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1.
Nat Commun ; 9(1): 3025, 2018 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-30072689

RESUMO

In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss during adult life. Here, we show that myelinating Schwann cells in a rat model of CMT1A exhibit a developmental defect that includes reduced transcription of genes required for myelin lipid biosynthesis. Consequently, lipid incorporation into myelin is reduced, leading to an overall distorted stoichiometry of myelin proteins and lipids with ultrastructural changes of the myelin sheath. Substitution of phosphatidylcholine and phosphatidylethanolamine in the diet is sufficient to overcome the myelination deficit of affected Schwann cells in vivo. This treatment rescues the number of myelinated axons in the peripheral nerves of the CMT rats and leads to a marked amelioration of neuropathic symptoms. We propose that lipid supplementation is an easily translatable potential therapeutic approach in CMT1A and possibly other dysmyelinating neuropathies.


Assuntos
Doença de Charcot-Marie-Tooth/terapia , Metabolismo dos Lipídeos , Bainha de Mielina/metabolismo , Animais , Axônios/metabolismo , Axônios/ultraestrutura , Gorduras na Dieta/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/biossíntese , Bainha de Mielina/ultraestrutura , Fosfolipídeos/metabolismo , Ratos Transgênicos , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Células de Schwann/patologia
2.
Acta Neurol Scand ; 137(6): 544-556, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29512131

RESUMO

For decades, B cells were ignored in multiple sclerosis (MS) pathogenesis, and the disease was always regarded as a T cell-mediated disorder. Recent evidence shows that there is an antigen-driven B-cell response in the central nervous system of patients with MS, and memory B cells/plasma cells are detectable in MS lesions. The striking efficacy of B cell-depleting therapies in reducing the inflammatory activity of the disease highlights that B cells may play more pathogenetic roles than expected. B cells express several unique characteristic markers on their surface, for example, CD19, CD20 molecules, that provide selective targets for monoclonal antibodies. In this respect, several B cell-targeted therapies emerged, including anti-CD20 antibodies (rituximab, ocrelizumab, and ofatumumab), anti-CD19 antibody (inebilizumab), and agents targeting the BAFF/APRIL signaling pathway (atacicept, belimumab, and LY2127399). In this review, we discuss, in detail, the immunobiology of B cells and their protective and destructive roles in MS pathogenesis. In the second part, we list the completed and ongoing clinical trials investigating the safety and efficacy of B cell-related monoclonal antibodies in MS.


Assuntos
Linfócitos B/imunologia , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos B/efeitos dos fármacos , Ensaios Clínicos como Assunto/métodos , Humanos , Imunossupressores/farmacologia , Rituximab/farmacologia , Rituximab/uso terapêutico
3.
J Neuroinflammation ; 14(1): 171, 2017 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-28851393

RESUMO

BACKGROUND: The diagnosis of multiple sclerosis (MS) is currently based solely on clinical and magnetic resonance imaging features. However, histopathological studies have revealed four different patterns of lesion pathology in patients diagnosed with MS, suggesting that MS may be a pathologically heterogeneous syndrome rather than a single disease entity. OBJECTIVE: The aim of this study was to investigate whether patients with pattern I MS differ from patients with pattern II or III MS with regard to cerebrospinal fluid (CSF) findings, especially with reference to intrathecal IgG synthesis, which is found in most patients with MS but is frequently missing in MS mimics such as aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-IgG-positive encephalomyelitis. METHODS: Findings from 68 lumbar punctures in patients who underwent brain biopsy as part of their diagnostic work-up and who could be unequivocally classified as having pattern I, pattern II or pattern III MS were analysed retrospectively. RESULTS: Oligoclonal bands (OCBs) were present in 88.2% of samples from pattern I MS patients but in only 27% of samples from patients with pattern II or pattern III MS (P < 0.00004); moreover, OCBs were present only transiently in some of the latter patients. A polyspecific intrathecal IgG response to measles, rubella and/or varicella zoster virus (so-called MRZ reaction) was previously reported in 60-80% of MS patients, but was absent in all pattern II or III MS patients tested (P < 0.00001 vs. previous cohorts). In contrast, the albumin CSF/serum ratio (QAlb), a marker of blood-CSF barrier function, was more frequently elevated in samples from pattern II and III MS patients (P < 0.002). Accordingly, QAlb values and albumin and total protein levels were higher in pattern II and III MS samples than in pattern I MS samples (P < 0.005, P < 0.009 and P < 0.006, respectively). CONCLUSIONS: Patients with pattern II or pattern III MS differ significantly from patients with pattern I MS as well as from previous, histologically non-classified MS cohorts with regard to both intrathecal IgG synthesis and blood-CSF barrier function. Our findings strongly corroborate the notion that pattern II and pattern III MS are entities distinct from pattern I MS.


