RESUMO
BACKGROUND: Familial adenomatous polyposis (FAP) predisposes individuals to duodenal adenomas. This study describes the histopathological features of endoscopic and surgical specimens from the duodenum, as well as genotype-phenotype associations. METHODS: All known FAP patients were included from the Danish Polyposis Register. FAP patients were defined as having more than 100 cumulative colorectal adenomas and/or having a known germline pathogenic variant in the APC gene. Endoscopic procedures, histopathology, and genetics were evaluated. RESULTS: Of 500 FAP patients, 70.6% underwent esophagogastroduodenoscopy (EGD) at least once. Of these, 59.2% presented with detectable duodenal adenomas. The most severe morphology was tubular in 62.7% patients, tubulovillous in 25.4%, and villous in 12.0%, while the most severe dysplasia was low-grade in 67.5% patients, high-grade in 25.4%, and 6.7% had adenocarcinoma. In 6.2% of FAP patients, duodenal resection was recommended, including 29% with duodenal adenocarcinoma. The risk of duodenal surgery was 1.31 per 1,000 person-years (median age: 53 years). The predominant reason for surgery was extensive polyposis (67.7%). Of the patients who underwent duodenal resection, a median of six (IQR: 4-8) EGDs were performed within five years prior to surgery, but 67.6% and 83.9% never underwent a duodenal polypectomy or endoscopic mucosa resection, respectively. Of note, seventeen of 500 patients (3.4%) developed duodenal adenocarcinoma, of which 47% were advanced at diagnosis. Genetic evaluations revealed various pathogenic variants in the APC gene, with no strong genotype-phenotype association. CONCLUSIONS: The prevalence of duodenal adenomas and cancer in FAP warrants vigilant endoscopic surveillance. Nevertheless, the need for duodenal surgery persists and should together with endoscopic practice be monitored in national registers.
RESUMO
Hepcidin deficiency leads to iron overload by increased dietary iron uptake and iron release from storage cells. The most frequent mutation in Hfe leads to reduced hepcidin expression and thereby causes iron overload. Recent findings suggested that HFE activates hepcidin expression predominantly via the BMP type I receptor ALK3. Here, we investigated whether HFE exclusively utilizes ALK3 or other signaling mechanisms also. We generated mice with double deficiency of Hfe and hepatocyte-specific Alk3 and compared the iron overload phenotypes of these double knockout mice to single hepatocyte-specific Alk3 deficient or Hfe knockout mice. Double Hfe-/-/hepatic Alk3fl/fl;Alb-Cre knockouts develop a similar iron overload phenotype compared to single hepatocyte-specific Alk3 deficient mice hallmarked by serum iron levels, tissue iron content and hepcidin levels of similar grades. HFE protein levels were increased in Alk3fl/fl;Alb-Cre mice compared to Alk3fl/fl mice, which was caused by iron overload - and not by Alk3 deficiency. The data provide evidence by genetic means that 1. HFE exclusively uses the BMP type I receptor ALK3 to induce hepcidin expression and 2. HFE protein expression is induced by iron overload, which further emphasizes the iron sensing function of HFE.
