RESUMO
INTRODUCTION: Inflammation is a key aspect of glioblastoma multiforme (GBM) although it remains unclear how it contributes to GBM pathogenesis. Inflammasomes are intracellular multi-protein complexes that are involved in innate immunity and are activated by cellular stress, principally in macrophages. This study examined the expression of inflammasome-associated genes in GBM, particularly absent in melanoma 2 (AIM2). METHODS: Tissue samples from surgically-resected GBM tumors (n = 10) were compared to resected brain specimens from patients with epilepsy (age- and sex-matched Other Disease Controls (ODC, n=5)) by qRT-PCR, western blotting and immunofluorescence. Gene expression studies in human astrocytoma U251 cells were performed and the effects of deleting the absent in melanoma 2 (AIM2) gene using the CRISPR-Cas9 system were analyzed. RESULTS: GBM tissues showed significantly elevated expression of multiple immune (CD3E, CD163, CD68, MX1, ARG1) and inflammasome (AIM2, NLRP1, IL18, CASP1, and IL-33) genes compared to ODC tissues, without induction of IL1B, IFNG or TNFA. An insert-containing AIM2 variant transcript was highly expressed in GBM tissues and in U251 cells. AIM2 immunoreactivity was concentrated in the tumor core in the absence of PCNA immunodetection and showed a predominant 52 kDa immunoreactive band on western blot. Deletion of AIM2 resulted in significantly enhanced proliferation of U251 cells, which also displayed increased resistance to temozolomide treatment. CONCLUSIONS: GBM tumors express a distinct profile of inflammasome-associated genes in a tumor-specific manner. AIM2 expression in tumor cells suppressed cell proliferation while also conferring increased susceptibility to contemporary GBM therapy.
Assuntos
Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Glioblastoma/patologia , Inflamassomos/metabolismo , Inflamação/patologia , Biomarcadores Tumorais , Estudos de Casos e Controles , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Inflamassomos/genética , Inflamação/genética , Inflamação/metabolismo , RNA Interferente Pequeno/genética , Células Tumorais CultivadasRESUMO
We report that 5 of 19 human malignant glioma cell lines have neither interferon alpha (IFNA) nor interferon beta (IFNB) genes that are detectable by Southern blotting. Of 5 other of these malignant glioma lines that have a single IFNB gene copy, 3 lack the IFNA genes entirely and two have one copy. One of the lines that lacks the IFNA genes entirely but has one copy of the IFNB gene has a rearrangement near the IFNB gene that is most easily interpreted as an insertion of a large segment of DNA (at least 50 kilobases) the 3' end of which is less than 1.3 kilobases 5' to the known regulatory sequences of the IFNB gene. In spite of the rearrangement, IFNB-specific RNA is highly inducible in this line by poly(I)-poly(C). The ability of interferon alpha or interferon beta to inhibit cell growth does not depend upon the presence or absence of the respective gene. This finding adds solid tumors to those tumor cell lines (acute lymphocytic leukemia, chronic myelogeneous leukemia) previously determined to lack the IFNA and IFNB genes (Diaz et al., Proc. Natl. Acad. Sci. USA, 85:5259-5263, 1988).
Assuntos
Deleção Cromossômica , Glioma/genética , Interferon Tipo I/genética , Mapeamento Cromossômico , DNA/análise , Rearranjo Gênico , Genes Reguladores , Glioma/patologia , Humanos , Interferon Tipo I/farmacologia , RNA Mensageiro/análise , Células Tumorais CultivadasRESUMO
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially triggers apoptosis in tumor cells versus normal cells, thus providing a therapeutic potential. In this study, we examined a large panel of human malignant glioma cell lines and primary cultures of normal human astrocytes for their sensitivity to TRAIL. Of 13 glioma cell lines, 3 were sensitive (80-100% death), 4 were partially resistant (30-79% death), and 6 were resistant (< 30% death). Normal astrocytes were also resistant. TRAIL-induced cell death was characterized by activation of caspase-8 and -3, poly(ADP-ribose) polymerase cleavage, and DNA fragmentation. Decoy receptor (DcR1 and DcR2) expression was limited in the glioma cell lines and did not correlate with TRAIL sensitivity. Both sensitive and resistant cell lines expressed TRAIL death receptor (DR5), adapter protein Fas-associated death domain (FADD), and caspase-8; but resistant cell lines expressed 2-fold higher levels of the apoptosis inhibitor phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes-15 kDa (PED/PEA-15). In contrast, cellular FADD-like IL-1beta-converting enzyme-like inhibitory protein (cFLIP) expression was similar in sensitive and resistant cells. Transfection of sense PED/PEA-15 cDNA in sensitive cells resulted in cell resistance, whereas transfection of antisense in resistant cells rendered them sensitive. Inhibition of protein kinase C (PKC) activity restored TRAIL sensitivity in resistant cells, suggesting that PED/ PEA-15 function might be dependent on PKC-mediated phosphorylation. In summary, TRAIL induces apoptosis in > 50% of glioma cell lines, and this killing occurs through activation of the DR pathway. This caspase-8-induced apoptotic cascade is regulated by intracellular PED/PEA-15, but not by cFLIP or decoy receptors. This pathway may be exploitable for glioma and possibly for other cancer therapies.
