bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: Results of a phase III, double‐blind, randomized, placebo‐controlled, flexible‐dose trial
Authors: Kwan Patrick , Trinka Eugen , Van Paesschen Wim , Rektor Ivan , Johnson Martin E. , Lu Sarah 
Published: October 2013

SummaryPurposeTo evaluate the safety and tolerability of adjunctive brivaracetam (BRV), a high‐affinity synaptic vesicle protein 2A (SV2A) ligand, in adults with uncontrolled epilepsy. Efficacy was also assessed in patients with focal seizures as a secondary objective, and explored by descriptive analysis in patients with generalized seizures.MethodsThis was a phase III, randomized, double‐blind, placebo (PBO)‐controlled flexible dose trial (N01254/NCT00504881) in adults (16–70 years) with uncontrolled epilepsy (up to 20% could be patients with generalized epilepsy). After a prospective 4‐week baseline, patients were randomized (3:1) to b.i.d. BRV or PBO, initiated at 20 mg/day and increased, as needed, to 150 mg/day during an 8‐week dose‐finding period. This was followed by an 8‐week stable‐dose maintenance period. The treatment period comprised the dose‐finding period plus the maintenance period (16 weeks).Key FindingsA total of 480 patients were randomized (BRV 359, PBO 121); of these, 431 had focal epilepsy and 49 had generalized epilepsy. Ninety percent BRV‐ and 91.7% PBO‐treated patients completed the study. Similar proportions of patients (BRV 66.0%, PBO 65.3%) reported adverse events (AEs) during the treatment period. AEs led to treatment discontinuation in 6.1% and 5.0% of BRV‐ and PBO‐treated patients, respectively. The incidence of AEs declined from the dose‐finding (BRV 56.0%, PBO 55.4%) to the maintenance (BRV 36.8%, PBO 40.9%) period. The most frequent AEs during the treatment period were headache (BRV 14.2% vs. PBO 19.8%), somnolence (BRV 11.1% vs. PBO 4.1%), and dizziness (BRV 8.6% vs. PBO 5.8%). The incidence of psychiatric AEs was similar for BRV and PBO (BRV 12.3%, PBO 11.6%). In patients with focal seizures, the baseline‐adjusted percent reduction in seizure frequency/week in the BRV group (n = 323) over PBO (n = 108) was 7.3% (p = 0.125) during the treatment period. The median percent reduction in baseline‐adjusted seizure frequency/week was 26.9% BRV versus 18.9% PBO (p = 0.070), and the ≥50% responder rate was 30.3% BRV versus 16.7% PBO (p = 0.006). In patients with generalized seizures only, the number of seizure days/week decreased from 1.42 at baseline to 0.63 during the treatment period in BRV‐treated patients (n = 36), and from 1.47 at baseline to 1.26 during the treatment period in PBO‐treated patients (n = 13). The median percent reduction from baseline in generalized seizure days/week was 42.6% versus 20.7%, and the ≥50% responder rate was 44.4% versus 15.4% in BRV‐treated and PBO‐treated patients, respectively.SignificanceAdjunctive BRV given at individualized tailored doses (20–150 mg/day) was well tolerated in adults with uncontrolled epilepsy, and our results provided support for further evaluation of efficacy in reducing focal and generalized seizures.
Lennox‐Gastaut syndrome of unknown cause: Phenotypic characteristics of patients in theEpilepsyPhenome/GenomeProject
Authors: Widdess‐Walsh Peter , Dlugos Dennis , Fahlstrom Robyn , Joshi Sucheta , Shellhaas Renée , Boro Alex , Sullivan Joseph , Geller Eric ,   the EPGP Investigators
Published: October 2013

