RESUMO
BACKGROUND AND PURPOSE: The influence of apolipoprotein E (ApoE) polymorphism on clinical severity of multiple sclerosis (MS) is still controversial. Cigarette smoking has been suggested to influence the progression of disability in these patients. In this study, we aimed to investigate whether an interaction of smoking with the ApoE polymorphism influences the progression of disability in MS patients. METHODS: Smoking history from 205 female patients with MS was obtained. Clinical data collected include age at onset, disease duration, annual relapse rate, the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS). ApoE polymorphism was examined in all patients and stratified according to smoking status and associations with the clinical data investigated. RESULTS: There were no significant associations between cigarette smoking and any of the clinical characteristics in the whole group of patients. In women carrying the ApoE E4 isoform, smokers had a lower EDSS (P = 0.033) and MSSS (P = 0.023) in comparison with non-smokers. CONCLUSION: Our data suggest that in women with MS carrying the ApoE E4 isoform, cigarette smoking may have a protective influence on disease progression and accumulation of disability. These findings need to be confirmed by future large longitudinal studies.
Assuntos
Predisposição Genética para Doença , Esclerose Múltipla/genética , Esclerose Múltipla/fisiopatologia , Polimorfismo Genético/genética , Fumar/genética , Adulto , Apolipoproteínas E/genética , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
Serum ferritin levels have been found to be increased in patients with active progressive multiple sclerosis (MS). However, its levels are reported to be unchanged in stable and in active relapsing-remitting (RR) form of the disease. No research to date has assessed the influence of interferon beta (IFN-beta) on ferritin concentrations. In this study, serum ferritin levels were measured in 43 individuals with RR-MS and 38 age- and sex-matched control volunteers. There were no significant differences between controls and patients under stable and untreated conditions. In patients at 12 months after the beginning of IFN-beta therapy, ferritin levels were higher in women and in men, in comparison with baseline (71.4 +/- 58.6 vs 43.4 +/- 29.9 ng/mL, P = 0.0006 and 216.0 +/- 124.3 vs 127.8 +/- 74.9 ng/mL, P = 0.0022, respectively). These results suggest that larger prospective studies are required to evaluate the role of serum ferritin in MS and its potential usefulness in monitoring responses to immunomodulatory therapies.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Ferritinas/sangue , Interferon beta/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Bilirrubina/sangue , Monitoramento de Medicamentos/métodos , Feminino , Hemoglobinas , Humanos , Interferon beta-1a , Interferon beta-1b , Masculino , Pessoa de Meia-Idade , Caracteres SexuaisRESUMO
To assess whether interferon beta1a (IFNbeta1a) therapy affects plasma lipoprotein metabolism, twelve patients with relapsing-remitting multiple sclerosis (MS) were studied during a two-year follow-up period. High density lipoprotein (HDL2) cholesterol and the HDL2/HDL3 ratio were increased at year 2 and lipoprotein (a) was transitorily increased at year 1, in comparison to baseline levels. Apolipoprotein A-I was lower and apolipoprotein E higher at year 1, only in a subgroup of patients who experienced relapses and/or progressed during therapy. These findings suggest that IFNbeta1a treatment is associated with changes in the lipoprotein metabolism. Alterations in this metabolism could be related to the immunomodulatory actions of the drug and the disease activity in multiple sclerosis patients.
Assuntos
Interferon beta/uso terapêutico , Lipoproteínas/sangue , Esclerose Múltipla/sangue , Esclerose Múltipla/tratamento farmacológico , Adulto , Apolipoproteína A-I/sangue , Feminino , Seguimentos , Humanos , Interferon beta-1a , Lipoproteínas HDL/sangue , Lipoproteínas HDL2 , Lipoproteínas HDL3 , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de TempoRESUMO
A clinically definite diagnosis of multiple sclerosis was done in a 61 year-old woman who displayed severe cerebellar and pyramidal tract involvement. Symptoms developed 5 years before with unsteadiness of gait and difficulties in walking. Diagnosis was supported by evoked potentials studies and magnetic resonance imaging. However, the cerebrospinal fluid (CSF) analysis was very unusual. CSF albumin and IgG concentrations were normal, as well as the IgG index. In contrast, the IgA level and the IgA index were markedly increased and the local synthesis of IgA was estimated at 31.36 mg/l. Reduction by dithiotreitol did not change the IgA level. On affinity immunoblots, oligoclonal IgA bands were not detected but oligoclonal IgG bands were present. The strong local production of IgA in this patient seems to be therefore polyclonal.
