A multicenter, open-label, long-term safety and tolerability study of DFN-02, an intranasal spray of sumatriptan 10 mg plus permeation enhancer DDM, for the acute treatment of episodic migraine.

BackgroundDFN-02 is a novel intranasal spray formulation composed of sumatriptan 10 mg and a permeation-enhancing excipient comprised of 0.2% 1-O-n-Dodecyl-β-D-Maltopyranoside (DDM). This composition of DFN-02 allows sumatriptan to be rapidly absorbed into the systemic circulation and exhibit pharmacokinetics comparable to subcutaneously administered sumatriptan. Rapid rate of absorption is suggested to be important for optimal efficacy. The objective of this study was to evaluate the safety and tolerability of DFN-02 (10 mg) in the acute treatment of episodic migraine with and without aura over a 6-month period based on the incidence of treatment-emergent adverse events and the evaluation of results of clinical laboratory tests, vital signs, physical examination, and electrocardiograms.MethodsThis was a multi-center, open-label, repeat-dose safety study in adults with episodic migraine with and without aura. Subjects diagnosed with migraine with or without aura according to the criteria set forth in the International Classification of Headache Disorders, 2nd edition, who experienced 2 to 6 attacks per month with fewer than 15 headache days per month and at least 48 headache-free hours between attacks, used DFN-02 to treat their migraine attacks acutely over the course of 6 months.ResultsA total of 173 subjects was enrolled, 167 (96.5%) subjects used at least 1 dose of study medication and were evaluable for safety, and 134 (77.5%) subjects completed the 6-month study. A total of 2211 migraine attacks was reported, and 3292 doses of DFN-02 were administered; mean per subject monthly use of DFN-02 was 3.6 doses. Adverse events were those expected for triptans, as well as for nasally administered compounds. No new safety signals emerged. Dysgeusia and application site pain were the most commonly reported treatment-emergent adverse events over 6 months (21% and 30.5%, respectively). Most of the treatment-emergent adverse events were mild. There were 5 serious adverse events, all considered unrelated to the study medication; the early discontinuation rate was 22.5% over the 6-month treatment period.ConclusionDFN-02 was shown to be well tolerated when used over 6 months to treat episodic migraine acutely

Design and characterization of all-cryogenic low phase-noise sapphire K-band oscillator for sattelite communication

An all-cryogenic oscillator consisting of a frequency-tunable sapphire resonator, a high-temperature superconducting filter and a pseudomorphic high electron-mobility transistor amplifier was designed for the K-band frequency range and investigated. Due to the high quality factor of the resonator above 1000 000 and the low amplifier phase noise of approximately -133 dBc/Hz at a frequency offset of 1kHz from the carrier, we have achieved oscillator phase-noise values superior to quartz-stabilized oscillators at the same carrier frequency for offset frequencies higher than 100 Hz. In addition to, low phase noise, our prototype oscillator possesses mechanical and electrical frequency tunability. We have implemented a two-step electrical tuning arrangement consisting of a varactor phase shifter integrated within the amplifier circuit (fine tuning by 5'kHz) and a dielectric plunger moved by a piezomechanical transducer inside the resonator housing (course tuning by 50 kHz). This tuning range is sufficient for phase locking and for electronic compensation of temperature drifts occurring during operation of the device employing a miniaturized closed-cycle Stirling-type cryocooler