Assuntos
Apoptose/efeitos dos fármacos , Glioma/patologia , Peptídeos e Proteínas de Sinalização Intracelular , Glicoproteínas de Membrana/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD , Proteínas de Transporte/biossíntese , Caspase 8 , Caspase 9 , Caspases/metabolismo , Caspases/fisiologia , Células Cultivadas , Ativação Enzimática , Proteínas Ligadas por GPI , Glioma/genética , Glioma/metabolismo , Humanos , Glicoproteínas de Membrana/fisiologia , Oligodesoxirribonucleotídeos Antissenso/genética , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Fosfoproteínas/genética , Inibidores da Síntese de Proteínas/farmacologia , Receptores do Fator de Necrose Tumoral/biossíntese , Membro 10c de Receptores do Fator de Necrose Tumoral , Proteínas Recombinantes/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF , Transfecção , Células Tumorais Cultivadas , Receptores Chamariz do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
A large-animal model was developed to facilitate the noninvasive investigation of the effect on the human glioma-derived D-54 MG (glioblastoma multiforme) continuous cell line of a variety of therapeutic regimens. Twenty random-bred male cats were inoculated intracerebrally with 1 x 10(7) D-54 MG tumor cells after being initiated on one of three preparatory regimens of cyclosporin A p.o. Reproducible success of D-54 MG xenotransplantation (100%, 6 of 6 cats) was achieved only after pretreatment with 120 mg cyclosporin A p.o. (24-30 mg/kg) daily for greater than or equal to 10 days prior to tumor implantation. High-performance liquid chromatography-derived whole blood cyclosporin A 12-h trough levels of greater than or equal to 640 ng/ml were seen in successful implants. Lesions ranging from 2 to 20 mm in diameter were seen in cats sacrificed 27-44 days after implantation with no growth seen in control animals. Histopathological examination revealed the tumors to be well-circumscribed anaplastic intracerebral tumors with some invasion into surrounding host parenchyma. Perivascular lymphocytic cuffing was observed, but intratumoral lymphocytic infiltration was minimal. Gadolinium-EDTA-enhanced nuclear magnetic resonance imaging provided accurate tumor localization in T1-weighted images (TE 26 ms; TR 600 ms). Biochemical tests of kidney, liver, and hematological function were within normal limits, although 10% (2 of 20) of the animals developed gingival hyperplasia, and 5% (1 of 20) developed intussusception. The reproducible growth of the D-54 MG human glioblastoma cell line in a large-animal model eliminates many of the limitations associated with the standard nude mouse/rat model, thereby providing a novel test bed for a variety of imaging modalities as well as for drug immunoconjugate localization and toxicity studies.
Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Rabdomiossarcoma/patologia , Animais , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Gatos , Ciclosporinas , Modelos Animais de Doenças , Glioma/diagnóstico , Glioma/genética , Humanos , Tolerância Imunológica , Cariotipagem , Imageamento por Ressonância Magnética , Masculino , Transplante de Neoplasias , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/genética , Células Tumorais Cultivadas/patologiaRESUMO
PURPOSE: To prospectively compare standard radiation therapy (RT) with an abbreviated course of RT in older patients with glioblastoma multiforme (GBM). PATIENTS AND METHODS: One hundred patients with GBM, age 60 years or older, were randomly assigned after surgery to receive either standard RT (60 Gy in 30 fractions over 6 weeks) or a shorter course of RT (40 Gy in 15 fractions over 3 weeks). The primary end point was overall survival. The secondary end points were proportionate survival at 6 months, health-related quality of life (HRQoL), and corticosteroid requirement. HRQoL was assessed using the Karnofsky performance status (KPS) and Functional Assessment of Cancer Therapy-Brain (FACT-Br). RESULTS: All patients had died at the time of analysis. Overall survival times measured from randomization were similar at 5.1 months for standard RT versus 5.6 months for the shorter course (log-rank test, P =.57). The survival probabilities at 6 months were also similar at 44.7% for standard RT versus 41.7% for the shorter course (lower-bound 95% CI, -13.7). KPS scores varied markedly but were not significantly different between the two groups (Wilcoxon test, P =.63). Low completion rates of the FACT-Br (45%) precluded meaningful comparisons between the two groups. Of patients completing RT as planned, 49% of patients (standard RT) versus 23% required an increase in posttreatment corticosteroid dosage (chi(2) test, P =.02). CONCLUSION: There is no difference in survival between patients receiving standard RT or short-course RT. In view of the similar KPS scores, decreased increment in corticosteroid requirement, and reduced treatment time, the abbreviated course of RT seems to be a reasonable treatment option for older patients with GBM.
Assuntos
Neoplasias Encefálicas/radioterapia , Glioblastoma/radioterapia , Corticosteroides/uso terapêutico , Fatores Etários , Idoso , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Fracionamento da Dose de Radiação , Feminino , Glioblastoma/patologia , Glioblastoma/cirurgia , Humanos , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Radioterapia Adjuvante , Análise de Sobrevida , Resultado do TratamentoRESUMO
Glioblastoma multiforme is the most common primary central nervous system neoplasm. Its dismal prognosis has led to investigation of new treatment strategies such as immunogene therapy. We transduced the human glioblastoma cell line D54MG in vitro with genes encoding the proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), the T cell co-stimulatory molecule B7-2, or both (in a bicistronic vector) via retroviral vectors. Therapeutic gene expression by D54MG was high after transduction and selection (30 ng/10(6) cells/day for GM-CSF and > 2 orders of magnitude fluorescence shift on flow cytometry for B7-2). The effect of GM-CSF and/or B7-2 transduction on D54MG tumor growth in vivo was monitored in a novel allogeneic human peripheral blood lymphocyte-severe combined immunodeficiency mouse (Hu-PBL-SCID) model. GM-CSF- or B7-2-transduced tumors showed growth suppression in hu-PBL-reconstituted mice compared to untransduced and/or unreconstituted controls. Growth suppression was greatest for B7-2. Furthermore, vaccination with irradiated GM-CSF/B7-2-transduced tumor cells markedly inhibited growth of wild-type tumors at distant sites. Thus, this study illustrates a potential gene therapy strategy for glioblastoma multiforme patients using GM-CSF and/or B7-2 transduced tumor vaccines. Although extension of these allogeneic studies to an autologous system is critical, this is the first demonstration of in vivo efficacy of combination GM-CSF and B7-2 immunogene therapy for human glioblastoma multiforme.
Assuntos
Antígenos CD/genética , Terapia Genética/métodos , Glioblastoma/imunologia , Glioblastoma/terapia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Glicoproteínas de Membrana/genética , Animais , Antígenos CD/metabolismo , Antígeno B7-2 , Divisão Celular/fisiologia , Modelos Animais de Doenças , Feminino , Vetores Genéticos/genética , Glioblastoma/patologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Linfócitos/imunologia , Linfócitos/efeitos da radiação , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos SCID , Retroviridae/genética , Transdução Genética , Células Tumorais Cultivadas , VacinaçãoRESUMO
We studied 6 parkinsonian patients 6 weeks after unilateral adrenal-to-caudate implants. We withheld medications the night before each of 2 study days and gave the patients a single test dose of either a combination of levodopa and carbidopa, or levodopa alone in double-blind random order. We administered the modified Columbia scale, objective measurements of rigidity and movement velocity, and the pegboard test at regular intervals after the single test dose. The results revealed that the improvements in performance recorded by the Columbia scale and the pegboard test were significantly less on the side contralateral to the operation when patients received carbidopa, whereas there was no significant difference in performance between the 2 observations on the ipsilateral side. Carbidopa apparently crossed the disrupted blood-brain barrier and lowered the efficacy of levodopa.