Assuntos
Imunoglobulina A/biossíntese , Esclerose Múltipla/imunologia , Medula Espinal/metabolismo , Ditioeritritol/farmacologia , Eletroencefalografia , Potenciais Somatossensoriais Evocados , Potenciais Evocados Visuais , Feminino , Humanos , Immunoblotting/métodos , Imunoglobulina A/líquido cefalorraquidiano , Imunoglobulina A/efeitos dos fármacos , Imunoglobulina G/biossíntese , Imunoglobulina G/líquido cefalorraquidiano , Pessoa de Meia-Idade , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/fisiopatologia , Medula Espinal/imunologia , Reagentes de Sulfidrila/farmacologiaRESUMO
The effect of low (physiological) concentrations of insulin (2 and 20 ng/ml) and L-triiodothyronine (T3) were studied on two myelin-related enzymes: (1) the 3'-phosphoadenosine-5'-phosphosulfate:cerebroside sulfotransferase (CST, EC 2.8.2.11) catalyzing the production of sulfatide, and (2) the myelin enzyme, 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP, EC 3.1.4.3.7) in myelinogenic cultures of cells dissociated from embryonic mouse brain. Insulin treatment (20 ng/ml) of the cells in the presence of serum increased CST activity at 18 and 25 days in vitro (DIV) by 86 and 211%, respectively. At 18 DIV and under the same conditions, CNP was significantly stimulated (95%) by high doses of insulin (2,000 ng/ml) only, while arylsulfatase A (EC 3.1.6.1) or cerebroside sulfatase activities, both of which are involved in sulfatide degradation, were unchanged. Thus, it can be assumed that the observed increase of the incorporation of [35S]O4 into sulfatide after insulin treatment of mixed cell cultures is the result of CST induction rather than a decreased catabolism. The level of CST activity in insulin-treated cells (20 ng/ml) in serum-free medium was also increased at 18 and 25 DIV by about 50 and 70%, respectively. Conversely, none of the insulin concentrations used in the absence of serum (even at high doses) had any effect, either at 18 or 25 DIV on CNP and ASA activities. The involvement of insulin in the regulation of sulfatide synthesis was further confirmed by dose-response curves relating the activity of CST to hormone concentration in the medium. The increase in the activity of CST in insulin-treated cells was due only to the increase in the Vmax of this enzyme, suggesting that it may be attributed to enzyme induction. A study of kinetic parameters of CST indicated that there were no differences in pH optimum and Km values between control and induced enzyme. Further experiments using cycloheximide point to a direct effect of insulin on oligodendrocyte CST induction. Data similar to those described above for insulin were also obtained with T3. As for insulin, T3 stimulated the induction of CST but in serum-free medium only. This effect was prevented by cycloheximide. In addition, the induction of CST by T3 was blocked by actinomycin D. This was not the case for insulin. These results suggest that T3 and insulin act on CST by different mechanisms, i.e. at transcriptional and post-translational levels, respectively. Apart from this, the insulin effect on CST activity was additive to that of T3.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Encéfalo/enzimologia , Insulina/farmacologia , Sulfotransferases , Sulfurtransferases/biossíntese , Tri-Iodotironina/farmacologia , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Células Cultivadas , Cicloeximida/farmacologia , Embrião de Mamíferos , Camundongos , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismoRESUMO
The effect of physiological concentrations of insulin (2 and 20 ng/ml) on glutamine synthetase (GS) and glutamate dehydrogenase (GDH) activities were compared in mouse and chick glial cells in culture. Addition of insulin to serum-containing medium increased the level of GS and GDH activities in glial cells prepared from 14-15-day-old embryonic mice. A similar but less pronounced effect was observed with glia derived from newborn mouse brain. In absence of serum, addition of insulin had no effect on the tested enzymes. The effects of insulin on enzymatic activities of glial cells from 14-15-day-old embryonic chick brain hemispheres were, in contrast, quite different. A significant decrease of GS activity was induced by the hormone, only in the absence of serum. Conversely, the presence of serum enhanced an inhibitory effect of insulin toward chick GDH. The different effects of insulin and the different serum dependence observed for the mammalian and the avian model could reflect fundamental chemical differences between both species as indicated by immunoelectrophoretic analysis. However, it can be concluded that insulin may be a physiological factor regulating glial maturation and amino acid neurotransmitter metabolism in the central nervous system.
