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

Three-decade neurological and neurocognitive follow-up of HIV-1-infected patients on best-available antiretroviral therapy in Finland

Objectives: Is it possible to live without neurocognitive or neurological symptoms after being infected with HIV for a very long time? These study patients with decades-long HIV infection in Finland were observed in this follow-up study during three time periods: 1986-1990, in 1997 and in 2013. Setting: Patients from greater Helsinki area were selected from outpatient's unit of infectious diseases. Participants: The study included 80 HIV patients. Patients with heavy alcohol consumption, central nervous system disorder or psychiatric disease were excluded. Primary and secondary outcome measures: The patients underwent neurological and neuropsychological examinations, MRI of the brain and laboratory tests, including blood CD4 cells and plasma HIV-1 RNA. Neuropsychological examination included several measures: subtests of Wechsler Adult Intelligence Scale, Wechsler Memory Scale-Revised, list learning, Stroop and Trail-Making-B test. The Beck Depression Inventory and Fatigue Severity Scale were also carried out. The obtained data from the three time periods were compared with each other. Results: Owing to high mortality among the original 80 patients, eventually, 17 participated in all three examinations performed between 1986 and 2013. The time from the HIV diagnosis was 27 (23-30) years. Blood CD4 cells at the diagnosis were 610 (29-870) cells/mm(3), and the nadir CD4 168 (4-408) cells/mm(3). The time on combined antiretroviral treatment was 13 (5-17) years. 9 patients suffered from fatigue, 5 had polyneuropathy and 3 had lacunar cerebral infarcts. There was a subtle increase of brain atrophy in 2 patients. Mild depressive symptoms were common. The neuropsychological follow-up showed typical age-related cognitive changes. No HIV-associated dementia features were detected. Conclusions: Polyneuropathy, fatigue and mild depression were common, but more severe neurological abnormalities were absent. These long-term surviving HIV-seropositive patients, while on best-available treatment, showed no evidence of HIV-associated neurocognitive disorder in neuropsychological and neuroradiological evaluations.Peer reviewe

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

Expression of chemokine receptors on peripheral blood lymphocytes in multiple sclerosis and neuromyelitis optica

<p>Abstract</p> <p>Background</p> <p>The role of different chemokine receptors in the pathogenesis of multiple sclerosis (MS) has been extensively investigated; however, little is known about the difference in the role of chemokine receptors between the pathogenesis of neuromyelitis optica (NMO) and MS. Therefore, we examined the expression of chemokine receptors on peripheral blood lymphocytes (PBL) in MS and NMO.</p> <p>Methods</p> <p>We used flow cytometry to analyse lymphocyte subsets in 12 patients with relapsing NMO, 24 with relapsing-remitting MS during relapse, 3 with NMO and 5 with MS during remission.</p> <p>Results</p> <p>Compared with healthy controls (HC), the percentage of lymphocytes in white blood cells was significantly lower in NMO and MS patients. The percentage of T cells expressing CD4⁺CD25⁺and CD4⁺CD45RO⁺was higher, while that of CD4⁺CC chemokine receptor (CCR)3⁺(T helper 2, Th2) was significantly lower in MS patients than in HC. The ratios of CD4⁺CXC chemokine receptors (CXCR)3⁺/CD4⁺CCR3⁺(Th1/Th2) and CD8⁺CXCR3⁺/CD8⁺CCR4⁺(T cytotoxic 1, Tc1/Tc2) were higher in MS patients than in HC. The percentage of CD8⁺CXCR3⁺T cell (Tc1) and CD4⁺CXCR3⁺T cell (Th1) decreased significantly during remission in MS patients (<it>P <</it>0.05). No significant differences were identified in the expression of the chemokine receptors on PBL in NMO patients compared with MS patients and HC.</p> <p>Conclusions</p> <p>Th1 dominance of chemokine receptors on blood T cells and the correlation between CXCR3⁺T cell (Th1 and Tc1) and disease activity in MS patients were confirmed by analysing chemokines receptors on PBL. In contrast, deviation in the Th1/Th2 balance was not observed in NMO patients.</p

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

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