Assuntos
Hepcidinas , Sobrecarga de Ferro , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo I , Proteína da Hemocromatose/genética , Hepcidinas/genética , Antígenos de Histocompatibilidade Classe I/genética , Sobrecarga de Ferro/genética , Fígado/metabolismo , Camundongos , Camundongos Knockout , Transdução de SinaisRESUMO
People punish transgressors with different intensity depending if they are members of their group or not. We explore this in a cross-sectional analytical study with paired samples in children with developmental disorders who watched two videos and expressed their opinion. In Video-1, a football-player from the participant's country scores a goal with his hand. In Video-2, a player from another country does the same against the country of the participant. Each subject watched the two videos and their answers were compared. The autism spectrum disorder (ASD) group showed negative feelings in Video 1 (M = - .1; CI 95% - .51 to .31); and in Video 2 (M = - .43; CI 95% .77 to - .09; t(8) = 1.64, p = .13), but the attention deficit hyperactivity disorder, learning disabilities, intellectual disability groups showed positive opinion in Video-1 and negative in Video-2. This suggests that children with ASD respect rules regardless of whether those who break them belong or not to their own group, possibly due to lower degrees of empathy.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno do Espectro Autista/psicologia , Emoções , Deficiência Intelectual/psicologia , Deficiências da Aprendizagem/psicologia , Adolescente , Criança , Estudos Transversais , Etnicidade/psicologia , Feminino , Humanos , Masculino , Estimulação Luminosa , Gravação em VídeoRESUMO
The differential diagnosis of lymphoid lesions in the central nervous system covers a broad spectrum of neoplastic and inflammatory disorders. Complex cases benefit from the combined expertise in the fields of hematopoietic and neuroepithelial tumors as well as neuroimmunology. The Network Lymphomas and Lymphomatoid Lesions in the Nervous System (NLLLN) recommends performing a biopsy prior to any therapeutic intervention as a precise diagnosis was impossible in approximately 50 % of patients pretreated with corticosteroids. This is based on the analysis of approximately 1,000 cases in the past 4 years. In addition to total NLLLN experiences the characteristics, pathogenesis and differential diagnosis of primary lymphoma of the central nervous system are discussed.
Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Linfoma/patologia , Pseudolinfoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biópsia , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Neoplasias do Sistema Nervoso Central/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Humanos , Linfoma/genética , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , Pseudolinfoma/genética , Receptores de Antígenos de Linfócitos B/genética , Transdução de Sinais/genética , Adulto JovemRESUMO
AIM: Although being one of the most common fractures in elderly patients, there is still no standardised treatment protocol for four-part fractures of the proximal humerus. However, a wide variety of angular-stable implants is available. The present retrospective study compares the clinical and radiological outcome following operative treatment of four-part fractures of the proximal humerus with the Philos system (Philos, proximal humeral internal locking system, Synthes GmbH, Umkirch Germany) and the angular-stable Königsee plate system (Königsee Implantate GmbH, Allendorf, Germany) in patients older than 65 years. METHODS: From July 2005 until December 2007 we identified 77 patients with a four-part fracture of the proximal humerus who were treated operatively with one of the two implant systems. Of the patients, 17 could not be located so that in total 60 patients (78 %) participated in this study. The mean age of the 30 patients (10 m, 20 f) in the Philos group was 69 years (65-92), whereas the mean age of the 30 patients (11 m, 19 f) in the Königsee group was 71 years (65-93). A comprehensive assessment was performed after a median of 17 months (12-24), including physical examination, radiographic examination and completion of the disabilities of the arm, shoulder and hand score (DASH) and the Constant score (CS) as patient-oriented, limb-specific questionnaires. RESULTS: Neither in the Philos nor in the Königsee group could excellent results be achieved. Using the CS 13 patients (43 %) of the Philos group achieved a good and 15 (50 %) a satisfactory result. Bad results were found in 2 patients (7 %). The mean CS was 61.53 points. In the Königsee group mean CS was 61.76 points. In detail, 14 patients (47 %) treated with the Königsee implant were rated as good and 15 (50 %) as satisfactory. Only 1 patient (3 %) was rated as poor. No significant statistical differences were found between the groups. Mean DASH score in the Philos group was 56.30 points and 55.37 points in the Königsee group. Again, no statistical difference was found. Partial humeral head necrosis was observed in 2 patients of the Philos and 1 of the Königsee group. In the remaining patients uneventful fracture consolidation was observed. There were no complications requiring further surgical intervention. To the date of follow-up all implants were still in situ and none of the patients reported discomfort with respect to the hardware. CONCLUSION: In this study we were able to demonstrate that good and satisfactory results can be achieved in the majority of patients, regardless of whether a Philos or a Königsee system was used. Significant differences between the two groups could not be found in any of the performed examinations. Both implants seem to be suitable in four-part fractures of the proximal humerus. However, the Königsee plate represents a more cost-effective option compared to the Philos system.
