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Key Clinical Message: Hypophyseal dysfunction may be overlooked by the currently generally accepted laboratory routine for the differential diagnosis in patients suffering from symptoms of depression or dementia. Abstract: Hypothyroidism is an important cause of depression and potentially reversible cognitive impairment. Whereas the determination of the plasma concentration of thyrotropin (TSH) is generally considered part of the laboratory screening tests for dementia, the measurement of total or free triiodothyronine (T3, FT3), thyroxine (T4, FT4) and cortisol in plasma does not belong to the routine diagnostic workup in patients with depression or suspected dementia. In an 87-year-old lady suffering from increasingly poor general health, decreased fluid and food intake, mood depression and lack of energy, three measurements of plasma TSH produced normal values. A cranial computed tomography (cCT) 2 days prior to hospital admission had been assessed as apparently normal. A second cCT performed following a loss of consciousness complicated by tongue bite showed a hypophyseal tumor. Then, low plasma levels of FT3, FT4 and cortisol were found. Following hormone replacement and transsphenoidal tumor resection, the patient recovered rapidly. The present case report illustrates the pitfalls of measuring merely the TSH level in the detection of thyroid and hypophyseal dysfunction.
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BACKGROUND: There is a paucity of knowledge regarding pediatric biomarkers, including the relevance of ErbB pathway aberrations in pediatric tumors. We investigated the occurrence of ErbB receptor aberrations across different pediatric malignancies, to identify patterns of ErbB dysregulation and define biomarkers suitable for patient enrichment in clinical studies. PROCEDURE: Tissue samples from 297 patients with nervous system tumors and rhabdomyosarcoma were analyzed for immunohistochemical expression or gene amplification of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Exploratory analyses of HER3/HER4 expression, and mRNA expression of ErbB receptors/ligands (NanoString) were performed. Assay validation followed general procedures, with additional validation to address Clinical Laboratory Improvement Amendments (CLIA) requirements. RESULTS: In most tumor types, samples with high ErbB receptor expression were found with heterogeneous distribution. We considered increased/aberrant ErbB pathway activation when greater than or equal to two EGFR/HER2 markers were simultaneously upregulated. ErbB pathway dysregulation was identified in â¼20%-30% of samples for most tumor types (medulloblastoma/primitive neuroectodermal tumors 31.1%, high-grade glioma 27.1%, neuroblastoma 22.7%, rhabdomyosarcoma 23.1%, ependymoma 18.8%), 4.2% of diffuse intrinsic pontine gliomas, and no recurrent or refractory low-grade astrocytomas. In medulloblastoma/primitive neuroectodermal tumors and neuroblastoma, this was attributed mainly to high EGFR polysomy/HER2 amplification, whereas EGFR gene amplification was observed in some high-grade glioma samples. EGFR/HER2 overexpression was most prevalent in ependymoma. CONCLUSIONS: Overexpression and/or amplification of EGFR/HER2 were identified as potential enrichment biomarkers for clinical trials of ErbB-targeted drugs.
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Neoplasias do Sistema Nervoso , Rabdomiossarcoma , Criança , Receptores ErbB , HumanosRESUMO
OBJECTIVE: Histology reveals that early active multiple sclerosis lesions can be classified into 3 main interindividually heterogeneous but intraindividually stable immunopathological patterns of active demyelination (patterns I-III). In patterns I and II, a T-cell- and macrophage-associated demyelination is suggested, with pattern II only showing signs of a humoral immune response. Pattern III is characterized by inflammatory lesions with an oligodendrocyte degeneration. Patterns suggest pathogenic heterogeneity, and we postulated that they have distinct magnetic resonance imaging (MRI) correlates that may serve as biomarkers. METHODS: We evaluated in an international collaborative retrospective cohort study the MRI lesion characteristics of 789 conventional prebiopsy and follow-up MRIs in relation to their histopathologically classified immunopathological patterns (n = 161 subjects) and lesion edge features (n = 112). RESULTS: A strong association of a ringlike enhancement and a hypointense T2-weighted (T2w) rim with patterns I and II, but not pattern III, was observed. Only a fraction of pattern III patients showed a ringlike enhancement, and this was always atypical. Ringlike enhancement and T2w rims colocalized, and ringlike enhancement showed a strong association with macrophage rims as shown by histology. A strong concordance of MRI lesion characteristics, meaning that different lesions showed the same features, was found when comparing biopsied and nonbiopsied lesions at a given time point, indicating lesion homogeneity within individual patients. INTERPRETATION: We provide robust evidence that MRI characteristics reflect specific morphological features of multiple sclerosis immunopatterns and that ringlike enhancement and T2w hypointense rims might serve as a valuable noninvasive biomarker to differentiate pathological patterns of demyelination. ANN NEUROL 2021;90:440-454.
