Pediatric-onset multiple sclerosis (POMS) prevalence and incidence rates are increasing globally. No disease-modifying therapy are approved for MS pediatric population. Hence, we aim to review the ...literature on POMS to guide treating physicians on the current understanding of diagnosis and management of pediatric MS.
The authors performed a literature search and reviewed the current understanding on risk factors and disease parameters in order to discuss the challenges in assessing and implementing diagnosis and therapy in clinical practice.
The revised International Pediatric MS group diagnostic criteria improved the accuracy of diagnosis. Identification of red flags and mimickers (e.g. acute disseminated encephalomyelitis and neuromyelitis optica) are vital before establishing a definitive diagnosis. Possible etiology and mechanisms including both environmental and genetic risk factors are highlighted. Pediatric MS patients tend to have active inflammatory disease course with a tendency to have brainstem / cerebellar presentations at onset. Due to efficient repair mechanisms at early life, pediatric MS patients tend to have longer time to reach EDSS 6 but reach it at earlier age. Although no therapeutic randomized clinical trials were conducted in pediatric cohorts, open-label multi-center studies reported efficacy and safety results with beta interferons, glatiramer acetate and natalizumab in similar adult cohorts. Several randomized clinical trials assessing the efficacy and safety of oral disease-modifying therapies are ongoing in pediatric MS patients.
Pediatric MS has been increasingly recognized to have a more inflammatory course with frequent infratentorial presentations at onset, which would have important implications in the future management of pediatric cohorts while awaiting the results of ongoing clinical trials.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Echinoderms are capable of asexual reproduction by fission. An individual divides into parts due to changes in the strength of connective tissue of the body wall. The structure of connective tissue ...and the mechanisms of variations in its strength in echinoderms remain poorly studied. An analysis of transcriptomes of individuals during the process of fission provides a new opportunity to understand the mechanisms of connective tissue mutability. In the holothurian Cladolabes schmeltzii, we have found a rather complex organization of connective tissue. Transcripts of genes encoding a wide range of structural proteins of extracellular matrix, as well as various proteases and their inhibitors, have been discovered. All these molecules may constitute a part of the mechanism of connective tissue mutability. According to our data, the extracellular matrix of echinoderms is substantially distinguished from that of vertebrates by the lack of elastin, fibronectins, and tenascins. In case of fission, a large number of genes of transcription factors and components of different signaling pathways are expressed. Products of these genes are probably involved in regulation of asexual reproduction, connective tissue mutability, and preparation of tissues for subsequent regeneration. It has been shown that holothurian tensilins are a special group of tissue inhibitors of metalloproteinases, which has formed within the class Holothuroidea and is absent from other echinoderms. Our data can serve a basis for the further study of the mechanisms of extracellular matrix mutability, as well as the mechanisms responsible for asexual reproduction in echinoderms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alemtuzumab is a humanized monoclonal antibody directed against CD52 to deplete circulating T and B lymphocytes; lymphocyte depletion is followed by a distinctive pattern of T- and B-cell ...repopulation, changing the balance of the immune system. This review reports the efficacy and safety findings of the phase 2 CAMMS223 trial and the phase 3 CARE-MS I and II trials investigating alemtuzumab for the treatment of active relapsing–remitting MS. Alemtuzumab, administered intravenously, was shown to improve relapse rate versus subcutaneous interferon beta-1a in patients who were treatment-naive (CAMMS223 and CARE-MS I) or had relapsed on prior therapy (CARE-MS II), and to reduce sustained accumulation of disability (CAMMS223 and CARE-MS II). Important adverse events were infusion-associated reactions, serious infections and autoimmune events. A safety monitoring program allowed for early detection and management of autoimmune events. Recommendations for the monitoring of adverse events are made. Alemtuzumab’s mechanism of action, pharmacodynamics and opportunities for future research are discussed.
The holothurian Eupentacta fraudatrix is a unique organism for studying regeneration mechanisms. Moreover, E. fraudatrix can quickly restore parts of its body and entire organ systems, yet at the ...moment, there is no data on the participation of stem cells in the process. To the contrary, it has been repeatedly confirmed that this process is only due to the transformation of terminally differentiated cells. In this study, we examine changes in gene expression during gut regeneration of the holothurian E. fraudatrix. Transcriptomes of intestinal anlage of the three stages of regeneration, as well as the normal gut, were sequenced with an Illumina sequencer (San Diego, CA, USA). We identified 14,617 sea urchin protein homologs, of which 308 were transcription factors. After analysing the dynamics of gene expression during regeneration and the map of biological processes in which they participate, we identified 11 factors: Ef-EGR1, Ef-ELF, Ef-GATA3, Ef-ID2, Ef-KLF1/2/4, Ef-MSC, Ef-PCGF2, Ef-PRDM9, Ef-SNAI2, Ef-TBX20, and Ef-TCF24. With the exception of TCF24, they are all involved in the regeneration, development, epithelial-mesenchymal transition, and immune response in other animals. We suggest that these transcription factors may also be involved in the transdifferentiation of coelomic epithelial cells into enterocytes in holothurians.
In this placebo-controlled, phase 3 trial involving patients with relapsing–remitting multiple sclerosis, oral laquinimod administered once daily reduced the number of clinical relapses and slowed ...disability progression.
