| 1. |
- Montagnese, Sara, et al.
(författare)
-
A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy
- 2021
-
Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 75:1, s. 98-107
-
Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis.Methods: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks’ dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days.Results: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well.Conclusion: Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone.Lay summary: Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug.Clinical trial registration number: EudraCT 2016-003651-30.
|
|
| 2. |
- Allard, Erik, et al.
(författare)
-
Comparing capillary electrophoresis : mass spectrometry fingerprints of urine samples obtained after intake of coffee, tea, or water.
- 2008
-
Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 80:23, s. 8946-8955
-
Tidskriftsartikel (refereegranskat)abstract
- Metabolomic fingerprinting is a growing strategy for characterizing complex biological samples without detailed prior knowledge about the metabolic system. A two-way analysis system with liquid separation and mass spectrometric detection provides detail-rich data suitable for such fingerprints. As a model study, human urine samples, obtained after intake of coffee, tea, or water, were analyzed with capillary electrophoresis electrospray ionization time-of-flight mass spectrometry (CE−ESI-TOF-MS). In-house-developed software (in Matlab) was utilized to manage and explore the large amount of data acquired (230 CE−MS runs, each with 50−100 million nonzero data points). After baseline and noise reduction, followed by suitable binning in time and m/z, the data sets comprised 9 and 14 million data points in negative and positive ESI mode, respectively. Finally, a signal threshold was applied, further reducing the number to about 100 000 data points per data set. A set of interactive exploratory tools, utilizing principal component analysis (PCA) and analysis of variance (ANOVA) results based on a general linear model, facilitated visual interpretation with score plots (for group assessment) and differential fingerprints (for “hot spot” detection). In the model study highly significant differences due to beverage intake were obtained among the 10 first principal components (p < 10−6 for two of the components in both ESI modes). Especially, the contrasts between “coffee” and “tea or water” indicated several “hot spots” with highly elevated intensities (e.g., for uncharged masses 93, 94, 109, 119, 123, 132, 148, 169, 178, 187, 190, and 193) suitable for further analysis, for example, with tandem MS.
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Angelstam, Per, et al.
(författare)
-
Learning about the history of landscape use for the future : consequences for ecological and social systems in Swedish Bergslagen
- 2013
-
Ingår i: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 42:2, s. 146-159
-
Tidskriftsartikel (refereegranskat)abstract
- Barriers and bridges to implement policies about sustainable development and sustainability commonly depend on the past development of social-ecological systems. Production of metals required integration of use of ore, streams for energy, and wood for bioenergy and construction, as well as of multiple societal actors. Focusing on the Swedish Bergslagen region as a case study we (1) describe the phases of natural resource use triggered by metallurgy, (2) the location and spatial extent of 22 definitions of Bergslagen divided into four zones as a proxy of cumulative pressure on landscapes, and (3) analyze the consequences for natural capital and society. We found clear gradients in industrial activity, stream alteration, and amount of natural forest from the core to the periphery of Bergslagen. Additionally, the legacy of top-down governance is linked to today's poorly diversified business sector and thus municipal vulnerability. Comparing the Bergslagen case study with other similar regions in Russia and Germany, we discuss the usefulness of multiple case studies.
|
|
| 6. |
- Botero, Carlos Alberto, et al.
(författare)
-
Microstructural and mechanical evaluation of a cr-mo-v cold-work tool steel produced via electron beam melting (Ebm)
- 2021
-
Ingår i: Materials. - : MDPI AG. - 1996-1944. ; 14:11
-
Tidskriftsartikel (refereegranskat)abstract
- In this work, a highly alloyed cold work tool steel, Uddeholm Vanadis 4 Extra, was manufactured via the electron beam melting (EBM) technique. The corresponding material microstructure and carbide precipitation behavior as well as the microstructural changes after heat treatment were characterized, and key mechanical properties were investigated. In the as-built condition, the mi-crostructure consists of a discontinuous network of very fine primary Mo-and V-rich carbides dispersed in an auto-tempered martensite matrix together with ≈15% of retained austenite. Adjusted heat treatment procedures allowed optimizing the microstructure by the elimination of Mo-rich carbides and the precipitation of fine and different sized V-rich carbides, along with a decrease in the retained austenite content below 2%. Hardness response, compressive strength, and abrasive wear properties of the EBM-manufactured material are similar or superior to its as-HIP forged counterparts manufactured using traditional powder metallurgy route. In the material as built by EBM, an impact toughness of 16–17 J was achieved. Hot isostatic pressing (HIP) was applied in order to further increase ductility and to investigate its impact upon the microstructure and properties of the material. After HIPing with optimized protocols, the ductility increased over 20 J.
|
|
| 7. |
|
|
| 8. |
- Botero Vega, Carlos Alberto, et al.
(författare)
-
Additive Manufacturing of a Cold-Work Tool Steel using Electron Beam Melting
- 2020
-
Ingår i: Steel Research International. - : Wiley. - 1611-3683 .- 1869-344X. ; 19:5, s. 1-6
-
Tidskriftsartikel (refereegranskat)abstract
- Metal additive manufacturing (AM) is on its way to industrialization. One of the most promising techniques within this field, electron beam melting (EBM), is nowadays used mostly for the fabrication of high‐performance Ti‐based alloy components for the aerospace and medical industry. Among the industrial applications envisioned for the future of EBM, the fabrication of high carbon steels for the tooling industry is of great interest. In this context, the process windows for dense and crack‐free specimens for a highly alloyed (Cr–Mo–V) cold‐work steel powder are presented in this article. High‐solidification rates during EBM processing lead to very fine and homogeneous microstructures. The influence of process parameters on the resulting microstructure and the chemical composition is investigated. In addition, preliminary results show very promising mechanical properties regarding the as‐built and heat‐treated microstructure of the obtained material.
|
|
| 9. |
|
|
| 10. |
- Bourdieu, Pierre, et al.
(författare)
-
Leve idrottspedagogiken : En vänbok tillägnad Lars-Magnus Engström
- 2005
-
Bok (övrigt vetenskapligt/konstnärligt)abstract
- Vem ägnar sig åt idrott? Vilken betydelse har fritiden i barns och ungdomars liv? Vad innebär hälsa i skolämnet idrott och hälsa?Leve idrottspedagogiken! tillägnas Lars-Magnus Engström. Texterna i boken speglar delar av det idrottspedagogiska forskningsområdet i Sverige, vars framväxt Lars-Magnus Engström varit den främste företrädaren för. Läsaren får här ta del av exempelvis idrottskulturen, fritidskulturen och skolans ämne idrott och hälsa. Genomgående handlar texterna om villkoren för barns och ungdomars deltagane och om de olika lärprocesser som sker i anslutning till idrottsutövning.Lars-Magnus Engström har gjort betydande insatser som forskare och lärare samt som professor vid Lärarhögskolan i Stockholm och vid Gymnastik- och idrottshögskolan. I snart fyrtion år har han arbetat med studier kring påverkans- och lärprocesser i idrott. Hans forskning har främst kretsat kring människors idrottsvanor och vilka som utvecklar en fysiskt aktiv livsstil. Idrotts- och motionsutövningar ger både ett så kallat egenvärde och investeringsvärde. Med dessa begrepp bland många andra har Lars-Magnus Engström bidragit till en fördjupad vetenskaplig förståelse av idrottskulturen.De flesta författarna har eller har haft Lars-Magnus Engström som handledare och tillhör forskningsgruppen för pedagogik, idrott och fritidskultur. Redaktörer för boken är Karin Redelius och Håkan Larsson.
|
|
