Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis.

Objective: Interferon (IFN) beta has repeatedly shown benefit in multiple sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with magnetic resonance imaging and, to some degree, the progression of disability; however, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage. This multicentre, double blind, placebo controlled study explored the dose–response curve by examining the clinical benefit of low dose IFN beta-1a (Rebif®), 22 µg subcutaneously once weekly, in patients with secondary progressive MS. Methods: A total of 371 patients with clinically definite SPMS were randomised to receive either placebo or subcutaneous IFN beta-1a, 22 µg once weekly, for 3 years. Clinical assessments were performed every 6 months. The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate. Results: Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 µg v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67). Other disability measures were also not significantly affected by treatment. Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted. Conclusions: This patient population was less clinically active than SPMS populations studied in other trials. Treatment with low dose, IFN beta-1a (Rebif®) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses. These results add a point at one extreme of the dose–response spectrum of IFN beta therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases

Core Polarization Effect in the Polarization Cross Section of Atomic Lithium

Purpose. The paper continues the authors’ studies devoted to transients in three-phase five-limb transformers. The main purpose of the work is to propose a method of evaluating model parameters, which cover transformer operations in saturation. This purpose is achieved by using the concept of the model reversibility.Methodology. The method of obtaining model parameters employs magnetic transformer model and is based on the idea of the model reversibility. The solution is found by equating input reluctances seen from the terminals of the innermost and outermost windings to the reluctances of the corresponding windings on air.Findings. The modeling of GIC events represented in the paper is the most accurate ever obtained for three-phase, five-leg transformers. The model is validated by close agreement of the predicted values and waveforms of the phase currents and reactive power with those measured in tests performed on two 400 MVA transformers connected back-to-back and to a 400 kV power network. The validity of the model was verified at 75 and 200 A dc currents in the transformer neutral. It is shown that the model is a reliable tool in evaluating inrush currents.Originality. The originality and advantage of the method proposed is its ability to determine the model parameters without fitting to experimental data obtained in regimes with highly saturated core. The method ensures the reversibility of the three-winding transformer model that is its correct behavior regardless of which winding is energized.Practical value. The practical value and significance of the paper is caused by the fact that the model proposed is a simple and reliable tool for power system studies. As a practically important example, time domain response of transformer subjected to geomagnetically induced currents (GIC) is analyzed and compared with results of a comprehensive field experiment.Цель работы. Статья продолжает исследования авторов, посвященные переходным процессам в трехфазных пятистержневых трансформаторах. Главная цель работы − предложить методику расчета параметров модели, охватывающих работу трансформатора с насыщенным сердечником. Эта цель достигается использованием концепции обратимости модели.Методы исследования. Расчет параметров модели выполняется с использованием магнитной схемы замещения трансформатора и основан на идее ее обратимости. Решение находится путем приравнивания входных магнитных сопротивлений, определяемых со стороны внутренней и внешней обмоток, и магнитных сопротивлений этих обмоток на воздухе.Полученные результаты. Точность моделирования процессов при наличии ГИТ превышает точность известных моделей трехфазных пятистержневых трансформаторов. Адекватность модели подтверждается близостью предсказанных фазных токов и потребляемой реактивной мощности, к соответствующим величинам, измененным в эксперименте на двух 400 MBA трансформаторах, подключенных к энергосистеме с напряжением 410 кВ. Обоснованность модели проверена при постоянных токах в нейтрали силой 75 и 200 А. Показана применимость модели для оценки бросков тока включения.Научная новизна. Оригинальность и новизна предложенного метода состоит в возможности определять параметры модели без использования экспериментальных данных, полученных при насыщенном сердечнике. Метод обеспечивает обратимость модели трехобмоточного трансформатора, то есть ее правильное поведение при возбуждении любой обмотки устройства.Практическая ценность. Практическая ценность и значение статьи обусловлено тем, что предложенная модель трансформатора является простым и надежным инструментом для исследования электрических сетей. В качестве практически важного результата, показано правильное предсказание моделью временного отклика трансформатора, наблюдаемого в эксперименте.Мета роботи. Стаття продовжує дослідження авторів, присвячені перехідним процесам в трифазних п’ятистрижневих трансформаторах. Головна мета роботи − запропонувати методику розрахунку параметрів моделі, що охоплюють роботу трансформатора з насиченим осердям. Ця мета досягається шляхом використанням концепції оберненості моделі.Методи дослідження. Розрахунок параметрів моделі виконується з використанням магнітної схеми заміщення трансформатора і побудований на юдеї її оберненості. Рішення знаходиться шляхом прирівнювання вхідних магнітних опорів, розрахованих з боку внутрішньої і зовнішньої обмоток, і магнітних опорів цих обмоток у повітрі.Отримані результати. Точність моделювання процесів в присутності ГІТ перевищує точність відомих моделей трифазних п’ятистрижневих трансформаторів. Адекватність моделі підтверджується близькістю прогнозованих фазних струмів і споживаної реактивної потужності, до відповідних величин, виміряним в експерименті на двох 400 МВА трансформаторах, які були під’єднані до енергосистеми напругою 410 кВ. Обґрунтованість моделі перевірена при постійних струмах в нейтралі силою 75 і 200 А. Показано застосовність моделі для оцінки кидків струму включення.Наукова новизна. Оригінальність і новизна методу полягає в можливості визначати параметри моделі без використання експериментальних даних, що отримані при насиченому осерді. Метод забезпечує оберненість моделі триобмоточного трансформатора, тобто її коректну поведінку при збудженні будь якої з обмоток.Практична цінність. Практична цінність і значимість статті обумовлені тим, що запропонована модель трансформатора являє собою простий і надійний інструмент для дослідження електричних систем. В якості практично важливого результату, показано правильне прогнозування моделлю часового відгуку трансформатора, що спостерігався в експерименті