Assuntos
Encéfalo/metabolismo , Glutamato Desidrogenase/metabolismo , Glutamato-Amônia Ligase/metabolismo , Glutamatos/metabolismo , Insulina/farmacologia , Neuroglia/metabolismo , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Células Cultivadas , Embrião de Galinha , Ácido Glutâmico , Camundongos , Camundongos Endogâmicos ICR , Neuroglia/citologia , Neuroglia/efeitos dos fármacosRESUMO
The evolution of L-triiodothyronine (T3) receptors was studied in developing cultures of cells dissociated from cerebral hemispheres of 14-day-old mouse embryos, which present successive distinct periods of cell proliferation and/or maturation. These periods are characterized essentially as neuronal from 1 to 12 days in vitro (DIV) and glial between 12 and 60 DIV. Furthermore myelin-related membranes are produced in this culture system. Binding capacities of the T3 nuclear receptors increased from 1 to 6 DIV, when it reached a maximum (16 fmol/100 micrograms DNA). A similar increase of the DNA content of the cell was observed until 8 DIV. Thereafter a sharp fall of receptor concentration leading to a 5-fold decrease in the binding capacity occurred until day 15, a period at which neurones disappeared from the cultures. From 25 to 50 DIV (coinciding with the glial period), the concentration of receptor remained more or less constant (1-2 fmol/100 micrograms DNA). In parallel, the DNA content did not vary greatly between 30 and 50 DIV. Scatchard analysis revealed the presence of a single class of receptors at 6 and 20 DIV, representative of 'neuronal' and 'glial' periods, respectively. The equilibrium dissociation constant (Kd) of the nuclear receptor from cells at 6 DIV (2 X 10(-10) M) was similar to that found at 20 DIV. These results were confirmed using pure cultured neurones and astrocytes prepared from embryonic chick brain. The effect of T3 on the cellular gangliosides used as an index of neuronal cell maturation, and on cerebroside sulfotransferase (CST), an enzyme involved in the production of myelin sulfatides, was studied to determine a possible correlation between the binding capacity of the T3 nuclear receptor and the response of the cultured cells to thyroid hormone. Our data demonstrate that T3 had no significant effect either on the content of gangliosides or on their developmental pattern, while it increased the level of CST activity by 75% between 18 and 25 DIV. These results show that, although the concentration of T3 receptors per 100 micrograms DNA in glial cells was lower than that in neurones, it was nevertheless sufficient to elicit a response in oligodendrocytes.
Assuntos
Química Encefálica , Neuroglia/análise , Receptores de Superfície Celular/análise , Sulfotransferases , Animais , Astrócitos/análise , Núcleo Celular/análise , Células Cultivadas , Embrião de Mamíferos , Gangliosídeos/análise , Camundongos , Neurônios/análise , Oligodendroglia/análise , Receptores dos Hormônios Tireóideos , Sulfurtransferases/metabolismoRESUMO
The development of cell cultures from embryonic mouse cerebral hemispheres has been followed in detail for periods up to 40 days in culture using a variety of approaches. Functionally well differentiated neurons (shown by receptor binding studies, immunocytochemistry and morphological examination) were found to be abundant early in culture and to form cell contacts with oligodendrocytes characterized both immunocytochemically and morphologically. Myelin-like membranes with the periodicity of classical myelin elaborated by oligodendrocytes were detected only after 30 days in culture when neurones were no longer present. These results are discussed with regard to possible mechanisms of initiation of myelin synthesis.