Assuntos
Imunoglobulina G/líquido cefalorraquidiano , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico , Bandas Oligoclonais/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
4.
Clin Neurol Neurosurg ; 156: 48-54, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28324788

RESUMO

OBJECTIVES: To compare clinical features and outcome, imaging characteristics, biopsy results and laboratory findings in a cohort of 69 patients with suspected or diagnosed primary central nervous system vasculitis (PCNSV) in adults; to identify risk factors and predictive features for PCNSV. PATIENTS AND METHODS: We performed a case-control-study including 69 patients referred with suspected PCNSV from whom 25 were confirmed by predetermined diagnostic criteria based on biopsy (72%) or angiography (28%). Forty-four patients turned out to have 15 distinct other diagnoses. Clinical and diagnostic data were compared between PCNSV and Non-PCNSV cohorts. RESULTS: Clinical presentation was not able to discriminate between PCNSV and its differential diagnoses. However, a worse clinical outcome was associated with PCNSV (p=0.005). Biopsy (p=0.004), contrast enhancement (p=0.000) or tumour-like mass lesion (p=0.008) in magnetic resonance imaging (MRI), intrathecal IgG increase (p=0.020), normal Duplex findings of cerebral arteries (p=0.022) and conventional angiography (p 0.010) were able to distinguish between the two cohorts. CONCLUSION: In a cohort of 69 patients with suspected PCNSV, a large number (64%) was misdiagnosed and partly received treatment, since mimicking diseases are very difficult to discriminate. Clinical presentation at manifestation does not help to differentiate PCNSV from its mimicking diseases. MRI and cerebrospinal fluid analysis are unlikely to be normal in PCNSV, though unspecific if pathological. Cerebral angiography and biopsy must complement other diagnostics when establishing the diagnosis in order to avoid misdiagnosis and mistreatment. CLINICAL TRIAL REGISTRATION: German clinical trials register: http://drks-neu.uniklinik-freiburg.de/drks_web/, Unique identifier: DRKS00005347.


Assuntos
Vasculite do Sistema Nervoso Central/terapia , Adulto , Biópsia , Estudos de Casos e Controles , Angiografia Cerebral , Artérias Cerebrais/diagnóstico por imagem , Estudos de Coortes , Comorbidade , Diagnóstico Diferencial , Erros de Diagnóstico/estatística & dados numéricos , Feminino , Humanos , Imunoglobulina G , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Vasculite do Sistema Nervoso Central/complicações , Vasculite do Sistema Nervoso Central/diagnóstico
5.
Neuropathol Appl Neurobiol ; 43(6): 514-532, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27543917

RESUMO

AIMS: In Wilson disease (WD), T2/T2*-weighted (T2*w) MRI frequently shows hypointensity in the basal ganglia that is suggestive of paramagnetic deposits. It is currently unknown whether this hypointensity is related to copper or iron deposition. We examined the neuropathological correlates of this MRI pattern, particularly in relation to iron and copper concentrations. METHODS: Brain slices from nine WD and six control cases were investigated using a 7T-MRI system. High-resolution T2*w images were acquired and R2* parametric maps were reconstructed using a multigradient recalled echo sequence. R2* was measured in the globus pallidus (GP) and the putamen. Corresponding histopathological sections containing the lentiform nucleus were examined using Turnbull iron staining, and double staining combining Turnbull with immunohistochemistry for macrophages or astrocytes. Quantitative densitometry of the iron staining as well as copper and iron concentrations were measured in the GP and putamen and correlated with R2* values. RESULTS: T2*w hypointensity in the GP and/or putamen was apparent in WD cases and R2* values correlated with quantitative densitometry of iron staining. In WD, iron and copper concentrations were increased in the putamen compared to controls. R2* was correlated with the iron concentration in the GP and putamen, whereas no correlation was observed for the copper concentration. Patients with more pronounced pathological severity in the putamen displayed increased iron concentration, which correlated with an elevated number of iron-containing macrophages. CONCLUSIONS: T2/T2*w hypointensity observed in vivo in the basal ganglia of WD patients is related to iron rather than copper deposits.