SummaryPurposeLennox‐Gastaut syndrome (LGS) is a devastating childhood‐onset epilepsy syndrome. The cause is unknown in 25% of cases. Little has been described about the specific clinical or electroencephalography (EEG) features ofLGSof unknown or genetic cause (LGSu). TheEpilepsyPhenome/GenomeProject (EPGP) aims to characterizeLGSuby phenotypic analysis of patients withLGSuand their parents.MethodsOne hundred thirty‐five patients withLGSwith no known etiology and their parents were enrolled from 19EPGPcenters in the United States andAustralia. Clinical data from medical records, standardized questionnaires, imaging, andEEGwere collected with use of online informatics systems developed forEPGP.Key FindingsLGSuin theEPGPcohort had a broad range of onset of epilepsy from 1 to 13 years, was male predominant (p < 0.0002), and was associated with normal development prior to seizure onset in 59.2% of patients. Despite the diagnosis, almost half of the adult patients withLGSucompleted secondary school. Parents were cognitively normal. All subjects hadEEGrecordings with generalized epileptiform abnormalities with a spike wave frequency range of 1–5 Hz (median 2 Hz), whereas 8.1% of subjects hadEEGstudies with a normal posterior dominant rhythm. Almost 12% of patients evolved fromWest syndrome.SignificanceLGSuhas distinctive characteristics including a broad age range of onset, male predominance, and often normal development prior to the onset of seizures. Cognitive achievements such as completion of secondary school were possible in half of adult patients. Our phenotypic description ofLGSucoupled with future genetic studies will advance our understanding of this epilepsy syndrome.
Stiripentol exhibits higher anticonvulsant properties in the immature than in the mature rat brain
Authors: Auvin Stéphane , Lecointe Cécile , Dupuis Nina , Desnous Béatrice , Lebon Sophie , Gressens Pierre , Dournaud Pascal 
Published: October 2013

SummaryPurposeAfter the first positive experimental data in rodents in the early 1970s demonstrating the anticonvulsant effect of stiripentol (STP), in vitro studies showed that STP acts directly on γ‐aminobutyric acid A (GABAA) receptors. Chloride influx is higher when these receptors contain an α3 subunit, leading to the hypothesis that STP might exhibit higher efficacy in the immature brain.MethodsWe explored this issue by studying the efficacy of STP in P21 and P75 rats using the pentylenetetrazol model of acute seizures or the lithium‐pilocarpine status epilepticus model. P21 and adult rats received vehicle, 150, 250, or 350 mg/kg of STP, i.p., 1 h before evaluating the anticonvulsant. We also studied the blood and brain levels of STP as well as the expression and the messenger RNA (mRNA) levels of the α3 subunit of the GABAA receptors at both ages.Keys FindingsSTP exhibited anticonvulsant properties in both models at both ages, but STP was more effective in P21 than in P75 rats. This was shown by the significant suppression of seizure or status epilepticus occurrence in P21 with 350 mg/kg STP, whereas the same dose had no significant effect at P75. The blood level, brain level, and blood/brain ratio of STP did not explain these differences between the two age groups. Moreover, the higher anticonvulsant properties in the immature brain were not explained by the mRNA level or protein expression of the GABAA α3 subunit at either age.SignificanceStiripentol exhibits higher anticonvulsant properties in the immature than in the mature brain. These findings require further investigation because it might lead to new clinical developments.
‘Playing the Judicial Card’: Litigation Strategies during the Process of Ratification of the Lisbon Treaty
Authors: Castillo Ortiz Pablo José 
Published: October 2013

AbstractDuring the process of ratification of the Lisbon Treaty, a number of constitutional jurisdictions were activated by political actors. In playing ‘the judicial card’, opponents of ratification decided to seek political goals through judicial means, and thus they were obliged to develop litigation strategies. This article explores such strategies and the responses that courts gave them. It shows that constitutional proceedings with regards to the Lisbon Treaty became a political battleground governed by legal logics, in which the interpretation of European clauses, the democratic deficit of the Union and the tensions underlying the European judicial dialogue were privileged objects of discussion between claimants and courts in which law and politics intertwined.
Endometrial tissue and blood plasma concentration of ceftiofur and metabolites following intramuscular administration of ceftiofur crystalline free acid to mares
Authors: Scofield D. , Black J. , Wittenburg L. , Gustafson D. , Ferris R. , Hatzel J. , Traub‐Dargatz J. , McCue P. 
Published: October 2013

