RESUMO
Classic rabies is a progressive and lethal infectious disease of animals, which may be transmitted to humans. Inter-human infections are extremely rare. The present case describes transmittal of rabies virus by lung transplantation from an infected donor. Histologically, a lymphocytic encephalomyelitis with neuronal cytoplasmic inclusion bodies was found. Immunohistochemically, rabies virus antigen was detected in the central, autonomous and peripheral nervous system. By means of electron microscopy, virions were demonstrated in the brain. A central task of health care in transplantations is the detection of uncommon infectious agents and the prevention of their transmittal.
Assuntos
Transplante de Pulmão , Raiva/patologia , Raiva/transmissão , Doadores de Tecidos , Adulto , Encéfalo/patologia , Complexo de Eisenmenger/cirurgia , Encefalomielite/patologia , Feminino , Humanos , Imuno-Histoquímica , Corpos de Inclusão Viral/patologia , Microscopia Eletrônica , Pessoa de Meia-Idade , Neurônios/patologia , VírionRESUMO
BACKGROUND: Although low (but increasing) rates of lung/lung-heart transplantations of scleroderma (systemic sclerosis [SSc]) patients have been reported, exclusive heart transplantation is a rare approach for treatment of heart failure due to SSc. CASES: We report on 2 cases of SSc patients receiving a heart transplantation (HTx) due to severe and progressive right heart failure without pulmonary artery hypertension. One patient received a hepatitis C virus (HCV)-positive donor heart and recovered excellently from viral transmission after administration of a direct-acting antiviral (DAA) regimen. This is the first published case of an SSc patient who underwent HTx using an HCV-positive donor heart. The clinical course of both patients was monitored by different serum SSc biomarkers. Only xylosyltransferase activity proved to be a promising biomarker for disease stage determination and therapeutic monitoring, precisely reflecting fibrotic remodeling and successful organ recovery. CONCLUSIONS: Successful implementation of the 2 cases described here demonstrates that HTx is a safe and effective therapeutic option for defined SSc sub-patient groups despite the progressive character of the underlying disease. In the future, xylosyltransferase activity might be conducive to simplify the identification of patients with low systemic involvement but a strong indication for single heart transplantation. Finally, we demonstrate that treatment of HCV viral transmission from HCV-positive donor to organ recipient using DAA gives us new opportunities to consider HCV-positive donor organs for HTx and might reveal new possibilities to ease the lack of donor organs.
Assuntos
Insuficiência Cardíaca/cirurgia , Transplante de Coração/métodos , Hepatite C Crônica/etiologia , Escleroderma Sistêmico/complicações , Doadores de Tecidos , Transplantes/virologia , Adulto , Antivirais/uso terapêutico , Feminino , Insuficiência Cardíaca/etiologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/transmissão , HumanosRESUMO
As the number of drugs with potential therapeutic use for T-cell-mediated diseases increases, there is a need to find methods of delivering such drugs to T cells. The major histocompatibility complex (MHC)--peptide complexes are the only antigen-specific ligands for the T-cell receptor (TCR) expressed on T cells, and they may be an appropriate drug delivery system. We engineered a soluble bivalent MHC class II-peptide chimera on the immunoglobulin scaffold (I-E(d)alpha beta/Fc gamma 2a/HA110-120, DEF) that binds stably and specifically to CD4 T cells recognizing the HA110-120 peptide. Doxorubicin, a powerful antimitogenic anthracycline, was enzymatically assembled on the galactose residues of a DEF chimera. The DEF-gal-Dox construct preserved both the binding capacity to hemagglutinin (HA)-specific T cells, and the drug toxicity. Brief exposure of HA-specific T cells to DEF-gal-Dox construct in vitro was followed by drug internalization in the lysosomes, translocation to the nucleus, and apoptosis. Administration of DEF-gal-Dox to mice expressing the TCR-HA transgene reduced the frequency of TCR-HA T cells in the spleen and thymus by 27% and 42%, and inhibited HA proliferative capacity by 40% and 60%, respectively. It has not been demonstrated previously that pharmacologically active drugs able to modulate T-cell functions can be delivered to T cells in an antigen-specific manner by soluble, bivalent MHC II-peptide chimeras.