Laquinimod is an oral quinoline-3-carboxamide small molecule selected for its efficacy and safety from a pool of 60 quinoline-3-carboxamide derivatives of the parent compound, roquinimex, a drug previously evaluated in phase 2 trials of treatment for multiple sclerosis but withdrawn because of safety concerns.
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Preclinical studies have shown that laquinimod reduces inflammatory cell infiltrates in the central nervous system, decreases demyelination, and prevents axonal loss.
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It is currently in clinical development for the treatment of multiple sclerosis.
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A 36-week, double-blind, placebo-controlled, phase 2 clinical trial showed a significant reduction in the primary end point, the cumulative number of gadolinium-enhancing . . .
Dopamine is a neurotransmitter that mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of dopamine on the cells of innate and ...adaptive immune systems, including Th17 cells, which play a critical role in inflammatory diseases of the CNS. This article reviews the literature data on the role of dopamine in the regulation of neuroinflammation in multiple sclerosis (MS). The influence of dopaminergic receptor targeting on experimental autoimmune encephalomyelitis (EAE) and MS pathogenesis, as well as the therapeutic potential of dopaminergic drugs as add-on pathogenetic therapy of MS, is discussed.
In this trial, daclizumab high-yield process (a monoclonal antibody that binds to CD25 and modulates interleukin-2 signaling) was more effective than interferon beta-1a in patients with ...relapsing–remitting multiple sclerosis. Infection and rash were more common with daclizumab.
Daclizumab is a humanized monoclonal antibody that binds to the alpha subunit (CD25) of the high-affinity interleukin-2 receptor.
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Daclizumab treatment prevents signaling through the high-affinity interleukin-2 receptor and increases the availability of interleukin-2 to signal at its intermediate-affinity receptor.
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The use of daclizumab in patients with multiple sclerosis was based initially on the hypothesis that it directly antagonizes activated CD25+ effector T cells, which have long been implicated as key mediators of the pathogenic effects of multiple sclerosis.
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Notably, effector T-cell numbers and recall responses appear to be largely unaffected by daclizumab in vivo.
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Other clinically important . . .
Summary Background Subcutaneous pegylated interferon (peginterferon) beta-1a is being developed for treatment of relapsing multiple sclerosis, with less frequent dosing than currently available ...first-line injectable treatments. We assessed the safety and efficacy of peginterferon beta-1a after 48 weeks of treatment in the placebo-controlled phase of the ADVANCE trial, a study of patients with relapsing-remitting multiple sclerosis. Methods We did this 2-year, double-blind, parallel group, phase 3 study, with a placebo-controlled design for the first 48 weeks, at 183 sites in 26 countries. Patients with relapsing-remitting multiple sclerosis (age 18–65 years, with Expanded Disability Status Scale score ≤5) were randomly assigned (1:1:1) via an interactive voice response or web system, and stratified by site, to placebo or subcutaneous peginterferon beta-1a 125 μg once every 2 weeks or every 4 weeks. The primary endpoint was annualised relapse rate at 48 weeks. This trial is registered with ClinicalTrials.gov , number NCT00906399. Findings We screened 1936 patients and enrolled 1516, of whom 1512 were randomly assigned (500 to placebo, 512 to peginterferon every 2 weeks, 500 to peginterferon every 4 weeks); 1332 (88%) patients completed 48 weeks of treatment. Adjusted annualised relapse rates were 0·397 (95% CI 0·328–0·481) in the placebo group versus 0·256 (0·206–0·318) in the every 2 weeks group and 0·288 (0·234–0·355) in the every 4 weeks group (rate ratio for every 2 weeks group 0·644, 95% CI 0·500–0·831, p=0·0007; rate ratio for the every 4 weeks group 0·725, 95% CI 0·565–0·930, p=0·0114). 417 (83%) patients taking placebo, 481 (94%) patients taking peginterferon every 2 weeks, and 472 (94%) patients taking peginterferon every 4 weeks reported adverse events including relapses. The most common adverse events associated with peginterferon beta-1a were injection site reactions, influenza-like symptoms, pyrexia, and headache. 76 (15%) patients taking placebo, 55 (11%) patients taking study drug every 2 weeks, and 71 (14%) patients taking study drug every 4 weeks reported serious adverse events; relapse, pneumonia, and urinary tract infection were the most common. Interpretation After 48 weeks, peginterferon beta-1a significantly reduced relapse rate compared with placebo. The drug might be an effective treatment for relapsing-remitting multiple sclerosis with less frequent administration than available treatments. Funding Biogen Idec.
The holothurian
is capable of fully restoring its muscles after transverse dissection. Although the regeneration of these structures is well studied at the cellular level, the molecular basis of the ...process remains poorly understood. To identify genes that may be involved in the regulation of muscle regeneration, the transcriptome of the longitudinal muscle band of
has been sequenced at different time periods post-injury. An analysis of the map of biological processes and pathways has shown that most genes associated with myogenesis decrease their expression during the regeneration. The only exception is the genes united by the GO term "heart valve development". This may indicate the antiquity of mechanisms of mesodermal structure transformation, which was co-opted into various morphogeneses in deuterostomes. Two groups of genes that play a key role in the regeneration have been analyzed: transcription factors and matrix metalloproteinases. A total of six transcription factor genes (
and
) and seven matrix metalloproteinase genes (
and
) showing differential expression during myogenesis have been revealed. The identified genes are assumed to be involved in the muscle regeneration in holothurians.
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