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Encéfalo/diagnóstico por imagem , Encéfalo/imunologia , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/imunologia , Adulto , Encéfalo/patologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Estudos RetrospectivosRESUMO
Demyelinated lesions in human pons observed after osmotic shifts in serum have been referred to as central pontine myelinolysis (CPM). Astrocytic damage, which is prominent in neuroinflammatory diseases like neuromyelitis optica (NMO) and multiple sclerosis (MS), is considered the primary event during formation of CPM lesions. Although more data on the effects of astrocyte-derived factors on oligodendrocyte precursor cells (OPCs) and remyelination are emerging, still little is known about remyelination of lesions with primary astrocytic loss. In autopsy tissue from patients with CPM as well as in an experimental model, we were able to characterize OPC activation and differentiation. Injections of the thymidine-analogue BrdU traced the maturation of OPCs activated in early astrocyte-depleted lesions. We observed rapid activation of the parenchymal NG2+ OPC reservoir in experimental astrocyte-depleted demyelinated lesions, leading to extensive OPC proliferation. One week after lesion initiation, most parenchyma-derived OPCs expressed breast carcinoma amplified sequence-1 (BCAS1), indicating the transition into a pre-myelinating state. Cells derived from this early parenchymal response often presented a dysfunctional morphology with condensed cytoplasm and few extending processes, and were only sparsely detected among myelin-producing or mature oligodendrocytes. Correspondingly, early stages of human CPM lesions also showed reduced astrocyte numbers and non-myelinating BCAS1+ oligodendrocytes with dysfunctional morphology. In the rat model, neural stem cells (NSCs) located in the subventricular zone (SVZ) were activated while the lesion was already partially repopulated with OPCs, giving rise to nestin+ progenitors that generated oligodendroglial lineage cells in the lesion, which was successively repopulated with astrocytes and remyelinated. These nestin+ stem cell-derived progenitors were absent in human CPM cases, which may have contributed to the inefficient lesion repair. The present study points to the importance of astrocyte-oligodendrocyte interactions for remyelination, highlighting the necessity to further determine the impact of astrocyte dysfunction on remyelination inefficiency in demyelinating disorders including MS.