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Antígenos de Histocompatibilidade Classe II/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/imunologia , Animais , Sítios de Ligação , DNA/química , Portadores de Fármacos , Epitopos/química , Epitopos/imunologia , Galactose , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/imunologia , Linfócitos T/efeitos dos fármacosRESUMO
We have developed a novel procedure to couple enzymatically the antineoplastic agent doxorubicin (Dox) on the galactose residues of a monoclonal antibody specific for the tumor-associated carcinoembryonic antigen. The synthesis of the immunoconjugate consists of covalent attachment of the NH2 terminus of Dox to oxidized galactose residues of desialylated monoclonal antibody, followed by concurrent stabilization of Schiff bases by mild reduction with pyridine borane. The immunoconjugate preserved both antibody specificity and drug cytotoxicity. At equimolar concentrations, the immunoconjugate was 8 times more cytotoxic against two carcinoembryonic antigen-expressing carcinoma cell lines, LoVo and SW-480, than Dox alone. The intracellular drug accumulation was 8-8.5 times higher than that obtained with free Dox, and >50% of the drug delivered by the conjugate was retained for 24 h in the tumor cells. Only 4 days after treatment with a single dose of immunoconjugate carrying 2.5 ng of Dox, LoVo and SW-480 tumor transplants on the chorioallantoic membrane of embryonated hen eggs showed reduced tumor-induced angiogenesis and tumor progression by half, with no detectable damage to surrounding tissues. In contrast, the same amount of free drug induced insignificant changes in tumor progression and tumor-induced angiogenesis. Enzymatically mediated, glycosidic coupling of antineoplastic agents to antibodies specific for tumor-associated antigens may represent a novel platform for the development of more efficient anticancer agents with reduced side effects.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno Carcinoembrionário/imunologia , Doxorrubicina/uso terapêutico , Imunoconjugados/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos/química , Embrião de Galinha , Doxorrubicina/química , Doxorrubicina/farmacologia , Galactose , Humanos , Imunoconjugados/química , Imunoconjugados/imunologia , Imunoconjugados/farmacologia , Microscopia Confocal , Neoplasias Experimentais/imunologia , Células Tumorais CultivadasRESUMO
Fibrillin-1 (Fbn-1) is a ubiquitous protein present in the extracellular matrix of various organs and it is a major component of microfibrils embedded in the core of elastic fibers. In humans, mutations or deletions of the Fbn-1 gene are associated with several genetic diseases. In addition, several microsatellite alleles near Fbn-1 gene were found associated with diffuse scleroderma. In TSK/+ mice, which develop a scleroderma-like syndrome, the Fbn-1 gene exhibits an inframe duplication of exons 17-40. In this study, we report that the synthesis and secretion of wild-type Fbn-1 in TSK/+ is higher than that of the mutated Fbn-1 protein excluding the possibility that TSK genetic defect is due to a loss of the wild allele. We also demonstrate for the first time that TGF-beta, which plays a crucial role in skin fibrosis, binds to both wild-type and mutated Fbn-1. The amount of bound TGF-beta was higher in mutated than wild-type Fbn-1 and appears related to the number of TGF-beta binding motifs.