Assuntos
Medula Suprarrenal/transplante , Carbidopa/administração & dosagem , Corpo Estriado/cirurgia , Levodopa/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Medula Suprarrenal/citologia , Adulto , Corpo Estriado/efeitos dos fármacos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/cirurgia , Desempenho Psicomotor/efeitos dos fármacos , Distribuição AleatóriaRESUMO
Treatment of refractory PD with autologous adrenal medullary implants utilizing two-stage surgery warrants further investigation. This transplantation technique is associated with prolonged transplant area BBB disruption which may require a change in medical treatment strategies including the withdrawal of peripheral dopa decarboxylase inhibitors and possible intravenous or intraventricular dopamine therapy. Of 5 patients receiving adrenal medullary transplants, 3 have demonstrated varying degrees of clinical improvement which has persisted for the duration of the study. The positive correlation between clinical outcome and caudate function (i.e., 6-fluorodopa PET scans) suggests a positive influence of the transplantation procedure on the diseased striatum. Whether or not the grafted tissue remains viable for an extended period is currently being investigated utilizing 6-FDG-PET studies. Because of the presence of persistent BBB disruption, we surmise that at least viability of implanted fenestrated adrenal medullary capillaries exists. We conclude that this prolonged leakage is the result of the implanted tissue rather than the cavitation procedure as prolonged BBB disruption was not witnessed in a control group of patients with post-traumatic cerebral contusions or in Parkinson's patients subjected to thalamotomies. Whether two-stage surgery results in increased graft viability, and host neuronal sprouting, leading to prolonged clinical improvement and slowing the progression of PD awaits continued longitudinal (greater than 24 months) studies.
Assuntos
Medula Suprarrenal/transplante , Núcleo Caudado , Doença de Parkinson/cirurgia , Transplante Heterotópico/métodos , Barreira Hematoencefálica , Núcleo Caudado/patologia , Núcleo Caudado/cirurgia , Di-Hidroxifenilalanina/análogos & derivados , Seguimentos , Humanos , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Tomografia Computadorizada de Emissão , Transplante Autólogo/métodos , Transplante Heterotópico/efeitos adversos , Transplante Heterotópico/patologiaRESUMO
Of 736 patients with intracranial aneurysms seen at the University of Alberta from 1968 to 1985, 437 were admitted on the day of or the day after subarachnoid hemorrhage (SAH) from a supratentorial aneurysm. Of these, 205 were managed from 1968 through 1977 and 232 were managed from 1978 through early 1985 after a policy of early aneurysm operation had been implemented. Postoperative and management mortality and morbidity rates were related to the grade of the patient at the time of admission and the time interval before operation. Overall management mortality (and postoperative mortality) rates for patients treated before 1978 were 47% (19%) for all grades, 17% (12%) for Grades 1 and 2, 51% (25%) for Grades 3 and 4, and 100% (100%) for Grade 5. Since 1978, mortality has been reduced to 38% (11%) for all grades, 10% (5%) for Grades 1 and 2, 39% (17%) for Grades 3 and 4, and 96% (60%) for Grade 5. Management mortality for patients operated on Day 0 to 3 was lower than for those operated later after SAH both before and after 1978. Postoperative mortality was lowered in all patients operated from 1978 to 1985 regardless of the interval from SAH to operation, and management mortality was reduced overall, as well as for patients operated on day 0 to 3, in those treated from 1978 to 1985. The authors conclude that a policy of early aneurysm operation has contributed to a reduction of both postoperative and management mortality.