20TH INTERNATIONAL CONFERENCE ON MAGNETISM

We report the growth of well-crystallized and epitaxially textured Pr0.6Ca0.4MnO3 thin films on SrTiO3 substrates by pulsed laser deposition at considerably low substrate temperatures, as low as 450 degrees C, without high-temperature post-annealing treatments. Although a strong ferromagnetic interaction as well as a large irreversible metamagnetic transition with a training effect have been observed for films grown at 450 degrees C, the in-plane and out-of-plane lattice ordering is slightly improved with increasing substrate temperature. Therefore, a lowest magnetic field of 2 T for melting the insulating charge-ordering state at 70 K has been observed for films grown with the substrate temperature between 550 degrees C and 600 degrees C. The formation and growth of Pr0.6Ca0.4MnO3 on SrTiO3 substrate at exceptionally low substrate temperature is qualitatively modelled by the combination of the kinetic energies and redox potentials of the components of the ablation plasma, while the heat flow from the substrate is assumed to be less important.</p

Structural and Biomolecular Analyses of Borrelia burgdorferi BmpD Reveal a Substrate-Binding Protein of an ABC-Type Nucleoside Transporter Family

Borrelia burgdorferisensu lato, the causative agent of tick-borne Lyme borreliosis (LB), has a limited metabolic capacity and needs to acquire nutrients, such as amino acids, fatty acids, and nucleic acids, from the host environment. Using X-ray crystallography, liquid chromatography-mass spectrometry, microscale thermophoresis, and cellular localization studies, we show that basic membrane protein D (BmpD) is a periplasmic substrate-binding protein of an ABC transporter system binding to purine nucleosides. Nucleosides are essential for bacterial survival in the host organism, and these studies suggest a key role for BmpD in the purine salvage pathway of B. burgdorferi sensu lato Because B. burgdorferisensu lato lacks the enzymes required for de novo purine synthesis, BmpD may play a vital role in ensuring access to the purines needed to sustain an infection in the host. Furthermore, we show that, although human LB patients develop anti-BmpD antibodies, immunization of mice with BmpD does not confer protection against B. burgdorferi sensu lato infection.</p

Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations

Background: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). Methods: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. Results: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. Conclusion: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.Peer Reviewe

A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice

This is the author's accepted manuscript.Purpose To investigate influence of inflammation on metabolism and pharmacokinetics (PK) of midazolam (MDZ) and construct a semi-physiologically based pharmacokinetic (PBPK) model to predict PK in mice with inflammatory disease. Methods Glucose-6-phosphate isomerase (GPI)-mediated inflammation was used as a preclinical model of arthritis in DBA/1 mice. CYP3A substrate MDZ was selected to study changes in metabolism and PK during the inflammation. The semi-PBPK model was constructed using mouse physiological parameters, liver microsome metabolism, and healthy animal PK data. In addition, serum cytokine, and liver-CYP (cytochrome P450 enzymes) mRNA levels were examined. Results The in vitro metabolite formation rate was suppressed in liver microsomes prepared from the GPI-treated mice as compared to the healthy mice. Further, clearance of MDZ was reduced during inflammation as compared to the healthy group. Finally, the semi-PBPK model was used to predict PK of MDZ after GPI-mediated inflammation. IL-6 and TNF-α levels were elevated and liver-cyp3a11 mRNA was reduced after GPI treatment. Conclusion The semi-PBPK model successfully predicted PK parameters of MDZ in the disease state. The model may be applied to predict PK of other drugs under disease conditions using healthy animal PK and liver microsomal data as inputs