Assuntos
Duplicação Gênica , Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/genética , Mutação/genética , Animais , Células COS , Células Cultivadas , Proteínas da Matriz Extracelular/química , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Feminino , Fibrilina-1 , Fibrilinas , Fibroblastos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas dos Microfilamentos/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Glioma invasiveness is a complex process involving recognition and attachment of tumor cells to particular extracellular matrix (ECM) molecules prior to migrating into proteolytically modified matrix and inducing angiogenesis. CD44 is a group of transmembrane adhesion molecules found on a wide variety of cells including gliomas that has been suggested as the principal mediator of migration/invasion. The aim of the present study was to demonstrate whether antibody specific for the standard form of CD44 (CD44s, 85-90 kDa) might prevent invasion, thus blocking growth of the 9L gliosarcoma in vivo. High expression of CD44s on the surface of 9L cells and brain tumors was demonstrated by immunochemistry. Fluorescence-activated cell sorting (FACS) demonstrated binding saturation of anti-CD44s monoclonal antibody (mAb) to the receptor at 1 microg/5 x 10(5) cells. Blocking of CD44s in vitro resulted in a dose-dependent progressive, up to 95%+/-2.5% detachment of 9L cells from ECM-coated culture surfaces. Blocking of CD44s in vivo resulted in significantly reduced 9L brain tumors (2.5%+/-0.4%)--measured as the quotient: tumor surface (mm2)/brain surface (mm2) x 100--as compared to untreated (16.1%+/-2.2%) or sham-treated rats (16%+/-3.7% to 16.1%+/-3%). We conclude that CD44s-targeted treatment with specific mAb may be an effective means for preventing glioma progression.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Gliossarcoma/tratamento farmacológico , Receptores de Hialuronatos/imunologia , Invasividade Neoplásica/prevenção & controle , Animais , Adesão Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Gliossarcoma/patologia , Imuno-Histoquímica , Masculino , Camundongos , Ratos , Ratos Nus , Testes de Toxicidade , Células Tumorais CultivadasRESUMO
L-arginine, the precursor of endogenous nitric oxide (NO), has been shown to enhance endothelial function and to reduce the progression of atherosclerosis in cholesterol-fed rabbits. In the present study, we investigated whether myointimal cell proliferation is enhanced in hypercholesterolaemic rabbit aorta and whether chronic treatment of the rabbits with L-arginine or with the NO synthase inhibitor L-NAME influences this proliferative response and vascular monocyte accumulation. Rabbits were fed 1% cholesterol or normal rabbit chow for 12 weeks. Subgroups of cholesterol-fed rabbits were treated with oral L-arginine (2.25%) or L-NAME (3 mg/dl) in drinking water. Myointimal cell proliferation was quantified in aortic segments by immunohistochemical detection of bromodeoxyuridine (BrdU) incorporation into nuclear DNA; vascular monocyte accumulation was assessed by immunohistochemistry using a monoclonal anti-macrophage/monocyte antibody (RAM-11). Plasma levels of L-arginine and the endogenous NO synthase inhibitor, ADMA, were quantified by high-performance liquid chromatography (HPLC). Cholesterol feeding increased the aortic intima/media (I/M) ratio, which was not measurable in the control group, to 1.9 +/- 0.3. This was paralleled by enhanced cell proliferation (cholesterol, 2.4 +/- 0.2%; P < 0.05; control, 0.02 +/- 0.001% BrdU-positive cells per 72 h) and vascular monocyte accumulation. Double immunostaining for BrdU and alpha-actin showed that about two thirds of the proliferating cells were smooth muscle cells. ADMA levels increased from 0.8 +/- 0.1 micromol/l to 2.2 +/- 0.2 micromol/l in cholesterol-fed rabbits, but were unchanged by L-arginine or L-NAME treatment. Myointimal proliferation and intima/media ratios were correlated with ADMA plasma levels. Dietary L-arginine reduced monocyte accumulation by 85 +/- 2% (P < 0.05 vs cholesterol), myointimal cell proliferation (1.8 +/- 0.3% per 72 h; P < 0.05) and intimal thickening (I/M ratio: 0.7 +/- 0.2), whereas the inhibitor of NO synthase, L-NAME, further increased cell proliferation to 3.1 +/- 0.4% per 72 h (P < 0.05). No significant difference was observed in vascular monocyte infiltration between the cholesterol and L-NAME groups. We conclude that cell proliferation and vascular monocyte accumulation are enhanced in hypercholesterolaemic rabbit aorta. These atherogenic effects can be attenuated by dietary L-arginine. Decreased NO formation might underlie the enhanced monocyte accumulation and cell proliferation in hypercholesterolaemic rabbit aorta. The observed inhibition of cell proliferation adds to our understanding of the antiatherosclerotic effects of L-arginine in vivo.
