RESUMEN
Since the discovery of aquaporin-4 (AQP4) antibody a decade ago, neuromyelitis optica (NMO) has been distinguished from multiple sclerosis (MS). MS mainly features T lymphocyte-oriented autoimmune responses while NMO is more precisely influenced by humoral immunity, among which the complement activation has always been reckoned as an important mechanism. The AQP4 antibody, namely NMO-IgG, adds to new evidence of how complement affects the severity of NMO. We compared the levels of complement (C3, C4, CH50) and immunoglobulins (IgG, IgM, IgA) between NMO patients and controls. Groups with AQP4 antibody positive and negative NMO patients were also compared with controls, respectively, aiming to elaborate on the relationship between complement activation and immunoglobulins. We also compared these indexes together with expanded disability status scale (EDSS) between two different groups in NMO patients and endeavored to figure out their correlations with each other. Complement and immunoglobulins were compared between NMO patients in acute phase and non-acute phase of the disease to find out the level fluctuation of CH50 and other indexes during different stages of NMO. We analyzed NMO patients (n = 88) and controls (n = 44) for IgG, IgM, IgA, other indexes like CH50, C3, C4 have also been explored between the two groups. Furthermore, we investigated whether these antibodies could mediate complement-dependent cytotoxicity. Thus, the NMO patients were split into two groups with or without AQP4 antibody to find out the status of NMO-IgG in the development and severity of the disease. EDSS was used as criteria for the evaluating the seriousness of NMO. Comparison between NMO patients in acute stage and non-acute stage of the disease was also made for a better understanding of the disease. Compared with controls, NMO patients had much higher IgG (13.984 ± 5.981 mg/ml, 11.430 ± 3.254 mg/ml, P < 0.01) but lower CH50 (respectively, 43.55 ± 12.172 U/L, 50.66 ± 12.523 U/L, P < 0.01). While IgG increased in Anti-AQP4 antibody-positive NMO patients, CH50 dropped in this group when compared with AQP4-negative patients. When compared with controls, both of the NMO groups had enhanced IgG and decreased CH50 though only AQP4-positive NMO patients showed significance (IgG 15.004 ± 6.613 mg/ml, 11.430 ± 3.254 mg/ml, P < 0.01) (CH50, respectively, 41.12 ± 12.581U/L, 50.66 ± 12.523 U/L, P < 0.01). C4 was also decreased though without evident significance (0.215 ± 0.118 mg/ml, 0.260 ± 0.133 mg/ml, P = 0.069). Those NMO patients in acute phase (with the course of newly attack of less than 1 month) had increased immunoglobulin (IgG 14.991 ± 6.639 mg/ml, 12.460 ± 4.490 mg/ml) but decreased complement (CH50 42.755 ± 12.403 U/L, 44.743 ± 11.890 U/L) than those who passed the acute phase. There was correlation between IgG and CH50 (R = -0.402, P < 0.01) in NMO patients. Relationship was also found between IgG and EDSS (R = 0.609, P < 0.001), CH50 and EDSS (R = -0.333, P < 0.01). These results indicate that NMO patients had enhanced immunoglobulin in acute phase but decreased complement. The complement was correlated with immunoglobulin. Among the two NMO groups, the complement system was only activated in NMO-IgG positive patients, which might indicate a potential different pathogenetic mechanism in NMO-IgG negative patients. Also, patients' disability of the former group was more serious than their counterparts. Those patients in acute phase obviously had increased immunoglobulin but decreased complement. Thus, we have come to the conclusion that in AQP4-positive NMO patients, immunoglobulin activates complement system, which influences the functions of NMO patients.