Assuntos
Gânglios da Base/metabolismo , Gânglios da Base/patologia , Degeneração Hepatolenticular/metabolismo , Degeneração Hepatolenticular/patologia , Ferro/metabolismo , Adulto , Astrócitos , Gânglios da Base/diagnóstico por imagem , Cobre/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Feminino , Degeneração Hepatolenticular/diagnóstico por imagem , Humanos , Macrófagos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
Nervenarzt ; 87(6): 645-59, 2016 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-26927677

RESUMO

With the approval of various substances for the immunotherapy of multiple sclerosis (MS), treatment possibilities have improved significantly over the last few years. Indeed, the choice of individually tailored preparations and treatment monitoring for the treating doctor is becoming increasingly more complex. This is particularly applicable for monitoring for a treatment-induced compromise of the immune system. The following article by members of the German Multiple Sclerosis Skills Network (KKNMS) and the task force "Provision Structures and Therapeutics" summarizes the practical recommendations for approved immunotherapy for mild to moderate and for (highly) active courses of MS. The focus is on elucidating the substance-specific relevance of particular laboratory parameters with regard to the mechanism of action and the side effects profile. To enable appropriate action to be taken in clinical practice, any blood work changes that can be expected, in addition to any undesirable laboratory findings and their causes and relevance, should be elucidated.


Assuntos
Imunoterapia/efeitos adversos , Imunoterapia/métodos , Monitorização Imunológica/métodos , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Humanos , Imunocompetência/efeitos dos fármacos , Imunocompetência/imunologia , Esclerose Múltipla/classificação
8.
HIV Med ; 17(2): 143-51, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26176591

RESUMO

OBJECTIVES: HIV infection affects the central nervous system (CNS), frequently causing cognitive impairment. Hippocampal injury impedes the ability to transfer information into memory. Therefore, we aimed to examine neuronal injury and repair in the hippocampal formation in HIV encephalopathy. METHODS: We compared neuropathological findings in 14 autopsy cases after death from systemic complications of HIV infection and in 15 age-matched HIV-negative control cases after sudden death from nonneurological causes using immunohistochemistry. RESULTS: The density of apoptotic granule cells in the dentate gyrus was higher in HIV-infected than in control cases (P = 0.048). Proliferation of neural progenitor cells in the dentate gyrus was increased in HIV infection (P = 0.028), whereas the density of recently generated TUC-4 [TOAD (turned on after division)/Ulip/CRMP family 4]-expressing neurons in this region was not significantly elevated in HIV-infected cases (P = 0.13). HIV infection caused microglial activation and astrocytosis in the neocortex and hippocampal formation. Conversely, we were unable to detect more pronounced axonal injury in HIV-infected than in control cases. CONCLUSIONS: As in other infections involving the CNS, apoptosis of hippocampal neurons accompanied by microglial activation and astrocytosis is a prominent feature of HIV encephalopathy. The regenerative potential, assessed using the density of young neurons in the hippocampal dentate gyrus, in HIV infection appears to be lower than in acute bacterial meningitis and septic encephalitis.


Assuntos
Complexo AIDS Demência/patologia , Hipocampo/patologia , Imuno-Histoquímica/métodos , Microglia/patologia , Complexo AIDS Demência/mortalidade , Complexo AIDS Demência/fisiopatologia , Adulto , Idoso , Autopsia , Feminino , Hipocampo/virologia , Humanos , Masculino , Microglia/virologia , Pessoa de Meia-Idade
9.
Nervenarzt ; 86(10): 1236-47, 2015 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-26269289

RESUMO

In recent years the approval of new substances has led to a substantial increase in the number of course-modifying immunotherapies available for multiple sclerosis. Therapy conversion therefore represents an increasing challenge. The treatment options sometimes show complex adverse effect profiles and necessitate a long-term and comprehensive monitoring. This article presents an overview of therapy conversion of immunotherapies for multiple sclerosis in accordance with the recommendations of the Disease-Related Competence Network for Multiple Sclerosis and the German Multiple Sclerosis Society as well as the guidelines on diagnostics and therapy for multiple sclerosis of the German Society of Neurology and the latest research results. At the present point in time it should be noted that no studies have been carried out for most of the approaches for therapy conversion given here; however, the recommendations are based on theoretical considerations and therefore correspond to recommendations at the level of expert consensus, which is currently essential for the clinical daily routine.


Assuntos
Alergia e Imunologia/normas , Imunossupressores/administração & dosagem , Imunoterapia/normas , Esclerose Múltipla/tratamento farmacológico , Neurologia/normas , Guias de Prática Clínica como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Alemanha , Humanos , Imunossupressores/normas , Esclerose Múltipla/imunologia
10.
Lett Appl Microbiol ; 61(1): 20-7, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25869996

RESUMO

UNLABELLED: In this study, a duplex qPCR assay was developed for the needs of the Irish fish industry to screen for the two major food-borne pathogens of fish, Listeria monocytogenes and Escherichia coli O157:H7. The assay can claim positive or negative results for two pathogens in one go in only 20 h including 16 h universal pre-enrichment and compared to traditional ISO approved plate culture methods the labour and the cost involved in testing of one sample is reduced to minimum. The highly specific genomic areas targeted for PCR amplification in the assay are the hly gene for listeriolysin O (LLO) of L. monocytogenes and the stx gene for Shiga-like toxin expressed by E. coli O157:H7. The detection limit of the assay is consistent with the consumer protection limits of 1 pg genomic DNA or 1 CFU 25 g(-1) fish meat (with enrichment) allowing the test to be considered as a substitute to standard plate culture methods. SIGNIFICANCE AND IMPACT OF THE STUDY: The study highlights a novel duplex qPCR for Listeria monocytogenes and Escherichia coli O157:H7 that could be used as an alternative to plate-based ISO or singleplex PCR methods while minimizing the costs. The assay uses rapid DNA extraction methods and locked nucleic acid probes. Sensitivity and specificity are 100 and 98·95% respectively. The potential for quantitative rage of the assay is 10(8) -10(1) CFU ml(-1) .


Assuntos
Toxinas Bacterianas/genética , Escherichia coli O157/isolamento & purificação , Microbiologia de Alimentos/métodos , Proteínas de Choque Térmico/genética , Proteínas Hemolisinas/genética , Listeria monocytogenes/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real/métodos , Toxinas Shiga/genética , Animais , DNA Bacteriano/genética , Escherichia coli O157/genética , Doenças dos Peixes/diagnóstico , Doenças dos Peixes/microbiologia , Pesqueiros , Irlanda , Limite de Detecção , Listeria monocytogenes/genética , Dados de Sequência Molecular , Sensibilidade e Especificidade
11.
J Appl Microbiol ; 118(4): 954-65, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25644656

RESUMO

AIMS: To isolate bacteria from soil for microbial pretreatment of brown crab (Cancer pagurus) shell waste and the production of chitin. METHODS AND RESULTS: Isolates were screened for protease enzymes and acid production in order to facilitate the removal of protein and calcium carbonate fractions from brown crab shell to yield a chitinous material. Selected isolates were applied in various combinations in successive, two-step fermentations with brown crab shell waste. These isolates were identified as: Exiguobacterium spp. (GenBank accession number: KP050496), Bacillus cereus (GenBank accession number: KP050499), B. subtilis (GenBank accession number: KP050498), Bacillus licheniformis (GenBank accession number: KP050497), Pseudomonas migulae (GenBank accession number: KP050501), Pseudomonas spp. (GenBank accession number: KP050500), Pseudomonas spp. (GenBank accession number: KP050502), Arthrobacter luteolus (GenBank accession number: KP050503), Lactobacillus spp. (GenBank accession number: KP072000) and Enterococcus spp. (GenBank accession number: KP071999). CONCLUSIONS: Successive two-step fermentations with isolates in certain combinations resulted in a demineralization of >94% and the extraction of a crude chitin fraction from brown crab processing waste. The highest demineralization, 98·9% was achieved when isolates identified as B. cereus and Pseudomonas spp. were used in combination. The transfer of fermentations to a larger scale requires further research for optimization. SIGNIFICANCE AND IMPACT OF THE STUDY: The successful application of these isolates in successive two-step fermentation of brown crab shell waste to extract chitin means with further research into optimization and scale up, this chitin extraction process may be applied on an industrial scale and provide further commercial value from brown crab shell waste.