Assuntos
Arginina/farmacologia , Colesterol na Dieta/farmacologia , Monócitos/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Arginina/administração & dosagem , Arteriosclerose/enzimologia , Arteriosclerose/patologia , Divisão Celular/efeitos dos fármacos , Dieta , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Inibidores Enzimáticos/farmacologia , Contração Isométrica , Contagem de Leucócitos , Masculino , Monócitos/efeitos dos fármacos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Coelhos , Vasodilatação/efeitos dos fármacosRESUMO
We have previously reported that in vivo-expression of granulocyte colony-stimulating factor (G-CSF) is a characteristic feature of reactive and neoplastic astrocytes. The aim of the present study was to analyze the expression of G-CSF protein in primary and recurrent astroglial, oligodendroglial and mixed glial-differentiated tumors. G-CSF expression was present in all GFAP-positive tumors excepting glioblastomas. G-CSF expression was significantly reduced in recurrent tumors more dedifferentiated than their primary counterparts. G-CSF expression was absent in all GFAP-negative tumors such as oligodendrogliomas. Our results demonstrate that G-CSF is a highly sensitive differentiation marker of neoplastic astrocytes, which is lost during tumor progression.
Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Fator Estimulador de Colônias de Granulócitos/biossíntese , Adolescente , Adulto , Astrócitos/química , Astrócitos/metabolismo , Astrócitos/patologia , Biomarcadores , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/metabolismo , Diferenciação Celular/imunologia , Densitometria , Progressão da Doença , Feminino , Proteína Glial Fibrilar Ácida/análise , Proteína Glial Fibrilar Ácida/biossíntese , Glioblastoma/imunologia , Glioblastoma/metabolismo , Fator Estimulador de Colônias de Granulócitos/análise , Fator Estimulador de Colônias de Granulócitos/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Oligodendroglia/química , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Oligodendroglioma/imunologia , Oligodendroglioma/metabolismo , Oligodendroglioma/patologia , RecidivaRESUMO
Children presenting with acute systemic illnesses that lack specific clinical or serological defining features may be diagnosed as having a chronic infection, an atypical systemic vasculitis or a connective tissue disease, but often turn out to have occult neoplasias. Cytokines have been implicated in causing many of the systemic effects in such cases. In this study, we describe the case of a 9-year-old boy presenting at an interval of 18 months with a marked acute-phase response due to a recurrent atypical meningioma with rhabdoid transformation of the tentorium cerebelli. Resection of the recurrent tumor was curative. We evaluated in detail the local and systemic production of cytokines released by the primary and the recurrent tumor. Blood and CSF samples were taken pre-, intra-, and postoperatively, and the production of IL-6, IL-1beta, and TNF-alpha was measured by enzyme-linked immunosorbent assays (ELISA). The level of IL-6 in CSF was about 150-fold increased before tumor resection, normalizing postoperatively. On the contrary, the levels of IL-1beta and TNF-alpha in CSF and of IL-6, IL-1beta, and TNF-alpha in serum were pre-, intra-, and postoperatively within normal limits. Cytokine production was also evaluated immunohistochemically, and confirmed strong IL-6 and TNF-alpha expression in the primary and the recurrent tumor, while expression of IL-1beta was lacking. The scattered MHC class II- and leukocyte common antigen (LCA)-expressing inflammatory cells, which were infiltrating exclusively the tumoral stroma, had no detectable cytokine immunoreactivity. We conclude that chronic IL-6 and TNF-alpha production by the tumor cells in this patient was responsible for the severe systemic illness with which he presented.