Assuntos
Placas Ósseas , Fixação Interna de Fraturas/instrumentação , Consolidação da Fratura , Fraturas do Ombro/diagnóstico , Fraturas do Ombro/cirurgia , Idoso , Idoso de 80 Anos ou mais , Análise de Falha de Equipamento , Feminino , Humanos , Masculino , Desenho de Prótese , Recuperação de Função Fisiológica , Resultado do TratamentoAssuntos
Dissuasores de Álcool/uso terapêutico , Alcoolismo/tratamento farmacológico , Alcoolismo/terapia , Fumar , Taurina/análogos & derivados , Tabagismo , Acamprosato , Consumo de Bebidas Alcoólicas , Alcoolismo/psicologia , Terapia Cognitivo-Comportamental , Etanol , Feminino , Humanos , Masculino , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/farmacologia , Taurina/uso terapêutico , TemperançaRESUMO
BACKGROUND: Immigration is a factor with effects on the course of substance abuse and treatment response, however there is little consistent data regarding outcome of inpatient opiate detoxification treatment in immigrants as compared to native patients. METHODS: Patient history and the success of current detoxification treatment were systematically documented in a multicenter study in Germany which included 10 psychiatric hospitals with specialized detoxification wards. RESULTS: Out of 893 patients, 240 (27%) had a migration history. We further analyzed the three main groups (German, n=653; Turkish, n=58; Russian origin, n=103). There were significant differences between groups regarding sociodemographic data, drug history, treatment experience and success of current treatment. However, considering the younger age of patients with Russian origin, analysis of younger patients (<31 years) detected only minor group differences. In multiple logistic regressions age and center showed statistically significant associations with all outcome variables (early dropout, achievement of drug-free urine screen, regular completion of detoxification treatment, and referral to further treatment), while (Russian) origin was associated only with premature termination of treatment. CONCLUSION: Young men were the main problem group regardless of origin. Significant center effects raise doubts regarding results from monocenter research.
Assuntos
Emigrantes e Imigrantes/psicologia , Emigrantes e Imigrantes/estatística & dados numéricos , Pacientes Internados/psicologia , Pacientes Internados/estatística & dados numéricos , Transtornos Relacionados ao Uso de Opioides/psicologia , Transtornos Relacionados ao Uso de Opioides/terapia , Adulto , Terapia Combinada/métodos , Feminino , Alemanha , Hospitais Psiquiátricos , Humanos , Modelos Logísticos , Masculino , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Psicoterapia/métodos , Federação Russa/etnologia , Resultado do Tratamento , Turquia/etnologiaRESUMO
Multiple sclerosis (MS) lesions are histopathologically characterized by inflammation, demyelination/remyelination, axonal damage and gliosis. Animal experimental and in vitro studies suggest that sex hormones influence the immune system and contribute to the increased likelihood in women of developing MS. However, a variety of studies have also shown that remyelination is more marked in female rodents or that female sex hormones are beneficial for myelin repair. To determine whether gender influences the histopathology of MS lesions, we compared the extent of inflammation, axonal damage and remyelination in MS lesions of female and male MS patients. We observed no differences in the composition of inflammatory infiltrates, axonal damage or cortical pathology. Similar numbers of oligodendroglial progenitor cells and mature oligodendrocytes were present in MS lesions. Remyelination is slightly, but not significantly, more extensive in women than men in early MS lesions. The absence of significant differences in lesion pathology between female and male MS patients might be explained by a lack of a gender influence, but also might be due to the limited number of tissue samples available for histopathological analysis.