Assuntos
Aneurisma Intracraniano/cirurgia , Hemorragia Subaracnóidea/cirurgia , Adulto , Humanos , Aneurisma Intracraniano/mortalidade , Pessoa de Meia-Idade , Cuidados Pós-Operatórios , Complicações Pós-Operatórias/mortalidade , Hemorragia Subaracnóidea/mortalidade , Fatores de TempoRESUMO
OBJECTIVE: Despite advances in conventional therapy, the prognosis for most glioma patients remains dismal. This has prompted an intensive search for effective treatment alternatives. Immunotherapy, one such alternative, has long been recognized as a potentially potent cancer treatment but has been limited by an inadequate understanding of the immune system. Now, increased insight into immunology is suggesting more rational approaches to immunotherapy. In this article, we explore key aspects of modern immunology and discuss their implications for glioma therapy. METHODS: A thorough literature review of glioma immunology and immunotherapy was undertaken to inquire into the basic immunology, central nervous system immunology, glioma immunobiology, standard glioma immunotherapy, and recent immunotherapeutic advances in glioma treatment. RESULTS: Although gliomas express tumor-associated antigens and appear potentially sensitive to immune responses, many factors work together to inhibit antiglioma immunity. Not surprisingly, most clinical attempts at glioma immunotherapy have met with little success to date. However, novel immunostimulatory strategies, such as immunogene therapy, directed cytokine delivery, and dendritic cell manipulation, have recently yielded dramatic preclinical results in glioma models. This suggests that glioma-derived immunosuppression can be overcome. CONCLUSION: Modern molecular biology and immunology techniques have yielded a wealth of new data about glioma immunobiology. Armed with this information, many investigators have proposed novel means to stimulate antiglioma immune responses. Although definitive clinical results remain to be seen, the current renaissance in glioma immunology and immunotherapy shows great promise for the future.
Assuntos
Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/terapia , Glioma/imunologia , Glioma/terapia , Imunoterapia , Vacinas Anticâncer/uso terapêutico , Humanos , Imunoterapia/métodos , Imunoterapia/tendênciasRESUMO
A 17-year-old girl suffered a traumatic acute subdural hematoma and rib fractures after a motor vehicle accident. Prolonged coma resulted, and significant galactorrhea began 4 weeks after the accident. The galactorrhea was treated successfully by the administration of 2-bromoergocryptine. The pathophysiology of this condition is discussed.
Assuntos
Lesões Encefálicas/complicações , Coma/complicações , Galactorreia/etiologia , Transtornos da Lactação/etiologia , Adolescente , Bromocriptina/uso terapêutico , Feminino , Galactorreia/tratamento farmacológico , Hematoma Subdural/complicações , Humanos , GravidezRESUMO
The first use of skull tongs for cervical spine traction is credited primarily to W.G. Crutchfield. In 1933, Crutchfield described his application of extension tongs to the calvaria of a 23-year-old woman with a traumatic C2-C3 fracture. Less recognized are the contributions of Howard H. Hepburn, who designed skull tongs for cervical spine traction at the University of Alberta several years before Crutchfield's first case. Hepburn was the first neurosurgeon at the University of Alberta in Edmonton. On the basis of his experience treating wounded soldiers in World War I, he developed the hypothesis that traction would promote healing in cervical spine injuries. Hepburn designed skull extension tongs that were modeled on common ice tongs, and he used an automobile inner tube as an elastic to keep the tongs firmly applied to the patient's head. These tongs were first used in the mid-1920s, and by 1930 they were applied routinely. Crutchfield's 1933 report refers to the application of "Edmonton extension tongs." This suggests that he was at least indirectly aware of Hepburn's work, although how this information reached him is not entirely clear. Hepburn attended a meeting of the British Medical Society in 1930, and he is thought to have discussed his tongs during the conference. Hepburn's work has received some attention previously; his original tongs were included in a 1973 Smithsonian Institute exhibit on cervical spine traction as an example of an early cranial traction device. However, his contributions are underappreciated in the neurosurgical community and deserve wider recognition.
Assuntos
Vértebras Cervicais , Neurocirurgia/história , Crânio , Tração/história , Canadá , Desenho de Equipamento , História do Século XX , Humanos , Tração/instrumentaçãoRESUMO
Neuropsychological testing of 48 patients who had undergone operation for subarachnoid hemorrhage (SAH) due to aneurysm was performed. Before this, the patients had their level of neurological recovery classified by neurosurgeons (37 good outcome vs. 9 poor outcome). These clinical categories correlated well with the results of neuropsychological testing. The degree of psychological impairment was related to age. The mean duration between SAH and clipping of the ruptured aneurysm was 4.6 days (range, 1-16 days), and 59% had operations on or before Day 3 post-SAH. Of the 37 patients with good neurological outcome, 26 patients had good neuropsychological outcome (no more than mild deficit). Poor neuropsychological outcome was associated with age and anterior communicating artery aneurysms. The incidence of significant neuropsychological deficit was considerably less than in previous reports, and possible explanations are discussed.