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Astrócitos/fisiologia , Diferenciação Celular , Mielinólise Central da Ponte/patologia , Células Precursoras de Oligodendrócitos/fisiologia , Oligodendroglia/fisiologia , Adulto , Idoso , Animais , Antidiuréticos , Astrócitos/patologia , Linhagem da Célula , Desamino Arginina Vasopressina , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Feminino , Humanos , Ventrículos Laterais/citologia , Ventrículos Laterais/metabolismo , Masculino , Pessoa de Meia-Idade , Bainha de Mielina , Mielinólise Central da Ponte/induzido quimicamente , Mielinólise Central da Ponte/metabolismo , Proteínas de Neoplasias/metabolismo , Nestina/metabolismo , Células-Tronco Neurais , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Ratos , Cloreto de SódioRESUMO
Immunohistochemical (IHC) α-synuclein (Asyn) pathology in peripheral biopsies may be a biomarker of Parkinson disease (PD). The multi-center Systemic Synuclein Sampling Study (S4) is evaluating IHC Asyn pathology within skin, colon and submandibular gland biopsies from 60 PD and 20 control subjects. Asyn pathology is being evaluated by a blinded panel of specially trained neuropathologists. Preliminary work assessed 2 candidate immunoperoxidase methods using a set of PD and control autopsy-derived sections from formalin-fixed, paraffin-embedded blocks of the 3 tissues. Both methods had 100% specificity; one, utilizing the 5C12 monoclonal antibody, was more sensitive in skin (67% vs 33%), and was chosen for further use in S4. Four trainee neuropathologists were trained to perform S4 histopathology readings; in subsequent testing, their scoring was compared to that of the trainer neuropathologist on both glass slides and digital images. Specificity and sensitivity were both close to 100% with all readers in all tissue types on both glass slides and digital images except for skin, where sensitivity averaged 75% with digital images and 83.5% with glass slides. Semiquantitative (0-3) density score agreement between trainees and trainer averaged 67% for glass slides and 62% for digital images.
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Histocitoquímica/métodos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Sinucleínas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biópsia , Colo/metabolismo , Feminino , Humanos , Masculino , Fibras Nervosas/metabolismo , Fibras Nervosas/patologia , Guias de Prática Clínica como Assunto , Estudos de Amostragem , Sensibilidade e Especificidade , Pele/metabolismo , Pele/patologia , Glândula Submandibular/metabolismo , Glândula Submandibular/patologiaRESUMO
Multiple sclerosis is a disease of the central nervous system characterized by recurrent inflammatory demyelinating lesions in the early disease stage. Lesion formation and mechanisms leading to lesion remyelination are not fully understood. Matrix Assisted Laser Desorption Ionisation Mass Spectrometry imaging (MALDI-IMS) is a technology which analyses proteins and peptides in tissue, preserves their spatial localization, and generates molecular maps within the tissue section. In a pilot study we employed MALDI imaging mass spectrometry to profile and identify peptides and proteins expressed in normal-appearing white matter, grey matter and multiple sclerosis brain lesions with different extents of remyelination. The unsupervised clustering analysis of the mass spectra generated images which reflected the tissue section morphology in luxol fast blue stain and in myelin basic protein immunohistochemistry. Lesions with low remyelination extent were defined by compounds with molecular weight smaller than 5300Da, while more completely remyelinated lesions showed compounds with molecular weights greater than 15,200Da. An in-depth analysis of the mass spectra enabled the detection of cortical lesions which were not seen by routine luxol fast blue histology. An ion mass, mainly distributed at the rim of multiple sclerosis lesions, was identified by liquid chromatography and tandem mass spectrometry as thymosin beta-4, a protein known to be involved in cell migration and in restorative processes. The ion mass of thymosin beta-4 was profiled by MALDI imaging mass spectrometry in brain slides of 12 multiple sclerosis patients and validated by immunohistochemical analysis. In summary, our results demonstrate the ability of the MALDI-IMS technology to map proteins within the brain parenchyma and multiple sclerosis lesions and to identify potential markers involved in multiple sclerosis pathogenesis and/or remyelination.