Assuntos
Encéfalo/patologia , Esclerose Múltipla/patologia , Animais , Doenças Desmielinizantes/etiologia , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/patologia , Masculino , Microglia/patologia , Esclerose Múltipla/complicações , Bainha de Mielina/patologia , Regeneração Nervosa , Neurônios/patologia , Fatores SexuaisAssuntos
Neoplasias Encefálicas/patologia , Perna (Membro)/fisiopatologia , Mieloma Múltiplo/complicações , Mieloma Múltiplo/patologia , Paresia/etiologia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/fisiopatologia , Feminino , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Mieloma Múltiplo/fisiopatologia , Reação em Cadeia da Polimerase , Transplante de Células-TroncoRESUMO
OBJECTIVE: To analyze and compare the extent of remyelination in lesions from patients with multiple sclerosis (MS) who have a short (early MS lesions) or a long (chronic MS lesions) disease duration and to determine the influence of anatomic localization on the extent of remyelination. In early MS lesions, remyelination has been described as a relatively frequent event, in contrast to chronic MS lesions, where remyelination is absent or limited to the lesion border in the majority of lesions. However, no studies have been published that have quantified and compared the extent of remyelination in early and chronic MS lesions. METHODS: We analyzed the occurrence of remyelination in 52 biopsies from 51 patients (early MS) and in 174 lesions from 36 autopsy cases (chronic MS) by immunohistochemistry for myelin proteins, and correlated our findings with anatomic localization, sex, age, and disease duration. RESULTS: Significantly more lesions were remyelinated in early than in chronic MS (80.7% vs 60%). In chronic MS, subcortical lesions showed more extensive remyelination than periventricular lesions. The majority of cerebellar lesions were completely demyelinated. CONCLUSION: In summary, our data demonstrate that remyelination is a frequent event in early multiple sclerosis lesions. Furthermore, the anatomic localization of a lesion might influence the extent of remyelination.
Assuntos
Envelhecimento/fisiologia , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Fibras Nervosas Mielinizadas/patologia , Regeneração Nervosa/fisiologia , Recuperação de Função Fisiológica/fisiologia , Adulto , Idade de Início , Idoso , Autopsia , Biomarcadores/análise , Biomarcadores/metabolismo , Biópsia , Doença Crônica , Corantes , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas da Mielina/análise , Proteínas da Mielina/metabolismo , Bainha de Mielina/patologia , Coloração e Rotulagem , Degeneração Walleriana/etiologia , Degeneração Walleriana/patologia , Degeneração Walleriana/fisiopatologia , Adulto JovemRESUMO
Impaired function/differentiation of progenitor cells might provide an explanation for the limited remyelination observed in the majority of chronic multiple sclerosis lesions. Here, we establish that in the normal adult human CNS, the transcription factors Nkx2.2 and Olig2 are strongly expressed in progenitor cells while mature oligodendrocytes are characterized by low levels of Olig2 or Nkx2.2. In vitro studies confirmed the expression of Olig2 in oligodendroglial progenitor cells and mature oligodendrocytes while astrocytes, microglial cells and neurons were negative for Olig2. In early multiple sclerosis lesions, we found Olig2-positive progenitor cells throughout all lesion stages and in periplaque white matter (PPWM). The number of progenitors in PPWM was significantly increased compared with the white matter from controls. In chronic multiple sclerosis lesions progenitor cells were still present, however, in significantly lower numbers than in early multiple sclerosis lesions. A subpopulation of progenitor cells in early multiple sclerosis lesions and PPWM but not in control cases co-expressed NogoA, a marker of mature oligodendrocytes. The co-expression of these two markers suggested that these cells were maturing oligodendrocytes recently recruited from the progenitor pool. In contrast, in chronic multiple sclerosis lesions maturing progenitors were only rarely present. In summary, we provide evidence that a differentiation block of oligodendroglial progenitors is a major determinant of remyelination failure in chronic multiple sclerosis lesions.
