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2.
Mult Scler ; 22(4): 533-43, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26362898

RESUMO

OBJECTIVES: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). METHODS: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. RESULTS: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. CONCLUSIONS: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.


Assuntos
Fatores Imunológicos/uso terapêutico , Interferon beta-1b/uso terapêutico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Adulto , Avaliação da Deficiência , Progressão da Doença , Método Duplo-Cego , Europa (Continente) , Feminino , Seguimentos , Humanos , Fatores Imunológicos/efeitos adversos , Interferon beta-1b/efeitos adversos , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Crônica Progressiva/mortalidade , Análise Multivariada , Fatores de Tempo , Resultado do Tratamento
3.
Mult Scler Relat Disord ; 68: 104166, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36115289

RESUMO

BACKGROUND: Assessment of the disease course by people with multiple sclerosis (pwMS) themselves is important for a better understanding of the complex disease, patient counseling and treatment decisions. This may also facilitate identifying the often-unnoticed transition from relapsing-remitting (RRMS) to secondary progressive multiple sclerosis (SPMS). OBJECTIVE: MS Perspectives was designed to collect data on patients' self-assessment of multiple sclerosis (MS) symptoms, relapse-independent progression, and impact on everyday life. METHODS: MS Perspectives is a cross-sectional online survey conducted among adult pwMS in Germany. The questionnaire included 36 items on sociodemographic and clinical characteristics as well as pharmacological and non-pharmacological treatment. RESULTS: In total, 4555 pwMS completed the survey between December 2021 and February 2022, 69.2% had RRMS, 15.1% had SPMS. Relapse-independent worsening of symptoms was reported by 88.9% of RRMS patients with marked to severe and by 61.8% with no or mild to moderate disability. Problems with walking were most frequently (32.1%) mentioned as most bothersome by RRMS patients with marked to severe disability, fatigue, and cognitive impairment by RRMS patients with no or mild to moderate disability. CONCLUSION: MS Perspectives gives an important insight in the self-assessed disease course and impact on daily life in a large-scale cohort of pwMS.


Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Adulto , Humanos , Esclerose Múltipla Crônica Progressiva/terapia , Esclerose Múltipla Crônica Progressiva/complicações , Esclerose Múltipla/complicações , Estudos Transversais , Autoavaliação (Psicologia) , Efeitos Psicossociais da Doença , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Progressão da Doença
4.
Acta Neurol Scand ; 124(4): 290-2, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21943035

RESUMO

BACKGROUND: Natalizumab is neither licensed for the use in adolescents nor during pregnancy. There are no reports of accidental natalizumab exposure during pregnancy continued as long as to the third trimester of pregnancy. AIMS: We report the outcome of pregnancy in a 17-year-old adolescent patient with multiple sclerosis (MS) treated with natalizumab from the age of 16, who was diagnosed to be pregnant in the 31st gestational week (gw) of pregnancy. To our knowledge, this report describes the first patient receiving natalizumab to the third trimester of pregnancy. CASE REPORT: Because of high relapse activity, natalizumab treatment was administered in an adolescent patient with MS. Pregnancy was diagnosed in the 31st gw after 17 natalizumab infusions, seven of them accidentally during pregnancy. RESULTS: Pre- and postnatal development of the child was normal. CONCLUSIONS: The case reported indicates that accidentally continued natalizumab treatment until few weeks before delivery may have no negative impact on the developing foetus.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Adolescente , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla Recidivante-Remitente/complicações , Natalizumab , Gravidez , Resultado da Gravidez , Terceiro Trimestre da Gravidez , Resultado do Tratamento
5.
medRxiv ; 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34611669

RESUMO

BACKGROUND: COVID-19 vaccines have been associated with a rare thrombotic and thrombocytopenic reaction, Vaccine-induced immune thrombotic thrombocytopenia (VITT) characterized by platelet-activating anti-PF4 antibodies. This study sought to assess clonality of VITT antibodies and evaluate their characteristics in antigen-based and functional platelet studies. METHODS: Anti-PF4 antibodies were isolated from five patients with VITT secondary to ChAdOx1 nCoV-19 (n=1) or Ad26.COV2.S (n=4) vaccination. For comparative studies with heparin-induced thrombocytopenia (HIT), anti-PF4 antibodies were isolated from one patient with spontaneous HIT, another with "classical" HIT, and two patients with non-pathogenic (non-platelet activating) anti-PF4 antibodies. Isolated antibodies were subject to ELISA and functional testing, and mass spectrometric evaluation for clonality determination. RESULTS: All five VITT patients had oligoclonal anti-PF4 antibodies (3 monoclonal, one bi- and one tri-clonal antibodies), while HIT anti-PF4 antibodies were polyclonal. Notably, like VITT antibodies, anti-PF4 antibodies from a spontaneous HIT patient were monoclonal. The techniques employed did not detect non-pathogenic anti-PF4 antibodies. The ChAdOx1 nCoV-19-associated VITT patient made an excellent recovery with heparin treatment. In vitro studies demonstrated strong inhibition of VITT antibody-induced platelet activation with therapeutic concentrations of heparin in this and one Ad26.COV2.S-associated VITT patient. Oligoclonal VITT antibodies with persistent platelet-activating potential were detected at 6 and 10 weeks after acute presentation in two patients tested. Two of the 5 VITT patients had recurrence of thrombocytopenia and one patient had focal seizures several weeks after acute presentation. CONCLUSION: Oligoclonal anti-PF4 antibodies mediate VITT. Heparin use in VITT needs to be further studied.

6.
Clin Exp Immunol ; 157(3): 332-42, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19664140

RESUMO

Plasmacytoid dendritic cells (pDCs) are of crucial importance in immune regulation and response to microbial factors. In multiple sclerosis (MS), pDCs from peripheral blood showed an immature phenotype, but its role in susceptibility to MS is not determined. Because infectious diseases are established triggers of exacerbations in MS, in this study we have characterized the expression of Toll-like receptors (TLR) and the maturation and functional properties of peripheral blood pDCs from clinically stable, untreated MS patients in response to signals of innate immunity. After stimulation of TLR-9, interferon (IFN)-alpha production by pDCs was significantly lower in MS (n = 12) compared to healthy controls (n = 9). In an allogenic two-step co-culture assay we found an impaired effect of TLR-9 stimulation on IFN-gamma expression of autologous naive T cells in MS patients (n = 4). In peripheral blood mononuclear cells, TLR-9 stimulation with type A CpG ODN resulted in a higher expression of TLR-1, -2, -4, -5 and -8 in MS patients (n = 7) compared with healthy controls (n = 11). These findings suggest an altered innate immune response to microbial stimuli in MS patients and may help understanding of why common infectious agents trigger MS attacks.


Assuntos
Infecções Bacterianas/imunologia , Células Dendríticas/imunologia , Esclerose Múltipla/imunologia , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Estudos de Casos e Controles , Células Dendríticas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Imunidade Inata , Imunização , Interferon gama/análise , Interferon gama/metabolismo , Leucaférese , Masculino , Esclerose Múltipla/metabolismo , Oligodesoxirribonucleotídeos/farmacologia , Reação em Cadeia da Polimerase/métodos , Estatísticas não Paramétricas , Receptor Toll-Like 9/agonistas , Receptores Toll-Like/análise , Receptores Toll-Like/metabolismo
9.
J Neuropathol Exp Neurol ; 60(4): 320-7, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11305867

RESUMO

Matrix metalloproteinases (MMPs) are Zn2+-endopeptidases that seem to play an important role in chronic inflammatory diseases of the central nervous system by disrupting the blood-brain barrier (BBB) and mediating the destruction of myelin components. We therefore investigated the influence of the pro-inflammatory cytokine TNF-alpha. on the expression and activation of several MMPs in human cerebral endothelial cells (HCEC). HCEC constitutively express MMP-2 and MMP-3 mRNA, but only MMP-3 is upregulated on mRNA and protein level after TNF-alpha stimulation. MMP-9 and MMP-12 mRNA could only be detected under inflammatory conditions. Furthermore, MMPs are involved in shedding of cell surface molecules. We therefore investigated the influence of MMPs on the release of soluble adhesion molecules using marimastat, a specific broad-spectrum MMP inhibitor and other protease inhibitors like aprotinin or leupeptin. Only marimastat inhibited the TNF-alpha mediated release of sVCAM-1 in the supernatants of HCEC. Western blot results of culture supernatants supported the time dependent release of the complete extracellular portion of the VCAM-1 molecule. These data suggest that MMPs produced by HCEC are actively involved in the shedding of soluble adhesion molecules at the BBB.


Assuntos
Moléculas de Adesão Celular/metabolismo , Córtex Cerebral/irrigação sanguínea , Endotélio Vascular/metabolismo , Metaloproteinases da Matriz/metabolismo , Processamento Alternativo , Northern Blotting , Células Cultivadas , Córtex Cerebral/citologia , Meios de Cultivo Condicionados/metabolismo , Proteínas de Ligação a DNA , Relação Dose-Resposta a Droga , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Deleção de Genes , Humanos , Metaloproteinases da Matriz/genética , Microcirculação/citologia , Inibidores de Proteases/farmacologia , RNA Mensageiro/biossíntese , Fatores de Transcrição , Fator de Necrose Tumoral alfa/farmacologia , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
10.
Drug Saf ; 22(2): 149-59, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10672896

RESUMO

Interferon-beta is an established therapy in relapsing-remitting multiple sclerosis. Recently, it has also been shown that interferon-beta-1b is effective in secondary progressive multiple sclerosis. However, adverse effects of interferon-beta treatment are common, particularly during the first weeks of treatment, and are a major concern. Flu-like symptoms, injection site reactions and laboratory abnormalities are the most common adverse effects, and may result in reduced compliance or even discontinuation of treatment in a number of patients. Therefore, efforts to minimise these reactions, e.g. appropriate comedication with analgesic/antipyretic drugs, use of correct preparation and injection technique and sometimes modification of the dosage of interferon-beta, are of considerable importance. This article provides an overview of the management of clinically relevant adverse effects related to treatment with interferon-beta, based on a literature review and personal experience. Essential aspects of patient information are also stressed. If these recommendations are followed, adverse effects related to interferon-beta may be substantially reduced in the majority of patients.


Assuntos
Interferon beta/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Ensaios Clínicos como Assunto , Humanos , Incidência , Interferon beta/uso terapêutico
11.
Neurosci Lett ; 335(3): 155-8, 2003 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-12531456

RESUMO

Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) exert various effects on immune cells. Here we studied, whether they influence the cytokine expression pattern in peripheral blood mononuclear cells (PBMCs) or antigen specific T-cells. In PBMCs BDNF and NGF had interindividually variable effects on T helper cell type (Th)1- and Th2-cytokines. However, there was a high correlation between the modulating properties of these neurotrophins (r=0.97) concerning the expression of interleukin (IL) 4, transforming growth factor-beta and tumour necrosis factor-alpha mRNA at a concentration of 100 ng/ml. In myelin basic protein-specific T-cell lines BDNF and NGF increased interferon -gamma mRNA to a moderate extent, but not IL4. No major effects were detected at the cytokine protein level. In conclusion, our results suggest a partial effect of neurotrophins on immune cells, which may be modified by other signals.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Leucócitos Mononucleares/metabolismo , Fator de Crescimento Neural/metabolismo , Linfócitos T/metabolismo , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Técnicas de Cultura de Células , Citocinas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Interferon gama/metabolismo , Interleucina-4/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Fator de Crescimento Neural/farmacologia , RNA Mensageiro/metabolismo , Linfócitos T/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
Nervenarzt ; 76(8): 1009-21; quiz 1022-3, 2005 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-16080020

RESUMO

The group of autoimmune neuropathies includes the Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuritis, multifocal motor neuropathy, neuropathies associated with monoclonal gammopathies, and vasculitic neuropathies. This educational review first addresses diagnostic pathways that facilitate more rational diagnostic decisions. Many therapies are effective for treating immune neuropathies. Unfortunately, none of the available therapies are specific. In the acute phase, glucocorticosteroids, plasmapheresis, and intravenous immunoglobulins play key roles. The list of long-term therapies includes azathioprine, cyclosporine, cyclophosphamide, and immunoglobulins. The therapeutic mechanisms involved are not clear for most of these compounds. Modern immunotherapy has to consider medical aspects, available therapeutic evidence, and long-term economic burden.


Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/terapia , Imunoterapia/métodos , Polineuropatias/diagnóstico , Polineuropatias/terapia , Doenças Autoimunes do Sistema Nervoso/imunologia , Humanos , Polineuropatias/imunologia , Guias de Prática Clínica como Assunto , Padrões de Prática Médica
14.
Fortschr Neurol Psychiatr ; 71(2): 61-6, 2003 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-12579468

RESUMO

Myopathies include a broad range of disorders. Diagnostic steps in muscle disorders should therefore be followed sequentially, in order not to miss important information and to avoid unnecessary and cost intensive diagnostic procedures. Specific care should be applied in taking patient's history to ascertain myopathy related complaints, triggers and concomitant diseases possibly being accompanied by a myopathy. Clinical examination may reveal a distribution pattern already suggestive for a specific disorder. An elevated creatine kinase, often leading to neurological evaluation, should at least be repeated once after resting. Metabolic myopathies might be detected by exercise testing. Electromyography, muscle imaging and, usually as the last diagnostic step, muscle biopsy represent further diagnostic tools in the assessment of myopathies. In some disorders molecular genetic techniques can be applied.


Assuntos
Doenças Musculares/diagnóstico , Biomarcadores , Técnicas de Laboratório Clínico , Eletromiografia , Humanos , Músculo Esquelético/patologia , Doenças Musculares/patologia , Doenças Musculares/fisiopatologia , Exame Físico
15.
Acta Neuropathol ; 88(5): 420-5, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-7847070

RESUMO

Interphase cytogenetics, i.e., in situ hybridization using probes to chromosome-specific DNA, enables histological identification of cells bearing numerical chromosome aberrations and cytogenetic analysis of composite tumors. We studied routinely processed tissues from seven glioblastomas and three gliosarcomas using biotinylated probes to pericentromeric alpha-satellite sequences on chromosomes 10, 17 and X. By applying various pretreatment protocols, an evaluable compromise between morphology and signal intensity was obtained in most cases. Compared to vascular cells with normal chromosomal counts, a significant subpopulation of glioblastoma cells showed monosomy 10 (four of five cases), monosomy 17 (one of seven cases) and loss of one X chromosome (one of seven cases). All monosomy 10 cases comprised additional areas where two copies of chromosome 10 were retained. Among the gliosarcomas, both the glioma and the sarcoma portion showed monosomy 10 in one case and monosomy 17 in another case. In contrast, in the third case of gliosarcoma, monosomy 10 was found only in the glioma portion, whereas a gain of chromosome X was observed in the sarcoma portion. We conclude that: (1) numerical chromosome aberrations can be detected in routinely processed brain tumor biopsy specimens using interphase cytogenetics, making retrospective studies feasible; (2) glioblastomas show intratumoral cytogenetic heterogeneity with formation of monoclonal cell clusters; and (3) sarcoma and glioma elements in gliosarcomas may exhibit the same or different numerical chromosome aberrations, suggesting various histogenetic pathways of the sarcoma-like portion.


Assuntos
Neoplasias Encefálicas/genética , Aberrações Cromossômicas , Glioblastoma/genética , Gliossarcoma/genética , Interfase , Adulto , Idoso , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 17 , Feminino , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Cromossomo X
16.
Cytokine ; 19(2): 55-8, 2002 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-12182839

RESUMO

Inflammatory stimuli within the central nervous system may not only induce tissue damage but may also convey neuroprotection. It has been shown that brain derived neurotrophic factor (BDNF) is a neuroprotective candidate. Here we show that BDNF is constitutively expressed in cultured human cerebral endothelial cells (HCEC) and can further be upregulated under proinflammatory conditions. TNF-alpha treatment resulted in an increase in BDNF mRNA expression and protein levels were significantly elevated after 72 h (69+/-33%, P<0.01). Using functional assays it was demonstrated that BDNF produced by HCEC is bioactive and supports motoneuron survival. In contrast, BDNF expression was reduced by TNF-alpha in human umbilical vein endothelial cells (HUVEC). We conclude that HCEC likely to contribute to neuronal survival under physiological and inflammatory conditions.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Endotélio/metabolismo , Telencéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Telencéfalo/citologia
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