Assuntos
Dano Encefálico Crônico/psicologia , Transtornos Neurocognitivos/psicologia , Testes Neuropsicológicos , Hemorragia Subaracnóidea/psicologia , Feminino , Seguimentos , Humanos , Aneurisma Intracraniano/psicologia , Aneurisma Intracraniano/cirurgia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/psicologia , Ruptura Espontânea , Hemorragia Subaracnóidea/cirurgiaRESUMO
OBJECTIVE: The absorption of cerebrospinal fluid occurs primarily by means of arachnoid granulations (AG) in the superior sagittal sinus (SSS) and the lacunae laterales (LL) in the parasagittal dura. Previous descriptions of this region suggest a network of intradural channels, but finer details of extent and relationship between channels and AG were not addressed. Therefore, we undertook an anatomic study of cadaveric parasagittal dura. METHODS: The SSS and parasagittal dura of 20 formalin-fixed adult cadavers and 15 autopsy specimens from patients ranging in age from 18 weeks of gestation to 80 years were studied by use of a light microscope, a scanning electron microscope, and corrosion casting. Intradural injections into the parasagittal region were performed in two formalin-fixed and four autopsy specimens from adults by use of normal saline and corrosion casting. RESULTS: Extensive networks of intradural channels from 0.02 to 2.0 mm in diameter were noted in all of the specimens. Channels either were connected to the SSS at intervals along the side wall or drained directly into the LL, which extended up to 3 cm from midline. Channels lined with endothelium stained positive for Factor VIII, as did the endothelium of the LL and SSS. In some places, the network of channels seemed to coalesce to form LL. The underside of the dura was coarse and trabeculated where the channels were abundant, and AG were interdigitated between these trabeculae. In regions of the dura where channels were sparse or absent, the dural underside was smooth and lacked AG. Underlying cortical veins opened directly into the SSS and were unrelated to intradural channels. Intradural parasagittal injections from the epidural side accessed the SSS by way of channels using pressures between 0 and 20 cm H2O at 1.5 ml/min. CONCLUSION: These channels may represent a pathway for the flow of cerebrospinal fluid from AG to the SSS.
Assuntos
Líquido Cefalorraquidiano/fisiologia , Cavidades Cranianas/anatomia & histologia , Dura-Máter/anatomia & histologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aracnoide-Máter/anatomia & histologia , Criança , Pré-Escolar , Molde por Corrosão , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Microscopia Eletrônica de Varredura , Pessoa de Meia-Idade , Gravidez , Valores de ReferênciaRESUMO
OBJECTIVE: Human gliomas are known to be immunosuppressive. Recent reports have suggested novel strategies to overcome this immunosuppression, including immunogene therapy. We examined expression of 10 immunologically important molecules by human gliomas in vitro, and we discuss the implications for immunogene therapy. METHODS: Early passage human glioma cultures and established human glioma cell lines were analyzed by flow cytometry for expression of Class I and II major histocompatibility complex (MHC), B7-2 (CD86), and Fas (CD95). Culture supernatants were assayed by enzyme-linked immunosorbent assay for interleukin (IL)-6, IL-10, IL-12, transforming growth factor beta2, prostaglandin E2, and granulocyte-macrophage colony-stimulating factor levels. RESULTS: All cultures (16 of 16 samples) expressed Class I MHC and Fas, but few expressed Class II MHC (1 of 16 samples) or B7-2 (0 of 16 samples). Nearly all expressed high levels of IL-6 (19 of 21 samples; mean, 36.5 +/- 10.8 ng/10(6) cells/d) and prostaglandin E2 (21 of 21 samples; mean, 15.6 +/- 4.5 ng/10(6) cells/d) levels, and many expressed transforming growth factor beta2 (13 of 21 samples; mean, 8.6 +/- 3.7 ng/10(6) cells/d). Although several cultures (6 of 14 samples) expressed granulocyte-macrophage colony-stimulating factor, expression levels were very low (mean, 0.2 +/- 0.1 ng/10(6) cells/d). Few cultures (4 of 21 samples) expressed measurable IL-10, and none (0 of 22 samples) expressed IL-12. CONCLUSION: Class I MHC and Fas expression suggests that human glioma cells may be susceptible to Class I MHC-dependent cytotoxic T cell recognition and Fas-mediated killing. Unfortunately, transforming growth factor beta2 and prostaglandin E2 probably impair T cell activation, and IL-6 may shift immunity to less effective humoral (T helper 2) responses. Proinflammatory gene expression (B7-2, granulocyte-macrophage colony-stimulating factor, and/or IL-12) is lacking. Together, these results suggest that modifying glioma cells via proinflammatory gene transfer or immunoinhibitory gene suppression might stimulate immune responses that are effective against unmodified tumors.
Assuntos
Neoplasias Encefálicas/imunologia , Genes MHC da Classe II/genética , Terapia Genética , Glioma/imunologia , Adulto , Idoso , Antígenos CD/genética , Antígeno B7-2 , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/fisiologia , Técnicas de Transferência de Genes , Genes MHC Classe I/genética , Glioma/genética , Glioma/terapia , Humanos , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Técnicas In Vitro , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Células Tumorais Cultivadas , Receptor fas/genéticaRESUMO
OBJECTIVE: Computed tomographic angiography (CTA) is a rapid and minimally invasive method of detecting intracranial aneurysms. We wished to determine whether CTA could replace digital subtraction angiography (DSA) in the diagnosis and operative planning of ruptured cerebral aneurysms. METHODS: In a prospective study, patients with subarachnoid hemorrhage diagnosed by plain computed tomography underwent CTA, DSA, or both. Computed tomographic scans and CTA studies were first reviewed by the treating surgeon, along with a neuroradiologist, and a decision to proceed to DSA or directly to surgery was made on the basis of the type and quality of information provided by CTA. All patients underwent postoperative DSA. RESULTS: A total of 173 patients were studied. In 24 patients, both CTA and DSA were negative for a source of subarachnoid hemorrhage. Twelve patients underwent DSA without prior CTA because a technologist capable of performing CTA was not available when the patient was evaluated. Nine patients in poor neurological condition underwent CTA, and all tested positive for aneurysms but died without surgical intervention. Of the 126 patients who underwent CTA and surgery, 65 (52%) also required preoperative DSA. The decision to proceed to DSA after CTA was influenced by aneurysm location; posterior communicating artery (62%) and posterior circulation locations (67-75%) more commonly proceeded to DSA than middle cerebral artery aneurysms (34%; 0.025 > P > 0.01). The sensitivity and specificity of CTA for the detection of all aneurysms, ruptured and unruptured, in the group of patients who underwent both types of angiograms preoperatively were 84 and 100%, respectively. In the group of 61 patients in whom aneurysm surgery was performed on the basis of CTA results alone, the sensitivity and specificity for the detection of all aneurysms, as compared with postoperative DSA, were 90 and 100%, respectively. Missed aneurysms (n = 24) were always small (<4 mm) and were usually found in patients with multiple aneurysms in whom the larger, ruptured aneurysm was identified by CTA. In one patient, the aneurysm missed by preoperative CTA would have resulted in a different operation if detected preoperatively. CONCLUSION: It is possible to proceed to ruptured aneurysm repair entirely on the basis of good-quality CTA studies that demonstrate an aneurysm consistent with the pattern of bleeding observed on plain computed tomography (48% of the patients in this series and most common middle cerebral artery aneurysms). However, detection of small unruptured aneurysms in patients with multiple lesions remains a problem.