Asunto(s)
Proteínas del Sistema Complemento/análisis , Isotipos de Inmunoglobulinas/sangre , Neuromielitis Óptica/inmunología , Enfermedad Aguda , Adulto , Anticuerpos/metabolismo , Acuaporina 4/inmunología , Complemento C3/análisis , Complemento C4/análisis , Ensayo de Actividad Hemolítica de Complemento , Femenino , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Masculino , Neuromielitis Óptica/diagnóstico , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To analyze the relationship between diabetics and the onset, clinical outcomes and prognosis of brainstem infarction, and to evaluate the impact of diabetes on brainstem infarction. METHOD: Compare 172 cases of acute brainstem infarction in patients with or without diabetes. Analyze the associated risk factors of patients with brain-stem infarction in diabetics by multi-variate logistic regression analysis. Compare the National Institutes of Health Stroke Scale (NIHSS) and Modified Rankin scale (mRS) Score, pathogenetic condition and the outcome of the two groups in different times. RESULTS: The systolic blood pressure (SBP), TG, LDL-C, apolipoprotein B (Apo B), glutamyl transpeptidase (γ-GT), fibrinogen (Fb), fasting blood glucose (FPG) and glycosylated hemoglobin(HbA1c)in diabetic group were higher than those in non-diabetic group, which was statistically significant (P < 0.05). From multi-variate logistic regression analysis, γ-GT, Apo B and FPG were the risk predictors of diabetes with brainstem infarction(OR = 1.017, 4.667 and 3.173, respectively), while HDL-C was protective (OR = 0.288). HbA1c was a risk predictor of severity for acute brainstem infarction (OR = 1.299), while Apo A was beneficial (OR = 0.212). Compared with brain-stem infarction in non-diabetic group, NIHSS score and intensive care therapy of diabetic groups on the admission had no statistically significance, while the NIHSS score on discharge and the outcome at 6 months' of follow-up were statistically significant. CONCLUSIONS: Diabetes is closely associated with brainstem infarction. Brainstem infarction with diabetes cause more rapid progression, poorer prognosis, higher rates of mortality as well as disability and higher recurrence rate of cerebral infarction.
Asunto(s)
Infartos del Tronco Encefálico/complicaciones , Infartos del Tronco Encefálico/diagnóstico , Complicaciones de la Diabetes/patología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Factores de Riesgo , Resultado del TratamientoRESUMEN
Previous studies have shown that vascular endothelial growth factor (VEGF) expression is up-regulated in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), a model for MS, and may exacerbate the disease. However, it remains unknown whether anti-VEGF modalities could serve as a potential treatment for such central nervous system (CNS) autoimmune diseases. We constructed a recombinant adenoviral vector carrying FLAG-tagged sFlt-1(1-3) (the first three extracellular domains of Flt-1, the hVEGF receptor-1). Intramuscular transfection of the recombinant adenoviral vector suppressed VEGF-induced inflammatory cell infiltration in matrigel plugs. When given intracerebrally to EAE rats, recombinant sFlt-1(1-3) adenoviral vector significantly reduced disease severity compared to untreated rats. sFlt-1(1-3) gene transfer blocked VEGF and greatly reduced the number of cells that express VEGF and ED1-positive cells in CNS in EAE rats. This study demonstrates that sFlt-1(1-3) gene transfer into the brain ameliorates the severity of EAE by inhibiting monocyte recruitment in the CNS of dark Agouti rats.
Asunto(s)
Adenoviridae/genética , Encefalomielitis Autoinmune Experimental/terapia , Terapia Genética , Vectores Genéticos/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/fisiología , Animales , Western Blotting , Química Encefálica/genética , Línea Celular , Movimiento Celular , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Inmunohistoquímica , Cinética , Masculino , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Médula Espinal/metabolismo , Transfección , Factor A de Crecimiento Endotelial Vascular/biosíntesisRESUMEN
Ngb (neuroglobin) is a newly discovered hexaco-ordinate globin that is expressed in vertebrate brain and peripheral nervous systems. Expression of Ngb increases in response to oxygen deprivation and protects neurons from hypoxia in vitro and in vivo. However, the lack of its transduction ability into cells resulted in limited neuroprotection. To educe its neuroprotection under hypoxia, a cell-permeable Ngb fusion protein was generated. A rat brain Ngb gene was cloned and fused with a gene fragment encoding the nine-amino-acid TAT PTD (transactivator-of-transcription protein-transduction domain; RKKRRQRRR) of HIV-1 in a prokaryotic expression vector to generate a genetic in-frame N-terminal hexahistidine-tagged) TAT PTD-Ngb fusion protein. It was expressed in soluble form in Escherichia coli BL21(DE3)plysS and purified with Ni(2+)-affinity chromatography. The results showed that the purified fusion protein TAT PTD-Ngb can enter into the primary cultured cortical neurons in a dose-dependent manner when added exogenously to the culture media and can be detected in cells within 48 h. The cell viability under hypoxia was increased and apoptosis induced by hypoxia was decreased after TAT PTD-Ngb was transduced into cortical neurons. The results provide a clue for the research of Ngb and suggest that transduction of TAT PTD-Ngb may be one of the ways for the therapy of CNS (central nervous system) diseases, especially cerebrovascular diseases and neurodegenerative diseases.