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Encéfalo/patologia , Esclerose Múltipla/patologia , Proteínas/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas Mielinizadas/patologia , Projetos Piloto , Proteômica/métodos , Timosina/análiseRESUMO
BACKGROUND: Histopathological studies have revealed four different immunopathological patterns of lesion pathology in early multiple sclerosis (MS). Pattern II MS is characterised by immunoglobulin and complement deposition in addition to T-cell and macrophage infiltration and is more likely to respond to plasma exchange therapy, suggesting a contribution of autoantibodies. OBJECTIVE: To assess the frequency of anti-myelin oligodendrocyte glycoprotein (MOG), anti-M1-aquaporin-4 (AQP4), anti-M23-AQP4, anti-N-methyl-d-aspartate-type glutamate receptors (NMDAR) and 25 other anti-neural antibodies in pattern II MS. METHODS: Thirty-nine serum samples from patients with MS who had undergone brain biopsy (n = 24; including 13 from patients with pattern II MS) and from histopathologically non-classified MS patients (n = 15) were tested for anti-MOG, anti-M1-AQP4, anti-M23-AQP4, anti-NMDAR, anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-type glutamate receptors (AMPAR), anti-gamma-aminobutyric acid receptors (GABABR), anti-leucine-rich, glioma-activated protein 1 (LGI1), anti-contactin-associated protein 2 (CASPR2), anti-dipeptidyl-peptidase-like protein-6 (DPPX), anti-Tr/Delta/notch-like epidermal growth factor-related receptor (DNER), anti-Hu, anti-Yo, anti-Ri, anti-Ma1/Ma2, anti-CV2/collapsin response mediator protein 5 (CRMP5), anti-glutamic acid decarboxylase (GAD), anti-amphiphysin, anti-Ca/RhoGTPase-activating protein 26 (ARHGAP26), anti-Sj/inositol-1,4,5-trisphosphate receptor 1 (ITPR1), anti-Homer3, anti-carbonic anhydrase-related protein (CARPVIII), anti-protein kinase gamma (PKCgamma), anti-glutamate receptor delta 2 (GluRdelta2), anti-metabotropic glutamate receptor 1 (mGluR1) and anti-mGluR5, as well as for anti-glial nuclei antibodies (AGNA) and Purkinje cell antibody 2 (PCA2). RESULTS: Antibodies to MOG belonging to the complement-activating immunoglobulin G1 (IgG1) subclass were detected in a patient with pattern II MS. Detailed brain biopsy findings are shown. CONCLUSION: This is the largest study on established anti-neural antibodies performed in MS so far. MOG-IgG may play a role in a small percentage of patients diagnosed with pattern II MS.
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Autoanticorpos/sangue , Encéfalo/patologia , Ativação do Complemento/imunologia , Esclerose Múltipla/sangue , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Proteínas do Tecido Nervoso/imunologia , Biópsia , Encéfalo/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , Pessoa de Meia-IdadeAssuntos
Encéfalo/patologia , Vírus JC , Leucoencefalopatia Multifocal Progressiva/patologia , Cirrose Hepática Biliar/patologia , Idoso , Progressão da Doença , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/complicações , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/virologia , Mefloquina/uso terapêutico , Mianserina/análogos & derivados , Mianserina/uso terapêutico , Mirtazapina , Resultado do TratamentoRESUMO
The extent of irreversible neuroaxonal damage is the key determinant of permanent disability in traumatic and inflammatory conditions of the central nervous system (CNS). Structural damage is nevertheless in part compensated by neuroplastic events. However, it is unknown whether the same kinetics and mechanisms of neuroaxonal de- and regeneration take place in inflammatory and traumatic conditions. We analyzed neuroaxonal degeneration and plasticity in early multiple sclerosis (MS) lesions and traumatic brain injury (TBI). Neuroaxonal degeneration identified by the presence of SMI31+ chromatolytic neurons and SMI32+ axonal profiles were characteristic features of leukocortical TBI lesions. Axonal transport disturbances as determined by amyloid precursor protein (APP)+ spheroids were present in both TBI and MS lesions to a similar degree. Neurons expressing growth-associated protein 43 (GAP43) and synaptophysin (Syn) were found under both pathological conditions. However, axonal swellings immunopositive for GAP43 and Syn clearly prevailed in subcortical MS lesions, suggesting a higher regenerative potential in MS. In this context, GAP43+/APP+ axonal spheroid ratios correlated with macrophage infiltration in TBI and MS lesions, supporting the idea that phagocyte activation might promote neuroplastic events. Furthermore, axonal GAP43+ and Syn+ swellings correlated with prolonged survival after TBI, indicating a sustained regenerative response.