Assuntos
Citocinas/metabolismo , Dura-Máter/patologia , Febre de Causa Desconhecida/etiologia , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , Recidiva Local de Neoplasia/metabolismo , Tumor Rabdoide/metabolismo , Doença Aguda , Criança , Fossa Craniana Posterior/patologia , Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Desmina/metabolismo , Dura-Máter/ultraestrutura , Ensaio de Imunoadsorção Enzimática , Febre de Causa Desconhecida/patologia , Febre de Causa Desconhecida/fisiopatologia , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Imuno-Histoquímica , Interleucina-1/sangue , Interleucina-1/líquido cefalorraquidiano , Interleucina-1/metabolismo , Interleucina-6/sangue , Interleucina-6/líquido cefalorraquidiano , Interleucina-6/metabolismo , Imageamento por Ressonância Magnética , Masculino , Neoplasias Meníngeas/líquido cefalorraquidiano , Neoplasias Meníngeas/patologia , Meningioma/líquido cefalorraquidiano , Meningioma/patologia , Microscopia Eletrônica , Recidiva Local de Neoplasia/líquido cefalorraquidiano , Recidiva Local de Neoplasia/patologia , Pirogênios/sangue , Pirogênios/líquido cefalorraquidiano , Pirogênios/metabolismo , Tumor Rabdoide/líquido cefalorraquidiano , Tumor Rabdoide/patologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano , Fator de Necrose Tumoral alfa/metabolismo , Vimentina/metabolismoRESUMO
OBJECTIVE AND IMPORTANCE: Vestibular schwannomas with meningioma islets have been rarely reported in the literature; they have been observed only among patients with neurofibromatosis Type II. We present a case of a sporadic mixed tumor in a patient without neurofibromatosis Type II that was not suspected before surgery. CLINICAL PRESENTATION: A 59-year-old female patient presented with clinical signs of progressive loss of hearing. Her family history did not include evidence of neurological diseases. Magnetic resonance imaging scans revealed a typical unilateral vestibular schwannoma. INTERVENTION: The tumor presented with invasion of the surrounding arachnoid membrane, as well as Cranial Nerves VII and VIII. Preservation of the facial nerve with complete removal of the tumor was not possible. Therefore, Cranial Nerve VII reconstruction was performed. CONCLUSION: The concomitant occurrence of schwannomas and meningiomas infiltrating the arachnoid membrane might be related to poor clinical outcomes for patients with neurofibromatosis Type II, with respect to preservation of facial and acoustic nerves. Among sporadic schwannomas, this phenomenon is extremely rare.
Assuntos
Neoplasias Meníngeas/patologia , Meningioma/patologia , Neoplasias Complexas Mistas/patologia , Neuroma Acústico/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/cirurgia , Meningioma/diagnóstico , Meningioma/cirurgia , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Neoplasias Complexas Mistas/cirurgia , Neuroma Acústico/diagnóstico , Neuroma Acústico/cirurgiaRESUMO
The effectiveness of in vivo suppression of neovascularization and growth of malignant glial tumors by in situ administration of an antibody directed against basic fibroblast growth factor (bFGF), a strong mitogen for cells of mesodermal origin, was tested. One hundred fifty congenitally athymic nude rats (han rnu/rnu) were implanted intracerebrally with U-87MG tumor cells, known constitutive producers of bFGF. The animals were randomly assigned to six groups of 25 animals each. Animals were treated by in situ application of saline (Group F), control antibody (Group D), or polyclonal anti-bFGF antibody (Group B). In additional groups a putative effect on tumor growth caused by the treatment application device itself (between growth control Groups A and E), and the effect of heat-inactivated tumor cells (negative control Group C) were tested. After 3 weeks of treatment, tumor progression and degree of neovascularization were morphometrically recorded. In the untreated Groups A and E massive tumor growth was recorded, consisting of 19.9% +/- 0.4% and 27.1% +/- 0.5%, respectively, of the total brain cross-sectional area. In Group C, no tumor growth occurred. In control Groups D and F tumor progression consisted of 18.6% +/- 0.4% and 18.5% +/- 0.4%, respectively, of the total brain cross-sectional area; whereas in the anti-bFGF treated Group B, significantly smaller tumor masses measuring 7.2% +/- 0.1% were recorded. New blood vessels were located both peritumorally and intratumorally and defined as numerical density and area fraction (number/area and area/area). Significantly more new blood vessels were found in Groups A, D, E, and F, ranging from 41,380/mm2 +/- 464/mm2 to 53,442/mm2 +/- 150/mm2 peritumorally and 51,846/mm2 +/- 495/mm2 to 64,660/mm2 +/- 183/mm2 intratumorally than in the anti-bFGF treated Group B, which numbered 8220/mm2 +/- 225/mm2 peritumorally and 16,554/mm2 +/- 236/mm2 intratumorally. The authors conclude that treatment with anti-bFGF antibody is effective in inhibiting tumor-induced angiogenesis and correlated tumor progression. However, owing to the character of the experimental system used, one cannot exclude the possibility that application of the specific anti-bFGF antibody also counteracts device-induced neovascularization. The authors suggest that combined surgical excision and adjuvant immunotherapy of tumors such as glioblastoma and other malignant brain tumors that express bFGF might prevent tumor recurrence.