Assuntos
Aneurisma Roto/diagnóstico por imagem , Angiografia Digital , Angiografia Cerebral , Aneurisma Intracraniano/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneurisma Roto/cirurgia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Aneurisma Intracraniano/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Hemorragia Subaracnóidea/diagnóstico por imagem , Hemorragia Subaracnóidea/cirurgiaRESUMO
A multicenter, randomized placebo-controlled double-blind trial of nimodipine in poor-grade aneurysm patients was carried out in 17 Canadian hospitals. Of 188 patients enrolled in the trial, 32 were excluded for protocol violations and two were excluded due to statistical considerations, leaving 154 patients for valid outcome analysis. Nimodipine treatment was associated with a significantly better outcome (p less than 0.001): 21 (29.2%) of 72 nimodipine-treated patients had a good outcome at 3 months after subarachnoid hemorrhage (SAH) compared to eight (9.8%) of 82 placebo-treated patients. Delayed ischemic deficits from vasospasm alone were significantly less frequent in the nimodipine group (p less than 0.05) with permanent deficits occurring in five nimodipine-treated patients (6.9%) and in 22 placebo-treated patients (26.8%). Improvement in the good outcome rate and reduction in delayed ischemic deficits from vasospasm alone occurred in both Grade 3 and 4 patients, with no difference between nimodipine- and placebo-treated patients being found in Grade 5 patients. Repeat angiography after Day 4 was carried out in 124 patients. There was no significant difference in the incidence of moderate or severe diffuse spasm, which was seen in 64.3% of nimodipine-treated patients and 66.2% of placebo-treated patients. The authors conclude that nimodipine treatment in poor-grade patients with SAH results in an increase in the number of good outcomes and a reduction in the incidence of delayed neurological deterioration due to vasospasm. This effect occurs by a mechanism other than prevention of large-vessel spasm as visualized on angiography.
Assuntos
Aneurisma Intracraniano/tratamento farmacológico , Nimodipina/uso terapêutico , Adolescente , Adulto , Idoso , Antifibrinolíticos/uso terapêutico , Isquemia Encefálica/etiologia , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/prevenção & controle , Angiografia Cerebral , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/etiologia , Ensaios Clínicos como Assunto , Método Duplo-Cego , Humanos , Aneurisma Intracraniano/complicações , Aneurisma Intracraniano/mortalidade , Aneurisma Intracraniano/fisiopatologia , Ataque Isquêmico Transitório/diagnóstico por imagem , Ataque Isquêmico Transitório/etiologia , Ataque Isquêmico Transitório/prevenção & controle , Pessoa de Meia-Idade , Nimodipina/efeitos adversos , Índice de Gravidade de Doença , Hemorragia Subaracnóidea , Tomografia Computadorizada por Raios XRESUMO
An electromechanical device is described which automatically injects the radiotracer bolus used in the measurement of cerebral blood flow. It consists of two electronically controlled, solenoid operated syringes, one containing the radiotracer solution and the other heparinized saline. Results are presented which show that use of the automatic bolus injector in place of hand injection leads to an improvement in the precision of measured flow values. Additional advantages of the device are discussed.
Assuntos
Circulação Cerebrovascular , Injeções Intra-Arteriais/instrumentação , Radioisótopos de Xenônio/administração & dosagem , Animais , HaplorrinosRESUMO
Prolonged waiting periods for patients with benign spinal surgical lesions led to the creation of a Dedicated Short Stay Spinal Surgical Unit. This unit was implemented in November, 1992, on a 29 bed Neuroscience Unit in a 1200 bed Acute Care Teaching Hospital. Considerations for implementation were many, including psychological impact of chronic pain for patients on prolonged waiting lists, the increased probability of permanent waiting lists, the increased probability of permanent neurological deficits, and the economic impact to patient, societal and hospital budgets. This paper will focus on explanation of the design of the unit, define the benefits and provide study results of the first 85 patients admitted to the unit.
Assuntos
Discotomia/enfermagem , Unidades Hospitalares/organização & administração , Laminectomia/enfermagem , Tempo de Internação , Adulto , Idoso , Pessoas com Deficiência , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA. In a separate experiment with five patients who had glioblastoma, we prospectively secured baseline and serial tumor tissue, developed patient-specific cell lines of glioblastoma and putative glioblastoma stem cells (CD133(+), nestin(+) cells), and treated each patient with oral DCA for up to 15 months. DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. The dose-limiting toxicity was a dose-dependent, reversible peripheral neuropathy, and there was no hematologic, hepatic, renal, or cardiac toxicity. Indications of clinical efficacy were present at a dose that did not cause peripheral neuropathy and at serum concentrations of DCA sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma.