153 research outputs found
Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS
Background Laquinimod is an oral immunomodulator in clinical development to
treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical
development for the treatment of multiple sclerosis and Huntington Disease
(HD). The objective of this study is to assess the safety, tolerability,
pharmacokinetics (PK) and cytoimmunologic effects following escalating doses
of laquinimod in patients with RRMS. Methods One hundred twelve patients were
randomly assigned to laquinimod/placebo in a series of separate dose-
escalating cohorts starting from a daily oral dose of 0.9 mg/1.2 mg escalating
to 2.7 mg, in 0.3 mg increments. Results Twenty-eight patients received
placebo and 84 received laquinimod ranging from 0.9 to 2.7 mg. No deaths
occurred. One serious adverse event (SAE) of perichondritis was reported,
which was unrelated to laquinimod (0.9 mg). There was no increased incidence
of adverse events (AEs) with escalating doses. Laquinimod-treated patients
showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive
protein (CRP), and fibrinogen, but most shifts were clinically non-
significant. The exposure of laquinimod was dose proportional and linear in
the tested dose range. An immunological substudy showed significant dose-
dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency
following laquinimod compared to placebo. Conclusion Laquinimod doses up to
2.7 mg were safely administered to patients with RRMS. An in vivo effect of
laquinimod on the innate immune system was demonstrated. Trial registration
EudraCT Number: 2009-011234-99. Registered 23 June 2009
Let your students speak: fun and effective ways to increase studentsā confidence to speak
In the communicative model of language teaching, we should help our students develop authentic practice for real-life communication situations since the main goal of English Language Teaching is to empower students to become independent learners. In order to do this, multi-sensory tasks requiring integrated skills should be offered to students. The teachersā feedback reveals that creating real-life communication situations can enrich and foster in-class speaking and prevent students from misunderstandings and communication breakdowns. Drawings, headlines, diagrams and cards are excellent sources to make lessons more memorable and enjoyable.The main purpose of this presentation is to introduce a series of innovative and creative activities increasing studentsā motivation and confidence to speak more voluntarily inside and outside class
Folateātargeted nanoparticles show efficacy in the treatment of inflammatory arthritis
Objective To investigate the uptake of a poly(amidoamine) dendrimer (generation 5 [G5]) nanoparticle covalently conjugated to polyvalent folic acid (FA) as the targeting ligand into macrophages, and to investigate the activity of an FAā and methotrexate (MTX)āconjugated dendrimer (G5āFAāMTX) as a therapeutic for the inflammatory disease of arthritis. Methods In vitro studies were performed in macrophage cell lines and in isolated mouse macrophages to check the cellular uptake of fluorescenceātagged G5āFA nanoparticles, using flow cytometry and confocal microscopy. In vivo studies were conducted in a rat model of collagenāinduced arthritis to evaluate the therapeutic potential of G5āFAāMTX. Results Folateātargeted dendrimer bound and internalized in a receptorāspecific manner into both folate receptor Ī²āexpressing macrophage cell lines and primary mouse macrophages. The conjugate G5āFAāMTX acted as a potent antiinflammatory agent and reduced arthritisāinduced parameters of inflammation such as ankle swelling, paw volume, cartilage damage, bone resorption, and body weight decrease. Conclusion The use of folateātargeted nanoparticles to specifically target MTX into macrophages may provide an effective clinical approach for antiinflammatory therapy in rheumatoid arthritis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86938/1/30459_ftp.pd
The Genetic Background of the Curly Tail Strain Confers Susceptibility to Folate-Deficiency-Induced Exencephaly
BACKGROUND: Suboptimal maternal folate status is considered a risk factor for neural tube defects (NTDs). However, the relationship between dietary folate status and risk of NTDs appears complex, as experimentally induced folate deficiency is insufficient to cause NTDs in nonmutant mice. In contrast, folate deficiency can exacerbate the effect of an NTD-causing mutation, as in splotch mice. The purpose of the present study was to determine whether folate deficiency can induce NTDs in mice with a permissive genetic background which do not normally exhibit defects. METHODS: Folate deficiency was induced in curly tail and genetically matched wild-type mice, and we analyzed the effect on maternal folate status, embryonic growth and development, and frequency of NTDs. RESULTS: Folate-deficient diets resulted in reduced maternal blood folate, elevated homocysteine, and a diminished embryonic folate content. Folate deficiency had a deleterious effect on reproductive success, resulting in smaller litter sizes and an increased rate of resorption. Notably, folate deficiency caused a similar-sized, statistically significant increase in the frequency of cranial NTDs among both curly tail (Grhl3 mutant) embryos and background-matched embryos that are wild type for Grhl3. The latter do not exhibit NTDs under normal dietary conditions. Maternal supplementation with myo-inositol reduced the incidence of NTDs in the folate-deficient wild-type strain. CONCLUSIONS: Dietary folate deficiency can induce cranial NTDs in nonmutant mice with a permissive genetic background, a situation that likely parallels gene-nutrient interactions in human NTDs. Our findings suggest that inositol supplementation may ameliorate NTDs resulting from insufficient dietary folate. Birth Defects Research (Part A), 2010. Ā© 2009 Wiley-Liss, Inc
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