Assuntos
Anticorpos/farmacologia , Neoplasias Encefálicas/patologia , Fator 2 de Crescimento de Fibroblastos/imunologia , Glioma/irrigação sanguínea , Glioma/patologia , Neovascularização Patológica/prevenção & controle , Animais , Neoplasias Encefálicas/irrigação sanguínea , Divisão Celular/efeitos dos fármacos , Feminino , Fator 2 de Crescimento de Fibroblastos/fisiologia , Humanos , Masculino , Transplante de Neoplasias , Ratos , Ratos Nus , Análise de Sobrevida , Transplante Heterólogo , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
OBJECT: Glioblastoma multiforme (GBM) invasiveness is a complex process that involves recognition and attachment of GBM cells to particular extracellular matrix (ECM) molecules before migrating into proteolytically modified matrix and inducing angiogenesis. The CD44 molecule, which is a transmembrane adhesion molecule found on a wide variety of cells including GBM, has been suggested as the principal mediator of migration and invasion. The aim of the present study was to demonstrate whether an antibody specific to the standard form of CD44 (CD44s, 85-90 kD) might prevent invasion and thus disrupt progression of C6 GBM in vivo. METHODS: Immunostaining demonstrated homogeneous expression of CD44s on the surface of C6 GBM cells and tumors. Flow cytometric analysis demonstrated binding saturation of anti-CD44s monoclonal antibody (mAb) to the receptor at 1 microg/5 x 10(5) cells. Blocking of CD44s in vitro resulted in a dose-dependent progressive (up to 94+/-2.7%; mean +/- standard deviation [SD]) detachment of C6 cells from ECM-coated culture. Blocking of CD44s in vivo resulted in significantly reduced C6 brain tumors (3.6+/-0.4% [SD])--measured as the quotient: tumor surface (mm2)/brain surface (mm2) x 100--compared with untreated (19.9+/-0.9%) or sham-treated (19.2+/-1.1 to 19.3+/-2.5% [SD]) rats. Disruption of C6 GBM progression correlated with an improved food intake; treated rats were significantly less cachectic (166.6+/-16.4 g [SD]) than those that were untreated (83+/-2.7 g [SD]) or sham-treated (83.4+/-1.1 to 83+/-2.2 g [SD]) rats. CONCLUSIONS: The authors conclude that CD44s-targeted treatment with specific mAb may represent an effective means for preventing progression of highly invasive GBMs.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Receptores de Hialuronatos/imunologia , Animais , Neoplasias Encefálicas/imunologia , Progressão da Doença , Feminino , Citometria de Fluxo , Glioblastoma/imunologia , Imuno-Histoquímica , Masculino , Camundongos , Microscopia Confocal , Ratos , Ratos NusRESUMO
Glioblastoma is the most invasive form of primary brain tumors, and is often refractory to chemotherapy. Herein, we provide evidence that two highly invasive human glioma cell lines U-87 MG and U-373 MG, entered apoptosis after 48 hours following 24 h growth arrest induced by Doxorubicin (10 micrograms/2 x 10(5) cells/ml). Apoptosis depended solely on the level of intracellular drug accumulation, and it was not related to a functional p53 tumor suppressor factor. The multidrug resistance gene 1 (mdr-1) encoded P-glycoprotein (P-gp) was weakly expressed in these cells upon exposure to Doxorubicin, and exerted no influence on the extent of cellular drug efflux. Drug efflux occurred only in U-373 MG glioma cells subsequent to physical damage of the membrane upon exposure to Doxorubicin. Pretreatment of tumor cells with 10 micrograms/ml Doxorubicin precluded tumor formation on the chorioallantoic membrane (CAM) of embryonated hen eggs. Single-dose application of 0.4 microgram Doxorubicin on CAM/U-87 MG and CAM/U-373 MG tumor transplants inhibited tumor invasion in CAM tissue by 40 to 50%. These data suggest that highly invasive glioblastomas can be driven to apoptosis following growth arrest induced by Doxorubicin, providing that intracellular drug accumulation suffices cytotoxic levels.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Doxorrubicina/farmacologia , Glioma/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/análise , Doxorrubicina/farmacocinética , Glioma/patologia , Humanos , Invasividade Neoplásica , Células Tumorais CultivadasRESUMO