Asunto(s)
Corteza Cerebral/metabolismo , Globinas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Transducción de Señal/fisiología , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/genética , Animales , Células Cultivadas , Corteza Cerebral/citología , Vectores Genéticos , Globinas/genética , VIH-1/genética , Hipoxia/patología , Hipoxia/terapia , Proteínas del Tejido Nervioso/genética , Neuroglobina , Estructura Terciaria de Proteína/genética , Transporte de Proteínas/fisiología , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes de Fusión/genética , Transducción Genética , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/fisiologíaRESUMEN
BACKGROUND: Disease-modifying therapy is the standard treatment for patients with multiple sclerosis (MS) in remission. The primary objective of the current analysis was to assess the efficacy and safety of two teriflunomide doses (7 mg and 14 mg) in the subgroup of Chinese patients with relapsing MS included in the TOWER study. METHODS: TOWER was a multicenter, multinational, randomized, double-blind, parallel-group (three groups), placebo-controlled study. This subgroup analysis includes 148 Chinese patients randomized to receive either teriflunomide 7 mg (n = 51), teriflunomide 14 mg (n = 43), or placebo (n = 54). RESULTS: Of the 148 patients in the intent-to-treat population, adjusted annualized relapse rates were 0.63 (95% confidence interval [CI]: 0.44, 0.92) in the placebo group, 0.48 (95% CI: 0.33, 0.70) in the teriflunomide 7 mg group, and 0.18 (95% CI: 0.09, 0.36) in the teriflunomide 14 mg group; this corresponded to a significant relative risk reduction in the teriflunomide 14 mg group versus placebo (-71.2%, P = 0.0012). Teriflunomide 14 mg also tended to reduce 12-week confirmed disability worsening by 68.1% compared with placebo (hazard ratio: 0.319, P = 0.1194). There were no differences across all treatment groups in the proportion of patients with treatment-emergent adverse events (TEAEs; 72.2% in the placebo group, 74.5% in the teriflunomide 7 mg group, and 69.8% in the teriflunomide 14 mg group); corresponding proportions for serious adverse events were 11.1%, 3.9%, and 11.6%, respectively. The most frequently reported TEAEs with teriflunomide versus placebo were neutropenia, increased alanine aminotransferase, and hair thinning. CONCLUSIONS: Teriflunomide was as effective and safe in the Chinese subpopulation as it was in the overall population of patients in the TOWER trial. Teriflunomide has the potential to meet unmet medical needs for MS patients in China. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00751881; https://clinicaltrials.gov/ct2/show/NCT00751881?term=NCT00751881&rank=1.
Asunto(s)
Crotonatos/uso terapéutico , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Toluidinas/uso terapéutico , China , Crotonatos/administración & dosificación , Crotonatos/efectos adversos , Método Doble Ciego , Esquema de Medicación , Humanos , Hidroxibutiratos , Inmunosupresores/administración & dosificación , Estudios Multicéntricos como Asunto , Esclerosis Múltiple/metabolismo , Nitrilos , Modelos de Riesgos Proporcionales , Toluidinas/administración & dosificación , Toluidinas/efectos adversosRESUMEN
OBJECTIVE: To investigate the effect of Buchang Naoxintong containing serum (BNCS) for antagonizing hypoxia-induced apoptosis of primary cultured cortical neurons with the sero-pharmacological method. METHODS: Primary cortical neurons from neonate rats (within 24 h) were cultured and induced into hypoxia model on the 7th day, which were then treated with different concentrations of BNCS. Cell apoptosis was detected qualitatively and quantitatively; and further verified by agarose gel electrophoresis through analyzing in-ternucleosomal DNA fragmentation of the neurons. Besides, neuron viability was tested by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and change of nuclear morphology was observed by Hoechst 33258 staining. RESULTS: After treatment with BNCS, the viability of the hypoxia neurons improved with significantly reduced neuron apoptosis. CONCLUSION: Buchang Naoxintong can protect cortical neurons from hypoxia-induced apoptosis.