Assuntos
Esclerose Múltipla/patologia , Bainha de Mielina/fisiologia , Regeneração Nervosa , Oligodendroglia/patologia , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular , Células Cultivadas , Doença Crônica , Progressão da Doença , Feminino , Proteína Homeobox Nkx-2.2 , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Esclerose Múltipla/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares , Fator de Transcrição 2 de Oligodendrócitos , Oligodendroglia/metabolismo , Estudos Retrospectivos , Células-Tronco/metabolismo , Células-Tronco/patologia , Fatores de Transcrição/metabolismo , Proteínas de Peixe-ZebraRESUMO
We present a new method for advanced image processing to separately quantify significant decreases and increases in the magnetization transfer ratio (MTR) of individual voxels of MS lesions as markers of demyelination and remyelination. We used this method to analyze the evolution of MTR in individual voxels of an acute, Gadolinium (Gd)-enhancing lesion that was available for pathology. Over 6.5 months following enhancement, MTR was low and stable in the lesion center (81% of the initially Gd-enhancing lesion volume (GdLV)) and MTR increased at the lesion border with normal-appearing white matter (14%GdLV). The estimated error of these measurements was less than 1.8%GdLV based on scan/rescan analysis. Histopathological analysis confirmed a demyelinated lesion centre with diffuse presence of macrophages/microglia and marked loss of oligodendrocytes and a partially remyelinated lesion border with diffuse presence of macrophages/microglia and relatively more oligodendrocytes compared to the lesion centre. The correlation of imaging and histopathological findings support the validity and sensitivity of our method of voxel-based MTR image processing for monitoring demyelination and remyelination in vivo.
Assuntos
Encéfalo/patologia , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla Crônica Progressiva/diagnóstico , Fibras Nervosas Mielinizadas/patologia , Regeneração Nervosa/fisiologia , Adulto , Ventrículos Cerebrais/patologia , Dominância Cerebral/fisiologia , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Técnicas Imunoenzimáticas , Macrófagos/patologia , Masculino , Microglia/patologia , Esclerose Múltipla Crônica Progressiva/patologia , Esclerose Múltipla Crônica Progressiva/terapia , Oligodendroglia/patologia , Sensibilidade e Especificidade , Lobo Temporal/patologiaRESUMO
Fatal familial insomnia (FFI) is a prion disease exhibiting the PRNP D178N/129M genotype. Features of this autosomal dominant illness are progressive insomnia, dysautonomia, myoclonus, cognitive decline and motor signs associated with thalamic nerve cell loss and gliosis. In contrast to the new variant of Creutzfeldt-Jakob disease (vCJD) the onset of FFI is in middle to late adulthood. We report two male patients who belong to a large German FFI kindred. They were examined clinically, and postmortem neuropathological examination was carried out in collaboration with the German reference centre for prion disease. Additionally, the prion protein gene (PRNP) was analysed. To identify further patients with disease onset under 30 years of age a comprehensive literature review was carried out. Two male patients presented with typical symptoms of FFI at the age of 23 and 24 years. In their kindred, the age of onset has never before been under 44 years of age. Our literature review identified five additional early onset cases who died at age 21 to 25 years. In all 22 reviewed FFI families the median manifestation age was 49.5 years. Although phenotypic variability of FFI is common, age of onset under 30 years has been considered to be a hallmark of vCJD with a mean manifestation at 27 years of age. Our findings underline that in addition to vCJD, FFI must be considered in cases of young-onset prion disease. This has considerable impact on clinical management and genetic counselling.
