stability of this drug in different stress conditions.</p> <p>Results</p> <p>Two new methods were developed for the determination of sertraline (SER). Both methods are based on coupling with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) in borate buffer of pH 7.8 and measuring the reaction product spectrophotometrically at 395 nm (Method I) or spectrofluorimetrically at 530 nm upon excitation at 480 nm (Method II). The response-concentration plots were rectilinear over the range 2-24 μg/mL and 0.25-5 μg/mL for methods I and II respectively with LOD of 0.18 μg/mL and 0.07 μg/mL, and LOQ of 0.56 μg/mL and 0.21 μg/mL for methods I and II, respectively.</p> <p>Conclusion</p> <p>Both methods were applied to the analysis of commercial tablets and the results were in good agreement with those obtained using a reference method. The fluorimetric method was further applied to the in vivo determination of SER in human plasma. A proposal of the reaction pathway was presented. The spectrophotometric method was extended to stability study of SER. The drug was exposed to alkaline, acidic, oxidative and photolytic degradation according to ICH guidelines. Moreover, the method was utilized to investigate the kinetics of oxidative degradation of the drug. The apparent first order rate constant and t_1/2of the degradation reaction were determined.</p

Malaria is an uncommon cause of adult sepsis in south-western Uganda

Malaria is often considered a cause of adult sepsis in malaria endemic areas. However, diagnostic limitations can make distinction between malaria and other infections challenging. Therefore, the objective of this study was to determine the relative contribution of malaria to adult sepsis in south-western Uganda

The Insertion and Transport of Anandamide in Synthetic Lipid Membranes Are Both Cholesterol-Dependent

International audienceBackground: Anandamide is a lipid neurotransmitter which belongs to a class of molecules termed the endocannabinoids involved in multiple physiological functions. Anandamide is readily taken up into cells, but there is considerable controversy as to the nature of this transport process (passive diffusion through the lipid bilayer vs. involvement of putative proteic transporters). This issue is of major importance since anandamide transport through the plasma membrane is crucial for its biological activity and intracellular degradation. The aim of the present study was to evaluate the involvement of cholesterol in membrane uptake and transport of anandamide.Methodology/Principal Findings: Molecular modeling simulations suggested that anandamide can adopt a shape that is remarkably complementary to cholesterol. Physicochemical studies showed that in the nanomolar concentration range, anandamide strongly interacted with cholesterol monolayers at the air-water interface. The specificity of this interaction was assessed by: i) the lack of activity of structurally related unsaturated fatty acids (oleic acid and arachidonic acid at 50 nM) on cholesterol monolayers, and ii) the weak insertion of anandamide into phosphatidylcholine or sphingomyelin monolayers. In agreement with these data, the presence of cholesterol in reconstituted planar lipid bilayers triggered the stable insertion of anandamide detected as an increase in bilayer capacitance. Kinetics transport studies showed that pure phosphatidylcholine bilayers were weakly permeable to anandamide. The incorporation of cholesterol in phosphatidylcholine bilayers dose-dependently stimulated the translocation of anandamide.Conclusions/Significance: Our results demonstrate that cholesterol stimulates both the insertion of anandamide into synthetic lipid monolayers and bilayers, and its transport across bilayer membranes. In this respect, we suggest that besides putative anandamide protein-transporters, cholesterol could be an important component of the anandamide transport machinery. Finally, this study provides a mechanistic explanation for the key regulatory activity played by membrane cholesterol in the responsiveness of cells to anandamide

Identification of Radiopure Titanium for the LZ Dark Matter Experiment and Future Rare Event Searches

The LUX-ZEPLIN (LZ) experiment will search for dark matter particle interactions with a detector containing a total of 10 tonnes of liquid xenon within a double-vessel cryostat. The large mass and proximity of the cryostat to the active detector volume demand the use of material with extremely low intrinsic radioactivity. We report on the radioassay campaign conducted to identify suitable metals, the determination of factors limiting radiopure production, and the selection of titanium for construction of the LZ cryostat and other detector components. This titanium has been measured with activities of $^{238}$U$_{e}$~$<$1.6~mBq/kg, $^{238}$U$_{l}$~$<$0.09~mBq/kg, $^{232}$Th$_{e}$~$=0.28\pm 0.03$~mBq/kg, $^{232}$Th$_{l}$~$=0.25\pm 0.02$~mBq/kg, $^{40}$K~$<$0.54~mBq/kg, and $^{60}$Co~$<$0.02~mBq/kg (68\% CL). Such low intrinsic activities, which are some of the lowest ever reported for titanium, enable its use for future dark matter and other rare event searches. Monte Carlo simulations have been performed to assess the expected background contribution from the LZ cryostat with this radioactivity. In 1,000 days of WIMP search exposure of a 5.6-tonne fiducial mass, the cryostat will contribute only a mean background of $0.160\pm0.001$(stat)$\pm0.030$(sys) counts.Comment: 13 pages, 3 figures, accepted for publication in Astroparticle Physic

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE