RESUMO
OBJECTIVES: A proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are B-cell stimulation and survival molecules. We have investigated whether APRIL and/or BAFF activity is enhanced in the systemic and/or intrathechal compartment of patients with neuropsychiatric systemic lupus erythematosus (NPSLE). In particular, the association between fatigue and APRIL/BAFF activity was investigated. METHODS: Twenty-eight NPSLE patients were evaluated clinically, with sampling of cerebrospinal fluid (CSF) and blood, and magnetic resonance imaging (MRI). CSF and blood samples from 13 multiple sclerosis (MS) patients and 17 patients with other neurological diseases (OND) were used as controls. Protein levels of BAFF and APRIL were quantified in CSF and plasma, mRNA expression levels of BAFF and APRIL were determined in peripheral blood (PBMC) and CSF mononuclear cells (CSF-MC). The Fatigue Severity Scale (FSS) was used to quantify the degree of fatigue. RESULTS: NPSLE patients had higher levels of APRIL in CSF as compared to OND (p < 0.01). No corresponding increase in APRIL mRNA levels was detected in CSF-MC. BAFF levels in plasma were higher in NPSLE than in OND (p < 0.001). BAFF mRNA expression in PBMC was also higher in NPSLE patients than in controls (p < 0.05). FSS scores in patients with NPSLE correlated significantly with APRIL levels in CSF. CONCLUSIONS: Protein levels of APRIL in CSF were increased in NPSLE as compared to OND. Moreover, there was a positive correlation between CSF APRIL levels and fatigue. Our results suggest that APRIL and possibly also BAFF may be involved in the pathogenesis of NPSLE and in SLE-related fatigue.
Assuntos
Vasculite Associada ao Lúpus do Sistema Nervoso Central/líquido cefalorraquidiano , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Fator Ativador de Células B/sangue , Fator Ativador de Células B/líquido cefalorraquidiano , Estudos de Coortes , Estudos Transversais , Fadiga/sangue , Fadiga/líquido cefalorraquidiano , Feminino , Humanos , Leucócitos Mononucleares/química , Vasculite Associada ao Lúpus do Sistema Nervoso Central/sangue , Masculino , Pessoa de Meia-Idade , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Adulto JovemRESUMO
Rat chromosome 1 harbors overlapping quantitative trait loci (QTL) for cytokine production and experimental models of inflammatory diseases. We fine-dissected this region that regulated cytokine production, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), anti-MOG antibodies and pristane-induced arthritis (PIA) in advanced intercross lines (AILs). Analysis in the tenth and twelfth generation of AILs resolved the region in two narrow QTL, Eae30 and Eae31. Eae30 showed linkage to MOG-EAE, anti-MOG antibodies and levels of interleukin-6 (IL-6). Eae31 showed linkage to EAE, PIA, anti-MOG antibodies and levels of tumor necrosis factor (TNF) and IL-6. Confidence intervals defined a limited set of potential candidate genes, with the most interesting being RGMA, IL21R and IL4R. We tested the association with multiple sclerosis (MS) in a Nordic case-control material. A single nucleotide polymorphism in RGMA associated with MS in males (odds ratio (OR)=1.33). Polymorphisms of RGMA also correlated with changes in the expression of interferon-gamma (IFN-gamma) and TNF in cerebrospinal fluid of MS patients. In IL21R, there was one positively associated (OR=1.14) and two protective (OR=0.87 and 0.68) haplotypes. One of the protective haplotypes correlated to lower IFN-gamma expression in peripheral blood mononuclear cells of MS patients. We conclude that RGMA and IL21R and their pathways are crucial in MS pathogenesis and warrant further studies as potential biomarkers and therapeutic targets.
Assuntos
Encefalomielite Autoimune Experimental/genética , Proteínas de Membrana/genética , Esclerose Múltipla/genética , Proteínas do Tecido Nervoso/genética , Receptores de Interleucina-21/genética , Animais , Feminino , Proteínas Ligadas por GPI , Ligação Genética , Haplótipos , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , RatosRESUMO
The mRNA expression of eight different cytokines in peripheral blood mononuclear cells in 19 individuals with multiple sclerosis was determined at baseline and after 6 months of open-label treatment with natalizumab. Cellular expression of tumor necrosis factor alpha (TNFalpha) mRNA and number of cells secreting TNFalpha and interferon gamma protein significantly increased over the 6 months. Kurtzke EDSS scores improved because of the resolution of relapses, but not fatigue severity scores. The observed increases in systemic proinflammatory cytokines by natalizumab treatment are discussed in relation to fatigue and systemic immunity.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Anticorpos Monoclonais Humanizados , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Citocinas/genética , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Natalizumab , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/imunologiaRESUMO
A series of phantom experiments were performed with the aim of estimating organ doses for patients undergoing conventional X-ray chest and pelvis examinations. The experiments were performed using physical phantoms corresponding to an adult and a 5-year-old child. Mean organ doses and entrance surface dose were measured using TL-dosemeters. The measured organ doses were compared with the data obtained by calculations using available software tools (EDEREX and PCXMC 2.0) based on the computational MIRD-5 stylized models. The differences between calculated and measured doses for organs located fully or partly in the primary radiation beam did not exceed ±33% with the probability of 95% for the tube voltage 60-140 kV both for an adult and a 5-year-old child phantom. This study suggests that EDEREX and PCXMC 2.0 can be used to estimate organ and effective dose for adult as well as pediatric patients undergoing conventional X-ray examinations.
Assuntos
Órgãos em Risco/efeitos da radiação , Imagens de Fantasmas , Doses de Radiação , Radiografia Abdominal , Radiografia Torácica , Adulto , Carga Corporal (Radioterapia) , Pré-Escolar , Humanos , Método de Monte Carlo , Dosimetria TermoluminescenteRESUMO
Experimental autoimmune encephalomyelitis (EAE) induced in the rat by active immunization with myelin-oligodendrocyte-glycoprotein (MOG) is mediated by synergy between MOG-specific T cells and demyelinating MOG-specific antibody responses. The resulting disease is chronic and displays demyelinating central nervous system (CNS) pathology that closely resembles multiple sclerosis. We analyzed major histocompatibility complex (MHC) haplotype influences on this disease. The MHC haplotype does not exert an all-or-none effect on disease susceptibility. Rather, it determines the degree of disease susceptibility, recruitment of MOG-specific immunocompetent cells, clinical course, and CNS pathology in a hierarchical and allele-specific manner. Major haplotype-specific effects on MOG-EAE map to the MHC class II gene region, but this effect is modified by other MHC genes. In addition, non-MHC genes directly influence both disease and T cell functions, such as the secretion of IFN-gamma. Thus, in MOG-EAE, allelic MHC class II effects are graded, strongly modified by other MHC genes, and overcome by effects of non-MHC genes and environment.
Assuntos
Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Haplótipos , Complexo Principal de Histocompatibilidade , Glicoproteína Associada a Mielina/imunologia , Animais , Autoantígenos/imunologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Feminino , Antígenos de Histocompatibilidade/imunologia , Esclerose Múltipla/imunologia , Proteínas da Mielina , Glicoproteína Mielina-Oligodendrócito , Ratos , Ratos Endogâmicos , Medula Espinal/patologiaRESUMO
Multiple sclerosis is a chronic inflammatory disease characterized by perivenous inflammation and focal destruction of myelin. Many attempts have been undertaken previously to create animal models of chronic inflammatory demyelinating diseases through autoimmunity or virus infection. Recently, however, a new model of myelin oligodendrocyte glycoprotein (MOG) induced autoimmune encephalomyelitis became available, which, in a very standardized and predictable way, leads to chronic (relapsing or progressive) disease and widespread CNS demyelination. In the present study we actively induced MOG-experimental autoimmune encephalomyelitis (EAE) in different inbred rat strains using different immunization protocols. The pathology found in our models closely reflects the spectrum of multiple sclerosis (MS) pathology: Classical MS as well as variants such as optic neuritis, Devic's disease and Marburg's type of acute MS are mimicked in rats immunized with MOG antigen. Furthermore we demonstrate, that by using the proper strain/sensitization regime, subforms of MS such as for instance neuromyelitis optica can be reproducibly induced. Our study further supports the notion, that incidence and expression of the disease in this model, alike the situation in multiple sclerosis, is determined by genetic and environmental factors.
Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Esclerose Múltipla/patologia , Glicoproteína Associada a Mielina/imunologia , Oligodendroglia/metabolismo , Animais , Imunização , Imuno-Histoquímica , Inflamação/patologia , Proteínas da Mielina , Glicoproteína Mielina-Oligodendrócito , Ratos , Ratos Endogâmicos BN , Proteínas Recombinantes/imunologia , Caracteres Sexuais , Especificidade da EspécieRESUMO
The definition of genes regulating the pathogenetic pathways of autoimmune neuroinflammation, may provide targets for new therapeutic strategies. This is not easily accomplished in human disease. Such genetic dissection can more readily be done by the use of inbred rodent strains. With these, genetic heterogeneity is avoided and variation in the environmental influences is minimized. Close mimicking of the human disease characteristics is desirable in such endeavors. Chronic relapsing experimental autoimmune encephalomyelitis (EAE) with MS-like histopathology is achieved after immunization of certain rat strains with myelin oligodendrocyte glycoprotein (MOG) or spinal cord homogenate. The major histocompatibility complex (MHC) regulate the ease by which the environmental trigger in the form of immunisation induces disease. Use of intra-MHC recombinant strains demonstrated major influences from the MHC class II genome region, but additional influences from both the MHC class I and III regions. These findings now provide a basis for studies of the mechanisms for MHC-controlled autoimmune pathogenicity leading to MS-like disease. Gene mapping of F2 crosses between susceptible and resistant rat strains demonstrated nine genome regions outside the MHC which regulate different phenotypes of rat EAE. Many of these co-localize with genome regions regulating other organ-specific disease such experimental arthritis, suggesting a sharing of disease pathways. Further finemapping can lead to the exact identification of disease regulating genes. Interestingly, we have also demonstrated a non-MHC gene control of the inflammatory response, in the form of glial cell activation, and neuronal degeneration, subsequent to anterior nerve root avulsion in rats. The genetic dissection of these influences may unravel pathways controlling CNS vulnerability.
Assuntos
Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Neuroimunomodulação/genética , Animais , Modelos Animais de Doenças , Humanos , Ratos , Ratos EndogâmicosRESUMO
Experimental autoimmune neuritis (EAN) is the principal animal model for Guillain-Barré syndrome (GBS), an inflammatory disease of the peripheral nervous system. Little is known on the genetic regulation of these diseases. We provide the first genetic linkage analysis of EAN. Susceptibility to EAN in a rat F2 population segregated with high levels of anti-PNM IgG, as well as IgG2b and IgG2c isotype levels, which support that disease genes regulate preferential Th1/Th2 differentiation. Linkage analysis demonstrated co-localization of EAN loci with reported susceptibility loci for experimental arthritis and/or encephalomyelitis and a new region on chromosome 17. Further dissection of these loci may disclose disease pathways in GBS.
Assuntos
Ligação Genética , Neurite Autoimune Experimental/genética , Neurite Autoimune Experimental/imunologia , Animais , Cromossomos , Modelos Animais de Doenças , Feminino , Genótipo , Imunoglobulina G/imunologia , Masculino , Sistema Nervoso Periférico/imunologia , Ratos , Ratos Endogâmicos ACI , Células Th1/imunologia , Células Th2/imunologiaRESUMO
Treatment of multiple sclerosis (MS) with interferon beta (IFNbeta) reduces relapse rate, magnetic resonance imaging (MRI) activity and progression of disability. It has been suggested that this beneficial effect is paralleled by an inhibition of proinflammatory cytokines such as interferon gamma (IFNgamma) and tumor necrosis factor alpha (TNFalpha) and an induction of anti-inflammatory cytokines such as interleukin-4 (IL-4) and interleukin-10 (IL-10). In this study, we record a reduced number of spontaneously IFNgamma mRNA-expressing cerebrospinal fluid mononuclear cells (CSF-MC) and IFNgamma, TNFalpha and IL-10 mRNA-expressing peripheral blood mononuclear cells (PBMC) after 6 months of IFNbeta-1a treatment, paralleled by a decreased purified protein derivate (PPD)-stimulated and unstimulated IFNgamma secretion by PBMC. These effects were not apparent after 2 weeks of treatment, and IFNbeta-1a induced IFNgamma production by naive PBMC in vitro. We did not record increased numbers of IL-4 mRNA-expressing CSF-MC or PBMC, increased plasma IL-10 levels, increased numbers of IgG, A or M secreting plasma cells or in vitro induction of IL-10 production by IFNbeta-1a. We conclude that long-term cytokine modulation by IFNbeta-1a differs from acute effects and that downregulation of both pro- and anti-inflammatory cytokines, rather than a shift in the cytokine profile, is apparent after 6 months of IFNbeta-1a treatment of MS patients.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Citocinas/metabolismo , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Adulto , Contagem de Células/efeitos dos fármacos , Células Cultivadas , Líquido Cefalorraquidiano/citologia , Líquido Cefalorraquidiano/metabolismo , Citocinas/genética , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Feminino , Seguimentos , Humanos , Interferon beta-1a , Interferon gama/genética , Interferon gama/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , RNA Mensageiro/biossíntese , Tuberculina/farmacologiaRESUMO
We have studied the effects of treatment with recombinant human (rh)IL-6 on clinical, histological and immunological parameters of protracted relapsing (PR) experimental allergic encephalomyelitis (EAE) in DA rats. rhIL-6 (50 microg/rat subcutaneously/day) was given under three different regimens, as early prophylaxis, from 1 day prior to 14 days after immunization, in late prophylaxis, from day +7 until day 21 post-immunization (p.i.) and therapeutically to rats with clinical signs of EAE from day 14 to day 28 p.i. Although rhIL-6 failed to modulate the course of PR-EAE when administered as the early prophylactic regimen, it exerted clear-cut favourable effects on the course of the disease if was administered either as later prophylactic or as therapeutic treatment. Under these conditions, rhIL-6 accelerated recovery from EAE attacks and reduced/milded subsequent EAE episodes as compared to either PBS- or heat-inactivated rhIL-6-treated control rats. In agreement with this clinical effect, relative to PBS-treated rats, the animals injected with rhIL-6 exhibited lower numbers of MHC class II(+) and CD4(+) cells in their spinal cords. rhIL-6-treatment also profoundly modulated the endogenous cytokine network, the treated rats displaying increased numbers of spleen cells expressing mRNA transcripts of the anti-inflammatory cytokines IL-10 and TGF-beta along with simultaneously reduced numbers of mRNAs for TNF-alpha. In addition, upon ex vivo exposure to either myelin basic protein peptide 63-88 (MBP63-88) or to phytoaemagglutinin A, the numbers of IFN-gamma secreting splenocytes was also significantly reduced (ELISPOT analysis) in rhIL-6-treated rats as compared to PBS-treated controls.
Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Interleucina-6/farmacologia , Animais , Células CHO , Cricetinae , Encefalomielite Autoimune Experimental/prevenção & controle , Expressão Gênica/imunologia , Cobaias , Imunoglobulina G/sangue , Interferon gama/genética , Interleucina-10/genética , Masculino , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos , Proteínas Recombinantes/farmacologia , Recidiva , Medula Espinal/imunologia , Baço/citologia , Baço/imunologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta1 , Fator de Necrose Tumoral alfa/genéticaRESUMO
We identified H-2(q) as a susceptible genotype for MOG-induced EAE by systematic screening of a series of H-2 congenic B10 mouse strains. A series of H-2(q)-bearing strains with divergent gene backgrounds were subsequently investigated. DBA/1 mice were highly susceptible to MOG(1-125)- and MOG(79-96)-induced EAE in the absence of pertussis toxin. Immunisation with MOG(1-125) and MOG(79-96) induced an autoreactive T-cell response in DBA/1 mice. Brain histopathology revealed T-cell and macrophage-infiltrated lesions with associated demyelination. The important features which make this an appropriate model of human disease are high sensitivity to MOG and dependence of an immunodominant peptide region homologous to that implicated in multiple sclerosis.
Assuntos
Adjuvantes Imunológicos/farmacologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Camundongos Congênicos/imunologia , Glicoproteína Associada a Mielina/imunologia , Animais , Autoanticorpos/imunologia , Divisão Celular/imunologia , Suscetibilidade a Doenças/imunologia , Encefalomielite Autoimune Experimental/patologia , Epitopos de Linfócito T/imunologia , Imunização/métodos , Epitopos Imunodominantes/imunologia , Linfonodos/citologia , Linfonodos/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Proteínas da Mielina , Glicoproteína Associada a Mielina/farmacologia , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/farmacologia , Toxina Pertussis , Medula Espinal/imunologia , Medula Espinal/patologia , Baço/citologia , Baço/imunologia , Fatores de Virulência de Bordetella/farmacologiaRESUMO
Memantine, a clinically employed drug with N-methyl-D-aspartate (NMDA) receptor antagonistic effects, dose-dependently ameliorates neurological deficits in Lewis rat experimental autoimmune encephalomyelitis (EAE). Interestingly, this therapeutic effect was not due to dampened CNS inflammation, as assessed by immunohistochemical evaluation of spinal cord tissue. Furthermore, numbers of interferon gamma (IFN gamma) mRNA expressing cells were not decreased, as assessed by in situ hybridization. Systemic immunity in terms of numbers of IFN gamma secreting cells in response to immunodominant myelin basic protein (MBP) peptides ex vivo was not reduced, and non-toxic doses of memantine did not affect lymphocyte proliferation or IFN gamma secretion in vitro. Considering these findings, we hypothesize that effector mechanisms responsible for reversible neurological deficits in EAE may involve NMDA receptors, and this highlights neurons as targets during autoimmune neuroinflammation.
Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Memantina/uso terapêutico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Imuno-Histoquímica , Interferon gama/biossíntese , Interferon gama/metabolismo , Interferon gama/fisiologia , Masculino , Proteína Básica da Mielina/metabolismo , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos Lew , Medula Espinal/química , Linfócitos T/imunologiaRESUMO
BACKGROUND AND PURPOSE: BAF312 is a next-generation sphingosine 1-phosphate (S1P) receptor modulator, selective for S1P(1) and S1P(5 ) receptors. S1P(1) receptors are essential for lymphocyte egress from lymph nodes and a drug target in immune-mediated diseases. Here, we have characterized the immunomodulatory potential of BAF312 and the S1P receptor-mediated effects on heart rate using preclinical and human data. EXPERIMENTAL APPROACH: BAF312 was tested in a rat experimental autoimmune encephalomyelitis (EAE) model. Electrophysiological recordings of G-protein-coupled inwardly rectifying potassium (GIRK) channels were carried out in human atrial myocytes. A Phase I multiple-dose trial studied the pharmacokinetics, pharmacodynamics and safety of BAF312 in 48 healthy subjects. KEY RESULTS: BAF312 effectively suppressed EAE in rats by internalizing S1P(1) receptors, rendering them insensitive to the egress signal from lymph nodes. In healthy volunteers, BAF312 caused preferential decreases in CD4(+) T cells, T(naïve) , T(central memory) and B cells within 4-6 h. Cell counts returned to normal ranges within a week after stopping treatment, in line with the elimination half-life of BAF312. Despite sparing S1P(3) receptors (associated with bradycardia in mice), BAF312 induced rapid, transient (day 1 only) bradycardia in humans. BAF312-mediated activation of GIRK channels in human atrial myocytes can fully explain the bradycardia. CONCLUSION AND IMPLICATIONS: This study illustrates species-specific differences in S1P receptor specificity for first-dose cardiac effects. Based on its profound but rapidly reversible inhibition of lymphocyte trafficking, BAF312 may have potential as a treatment for immune-mediated diseases.
Assuntos
Frequência Cardíaca/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Linfócitos/efeitos dos fármacos , Receptores de Lisoesfingolipídeo/fisiologia , Adolescente , Adulto , Animais , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Compostos de Benzil/farmacologia , Compostos de Benzil/uso terapêutico , Células CHO , Cricetinae , Cricetulus , Método Duplo-Cego , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/fisiopatologia , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Contagem de Linfócitos , Linfócitos/fisiologia , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Ratos , Especificidade da Espécie , Adulto JovemAssuntos
Encefalomielite Autoimune Experimental/imunologia , Antígenos de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade , Animais , Encefalomielite Autoimune Experimental/epidemiologia , Encefalomielite Autoimune Experimental/fisiopatologia , Haplótipos , Incidência , Proteínas da Mielina , Glicoproteína Associada a Mielina/imunologia , Glicoproteína Mielina-Oligodendrócito , Oligodendroglia , Ratos , Ratos Endogâmicos Lew , Ratos Endogâmicos , Recidiva , Especificidade da Espécie , Medula Espinal/imunologia , Fatores de TempoRESUMO
OBJECTIVE: 1) To determine whether JC virus (JCV) DNA was present in the cerebrospinal fluid (CSF) and blood from patients with multiple sclerosis (MS) in comparison with controls and 2) to find out if our clinical material, based on presence of JCV DNA, included any patient at risk for progressive multifocal leukoencephalopathy (PML). METHODS: The prevalence of JCV DNA was analyzed in CSF and plasma from 217 patients with MS, 86 patients with clinically isolated syndrome (CIS), and 212 patients with other neurological diseases (OND). In addition, we analyzed CSF cells, the first report of JCV DNA in CSF cells in a single sample, and peripheral blood cells in a subgroup of MS (n = 49), CIS (n = 14) and OND (n = 53). RESULTS: A low copy number of JCV DNA was detected in one MS cell free CSF sample and in one MS CSF cell samples. None of these had any signs of PML or developed this disease during follow-up. In addition, two OND plasma samples were JCV DNA positive, whereas all the other samples had no detectable virus. CONCLUSION: A low copy number of JCV DNA may occasionally be observed both in MS and other diseases and may occur as part of the normal biology of JC virus in humans. This study does not support the hypothesis that patients with MS would be at increased risk to develop PML, and consequently screening of CSF as a measurable risk for PML is not useful.
Assuntos
Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/virologia , Esclerose Múltipla Crônica Progressiva/virologia , Esclerose Múltipla Recidivante-Remitente/virologia , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/líquido cefalorraquidiano , Líquido Cefalorraquidiano/citologia , Líquido Cefalorraquidiano/virologia , DNA Viral/sangue , DNA Viral/líquido cefalorraquidiano , Feminino , Humanos , Vírus JC/genética , Vírus JC/imunologia , Leucócitos/virologia , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/epidemiologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Crônica Progressiva/epidemiologia , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Fatores de Risco , Estudos SoroepidemiológicosRESUMO
Conversion coefficients from measurable quantities such as air kerma free-in-air or personal dose equivalent to effective dose were determined by phantom experiments. Heterogenic anthropomorphic phantoms representing children of one and five years age, and a Rando phantom representing an adult were exposed in the open field contaminated by different levels of radiocesium in the upper soil layer, in a forest site and inside a wooden house. LiF thermoluminescent (TL) detectors were used inside the phantoms for the estimation of organ doses and effective dose. Personal dosimeters similar to those used in radiation protection for individual dose measurements were placed onto the phantom surface (chest area). The ratios of dose values in separate organs to air kerma free-in-air varied from 0.69 to 1.15 for the children phantoms, and from 0.55 to 0.94 for the adult phantom, respectively, when irradiated in the open field. Body size (weight) was found to be the most important factor influencing the values of the conversion coefficients. The differences observed can reach approximately 40% when comparing conversion factors from air kerma free-in-air to effective dose for adults and newborns. For conversion coefficients from personal dose to effective dose, these differences can reach approximately 15%. The dependences of the various conversion coefficients on body mass were quantified by regression analysis. The results were compared with those calculated for a plane mono-energetic photon source having an energy of 700 keV and being located in the ground at a depth of 0.5 g cm(-2). Calculated and measured conversion coefficients from air kerma free-in-air to effective dose agreed within 12%.
Assuntos
Carga Corporal (Radioterapia) , Exposição Ambiental/análise , Monitoramento de Radiação/instrumentação , Monitoramento de Radiação/métodos , Medição de Risco/métodos , Poluentes Radioativos do Solo/análise , Contagem Corporal Total/métodos , Adulto , Pré-Escolar , Humanos , Lactente , Especificidade de Órgãos , Doses de Radiação , Eficiência Biológica Relativa , Fatores de RiscoRESUMO
Neuroinflammatory (demyelinating) disease is a rare but feared complication of treatment with anti-tumour necrosis factor (TNF)alpha in patients with polyarthritis. In this study, blood and cerebrospinal fluid markers of inflammation were analysed in 10 people with polyarthritis before and during treatment with infliximab. An increased systemic expression of interferon (IFN)gamma was detected. Systemic administration of IFNgamma is known to exacerbate multiple sclerosis. However, the present study failed to detect signs of inflammation in the cerebrospinal fluid samples-that is, pleocytosis, oligoclonal immunoglobulin G bands, increased expression of IFNgamma, TNFalpha or interleukin 10, or increased levels of nitric oxide oxidation products. Our initial hypothesis, that the few cases of clinical neuroinflammatory disorders observed during treatment of polyarthritis with anti-TNFalpha represent the extreme end of a commonly occurring minor intrathecal immune activation, which in most cases does not give any overt neurological dysfunction, was not supported. Induction of systemic IFNgamma production may still be relevant in neuroinflammation associated with treatment with anti-TNFalpha.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite/líquido cefalorraquidiano , Mediadores da Inflamação/líquido cefalorraquidiano , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite/tratamento farmacológico , Artrite/imunologia , Proteína C-Reativa/metabolismo , Feminino , Humanos , Imunoglobulina G/líquido cefalorraquidiano , Mediadores da Inflamação/sangue , Infliximab , Interferon gama/biossíntese , Interferon gama/genética , Interleucina-10/biossíntese , Pessoa de Meia-Idade , Óxido Nítrico/sangue , Óxido Nítrico/líquido cefalorraquidiano , Oxirredução , RNA Mensageiro/genética , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Regulação para Cima/efeitos dos fármacosRESUMO
In 1990, a joint Nordic-Russian project was initiated in order to make independent estimations of the effective dose to selected groups of inhabitants in a highly contaminated area around the city of Novozybkov in the western Bryansk region of Russia. The inhabitants were living in six villages with initial contamination levels of (137)Cs between 0.9 and 2.7 MBq m(-2). Some villages had been decontaminated, others not. Both school children and adults participated in the study. The external irradiation of 100-130 inhabitants was determined during 1 month in September-October each year from 1990 to 2000 (except 1999), using individual thermoluminescent dosemeters. The body burden of (137,134)Cs was determined by in vivo measurements in about 500 inhabitants annually from 1991 to 2000, and for a subgroup also with analysis of the (137)Cs concentration in urine. The mean effective dose (E) from external and internal irradiation due to (137,134)Cs deposition varied between 2.5 and 1.2 mSv per year between 1990 and 2000. The total mean E decreased, on average, by 9% per year, while the mean external dose decreased by 16% per year. The dose rate from internal radiation decreased more slowly than the dose rate from external radiation, and also showed an irregular time variation. The contribution from the internal dose to the total E was 30-50%, depending on the village. Predictions for the long-term changes in the effective dose to people living in the areas are presented. The cumulated E for the 70 years following the accident was estimated to be about 90 mSv with the assumption that both internal and external dose decrease by 2% per year after year 2000. The highest E during a life-time received by single individuals living in the area may amount to around 500 mSv considering the individual variations in E.
Assuntos
Acidente Nuclear de Chernobyl , Adulto , Fenômenos Biofísicos , Biofísica , Carga Corporal (Radioterapia) , Radioisótopos de Césio/efeitos adversos , Radioisótopos de Césio/análise , Criança , Feminino , Humanos , Masculino , Doses de Radiação , População Rural , Federação Russa , Fatores de TempoRESUMO
The polyamines are ubiquitous in nature and appear to fulfil several important functions, mostly related to growth, in the cell. The first, and often rate-limiting, step in the biosynthesis of the polyamines is catalysed by ornithine decarboxylase (ODC), which is subject to a variety of control mechanisms. The polyamines exert a strong feedback regulation of the expression - as well as the degradation of the enzyme. The regulation of ODC expression appears to occur at the translational level. The ODC mRNA contains a long GC-rich 5' untranslated region (UTR), which has been demonstrated to hamper the translation of the mRNA. However, it has not yet been conclusively established whether this part of the mRNA fulfils any function in relation to the polyamine-mediated control of ODC synthesis. In the present study, we have used stable transgenic CHO cells, expressing either full-length ODC mRNA or 5' UTR-truncated ODC mRNA, to elucidate the role, if any, of the 5' UTR in the translational regulation of the enzyme by polyamines. No differences in regulatory properties were observed between the cells expressing the full-length ODC mRNA and those expressing the ODC mRNA devoid of most the 5' UTR. The cell lines down-regulated ODC (synthesis as well as activity) to the same extent upon exposure to an excess of polyamines, demonstrating that the feedback control of ODC mRNA translation occurs by a mechanism independent of the major part of the 5' UTR of the ODC mRNA.