Assuntos
Saúde da Família , Insônia Familiar Fatal/genética , Insônia Familiar Fatal/fisiopatologia , Adulto , Idade de Início , Asparagina/genética , Ácido Aspártico/genética , Análise Mutacional de DNA/métodos , Aconselhamento Genético/métodos , Glucose/metabolismo , Humanos , Imuno-Histoquímica/métodos , Insônia Familiar Fatal/metabolismo , Insônia Familiar Fatal/patologia , Masculino , Metionina/metabolismo , Pessoa de Meia-Idade , Exame Neurológico , Linhagem , Mudanças Depois da Morte , Príons/genética , Príons/metabolismo , Literatura de Revisão como Assunto , Tálamo/metabolismo , Tálamo/patologia , Tomografia Computadorizada de Emissão/métodosRESUMO
Clinical course, outcome, radiological features, severity, and histopathology are heterogenous in multiple sclerosis (MS). Since MS is considered to be a polygenic disease, the genetic background may at least partly be responsible for this variability. Some MS cases are histopathologically characterized by a dramatic oligodendrocyte loss that is in part caused by apoptosis. A dysregulated apoptotic elimination of self-reactive T cells may also contribute to disease susceptibility. To analyze genetic differences in the apoptosis regulating factors bcl-2, bax, bcl-x and p53 we investigated polymorphisms of these genes in 105 patients with a relapsing remitting disease course and 99 controls by PCR-SSCP and direct sequencing. We identified so far unpublished sequence alterations in the promotor region of the bxl-x gene, in exon 7 of the p53 gene, and in exon 1 of the bax gene. No differences were observed between MS patients and controls. Additional known polymorphisms were found in intron 3 of the bax gene and in exon 6 of the p53 gene. No significant differences in the frequency of gene sequence variations were found between MS patients and controls. The apoptosis genes studied here therefore appear less likely to be important effector genes in MS.
Assuntos
Apoptose/genética , Genes bcl-2/genética , Esclerose Múltipla/genética , Polimorfismo Genético/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas/genética , Proteína Supressora de Tumor p53/genética , Sequência de Bases/genética , Códon/genética , Análise Mutacional de DNA , Éxons/genética , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Testes Genéticos , Humanos , Íntrons/genética , Linfócitos T/metabolismo , Proteína X Associada a bcl-2 , Proteína bcl-XRESUMO
Oncostatin M (OSM) is a member of the interleukin (IL)-6 cytokine family and modulates inflammatory responses. Here we investigated the role of OSM as an immunoregulatory factor for human cerebral endothelial cells (HCEC). Using RT-PCR we detected transcripts of the receptor components involved in OSM signaling, gp130, OSM receptor (OSMR)-beta, and leukemia inhibitory factor receptor (LIFR), in HCEC. A parallel FACS analysis revealed surface expression of gp130 and OSMR-beta, but not of LIFR on these cells. Functionally, OSM upregulated intercellular adhesion molecule-1, but did not induce vascular cell adhesion molecule-1 in HCEC. Further, OSM upregulated IL-6 and monocyte chemoattractant protein (MCP)-1, whereas IL-8 was unaffected. Combined application of tumor necrosis factor (TNF)-alpha and OSM synergistically enhanced IL-6 and MCP-1 production, but downregulated TNF-alpha-induced IL-8. As OSM regulated molecules relevant in inflammatory brain diseases, we investigated its expression in normal and pathological human brains. OSM was detected by immunohistochemistry in brains from multiple sclerosis patients in microglia, reactive astrocytes, and infiltrating leukocytes, whereas in normal brains and noninflammatory neurological diseases. immunoreactivity was absent from the parenchyma. These data suggest that immunoregulatory functions in human cerebral endothelial cells may be a mechanism by which OSM participates in the pathophysiology of inflammatory brain disease.
