Disease modification in multiple sclerosis by flupirtine-results of a randomized placebo controlled phase II trial

Central nervous system inflammation and neurodegeneration are the pathophysiological hallmarks of multiple sclerosis (MS). While inflammation can readily be targeted by current disease modifying drugs, neurodegeneration is by far less accessible to treatment. Based on suggested additional neuroprotective capacities of the orally available non-opioid and centrally acting analgesic drug flupirtine maleate we hypothesized that treatment with flupirtine maleate might be beneficial in MS patients. The flupirtine as oral treatment in multiple sclerosis (FLORIMS) study was a multi-center, randomized and stratified, placebo-controlled double-blind phase II trial to investigate safety and efficacy in terms of clinical and radiographical activity of flupirtine maleate (300 mg per day) given orally for 12 months, add-on to interferon beta 1b subcutaneously in patients with relapsing remitting MS. Due to a substantial delay in recruitment, enrolment of patients was prematurely terminated after randomization of only 30 of the originally planned 80 patients. Of these, 24 regularly terminated study after 12 months of treatment. Data were analyzed as originally planned. Treatment with flupirtine maleate was overall well tolerated. We observed moderate and asymptomatic elevations of liver enzymes in several cases but no overt hepatotoxicity. Neither the intention to treat nor the per protocol analysis revealed any significant treatment effects of flupirtine maleate with respect to occurrence of MS relapses, disability progression, or development of new lesions on cranial MRI. However, substantial methodological limitations need to be considered when interpreting these results. In conclusion, the results of the FLORIMS study neither add further evidence to nor argue against the hypothesized neuroprotective or disease modifying effects of flupirtine maleate in MS

Abundance Analysis of HE2148-1247, A Star With Extremely Enhanced Neutron Capture Elements

Abundances for 27 elements in the very metal poor dwarf star HE2148-1247 are presented, including many of the neutron capture elements. We establish that HE2148-1247 is a very highly s-process enhanced star with anomalously high Eu as well, Eu/H about half Solar, demonstrating the large addition of heavy nuclei at [Fe/H] = -2.3 dex. Ba and La are enhanced by a somewhat larger factor and reach the solar abundance, while Pb significantly exceeds it. Ba/Eu is ten times the solar r-process ratio but much less than that of the s-process, indicating a substantial r-process addition as well. C and N are also very highly enhanced. We have found that HE2148-1247 is a radial velocity variable. The C, N and the s-process element enhancements thus presumably were produced through mass transfer from a former AGB binary companion. The large enhancement of heavy r-nuclides also requires an additional source as this is far above any inventory in the ISM at such low [Fe/H]. We further hypothesize that accretion onto the white dwarf from the envelope of the star caused accretion induced collapse of the white dwarf, forming a neutron star, which then produced heavy r-nuclides and again contaminated its companion. (abridged)Comment: Accepted by the Astrophysical Journal. Companion paper by Qian and Wasserburg follow

The CommitmentBank: Investigating projection in naturally occurring discourse

This paper describes a new resource, the CommitmentBank, developed for the empirical investigation of the projection of finite clausal complements. A clausal complement is said to project when its content is understood as a commitment of the speaker even though the clause occurs under the scope of an entailment canceling operator such as negation or a question. The study of projection is therefore part of the study of commitments expressed by speakers to non-asserted sentence content. The content of clausal complements has been a central case for the study of projection, as there is a long-standing claim that clause-taking predicates fall into two classes—factives and nonfactives—distinguished on the basis of whether the contents of their complements project. This claim identifies the embedding predicate as the primary determinant of the projection behavior of these contents. The CommitmentBank is a corpus of naturally occurring discourses whose final sentence contains a clause-embedding predicate under an entailment canceling operator. In this paper, we describe the CommitmentBank and present initial results of analyses designed to evaluate the factive/nonfactive distinction and to investigate additional factors which affect the projectivity of clausal complements

Caveolae in Rabbit Ventricular Myocytes: Distribution and Dynamic Diminution after Cell Isolation