Asunto(s)
Apoptosis/efectos de los fármacos , Corteza Cerebral/citología , Medicamentos Herbarios Chinos/farmacología , Neuronas/efectos de los fármacos , Animales , Animales Recién Nacidos , Hipoxia de la Célula , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Fragmentación del ADN/efectos de los fármacos , Femenino , Masculino , Neuronas/citología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , SueroRESUMEN
BACKGROUND: Th9 cells are a newly discovered CD4+ T helper cell subtype, characterized by high interleukin (IL)-9 secretion. Growing evidences suggest that Th9 cells are involved in the pathogenic mechanism of multiple sclerosis (MS). Mast cells are multifunctional innate immune cells, which are perhaps best known for their role as dominant effector cells in allergies and asthma. Several lines of evidence point to an important role for mast cells in MS and its animal models. Simultaneously, there is dynamic "cross-talk" between Th9 and mast cells. The aim of the present study was to examine the IL-9-mast cell axis in experimental autoimmune encephalomyelitis (EAE) and determine its interaction after neutralizing anti-IL-9 antibody treatment. METHODS: Female C57BL/6 mice were randomly divided into three groups (n = 5 in each group): mice with myelin oligodendrocyte glycoprotein (MOG)-induced EAE (EAE group), EAE mice treated with anti-IL-9 antibody (anti-IL-9 Abs group), and EAE mice treated with IgG isotype control (IgG group). EAE clinical score was evaluated. Mast cells from central nervous system (CNS) were detected by flow cytometry. The production of chemokine recruiting mast cells in the CNS was explored by reverse transcription-polymerase chain reaction (RT-PCR). In mice with MOG-induced EAE, the expression of IL-9 receptor (IL-9R) complexes in CNS and spleen mast cells was also explored by RT-PCR, and then was repeating validated by immunocytochemistry. In vitro, spleen cells from EAE mice were cultured with anti-IL-9 antibody, and quantity of mast cells was counted by flow cytometry after co-culture. RESULTS: Compared with IgG group, IL-9 blockade delayed clinical disease onset and ameliorated EAE severity (t = -2.217, P = 0.031), accompany with mast cells infiltration decreases (day 5: t = -8.005, P < 0.001; day 15: t = -11.857, P < 0.001; day 20: t = -5.243, P = 0.001) in anti-IL-9 Abs group. The messenger RNA expressions of C-C motif chemokine ligand 5 (t = -5.932, P = 0.003) and vascular cell adhesion molecule-1 (t = -4.029, P = 0.004) were significantly decreased after IL-9 neutralization in anti-IL-9 Abs group, compared with IgG group. In MOG-induced EAE, the IL-9R complexes were expressed in CNS and spleen mast cells. In vitro, splenocytes cultured with anti-IL-9 antibody showed significantly lower levels of mast cells in a dose-dependent manner, compared with splenocytes cultured with anti-mouse IgG (5 µg/ml: t = -0.894, P = 0.397; 10 µg/ml: t = -3.348, P = 0.019; 20 µg/ml: t = -7.639, P < 0.001). CONCLUSIONS: This study revealed that IL-9 neutralization reduced mast cell infiltration in CNS and ameliorated EAE, which might be relate to the interaction between IL-9 and mast cells.