SummaryReasons for performing studySystemic administration of ceftiofur crystalline free acid (CCFA) may be a potential treatment for infectious endometritis caused byStreptococcus equissp.zooepidemicus(S. zooepidemicus) and other susceptible bacterial organisms in the mare.ObjectiveTo determine if i.m. administration ofCCFAat the label dose will exceed the minimum inhibitory concentration (MIC) ofS. zooepidemicusin the endometrium following single administration and multiple administration protocols.Study designExperimental pharmacokinetic study.MethodsThree mares (Group 1) were administered a single i.m. dose ofCCFA(6.6 mg/kg bwt) and blood and endometrial biopsies were collected at selected intervals for 144 h. Six additional mares (Groups 2and3) receivedCCFAat times 0, 4, 11 and 18 days, and were sampled at predetermined times for 25 or 49 days, respectively. Plasma and tissue samples were analysed by high‐pressure liquid chromatography with tandem mass spectrometry for desfuroylceftiofur acetamide concentration, which is a direct measure of all ceftofur and ceftiofur metabolites in the sample.ResultsA mean plasma desfuroylceftiofur acetamide concentration of 0.367 ± 0.0162 μg/ml (mean ± s.e.) was detected at 96 h following administration. Mean endometrial tissue concentration was 0.510 ± 0.0418 μg/g at 96 h and exceeded theMICforS. zooepidemicus(0.25 μg/ml) throughout the 144 h monitoring period forGroup 1. Mares inGroups 2and3, given multiple doses ofCCFA, maintained plasma concentrations above theMICforS. zooepidemicusfor 25 days. Endometrial tissue levels remained above theMICat most data collection points for 25 days.ConclusionsCeftiofur crystalline free acid reaches appropriate endometrial tissue values to exceed theMICofS. zooepidemicus, a common cause of bacterial endometritis. Therefore,CCFAshould be effective in the treatment of equine bacterial endometritis caused byS. zooepidemicusand other susceptible bacterial pathogens in the mare.
Hair miR‐29a levels are decreased in patients with scleroderma
Authors: Takemoto Risa , Jinnin Masatoshi , Wang Zhongzhi , Kudo Hideo , Inoue Kuniko , Nakayama Wakana , Ichihara Asako , Igata Toshikatsu , Kajihara Ikko , Fukushima Satoshi , Ihn Hironobu 
Published: October 2013

AbstractIn the present study, we evaluated the possibility that we can utilize hair shaft miR‐29a levels as disease marker of scleroderma. Hair samples were obtained from 20 scleroderma patients, five dermatomyositis patients and 13 controls. microRNAs were purified from hairs as well as skins or sera, and miR‐29a levels were measured with quantitative real‐time polymerase chain reaction. Mean hair miR‐29a levels in scleroderma patients were significantly lower than those in control subjects or dermatomyositis, while expression levels of hair shaft marker keratin 34 were similar among them. There was no strong correlation among the miR‐29a levels in the hair, skin and serum of each patient, suggesting that hair microRNAs can be independent biomarkers. We found scleroderma patients with decreased miR‐29a levels had contracture of the phalanges at a significantly higher prevalence than those without. To confirm the clinical usefulness of hair microRNAs, large‐scale researches are needed in the future.
Canonical Wnt signalling as a key regulator of fibrogenesis – implications for targeted therapies?
Authors: Dees Clara , Distler Jörg H. W. 
Published: October 2013

AbstractCanonical Wnt signalling belongs to the so‐called morphogen pathways and plays essential roles in development and tissue homeostasis. Being such a crucial regulatory pathway, Wnt signalling is tightly controlled at different levels. However, uncontrolled activation of canonical Wnt signalling has been implicated into the pathogenesis of various human disorders. In the last years, aberrant Wnt signalling has been demonstrated in fibrotic diseases including systemic sclerosis (SSc). In this review, we will discuss the current state of research on canonical Wnt signalling in SSc. Activation of canonical Wnt signalling induces fibroblast activation with subsequent myofibroblast differentiation and excessive collagen release resulting in tissue fibrosis. Genetic or pharmacological blockade of Wnt activation ameliorates experimental fibrosis in different preclinical models. These findings have direct translational implications because several small molecule inhibitors of Wnt signalling are currently evaluated in clinical trials and some already showed first promising results.
Bleomycin inhibits adipogenesis and accelerates fibrosis in the subcutaneous adipose layer through TGF‐β1
Authors: Ohgo Shiro , Hasegawa Seiji , Hasebe Yuichi , Mizutani Hiroshi , Nakata Satoru , Akamatsu Hirohiko 
Published: October 2013