Caveolae are signal transduction centers, yet their subcellular distribution and preservation in cardiac myocytes after cell isolation are not well documented. Here, we quantify caveolae located within 100 nm of the outer cell surface membrane in rabbit single-ventricular cardiomyocytes over 8 h post-isolation and relate this to the presence of caveolae in intact tissue. Hearts from New Zealand white rabbits were either chemically fixed by coronary perfusion or enzymatically digested to isolate ventricular myocytes, which were subsequently fixed at 0, 3, and 8 h post-isolation. In live cells, the patch-clamp technique was used to measure whole-cell plasma membrane capacitance, and in fixed cells, caveolae were quantified by transmission electron microscopy. Changes in cell-surface topology were assessed using scanning electron microscopy. In fixed ventricular myocardium, dual-axis electron tomography was used for three-dimensional reconstruction and analysis of caveolae in situ. The presence and distribution of surface-sarcolemmal caveolae in freshly isolated cells matches that of intact myocardium. With time, the number of surface-sarcolemmal caveolae decreases in isolated cardiomyocytes. This is associated with a gradual increase in whole-cell membrane capacitance. Concurrently, there is a significant increase in area, diameter, and circularity of sub-sarcolemmal mitochondria, indicative of swelling. In addition, electron tomography data from intact heart illustrate the regular presence of caveolae not only at the surface sarcolemma, but also on transverse-tubular membranes in ventricular myocardium. Thus, caveolae are dynamic structures, present both at surface-sarcolemmal and transverse-tubular membranes. After cell isolation, the number of surface-sarcolemmal caveolae decreases significantly within a time frame relevant for single-cell research. The concurrent increase in cell capacitance suggests that membrane incorporation of surface-sarcolemmal caveolae underlies this, but internalization and/or micro-vesicle loss to the extracellular space may also contribute. Given that much of the research into cardiac caveolae-dependent signaling utilizes isolated cells, and since caveolae-dependent pathways matter for a wide range of other study targets, analysis of isolated cell data should take the time post-isolation into account

Shifting the focus: sequential methods of analysis with qualitative data

The purpose of this article is to illustrate both the processes of data analysis and the methodological developmentinvolved in adopting the sequential use of two data analysis methods applied to the same data set. Understanding ofthe phenomena of interest was sought through examining both the content and the form of nurses’ accounts of practiceexperiences. Initially, a method of thematic content analysis was applied to understand what the nurses said abouttheir experiences. The core theme of nurses’ change agency derived from this analysis was examined further througha method of narrative analysis. In the second analysis, the focus was shifted to how the nurses accounted for theirexperiences. The innovative use of iterative, sequential methods of analysis revealed greater complexity and depth ofunderstanding of the phenomena than would have been achieved with one method alone

Distribution of Submerged Aquatic Vegetation in the Chesapeake Bay and Tributaries - 1985

Virginia Institute of Marine Scienc

What projects and why

The empirical phenomenon at the center of this paper is projection, which we define (uncontroversially) as follows: (1) Definition of projection An implication projects if and only if it survives as an utterance implicatio

Innovation Challenges in the Lighting Industry From 1990 to 2006

The lighting industry faces major competitive challenges with the introduction of new solid-state lighting technologies. Solid-state lighting’s greater energy efficiency, lifetime, and other features have led to widespread adoption in backlights, traffic lights, signs, and automobile brake lights, and the technology is targeted to replace ordinary white light bulbs beginning in 2010. The purpose of this study is to assess the state of the emerging solid-state lighting industry and the traditional lighting industry, probing implications for North American industry competitiveness, the location of R&D, and government policy. The methods of the study combined discussions with industry experts, review of trade literature and government policy, and analysis of industry statistics and patent data. Although the big three traditional lighting firms have invested substantially in solid-state lighting, many new firms in the United States, Japan and Taiwan are likely to participate in solid-state lighting. R&D in a reshaped lighting industry may shift somewhat away from the United States and to Asian nations. In Japan, Europe, and the United States, both government funded basic R&D and technology programs and diffusion spurred by energy costs and government incentives have helped aid ongoing developments. This paper reports findings of a study recently carried out for the National Academies, Board on Science, Technology, and Economic Policy. The Alfred P. Sloan Foundation, the National Academies, and the RPI Center for Future Energy Systems provided funding