Assuntos
Barreira Hematoencefálica/fisiologia , Endotélio Vascular/química , Esclerose Múltipla/imunologia , Esclerose Múltipla/fisiopatologia , Peptídeos/análise , Adulto , Idoso , Antígenos CD/análise , Antígenos CD/genética , Células Cultivadas , Quimiocina CCL2/análise , Quimiocina CCL2/genética , Receptor gp130 de Citocina , Endotélio Vascular/citologia , Feminino , Citometria de Fluxo , Expressão Gênica/imunologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/análise , Interleucina-6/genética , Subunidade alfa de Receptor de Fator Inibidor de Leucemia , Masculino , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Oncostatina M , Peptídeos/genética , RNA Mensageiro/análise , Receptor do Fator Neutrófico Ciliar/genética , Receptores de Citocinas/análise , Receptores de Citocinas/genética , Receptores de Interleucina-6/genética , Receptores de OSM-LIF , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/imunologia , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Severe tissue destruction is the presumed histopathological correlate of hypointense multiple sclerosis (MS) lesions. In this study we correlated changes of lesion hypointensity over time with initial histopathological features in 14 biopsied MS lesions. The extent of hypointensity increased in initially demyelinated plaques and decreased in remyelinating lesions. The initial axonal loss determined the increase of hypointensity over time. In conclusion, both axonal loss and demyelinating activity determine the evolution of hypointensity over time.
Assuntos
Imageamento por Ressonância Magnética , Esclerose Múltipla/patologia , Adulto , Axônios/patologia , Biópsia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
The present study investigated the fate of macrophages in peripheral nerves undergoing Wallerian degeneration, especially their disappearance from the injured nerves after phagocytosis of axonal and myelin debris. Wallerian degeneration was induced in adult male C57Bl/6 mice by transecting the right sciatic nerve. Five days after transection, the male sciatic nerves were transplanted into female recipient mice by placing them exactly parallel to the host sciatic nerves. Nerves of the female recipient mice were also transected to induce breakdown of the blood-nerve barrier in the host animal. Apoptosis was assessed by morphological, immunohistochemical (activated caspase-3), and molecular (DNA fragmentation) methods in transplanted, recipient, and in control nerves. A subpopulation of macrophages within the degenerating nerves died locally by apoptosis in each experiment. The fate of the male macrophages within the transplanted nerves and the host organism was investigated by in situ hybridization with a Y-chromosome-specific DNA probe (145SC5). In situ hybridization specifically stained cells within the transplanted male nerve. Y-chromosome-positive cells were detected not only inside the transplanted nerve, but also inside the female host nerve, the perineurial tissue, the local perineurial blood vessels, draining lymph nodes and the spleen of the female host, suggesting hematogenous as well as lymphatic elimination of macrophages from the injured nerve. These data indicate that local apoptosis and systemic elimination via circulation to the local lymph nodes and the spleen are involved in the disappearance of macrophages from the injured peripheral nervous system.
Assuntos
Apoptose , Linfonodos/citologia , Macrófagos/patologia , Nervo Isquiático/lesões , Baço/citologia , Animais , Axotomia , Caspase 3 , Caspases/metabolismo , Contagem de Células , Movimento Celular , Fragmentação do DNA , Modelos Animais de Doenças , Feminino , Imuno-Histoquímica , Hibridização In Situ , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transferência de Nervo , Nervos Periféricos/metabolismo , Nervos Periféricos/patologia , Nervo Isquiático/patologia , Nervo Isquiático/transplante , Degeneração Walleriana/metabolismo , Degeneração Walleriana/patologia , Cromossomo Y/metabolismo , Cromossomo Y/ultraestruturaRESUMO
Single voxel proton magnetic resonance spectroscopy (MRS) provides a rapid non-invasive fingerprint of tissue chemistry. A case history is presented in which a B cell lymphoma with antecedent demyelinating lesions of the CNS was suspected by MRS and confirmed by neuropathological examination and immunoglobulin gene rearrangement.