AbstractSystemic sclerosis [scleroderma (SSc)]‐associated skin fibrosis is characterized by increased fibrosis in the dermis and a reduction in the thickness of the subcutaneous adipose tissue layer. Although many studies have examined fibrosis in SSc, only a few studies have focused on the associated reduction in the thickness of the subcutaneous adipose tissue layer. In this study, we investigated the effects of SSc‐induced fibrosis on adipose tissue. We found that bleomycin suppresses adipogenesis in adipose‐derived stem cells (ASCs) and stimulates ASCs to express transforming growth factor β1 (TGF‐β1), which suppresses adipogenesis and promotes fibrosis. Furthermore, we found that adipocyte‐conditioned medium suppressed collagen synthesis by fibroblasts in fibrosis‐like conditions. We concluded that in the skin affected by bleomycin‐induced fibrosis, increased TGF‐β1 expression suppresses adipogenesis and promotes adipocyte fibrosis. It was also suggested that adipocytes have an inhibitory effect on the progression of fibrosis.
Gentian Violet: a 19th century drug re‐emerges in the 21st century
Authors: Maley Alexander M. , Arbiser Jack L. 
Published: October 2013

AbstractGentian violet (GV) has a long and varied history as a medicinal agent. Historically used as an antibacterial and antifungal, recent reports have shown its utility as an antitypranosomal, antiviral and anti‐angiogenic agent. The objective of this article is to summarize evidence regarding the efficacy and safety ofGVuse in dermatology. Recent discoveries have found novel targets ofGV, namelyNADPHoxidase in mammalian cells and thioredoxin reductase 2 in bacterial, fungal and parasitic cells. These discoveries have expanded the use ofGVin the 21st century. Given thatGVis well tolerated, effective and inexpensive, its use in dermatology is predicted to increase.
Characterization of tryptophan aminotransferase 1 of Malassezia furfur, the key enzyme in the production of indolic compounds by M. furfur
Authors: Preuss Janina , Hort Wiebke , Lang Sarah , Netsch Anette , Rahlfs Stefan , Lochnit Günter , Jortzik Esther , Becker Katja , Mayser Peter A. 
Published: October 2013

AbstractMalassezia yeasts are responsible for the widely distributed skin disease Pityriasis versicolor (PV), which is characterized by a hyper‐ or hypopigmentation of affected skin areas. For Malassezia furfur, it has been shown that pigment production relies on tryptophan metabolism. A tryptophan aminotransferase was found to catalyse the initial catalytic step in pigment formation in the model organism Ustilago maydis. Here, we describe the sequence determination, recombinant production and biochemical characterization of tryptophan aminotransferase MfTam1 from M. furfur. The enzyme catalyses the transamination from l‐tryptophan to keto acids such as α‐ketoglutarate with Km values for both substrates in the low millimolar range. Furthermore, MfTam1 presents a temperature optimum at 40°C and a pH optimum at 8.0. MfTam1 activity is highly dependent on pyridoxal phosphate (PLP), whereas compounds interfering with PLP, such as cycloserine (CS) and aminooxyacetate, inhibit the MfTam1 reaction. CS is known to reverse hyperpigmentation in PV. Thus, the results of the present study give a deeper insight into the role of MfTam1 in PV pathogenesis and as potential target for the development of novel PV therapeutics.
Opposing effects on immune function and skin barrier regulation by the proteasome inhibitor bortezomib in an allergen‐induced eczema model
Authors: Mudnakudu Nagaraju Kiran Kumar , Babina Magda , Worm Margitta 
Published: October 2013

AbstractProteasome inhibition (PI) has been reported to interfere with antibody‐driven autoimmune diseases. The impact of PI on the allergic immune response and on skin diseases like atopic dermatitis (AD) has not been thoroughly explored, however. Here, we examined whether the PI bortezomib interferes with the allergic immune response and the severity of AD by using an established mouse model of allergen‐driven dermatitis, to which bortezomib was applied after the establishment of systemic sensitization to ovalbumin. The treatment indeed resulted in a remarkable decrease in total and allergen‐specific plasma cells/antibody‐secreting cells, as evidenced by flow cytometry and ELISpot, respectively. This was accompanied by rapid reductions in serum antibody titres, including a prominent reduction of the IgE isotype. CD4+ and CD8+ cells were greatly diminished in lesional skin on immunohistological staining. The impressive effects at the level of immune modulation did not result in any improvement in the eczema, however. Following up on this unexpected result, we found that the skin itself was susceptible to bortezomib, by which it was instructed to lower the expression of critical skin barrier genes, especially transglutaminase‐1 and filaggrin. Together, bortezomib eliminates plasma cells and decreases immunoglobulin responses, including allergenic IgE. Although anti‐inflammatory effects are detectable in the skin, counter‐regulatory effects from PI on resident skin cells likely undermine improvement in the eczema. These results caution against the therapeutic use of bortezomib for inflammatory skin disorders, which are characterized by inherently impaired barrier function, especially AD.
A new KRT16 mutation associated with a phenotype of pachyonychia congenita
Authors: Paris Francesc , Hurtado Cristina , Azón Antoni , Aguado Leyre , Vizmanos José L. 
Published: October 2013