Assuntos
Bactérias/enzimologia , Braquiúros/química , Quitina/isolamento & purificação , Resíduos , Animais , Bactérias/química , Bactérias/isolamento & purificação , Quitina/química , Quitina/metabolismo , Fermentação , Dados de Sequência Molecular , Peptídeo Hidrolases/metabolismo
12.
Neurosci Res ; 95: 51-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25615850

RESUMO

Chronic muscular limb pain requires the adoption of motor patterns distinct from the classic ipsilateral flexion, crossed extension and corresponding reciprocal inhibitions to acute exteroceptive stimulation. Using selective chemical activation of group III/IV afferents in gastrocnemius-soleus (GS) muscles we investigated bilaterally their reflex responses conditioned by (a) acute 'myositis' induced by intramuscular carrageenan; and (b) sub-acute 'myositis' induced by infusion of complete Freund's adjuvant (CFA). Reflex transmission was detected by monosynaptic testing and c-fos staining used to identify increased neuronal activity. In all control experiments with chemical stimulation of group III/IV afferents, ipsilateral responses conformed to the flexor reflex pattern. However, the expected contralateral facilitation of GS motoneurones occurred in fewer than 50% trials while only 9% of trials induced contralateral inhibition of flexor posterior-biceps-semitendinosus (PBSt) motoneurones. During carrageenan acute myositis contralateral PBSt was transiently facilitated by selective activation of group III/IV afferents. During CFA-induced myositis, contralateral only inhibition of GS motoneurones occurred instead of any facilitation, while bidirectionally a crossed facilitation of PBST dominated. These reflex changes were mirrored in an enhanced number of neurones with enhanced c-fos expression. Muscle pain, particularly if chronically persistent, requires another behavioural response pattern than acute exteroceptive pain.


Assuntos
Mialgia/fisiopatologia , Miosite/fisiopatologia , Nociceptores/fisiologia , Reflexo Anormal/fisiologia , Reflexo Monosináptico , Medula Espinal/fisiopatologia , Animais , Carragenina/farmacologia , Gatos , Estimulação Elétrica , Adjuvante de Freund/farmacologia , Neurônios Motores/metabolismo , Músculo Esquelético/inervação , Músculo Esquelético/fisiopatologia , Mialgia/induzido quimicamente , Miosite/induzido quimicamente , Proteínas Proto-Oncogênicas c-fos
13.
Mult Scler ; 20(7): 882-8, 2014 06.
Artigo em Inglês | MEDLINE | ID: mdl-24192218

RESUMO

Longitudinally extensive transverse myelitis is characteristic but not pathognomonic for neuromyelitis optica spectrum disorders (NMOSDs) and may mimic local tumors. In this retrospective study based on a cohort of 175 NMOSD patients we identified seven patients who initially presented with a longitudinally extensive spinal cord lesion and underwent spinal cord biopsy due to magnetic resonance imaging (MRI)-suspected malignancies. Remarkably, routine neuropathology was inconclusive and did not guide the diagnostic process to anti-aquaporin-4 (AQP4)-seropositive NMOSD. Serious postoperative complications occurred in 5/7 patients and persisted during follow-up in 2/7 patients (29%). Considering these sequelae, AQP4-antibody testing should be mandatory in patients with inconclusive longitudinally extensive spinal cord lesions prior to biopsy.


Assuntos
Aquaporina 4/imunologia , Autoanticorpos/sangue , Neuromielite Óptica/diagnóstico , Medula Espinal/patologia , Adulto , Biomarcadores/sangue , Biópsia , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Neuromielite Óptica/imunologia , Neuromielite Óptica/patologia , Neuromielite Óptica/terapia , Valor Preditivo dos Testes , Estudos Retrospectivos , Testes Sorológicos , Fatores de Tempo , Adulto Jovem
14.
Neurodegener Dis ; 13(1): 38-44, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24021982