Assuntos
Doenças do Sistema Nervoso Central/diagnóstico , Doenças Desmielinizantes/diagnóstico , Linfoma de Células B/diagnóstico , Espectroscopia de Ressonância Magnética , Idoso , Humanos , Imageamento por Ressonância Magnética , Masculino , PrótonsRESUMO
High-dose Ag administration induces apoptotic death of autoreactive T cells and is an effective therapy of experimental autoimmune diseases of the nervous system. To explore the role of cytokines in Ag-specific immunotherapy, we analyzed mRNA induction and protein expression for the proinflammatory cytokines TNF-alpha and IFN-gamma, the anti-inflammatory cytokine IL-10, and the cytokine-inducible NO synthase (iNOS) during high-dose Ag therapy of adoptive transfer experimental autoimmune encephalomyelitis (AT-EAE) in the Lewis rat. Using semiquantitative and competitive RT-PCR, we found 5- to 6-fold induction of TNF-alpha mRNA and 3-fold induction of IFN-gamma mRNA in the spinal cord that occurred within 1 h after i.v. injection of Ag and was accompanied by a 2-fold increase of iNOS mRNA. Both IFN-gamma and iNOS mRNA remained elevated for at least 6 h, whereas TNF-alpha mRNA was already down-regulated 6 h after Ag injection. A comparable time course was found for circulating serum levels of TNF-alpha and IFN-gamma. IL-10 mRNA levels did not change significantly following Ag injection. Neutralization of TNF-alpha by anti-TNF-alpha antiserum in vivo led to a significant decrease in the rate of T cell and oligodendrocyte apoptosis induced by high-dose Ag administration, but did not change the beneficial clinical effect of Ag therapy. Our data suggest profound activation of proinflammatory but not of anti-inflammatory cytokine gene expression by high-dose Ag injection. Functionally, TNF-alpha contributes to increased apoptosis of both autoaggressive T cells and oligodendrocytes in the target organ and may thereby play a dual role in this model of Ag-specific therapy of CNS autoimmune diseases.
Assuntos
Autoantígenos/uso terapêutico , Citocinas/biossíntese , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/terapia , Proteína Básica da Mielina/imunologia , Proteína Básica da Mielina/uso terapêutico , Óxido Nítrico Sintase/biossíntese , Células Th1/metabolismo , Animais , Apoptose/imunologia , Autoantígenos/administração & dosagem , Movimento Celular/imunologia , Citocinas/sangue , Progressão da Doença , Relação Dose-Resposta Imunológica , Esquema de Medicação , Encefalomielite Autoimune Experimental/enzimologia , Encefalomielite Autoimune Experimental/patologia , Indução Enzimática/genética , Indução Enzimática/imunologia , Feminino , Regulação da Expressão Gênica/imunologia , Cobaias , Soros Imunes/administração & dosagem , Injeções Intravenosas , Proteína Básica da Mielina/administração & dosagem , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , RNA Mensageiro/biossíntese , Ratos , Ratos Endogâmicos Lew , Medula Espinal/enzimologia , Medula Espinal/imunologia , Medula Espinal/patologia , Células Th1/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
The present study investigated the effects of flupirtine (Katadolon) on tumor necrosis factor (TNF)-alpha-mediated cell death and Bcl-2 expression in the permanent rat oligodendrocyte cell line OLN-93 (OLN cells). TNF-alpha (500 U/ml) induced apoptosis of OLN cells, which was confirmed by DNA fragmentation using an in situ end-labeling technique and ultrastructural analysis. Flupirtine significantly reduced the rate of spontaneous cell death of OLN cells already at low concentrations; TNF-alpha-mediated apoptosis was suppressed only with higher concentrations of flupirtine (100 microM:). Expression of Bcl-2 protein and mRNA in OLN cells was detected by immunocytochemistry, western blot, and RT-PCR. Quantitative analysis of western blots revealed an approximately 2. 5-fold up-regulation of Bcl-2 protein during TNF-alpha treatment. Furthermore, addition of 10 or 100 microM: flupirtine before incubation with TNF-alpha led to an approximately threefold increase of Bcl-2 expression. Exposure of OLN cells to flupirtine alone moderately augmented the expression of Bcl-2 protein. Our data demonstrate that flupirtine up-regulates the expression of Bcl-2 protein in OLN cells; this Bcl-2 induction is associated with a reduced rate of TNF-alpha-induced cell death.