AbstractPachyonychia congenita is a rare, autosomal dominant genetic disease characterized by painful palmoplantar keratoderma and hypertrophic nail dystrophy. This disorder is caused by mutations in any one of five cytoskeletal keratin proteins, K6a, K6b, K6c, K16 and K17. Here, we describe a new p.Leu421Pro (c.1262T>C) mutation in the highly conserved helix termination motif of K16 in a large Spanish family. Bioinformatic analyses as well as previous descriptions in the literature of homologous mutations in other keratin‐coding genes show that this mutation is probably causative of the disease.
Overlooked impacts and challenges of the new European discard ban
Authors: Sardà Francesc , Coll Marta , Heymans Johanna J , Stergiou Konstantinos I 
Published: October 2013

AbstractDiscards are the portion of animal and plant material in the catch that is dumped back at sea. The Common Fisheries Policy plan proposed by the European Commission for 2014–2020 presents a controversial goal: to enforce the landing of fishing discards as a measure to encourage their reduction. This historical and political decision will shape the future of the fishing exploitation in European Seas. Discards generated by European fleets are not negligible, and its reduction is an ecological, socioeconomical and moral imperative. However, it must be achieved through the reduction in discards at source and the promotion of selective and non‐destructive gears. We argue it is doubtful that this discard ban will result in an effective reduction of discards. The proposed measure may, in fact, negatively affect ecosystems at all levels of biological hierarchy by disregarding the Ecosystem‐Based Approach to Fisheries and the Precautionary Principle. It could negatively impact several species by increasing fishing mortality, also commercial species if discards are not accounted in the total allowable catch. Communities preying on discards will likely be affected. The role discards currently play in the energy turnover of current ecosystems will be modified and should be fully evaluated. The landing of discards will likely generate new markets of fishmeal due to the growing demands for marine living resources. The ban will require substantial public investment to deal with technical problems on board and to control and enforce. Therefore, this measure should be only implemented after rigorous scientific and technical studies have been developed.
Bridge fatigue life prediction using Mittag–Leffler distribution
Authors: Liang Y. J. , Chen W. 
Published: October 2013

ABSTRACTThis paper is aimed at developing a statistical approach for fatigue life prediction of steel bridges with structural health monitoring data. The present approach obtains the static cumulative damage index by using the Mittag–Leffler distribution in conjunction with the statistical form of Miner's rule and investigates the influence of annual traffic increase on the evolution of the dynamic service life by a modified statistical formula of Miner's rule, which includes the relationship between the levels of stress range and the annual traffic increase rate. The proposed method is exemplified to specifically predict the static fatigue life of the Neville Island Bridge and the dynamic fatigue life of the Birmingham Bridge.
Fishers' targeting behaviour in Mediterranean: does vessel size matter?
Authors: Maravelias C. D. , Tsitsika E. V. 
Published: October 2013

AbstractFishers have a considerable knowledge about how fish stocks behave; knowledge that is difficult to acquire in other ways. Short‐term fisher tactics employed on trip by trip basis can change significantly due to their targeting behaviour, which in turn can lead to changes in catch composition and production output. A stochastic distance function was used to examine a Mediterranean pelagic fleet's technical efficiency and fishers' ability to modulate their targeting behaviour. The purse seine fleet operated under increasing returns to scale, suggesting that the larger vessels could potentially amplify their short‐term profitability by increasing the levels of inputs and harvests. Production was mainly joint, yet the possibility for limited substitution between species existed. The observed fishers' targeting behaviour was dissimilar between fleet segments due to differences in fishing effort and vessel characteristics, with larger vessels able to modify their revenue more than smaller ones. The estimated differences between the two fleet segments could be important in designing effective management regimes aimed at reducing resource overexploitation through individual input controls.