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Plasma 24S-hydroxycholesterol levels in elderly subjects with late onset Alzheimer's disease or vascular dementia: a case-control study

<p>Abstract</p> <p>Background</p> <p>In central nervous system cholesterol cannot be degraded but is secreted into circulation predominantly in the form of its polar metabolite 24(<it>S</it>)-hydroxycholesterol (24S-OH-Chol). Some studies suggested an association between 24S-OH-Chol metabolism and different neurological diseases including dementia. A possible decrease in 24S-OH-Chol plasma levels has been reported late onset Alzheimer's disease (LOAD) and vascular dementia (VD), but results of previous studies are partially contradictory.</p> <p>Methods</p> <p>By high-speed liquid chromatography/tandem mass spectrometry we evaluated the plasma levels of 24S-OH-Chol in a sample of 160 older individuals: 60 patients with LOAD, 35 patients with VD, 25 subjects affected by cognitive impairment no-dementia (CIND), and 40 (144 for genetics study) cognitively normal Controls. We also investigated the possible association between PPARgamma Pro12Ala polymorphism and dementia or 24S-OH-Chol levels.</p> <p>Results</p> <p>Compared with Controls, plasma 24S-OH-Chol levels were higher in LOAD and lower in VD; a slight not-significant increase in CIND was observed (ANOVA p: 0.001). A positive correlation between 24S-OH-Chol/TC ratio and plasma C reactive protein (CRP) levels was found in the whole sample, independent of possible confounders (multiple regression p: 0.04; r²: 0.10). This correlation was strong in LOAD (r: 0.39), still present in CIND (r: 0.20), but was absent in VD patients (r: 0.08). The PPARgamma Pro12Ala polymorphism was not associated with the diagnosis of LOAD, VD, or CIND; no correlation emerged between the Ala allele and 24S-OH-Chol plasma levels.</p> <p>Conclusions</p> <p>Our results suggest that plasma 24S-OH-Chol levels might be increased in the first stages of LOAD, and this phenomenon might be related with systemic inflammation. The finding of lower 24S-OH-Chol concentrations in VD might be related with a more advanced stage of VD compared with LOAD in our sample, and/or to different pathogenetic mechanisms and evolution of these two forms of dementia.</p

Is Intracranial Atherosclerosis an Independent Risk Factor for Cerebral Atrophy? A Retrospective Evaluation

<p>Abstract</p> <p>Background</p> <p>Our purpose was to study the association between the intracranial atherosclerosis as measured by cavernous carotid artery calcification (ICAC) observed on head CT and atrophic changes of supra-tentorial brain demonstrated by MRI.</p> <p>Methods</p> <p>Institutional review board approval was obtained for this retrospective study incorporating 65 consecutive patients presenting acutely who had both head CT and MRI. Arterial calcifications of the intracranial cavernous carotids (ICAC) were assigned a number (1 to 4) in the bone window images from CT scans. These 4 groups were then combined into high (grades 3 and 4) and low calcium (grades 1 and 2) subgroups. Brain MRI was independently evaluated to identify cortical and central atrophy. Demographics and cardiovascular risk factors were evaluated in subjects with high and low ICAC. Relationship between CT demonstrated ICAC and brain atrophy patterns were evaluated both without and with adjustment for cerebral ischemic scores and cardiovascular risk factors.</p> <p>Results</p> <p>Forty-six of the 65 (71%) patients had high ICAC on head CT. Subjects with high ICAC were older, and had higher prevalence of hypertension, diabetes, coronary artery disease (CAD), atrial fibrillation and history of previous stroke (CVA) compared to those with low ICAC. Age demonstrated strong correlation with both supratentorial atrophy patterns. There was no correlation between ICAC and cortical atrophy. There was correlation however between central atrophy and ICAC. This persisted even after adjustment for age.</p> <p>Conclusion</p> <p>Age is the most important determinant of atrophic cerebral changes. However, high ICAC demonstrated age independent association with central atrophy.</p