The Container Selection Problem

We introduce and study a network resource management problem that is a special case of non-metric k-median, naturally arising in cross platform scheduling and cloud computing. In the continuous d-dimensional container selection problem, we are given a set C of input points in d-dimensional Euclidean space, for some d >= 2, and a budget k. An input point p can be assigned to a "container point" c only if c dominates p in every dimension. The assignment cost is then equal to the L1-norm of the container point. The goal is to find k container points in the d-dimensional space, such that the total assignment cost for all input points is minimized. The discrete variant of the problem has one key distinction, namely, the container points must be chosen from a given set F of points. For the continuous version, we obtain a polynomial time approximation scheme for any fixed dimension d>= 2. On the negative side, we show that the problem is NP-hard for any d>=3. We further show that the discrete version is significantly harder, as it is NP-hard to approximate without violating the budget k in any dimension d>=3. Thus, we focus on obtaining bi-approximation algorithms. For d=2, the bi-approximation guarantee is (1+epsilon,3), i.e., for any epsilon>0, our scheme outputs a solution of size 3k and cost at most (1+epsilon) times the optimum. For fixed d>2, we present a (1+epsilon,O((1/epsilon)log k)) bi-approximation algorithm

Impaired microcirculatory function, mitochondrial respiration, and oxygen utilization in skeletal muscle of claudicating patients with peripheral artery disease

Peripheral artery disease (PAD) is an atherosclerotic disease that impairs blood flow and muscle function in the lower limbs. A skeletal muscle myopathy characterized by mitochondrial dysfunction and oxidative damage is present in PAD; however, the underlying mechanisms are not well established. We investigated the impact of chronic ischemia on skeletal muscle microcirculatory function and its association with leg skeletal muscle mitochondrial function and oxygen delivery and utilization capacity in PAD. Gastrocnemius samples and arterioles were harvested from patients with PAD (n = 10) and age-matched controls (Con, n = 11). Endothelium-dependent and independent vasodilation was assessed in response to flow (30 μL·min−1), acetylcholine, and sodium nitroprusside (SNP). Skeletal muscle mitochondrial respiration was quantified by high-resolution respirometry, microvascular oxygen delivery, and utilization capacity (tissue oxygenation index, TOI) were assessed by near-infrared spectroscopy. Vasodilation was attenuated in PAD (P \u3c 0.05) in response to acetylcholine (Con: 71.1 ± 11.1%, PAD: 45.7 ± 18.1%) and flow (Con: 46.6 ± 20.1%, PAD: 29.3 ± 10.5%) but not SNP (P = 0.30). Complex I + II state 3 respiration (P \u3c 0.01) and TOI recovery rate were impaired in PAD (P \u3c 0.05). Both flow and acetylcholine-mediated vasodilation were positively associated with complex I + II state 3 respiration (r = 0.5 and r = 0.5, respectively, P \u3c 0.05). Flow-mediated vasodilation and complex I + II state 3 respiration were positively associated with TOI recovery rate (r = 0.8 and r = 0.7, respectively, P \u3c 0.05). These findings suggest that chronic ischemia attenuates skeletal muscle arteriole endothelial function, which may be a key mediator for mitochondrial and microcirculatory dysfunction in the PAD leg skeletal muscle. Targeting microvascular dysfunction may be an effective strategy to prevent and/or reverse disease progression in PAD

Polymer transport in random flow

The dynamics of polymers in a random smooth flow is investigated in the framework of the Hookean dumbbell model. The analytical expression of the time-dependent probability density function of polymer elongation is derived explicitly for a Gaussian, rapidly changing flow. When polymers are in the coiled state the pdf reaches a stationary state characterized by power-law tails both for small and large arguments compared to the equilibrium length. The characteristic relaxation time is computed as a function of the Weissenberg number. In the stretched state the pdf is unstationary and exhibits multiscaling. Numerical simulations for the two-dimensional Navier-Stokes flow confirm the relevance of theoretical results obtained for the delta-correlated model.Comment: 28 pages, 6 figure

Molecular evidence of Late Archean archaea and the presence of a subsurface hydrothermal biosphere