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Axônios/fisiologia , Lesões Encefálicas/patologia , Córtex Cerebral/patologia , Esclerose Múltipla/patologia , Neurônios/patologia , Regeneração/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Precursor de Proteína beta-Amiloide/metabolismo , Axônios/patologia , Biópsia , Lesões Encefálicas/fisiopatologia , Córtex Cerebral/metabolismo , Feminino , Proteína GAP-43/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/fisiopatologia , Degeneração Neural/etiologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Neurofilamentos/metabolismo , Neurônios/metabolismo , Sinaptofisina/metabolismo , Adulto JovemRESUMO
Impaired suppressive capacity of CD4(+)CD25(+)FOXP3(+) regulatory T cells (Treg) from peripheral blood of patients with multiple sclerosis (MS) has been reported by multiple laboratories. It is, however, currently unresolved whether Treg dysfunction in MS patients is limited to reduced control of peripheral T cell activation since most studies analyzed peripheral blood samples only. Here, we assessed early active MS lesions in brain biopsies obtained from 16 patients with MS by FOXP3 immunohistochemistry. In addition, we used six-color flow cytometry to determine numbers of Treg by analysis of FOXP3/CD127 expression in peripheral blood and cerebrospinal fluid (CSF) of 17 treatment-naïve MS patients as well as quantities of apoptosis sensitive CD45RO(hi)CD95(hi) cells in circulating and CSF Treg subsets. Absolute numbers of FOXP3(+) and CD4(+) cells were rather low in MS brain lesions and Treg were not detectable in 30% of MS biopsies despite the presence of CD4(+) cell infiltrates. In contrast, Treg were detectable in all CSF samples and Treg with a CD45RO(hi)CD95(hi) phenotype previously shown to be highly apoptosis sensitive were found to be enriched in the CSF compared to peripheral blood of MS patients. We suggest a hypothetical model of intracerebral elimination of Treg by CD95L-mediated apoptosis within the MS lesion.
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Encéfalo/imunologia , Encéfalo/patologia , Fatores de Transcrição Forkhead/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/imunologia , Linfócitos T Reguladores/imunologia , Quimiotaxia , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Antígenos Comuns de Leucócito/metabolismo , Subpopulações de Linfócitos/imunologia , Receptor fas/metabolismoRESUMO
A-76-year old woman was admitted to the hospital with paraplegia after a collapse at home. Magnetic resonance imaging showed white matter lesions from Th4 to L2 as well as large confluent white matter lesions in the cerebrum. Within 3 days, the patient's mental status decreased dramatically and she finally died on day 16 after her fall. Autopsy examination revealed an acute myeloid leukemia, which had not previously been diagnosed and which had never been treated. In the CNS, we found spread of myeloblasts in combination with acute demyelinating lesions which corresponded to the antibody- and complement-mediated pattern II of multiple sclerosis lesions. This case implies that association of acute myeloid leukemia and acute CNS demyelination needs to be discussed and suggests that AML patients need to be strictly monitored for CNS functions.