RESUMO

BACKGROUND: Primary angiitis of the central nervous system (PACNS) is a rare but serious condition. A fraction of patients suffering from PACNS concurrently exhibit pronounced cerebral amyloid angiopathy (CAA) which is characterized by deposits of amyloid-ß (Aß) in and around the walls of small and medium-sized arteries of the brain. PACNS with CAA has been identified as a distinct disease entity, termed Aß-related angiitis (ABRA). Evidence points to an immune reaction to vessel wall Aß as the trigger of vasculitis. OBJECTIVE: To investigate whether the inflammatory response to Aß has (1) any effect on the status of immune activation in the brain parenchyma and (2) leads to clearance of Aß from brain parenchyma. METHODS: We studied immune activation and Aß load by quantitative immunohistochemical analysis in brain parenchyma adjacent to affected vessels in 11 ABRA patients and 10 matched CAA controls. RESULTS: ABRA patients showed significantly increased immune activation and decreased Aß loads in the brain parenchyma adjacent to affected vessels. CONCLUSION: Our results are in line with the hypothesis of ABRA being the result of an excessive immune response to Aß and show that this can lead to enhanced clearance of Aß from the brain parenchyma by immune-mediated mechanisms.


Assuntos
Peptídeos beta-Amiloides/imunologia , Encéfalo/imunologia , Encéfalo/patologia , Vasculite do Sistema Nervoso Central/imunologia , Vasculite do Sistema Nervoso Central/patologia , Idoso , Peptídeos beta-Amiloides/análise , Estudos de Casos e Controles , Angiopatia Amiloide Cerebral/imunologia , Angiopatia Amiloide Cerebral/patologia , Feminino , Humanos , Imuno-Histoquímica , Ativação de Macrófagos , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Placa Amiloide/imunologia , Placa Amiloide/patologia
15.
Br J Neurosurg ; 27(6): 772-8, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23662801

RESUMO

The prognostic role of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastoma patients treated with carmustine (BCNU) wafer implantation is unclear. Here, we report on a retrospective study of 47 patients with either newly diagnosed (30 patients) or recurrent (17 patients) glioblastoma (WHO grade IV) treated with BCNU (bis-chloroethylnitrosourea) wafers. Thirteen of the newly diagnosed patients received local BCNU and irradiation only (first-line BCNU), while 17 patients additionally received concomitant and adjuvant temozolomide (TMZ) radiochemotherapy (first-line BCNU + TMZ). Of the 17 patients treated for recurrent glioblastoma (second-line BCNU), 16 had received radiotherapy with concomitant and adjuvant TMZ as an initial treatment. Median overall survival (OS) did not significantly differ between 19 patients with MGMT promoter methylated tumors when compared to 28 patients with unmethylated tumors (18.9 vs 15.0 months; p = 0.1054). In the first-line BCNU + TMZ group, MGMT promoter methylation was associated with longer OS (21.0 vs 11.1 months, p = 0.0127), while no significant survival differences were detected in the other two subgroups. Progression-free survival did not significantly differ between patients with and without MGMT promoter methylated tumors in the entire patient cohort or any of the three subgroups. The first-line BCNU + TMZ group showed no significant difference in OS when compared to the first-line BCNU group (18.9 vs 14.7 months), but tended to have more therapy-related adverse effects (53% vs 24%, p = 0.105). In summary, MGMT promoter methylation showed a non-significant trend toward longer survival in our patient cohort. The combination of TMZ radiochemotherapy with local delivery of BCNU did not provide a significant survival benefit compared to local BCNU alone, but was associated with a higher rate of adverse effects. Owing to the small number of patients investigated, however, these findings would need to be corroborated in larger patient cohorts.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Carmustina/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , O(6)-Metilguanina-DNA Metiltransferase/genética , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Quimiorradioterapia/métodos , Terapia Combinada , Metilação de DNA , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas/genética , Estudos Retrospectivos , Análise de Sobrevida , Temozolomida
16.
Pathologe ; 34(3): 186-97, 2013 May.
Artigo em Alemão | MEDLINE | ID: mdl-23471726

RESUMO

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 Jovem
17.
Acta Neurochir (Wien) ; 155(3): 429-35, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23254891