Author Posting. © National Academy of Sciences of the USA, 2007. This is the author's version of the work. It is posted here by permission of National Academy of Sciences of the USA for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences 104 (2007): 14260-14265, doi:10.1073/pnas.0610903104.Highly cracked and isomerized archaeal lipids and bacterial lipids, structurally changed by thermal stress, are present in solvent extracts of 2,707-2,685 million year old (Ma) metasedimentary rocks from Timmins, Ontario, Canada. These lipids appear in conventional gas chromatograms as unresolved complex mixtures (UCMs) and include cyclic and acyclic biphytanes, C36-C39 derivatives of the biphytanes, and C31-C35 extended hopanes. Biphytane and extended hopanes are also found in high pressure catalytic hydrogenation (HPCH) products released from solvent-extracted sediments,indicating that archaea and bacteria were present in Late Archean sedimentary environments. Post-depositional, hydrothermal gold mineralization and graphite precipitation occurred prior to metamorphism (~2,665 Ma). Late Archean metamorphism significantly reduced the kerogen’s adsorptive capacity and severely restricted sediment porosity, limiting the potential for post-Archean additions of organic matter to the samples. Argillites exposed to hydrothermal gold mineralization have disproportionately high concentrations of extractable archaeal and bacterial lipids relative to what is releasable from their respective HPCH product and what is observed for argillites deposited away from these hydrothermal settings. The addition of these lipids to the sediments likely results from a Late Archean subsurface hydrothermal biosphere of archaea and bacteria.This project was supported by NASA Exobiology grant #NAG5-13446 to Fabien Kenig. SEM analysis was supported by NSF grant EAR 0318769 to Juergen Schieber. GC×GC analysis was supported by NSF grant IIS-0430835 and the Seaver Foundation to Christopher M. Reddy

A demonstration of an affinity between pyrite and organic matter in a hydrothermal setting

One of the key-principles of the iron-sulphur world theory is to bring organic molecules close enough to interact with each other, using the surface of pyrite as a substrate in a hydrothermal setting. The present paper explores the relationship of pyrite and organic matter in a hydrothermal setting from the geological record; in hydrothermal calcite veins from Carboniferous limestones in central Ireland. Here, the organic matter is accumulated as coatings around, and through, pyrite grains. Most of the pyrite grains are euhedral-subhedral crystals, ranging in size from ca 0.1-0.5 mm in diameter, and they are scattered throughout the matrix of the vein calcite. The organic matter was deposited from a hydrothermal fluid at a temperature of at least 200°C, and gives a Raman signature of disordered carbon. This study points to an example from a hydrothermal setting in the geological record, demonstrating that pyrite can have a high potential for the concentration and accumulation of organic materials

SeaWiFS technical report series. Volume 19: Case studies for SeaWiFS calibration and validation, part 2

This document provides brief reports, or case studies, on a number of investigations and data set development activities sponsored by the Calibration and Validation Team (CVT) within the Sea-viewing Wide Field-of-view Sensor (SeaWiFS) Project. Chapter 1 is a comparison with the atmospheric correction of Coastal Zone Color Scanner (CZCS) data using two independent radiative transfer formulations. Chapter 2 is a study on lunar reflectance at the SeaWiFS wavelengths which was useful in establishing the SeaWiFS lunar gain. Chapter 3 reports the results of the first ground-based solar calibration of the SeaWiFS instrument. The experiment was repeated in the fall of 1993 after the instrument was modified to reduce stray light; the results from the second experiment will be provided in the next case studies volume. Chapter 4 is a laboratory experiment using trap detectors which may be useful tools in the calibration round-robin program. Chapter 5 is the original data format evaluation study conducted in 1992 which outlines the technical criteria used in considering three candidate formats, the hierarchical data format (HDF), the common data format (CDF), and the network CDF (netCDF). Chapter 6 summarizes the meteorological data sets accumulated during the first three years of CZCS operation which are being used for initial testing of the operational SeaWiFS algorithms and systems and would be used during a second global processing of the CZCS data set. Chapter 7 describes how near-real time surface meteorological and total ozone data required for the atmospheric correction algorithm will be retrieved and processed. Finally, Chapter 8 is a comparison of surface wind products from various operational meteorological centers and field observations. Surface winds are used in the atmospheric correction scheme to estimate glint and foam radiances