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Encéfalo/patologia , Doenças Desmielinizantes/patologia , Leucemia Mieloide Aguda/patologia , Paraplegia/patologia , Doença Aguda , Idoso , Encéfalo/metabolismo , Doenças Desmielinizantes/diagnóstico , Doenças Desmielinizantes/metabolismo , Diagnóstico Diferencial , Evolução Fatal , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Paraplegia/diagnóstico , Paraplegia/metabolismoRESUMO
We report a case of a 27-year-old female with thrombotic microangiopathy as an initial presentation of an unexpected disseminated gastric carcinoma. Based on clinical features and laboratory findings, thrombotic thrombocytopenic purpura (TTP) was diagnosed and plasma exchange started. However, she had responded poorly to plasmapheresis, developed multiorgan failure and died 72 h after admission. Autopsy revealed a disseminated gastric adenocarcinoma with metastatic infiltration of dura mater and disseminated tumor cell emboli in the microcirculation of the liver and lungs. Genetic analysis revealed amplification of KRAS oncogene and aberrations in DCC tumor suppressor gene, which can explain the young age and advanced disease at presentation. The role of plasmapheresis in cancer-associated TTP is uncertain. Plasmapheresis delivers fresh coagulation factors and may theoretically promote microthrombi formation and lead to worsening of the disease. Thrombotic thrombocytopenic purpura seems to be a late and prognostically poor manifestation of an underlying malignancy, with majority of patients dying soon after diagnosis. It is important to be aware of this possibility in thrombotic microangiopathy, especially with atypical features and poor response to standard treatment.
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Plasmaferese/métodos , Púrpura Trombocitopênica Trombótica/etiologia , Neoplasias Gástricas/complicações , Adenocarcinoma/complicações , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adulto , Evolução Fatal , Feminino , Humanos , Insuficiência de Múltiplos Órgãos/etiologia , Púrpura Trombocitopênica Trombótica/terapia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Falha de TratamentoRESUMO
Axonal loss is a major component of the pathology of multiple sclerosis (MS) and the morphological basis of permanent clinical disability. It occurs in demyelinating plaques but also in the so-called normal-appearing white matter (NAWM). However, the contribution of Wallerian degeneration to axonal pathology is not known. Here, we analyzed the extent of Wallerian degeneration and axonal pathology in periplaque white matter (PPWM) and lesions in early multiple sclerosis biopsy tissue from 63 MS patients. Wallerian degeneration was visualized using an antibody against the neuropeptide Y receptor Y1 (NPY-Y1R). The number of SMI-32-positive axons with non-phosphorylated neurofilaments was significantly higher in both PPWM and plaques compared to control white matter. APP-positive, acutely damaged axons were found in significantly higher numbers in plaques compared to PPWM. Strikingly, the number of NPY-Y1R-positive axons undergoing Wallerian degeneration was significantly higher in PPWM and plaques than in control WM. NPY-Y1R-positive axons in PPWM were strongly correlated to those in the lesions. Our results show that Wallerian degeneration is a major component of axonal pathology in the periplaque white matter in early MS. It may contribute to radiological changes observed in early MS and most likely plays a major role in the development of disability.
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Axônios/patologia , Esclerose Múltipla/complicações , Fibras Nervosas Mielinizadas/patologia , Nervos Periféricos/patologia , Degeneração Walleriana/etiologia , Adolescente , Adulto , Idoso , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Criança , Encefalomielite Autoimune Experimental/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Estatísticas não Paramétricas , Adulto JovemRESUMO
OBJECTIVE: The aim of this rat study was to investigate the safety limits of extended transcranial direct current stimulation (tDCS). tDCS may be of therapeutic value in several neuro-psychiatric disorders. For its clinical applicability, however, more stable effects are required, which may be induced by intensified stimulations. METHODS: Fifty-eight rats received single cathodal stimulations at 1-1000 microA for up to 270 min through an epicranial electrode (3.5 mm(2)). Histological evaluation (H&E) was performed 48 h later. A threshold estimate was calculated from volumes of DC-induced lesions. RESULTS: Brain lesions occurred at a current density of 142.9 A/m(2) for durations greater than 10 min. For current densities between 142.9 and 285.7 A/m(2), lesion size increased linearly with charge density; with a calculated zero lesion size intercept of 52,400 C/m(2). Brains stimulated below either this current density or charge density threshold, including stimulations over 5 consecutive days, were morphologically intact. CONCLUSION: The experimentally determined threshold estimate is two orders of magnitude higher than the charge density currently applied in humans (171-480 C/m(2)). In relation to transcranial DC stimulation in humans the rat epicranial electrode montage may provide for an additional safety margin. SIGNIFICANCE: Although these results cannot be directly transferred to humans, they encourage the development intensified tDCS protocols. Further animal studies are required, before such protocols can be applied in humans.
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Lesões Encefálicas/prevenção & controle , Terapia por Estimulação Elétrica/normas , Gestão da Segurança/métodos , Animais , Encéfalo/patologia , Encéfalo/fisiologia , Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Terapia por Estimulação Elétrica/efeitos adversos , Terapia por Estimulação Elétrica/métodos , Eletrodos , Feminino , Masculino , Modelos Animais , Ratos , Ratos Wistar , Fatores de TempoRESUMO
BACKGROUND: Multiple sclerosis (MS) is a heterogeneous autoimmune disease of the central nervous system. The identification of 4 different immunopathological subtypes of MS raises the question of whether these subtypes represent different patient subgroups that can be distinguished according to their leading mechanism of myelin destruction or whether this is a stage-dependent process in the development of lesions in a given patient. OBJECTIVE: To document intraindividual immunopathological and radiological homogeneity of 2 different lesions in a single patient with relapsing-remitting MS over time. DESIGN: Case report. SETTING: A neuropathological referral center for inflammatory demyelinating diseases of the central nervous system. PATIENT: A 49-year-old woman with clinically definite relapsing-remitting MS. MAIN OUTCOME MEASURES: Radiological and immunopathological analysis of MS lesions. RESULTS: Identical pathological findings in 2 different MS lesions separated by more than 2 years were identified. These lesions displayed similar and distinct radiological features on cranial imaging. CONCLUSIONS: In this patient we were able to show the same antibody/complement-mediated lesion pathological findings with compatible identical ring enhancement on T1-weighted magnetic resonance images and hypointense rims on T2-weighted images after an interval of 26 months. Our observations support the concept of intraindividual homogeneity of a given immunopathological MS subtype.
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Encéfalo/patologia , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/imunologia , Anticorpos/sangue , Biópsia , Feminino , Lobo Frontal/patologia , Humanos , Imunoglobulina G/sangue , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Proteínas da Mielina , Glicoproteína Associada a Mielina/imunologia , Glicoproteína Mielina-Oligodendrócito , Lobo Parietal/patologia , Fatores de TempoAssuntos
Doenças Desmielinizantes/etiologia , Doenças Desmielinizantes/patologia , Esclerose Múltipla/complicações , Esclerose Múltipla/patologia , Adulto , Antígenos CD13/metabolismo , Calgranulina B/metabolismo , Feminino , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Imageamento por Ressonância Magnética , Esclerose Múltipla/terapia , Proteínas da Mielina , Glicoproteína Associada a Mielina/metabolismo , Glicoproteína Mielina-OligodendrócitoRESUMO
Early, active multiple sclerosis lesions show four immunopathological patterns of demyelination. Although these patterns differ between patients, multiple active lesions from a given patient have an identical pattern, which suggests pathogenic heterogeneity. Therapeutic plasma exchange (TPE) has been successfully used to treat fulminant demyelinating attacks unresponsive to steroids. We postulated that patients with pattern II would be more likely to improve after TPE than those with other patterns since pattern II lesions are distinguished by prominent immunoglobulin deposition and complement activation. We retrospectively studied 19 patients treated with TPE for an attack of fulminant CNS inflammatory demyelinating disease. All patients with pattern II (n=10), but none with pattern I (n=3) or pattern III (n=6), achieved moderate to substantial functional neurological improvement after TPE (p<0.0001). Patients with multiple sclerosis with pattern II pathology are more likely to respond favourably to TPE than are patients with patterns I or III.