RESUMO

BACKGROUND: To compare survival and hematological toxicity rates between two postoperative therapy regimens in patients with primary glioblastoma (GBM), namely temozolomide (TMZ) concomitant to radiation, followed by adjuvant TMZ, versus adjuvant TMZ after radiation only. PATIENTS AND METHODS: A total of 191 patients with primary GBM were postoperatively treated with either radiation and concomitant TMZ, followed by adjuvant TMZ (Stupp protocol) (n = 154), or radiation followed by adjuvant TMZ (n = 37). The incidence of hematological adverse effects (AE) was recorded for all patients. From both treatment groups, 26 patients were matched according to age, Karnofsky performance scale (KPS) score, and O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation. RESULTS: Hematological AEs were mild in both unmatched groups, but were significantly more frequent in the concomitant plus adjuvant TMZ group (p < 0.001). Matched-pair analysis confirmed significantly more frequent hematological AEs in the concomitant and adjuvant group compared to the sequential (adjuvant) TMZ group (p = 0,012). Patients treated with concomitant plus adjuvant TMZ showed significantly longer progression-free survival (PFS) (10.6 versus 6.6 months; p = 0.014), but no prolonged overall survival (OS) (16.9 vs. 15.6 months; p = 0.717) compared to patients who received the sequential treatment regimen. CONCLUSION: In this retrospective study, the OS in patients with primary GBM treated with sequential TMZ following radiation appeared to be similar to that in patients treated with concomitant plus adjuvant TMZ. Given the significantly higher risk of hematological AE for concomitant treatment, the role of concomitant plus adjuvant TMZ use compared to sequential administration of TMZ, especially for patients with MGMT-unmethylated tumors, should be further evaluated.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/toxicidade , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Quimiorradioterapia Adjuvante , Quimiorradioterapia , Dacarbazina/análogos & derivados , Glioblastoma/mortalidade , Glioblastoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Dacarbazina/administração & dosagem , Dacarbazina/toxicidade , Feminino , Humanos , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Temozolomida
18.
Neurology ; 78(7): 458-67; discussion 465, 2012 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-22302546

RESUMO

OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) has become much more common with monoclonal antibody treatment for multiple sclerosis and other immune-mediated disorders. METHODS: We report 2 patients with severe psoriasis and fatal PML treated for ≥3 years with efalizumab, a neutralizing antibody to αLß2-leukointegrin (LFA-1). In one patient, we conducted serial studies of peripheral blood and CSF including analyses of leukocyte phenotypes, migration ex vivo, and CDR3 spectratypes with controls coming from HIV-infected patients with PML. Extensive pathologic and histologic analysis was done on autopsy CNS tissue of both patients. RESULTS: Both patients developed progressive cognitive and motor deficits, and JC virus was identified in CSF. Despite treatment including plasma exchange (PE) and signs of immune reconstitution, both died of PML 2 and 6 months after disease onset. Neuropathologic examination confirmed PML. Efalizumab treatment was associated with reduced transendothelial migration by peripheral T cells in vitro. As expression levels of LFA-1 on peripheral T cells gradually rose after PE, in vitro migration increased. Peripheral and CSF T-cell spectratyping showed CD8+ T-cell clonal expansion but blunted activation, which was restored after PE. CONCLUSIONS: From these data we propose that inhibition of peripheral and intrathecal T-cell activation and suppression of CNS effector-phase migration both characterize efalizumab-associated PML. LFA-1 may be a crucial factor in homeostatic JC virus control.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Vírus JC/fisiologia , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Antígeno-1 Associado à Função Linfocitária/fisiologia , Idoso , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Encéfalo/patologia , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD8-Positivos/fisiologia , Movimento Celular , Evolução Fatal , Humanos , Síndrome Inflamatória da Reconstituição Imune/induzido quimicamente , Síndrome Inflamatória da Reconstituição Imune/complicações , Síndrome Inflamatória da Reconstituição Imune/psicologia , Imuno-Histoquímica , Leucoencefalopatia Multifocal Progressiva/virologia , Imageamento por Ressonância Magnética , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos Mentais/induzido quimicamente , Transtornos Mentais/psicologia , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/psicologia , Paresia/induzido quimicamente , Transtornos da Percepção/induzido quimicamente , Troca Plasmática , Psoríase/complicações , Psoríase/tratamento farmacológico
19.
Leukemia ; 25(12): 1797-807, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21818113

RESUMO

Recent studies addressing the molecular characteristics of PCNSL, which is defined as malignant B-cell lymphoma with morphological features of DLBCL, have significantly improved our understanding of the pathogenesis of this lymphoma entity, which is associated with an inferior prognosis as compared with DLBCL outside the CNS. This unfavorable prognosis stimulated intense efforts to improve therapy and induced recent series of clinical studies, which addressed the role of radiotherapy and various chemotherapeutic regimens. This review combines the discussion of diagnosis, differential diagnosis and recent progress in studies addressing the molecular pathogenesis as well as therapeutic options in PCNSL.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/terapia , Humanos
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