Asunto(s)
Anticuerpos/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/metabolismo , Interleucina-9/antagonistas & inhibidores , Interleucina-9/metabolismo , Mastocitos/metabolismo , Animales , Sistema Nervioso Central/metabolismo , Femenino , Inmunohistoquímica , Interleucina-9/inmunología , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
OBJECTIVE: To evaluate the effect of tertiary rehabilitation treatment on acute cerebrovascular diseases. METHODS: Fifteen tertiary rehabilitation networks were set up throughout the country. 1078 patients with acute cerebrovascular diseases were randomly divided into 2 groups: rehabilitation group and control group, out of which 19 patients died, 157 dropped out, and 7 successive evaluations were completed in 902 patients that. 439 of the remaining 902 patients in the rehabilitation group, 266 males and 173 females, aged 61 +/- 11, 278 cases with cerebral infarction and 161 with cerebral hemorrhage, received routine treatment and early rehabilitation for 28 days in the ward of neurology, and then went home and received community rehabilitation for 6 months or underwent specialized reinforcement training for 2 months and after that went home and received community rehabilitation for 4 months. The 463 patients in the control group, 281 males and 182 females, aged 60 +/- 11, 291 of which with cerebral infarction and 172 with cerebral hemorrhage, received only routine treatment and early rehabilitation for 28 days in the ward of neurology, and then went home to conduct rehabilitation training by themselves or their family members for 6 months. Evaluation was conducted 7 times, with National Institutes of Health Stroke Scale (NIHSS), Fugl-Meyer motor function scale, Barthel index, SF-36 scale, Lowenstein occupational therapy cognitive assessment (LOTCA), Westen aphasia battery, Hamilton depression scale, and modified Ashworth spasm scale, one week after the onset and by the ends of 1, 2, 3, 4, 5, and 6 months after the onset respectively. RESULTS: The scores of clinical neurological impairment, Fugl-Meyer scores, SF-36 scores, incidence of PSD, and modified Ashworth scores (for upper and lower limbs) were lower, and LOTCA scores and Barthel indexes were higher at different time points in the rehabilitation group than in the control group; and the differences were statistically significant since the 2nd month after the onset. By the end of the 6th month, the patients of the rehabilitation group basically re-achieved the ability of self-care in daily activities with a Barthel index of 84 +/- 33. The patients of the control group also recovered to a certain degree, however, to a smaller extent in comparison with the rehabilitation group. CONCLUSION: Tertiary rehabilitation treatment of cerebrovascular diseases is effective in improving motor function, ability of daily living activities, and quality of life and reducing the incidence rates of secondary complications.
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Hemorragia Cerebral/rehabilitación , Infarto Cerebral/rehabilitación , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Calidad de Vida , Resultado del TratamientoRESUMEN
BACKGROUND: A recent study demonstrated that the inflammatory response accompanying necrotic brain injury played an important role in stroke. Thus, inhibition of this response may help to stop the expansion of infarcts. It has been also shown that the spleen, a major peripheral immune organ, plays a role in stroke-induced immune responses. This study aimed to establish rat models of middle cerebral artery occlusion (MCAO) and to investigate the effect of splenectomy and possible mechanisms in that rat models. METHODS: Infarct size in a stroke model was measured with the Nissl body staining method, numbers of inflammatory cells in ischemic regions were detected by immunofluorescence staining, and inflammatory factors were assayed by enzyme-linked immunosorbent assay and real-time polymerase chain reaction (PCR) in brain homogenates and sera. The significance of differences was determined by one-way analysis of variance (ANOVA) followed by the least significant difference post hoc test. RESULTS: Infarct size in the brain of rats that underwent splenectomies 2 weeks before permanent MCAO ((34.93 ± 3.23)%) was over 50% smaller than that of rats subjected to the stroke surgery alone ((74.33 ± 2.36)%, P < 0.001; (77.30 ± 2.62)%, P < 0.001). Lower numbers of T cells, neutrophils, and macrophages in brain tissue and lower levels of pro-inflammatory cytokines, such as interleukin (IL)-1ß and tumor necrosis factor (TNF)-α, were observed in rats that underwent splenectomies, compared with the two other groups, but splenectomized rats showed higher levels of the anti-inflammatory factor IL-10 in the brain. CONCLUSION: The mechanism(s) by which splenectomy protects brain from damage induced by stroke may correlate with the decreased numbers of inflammatory cells and changes in inflammatory cytokines.