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Esclerose Múltipla/terapia , Troca Plasmática , Atividades Cotidianas , Adulto , Encéfalo/patologia , Humanos , Esclerose Múltipla/sangue , Esclerose Múltipla/patologiaRESUMO
Brain metastases, including those of malignant melanoma (known for its high genomic instability), are the most common intracranial tumors. The main objective of this study was to investigate expression and mutation in the DNA mismatch repair system in melanoma brain metastases. Expression of MLH1, MSH2, PMS1 and PMS2 was investigated immunohistochemically in 31 melanoma metastatic tumors. Mutational analysis of MLH1 and MSH2 was performed in 17 melanoma brain metastases. Loss of MLH1 and MSH2 expression was found in 10/31 and 12/31 tumors. PMS1 (27/31) and PMS2 (28/31) expression was preserved in the majority of lesions. Potential missense mutation was found in MSH2 (exon 13) in 2/17 melanomas. Mutation in the intron sequence between exon 14 and 15 of MLH1 (exon 15) was observed in 4/17 cases. Our results indicate that the two major DNA mismatch repair genes, MLH1 and MSH2, are more frequently affected by alterations in the DNA mismatch repair system than the helper genes PMS1 and PMS2. The presence of mutations of MSH2 and MLH1 in melanoma brain metastases, which has not been found in primary melanomas, indicates the high genomic instability of melanoma brain metastases.
Assuntos
Pareamento Incorreto de Bases , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Melanoma/genética , Melanoma/secundário , Mutação , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Neoplasias Encefálicas/metabolismo , Proteínas de Transporte , Proteínas de Ligação a DNA/biossíntese , Feminino , Expressão Gênica , Instabilidade Genômica/genética , Humanos , Imuno-Histoquímica , Masculino , Melanoma/metabolismo , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS , Proteínas de Neoplasias/biossíntese , Proteínas Nucleares , Proteínas Proto-Oncogênicas/biossínteseRESUMO
BACKGROUND: Altered expression and prognostic significance of DNA double-strand repair genes Ku70 and Ku80 has been shown by our research group for malignant melanomas. High genomic instability known for melanoma brain metastases stimulated us to analyze Ku70 and Ku80 expression in melanoma brain metastases. MATERIALS AND METHODS: Quantitative evaluation of mRNA Ku70 and Ku80 expression was performed in 13 melanoma brain metastases. Immunohistochemistry and in situ hybridization for Ku70 and Ku80 were applied to 34 metastatic tumours. RESULTS: Quantitative analysis of Ku70 mRNA expression demonstrated values between 0.01 and 0.33. Ku80 mRNA expression ranged between 0.001 and 0.54. Immunohistochemistry demonstrated Ku70 and Ku80 expression in 34 and in 25 metastatic tumours, respectively. In situ hybridization detected Ku70 expression in 19/34 and Ku80 expression in 13/34 metastatic tumours. Correlation between Ku70 and Ku80 expression in melanoma brain metastases was lost. CONCLUSION: Ku70 and especially Ku80 expression is altered in melanoma brain metastases and corresponds with the high genomic instability of these lesions.
RESUMO
In an attempt to determine the susceptibility of spermatogonia to malignant transformation transgenic mice were generated harboring a 1.3 kb 5'-flanking region of the germ cell specific expressed human testis specific protein, Y-encoded gene fused with the simian virus 40 large T antigen (TAg). Unexpectedly, TAg expression in transgenic mice was also detected in somatic tissues. Between days 65 and 85 after birth most of the transgenic mice developed anterior lobe tumors of the pituitary gland and to a less extent medulla type tumors of the adrenal gland. In addition, a few older transgenic mice developed tumors of the seminal vesicle, but no testicular tumors were observed in transgenic mice up to an age of 5 months. The pituitary tumors were immunoreactive for anti-prolactin (PRL) and anti-adrenocorticotropic hormone (ACTH). PRL and corticosterone concentrations in serum of transgenic mice were significantly increased. Taken together, our studies provide a novel mouse model for pituitary adenomas displaying a unique combination of hormone expression by tumor cells secreting PRL and ACTH.