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Infarto Cerebral/prevención & control , Inflamación/prevención & control , Esplenectomía , Accidente Cerebrovascular/complicaciones , Animales , Citocinas/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: High levels of nitric oxide (NO) produced by inducible NO synthase (iNOS) have been associated with atherosclerosis processes. Naoxintong is a traditional Chinese medicine for treatment of cerebrovascular and cardiovascular disease. The aim of the present study was to detect and quantify changes of iNOS mRNA and NO levels in the vessel wall after the administration of Naoxintong in an atherosclerotic rabbit model. METHODS: Forty New Zealand white rabbits were randomly divided into five groups (n = 8). Rabbits were fed a standard diet (group A), an atherogenic diet consisting of 79% standard feed + 1% cholesterol + 5% lard + 15% egg yolk powder (group B), an atherogenic diet with Naoxintong 0.25 mg×kg(-1)×d(-1) (group C), an atherogenic diet with Naoxintong 0.5 mg×kg(-1)×d(-1) (group D), or atherogenic diet with Naoxintong 1.0 mg×kg(-1)×d(-1) (group E) for 12 weeks. RESULTS: Supplemented administration of Naoxintong led to a down-regulation of cholesterol (CHOL) (P < 0.001) and low-density lipoprotein (LDL) (P < 0.001). The trend became more notable as the dose of Naoxintong increased; group C vs. group B (CHOL, P = 0.568; LDL-cholesterol (LDL-C), P = 0.119), group D vs. group B (CHOL, P = 0.264; LDL-C, P = 0.027), group E vs. group B (CHOL, P = 0.028; LDL-C, P = 0.002). Atherosclerotic lesions in aorta were reduced in Naoxintong groups (groups C, D, E) compared to group B. Group B had higher iNOS mRNA (P = 0.001) and NO level (P < 0.001) than group A. Compared with the atherogenic diet fed-rabbits, Naoxintong supplements decreased the expression of iNOS mRNA (P < 0.001) and the NO level (P < 0.001) in the vessel wall. Groups given a higher Naoxintong dose exhibited greater benefits. iNOS mRNA and NO levels seemed to be reduced in group C, although the difference did not quite reach statistical significance (iNOS mRNA, P = 0.130; NO, P = 0.038). iNOS mRNA and NO levels significantly decreased in group D (iNOS mRNA, P = 0.019; NO, P = 0.018) and group E (iNOS mRNA, P = 0.004; NO, P < 0.001). CONCLUSION: Naoxintong has beneficial effects on atherosclerosis treatment by reducing expression of iNOS mRNA and the NO level in the vessel wall.
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Aterosclerosis/tratamiento farmacológico , Aterosclerosis/enzimología , Medicamentos Herbarios Chinos/uso terapéutico , Óxido Nítrico Sintasa de Tipo II/metabolismo , Animales , Aterosclerosis/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , ConejosRESUMEN
BACKGROUND: Our previous study had demonstrated that ulinastatin (UTI) had a neuroprotective effect in experimental autoimmune encephalomyelitis (EAE). Methylprednisolone has been recommended to be a standard drug in multiple sclerosis (MS) therapies. The present study was to investigate the protective effects of UTI combined methylprednisolone in EAE. METHODS: Mice were divided into a UTI treatment group, a methylprednisolone treatment group, a combined treatment group with UTI and methylprednisolone, a normal saline treatment group, and a normal control group. EAE mice were induced in groups receiving different combined treatments, or respective monotherapies. Demyelination was evaluated by Solochrome cyanin staining. 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP)/ myelin basic protein (MBP)/ the precursor form of nerve growth factor (proNGF)/p75/ inducible nitric oxide synthase (iNOS) proteins in cerebral cortex of EAE were detected by Western blotting. RESULTS: The combined treatment group had a lower clinical score (0.61 ± 0.06) and demyelinating score (1.33 ± 0.33) than the groups with normal saline (clinical score: 1.39 ± 0.08, P < 0.001; demyelinating score: 2.75 ± 0.49, P < 0.05) or monotheraphies. Compared with the saline treated EAE group, UTI combined methylprednisolone significantly increased expressions of CNP (1.14 ± 0.06 vs. 0.65 ± 0.04, P < 0.001), MBP (1.28 ± 0.14 vs. 0.44 ± 0.17, P < 0.001), and decreased expressions of proNGF (1.08 ± 0.10 vs. 2.32 ± 0.12, P < 0.001), p75 (1.13 ± 0.13 vs. 2.33 ± 0.17, P < 0.001), and iNOS (1.05 ± 0.31 vs. 2.17 ± 0.13, P < 0.001) proteins in EAE. Furthermore, UTI combined methylprednisolone could significantly upregulate MBP (1.28 ± 0.14 vs. 1.01 ± 0.15, P < 0.05) expression and downregulate iNOS (1.05 ± 0.31 vs. 1.35 ± 0.14, P < 0.05) expression compared to methylprednisolone treatment EAE group. And proNGF expression was significantly lower in combined treatment (1.08 ± 0.10) than that in UTI (1.51 ± 0.24, P < 0.05) or methylprednisolone (1.31 ± 0.04, P < 0.05) treatment group. CONCLUSION: Combination treatment of UTI with methylprednisolone was shown to protect EAE, suggesting that combination therapy is a potential novel treatment in MS.
Asunto(s)
Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Glicoproteínas/uso terapéutico , Metilprednisolona/uso terapéutico , Animales , Combinación de Medicamentos , Femenino , Glicoproteínas/administración & dosificación , Metilprednisolona/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/tratamiento farmacológicoRESUMEN
Multiple sclerosis (MS) is a common disabling autoimmune disease in young adults which does not have an effective treatment. The prevalence of immune-mediated diseases is higher in developed countries with hygienic environments, suggesting that helminthic infection may protect from autoimmune diseases. Previously, we reported that soluble egg antigens (SEA) from Schistosoma japonicum suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of MS, through up-regulating T helper-2 (Th2) immune responses in both the peripheral and central target organs. Neurotrophins (NTs) are not exclusive to the nervous system. While immune cells, especially Th2 cells, can produce and secrete a variety of NTs resulting in neuroprotective immunity. NTs can also modulate immune responses by augmenting Th2 responses and downregulating Th1 responses. Interestingly, nerve growth factor (NGF) has been found in liver granulomas of Schistosoma mansoni-infected mice. Moreover, in the central nervous system of chronic schistosomiasis, NGF is increased. A hypothesis is hereby proposed - SEA derived from S. japonicum bears neuroprotective properties beyond its immunomodulatory effects. SEA can induce the expression of NTs, which in turn augment Th2 immune responses induced by SEA; whereby a positive regulatory circuit between Th2 responses and NTs comes into being.
Asunto(s)
Antígenos Helmínticos/inmunología , Regulación de la Expresión Génica/inmunología , Proteínas del Helminto/inmunología , Helmintiasis/inmunología , Modelos Inmunológicos , Esclerosis Múltiple/inmunología , Fármacos Neuroprotectores/inmunología , Schistosoma japonicum/inmunología , Animales , Antígenos Helmínticos/metabolismo , Proteínas del Helminto/metabolismo , Humanos , Factor de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/inmunología , Factores de Crecimiento Nervioso/metabolismo , Fármacos Neuroprotectores/metabolismo , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
BACKGROUND: Despite the large scale technical innovations that have been made, a number of patients with neuromyelitis optica (NMO) are lacking NMO-IgG in both serum and cerebrospinal fluid. Longitudinally extensive spinal cord (LESC) lesions and linear lesions are associated with NMO. However, differences of spinal cord magnetic resonance imaging (MRI) features, including LESC lesions and linear lesions, between NMO-IgG positive and negative patients still remain unknown. The aim of the present study was to analyze the relationship between NMO-IgG status and spinal cord MRI features in NMO patients, particularly concerned about LESC lesions and linear lesions. METHODS: Clinical data and spinal cord MRI of 52 NMO patients were retrospectively analyzed. Eight patients were NMO-IgG negative in both serum and cerebrospinal fluid, while 44 were NMO-IgG positive. Quantitative data between the two cohorts were compared by the Student's t test or Mann-Whitney U test, the chi-square test or Fisher's exact test was used to evaluate qualitative data. RESULTS: NMO-IgG negative patients had a higher sex ratio (male/female) (P = 0.014). On axial MRI, lesions in the NMO-IgG negative group were mostly located in the peripheral cord (50%), and central lesions (55%) were more common in the NMO-IgG positive group (P = 0.051). LESC lesions were common in both cohorts. None of linear lesions was found in NMO-IgG negative patients, while the NMO-IgG positive cohort had significantly more linear lesions (48%) (P = 0.016). CONCLUSIONS: Patients with NMO-IgG negativity may have different spinal cord lesion features compared to NMO-IgG positive patients. Diagnosis of NMO cannot be excluded even when NMO-IgG negativity and non-specific spinal lesions occur.
Asunto(s)
Inmunoglobulina G/sangre , Inmunoglobulina G/líquido cefalorraquídeo , Neuromielitis Óptica/sangre , Neuromielitis Óptica/líquido cefalorraquídeo , Médula Espinal/patología , Adulto , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuromielitis Óptica/patología , Estudios Retrospectivos , Adulto JovenAsunto(s)
Síndrome POEMS/diagnóstico , Sífilis/diagnóstico , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To investigate the anti-inflammatory effect of bone marrow stromal cells (MSCs) transfected with recombinant adenovirus-mediated ciliary neurotrophic factor (CNTF) gene in C57BL/6 mice with experimental allergic encephalomyelitis (EAE). METHODS: An adenovirus vector containing CNTF gene Ad-CNTF-IRES-GFP was constructed and transfected in the MSCs (MSC-CNTF). After examination of CNTF expression, the transfected cells were transplanted in C57BL/6 mice with MOG 35-55-induced EAE, which were monitored for the changes in the symptoms scores. The levels of tumor necrosis factor-alpha (TNF-alpha), inteferon-gamma (IFN-gamma), interleukin-12P35 (IL-12P35), and IL-10 in the peripheral blood of the mice were detected, and the number of MSC-CNTF cells in the spleen and spinal cord was counted. CD3+ T cell infiltration and TNF-alpha and IFN-gamma expressions in the lesions were also observed after the cell transplantation. RESULTS: CNTF gene transfection resulted in significantly increased CNTF expression in the MSCs. The mice receiving MSC-CNTF transplantation exhibited significantly improved symptoms with shortened disease course and lessened disease severity. The cell transplantation also resulted in significantly decreased peripheral blood TNF-alpha levels, ameliorated CD3+T cell infiltrations and lowered TNF-alpha expression in the lesions, while the levels of IFN-gamma underwent no significant changes. CONCLUSION: Transplantation of CNTF gene-transfected MSCs results in decreased peripheral blood TNF-alpha and IFN-gamma levels and reduced inflammatory cells, CD3-positive cells and TNF-alpha expression in the lesion of EAE, therefore providing better effect than MSCs in relieving the symptoms of EAE in mice.
Asunto(s)
Células de la Médula Ósea/metabolismo , Factor Neurotrófico Ciliar/uso terapéutico , Encefalomielitis Autoinmune Experimental/terapia , Terapia Genética , Adenoviridae/genética , Adenoviridae/metabolismo , Animales , Factor Neurotrófico Ciliar/biosíntesis , Factor Neurotrófico Ciliar/genética , Femenino , Interferón gamma/sangre , Ratones , Ratones Endogámicos C57BL , Distribución Aleatoria , Células del Estroma/metabolismo , Linfocitos T/inmunología , Transfección , Factor de Necrosis Tumoral alfa/sangreRESUMEN
OBJECTIVE: To analyze the characteristics of leptomeningeal carcinomatosis. METHODS: We summarized the clinical presentation, magnetic resonance imaging (MRI) findings and cerebrospinal fluid (CSF) cytological findings in 4 cases of leptomeningeal carcinomatosis. RESULTS: All the patients presented with signs of elevated intracranial pressure such as headache. Enlarged cerebral ventricles and dural enhancement were found by MRI, with also the presence of malignant cells in cytological slides. CONCLUSION: CSF cytological examination is important for diagnosis of leptomeningeal carcinomatosis.