The aim of this report is to demonstrate the correlation between an extremely short time acting but strong force leading to incomplete rupture of the ponto-medullary junction (PMJ) accompanied by rupture of the basilar artery. Potential mechanisms involved in a combined hyperextension and axial torsion of the head followed by characteristic lesions at the PMJ are discussed. A 33-year-old male suffered a blunt head injury following a blow to the head, i.e. a head-butt. Resuscitation was performed for 45 min without success. At post mortem, there was a superficial periorbital haematoma on the right and a deep soft tissue bruise in the right fronto-parieto-temporal area, but no evidence of skull or dens axis fracture. A deep tear at the ponto-medullary junction was identified with rupture of the basilar artery, whereas at the tip of the tear, i.e. the floor of the IVth ventricle, only a thin tissue layer of about 2 mm remained intact. In contrast to the severity of these lesions, only mild subarachnoid hemorrhage was observed, but the ventricular system was filled with blood clot resulting from the retrograde flow of subarachnoid hemorrhage.
Assuntos
Artéria Basilar/lesões , Bulbo/lesões , Ponte/lesões , Ferimentos não Penetrantes/patologia , Adulto , Cocaína/análogos & derivados , Cocaína/sangue , Cocaína/urina , Etanol/sangue , Etanol/urina , Medicina Legal , Humanos , Masculino , Bulbo/patologia , Ponte/patologia , RupturaRESUMO
The combination of new and rapidly developing interactive multimedia computers and applications with electronic networks will require a restructuring of our traditional approach to strategic planning and organizational structure. Worldwide telecommunication networks (using satellites, cable) are now facilitating the global pooling of healthcare information and medical knowledge independent of location. The development of multimedia information and communication systems demands cooperative working teams of authors, who are able to master several areas of medical knowledge as well as the presentation of these in different multimedia forms. The assemblage of telematics and services offers a base for multimedia applications, for example teleteaching, telelearning, telepublishing, teleconsulting, teleconferencing, telemedicine etc. The expansion of the internet will also lead to the formation of interdisciplinary "Global Education Networks". The theory and practice of education are undergoing dramatic changes. Lifelong learning and adaptation of medical practice to new knowledge and new techniques will be even more important in the future.
Assuntos
Instrução por Computador , Educação Médica , Internet , Multimídia , Educação de Pacientes como Assunto , Currículo , Alemanha , Humanos , Informática Médica , Consulta Remota , Design de SoftwareRESUMO
The commercial use of the World Wide Web causes an extensive change in information technology. Web browser are becoming the universal front-end for all kinds of client-server applications. The possibilities of telematics offer a base for multimedia applications, for instance telelearning. Learning is not limited by geography and does not cause pressure of time by the user. The development of such multimedia information and communication systems demands cooperative working teams of authors, who are able to master several areas of medical knowledge as well as the presentation of these using different multimedia facilities. A very important part of graphic design in the context of multimedia applications is the creation and interactive use of images (still, moving). The growth and the complexity of medical knowledge as well as the need for continuous, fast, and economically feasible maintenance impose requirements on the media used for medical education and training. Web-based courseware in the Virtual Learning Center at the Hannover Medical School is an innovative education resource for medical students and professionals.
Assuntos
Instrução por Computador , Educação Médica , Internet , Multimídia , Interface Usuário-Computador , Currículo , Alemanha , HumanosAssuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/veterinária , Doenças dos Roedores/patologia , Animais , Astrocitoma/induzido quimicamente , Astrocitoma/patologia , Astrocitoma/veterinária , Neoplasias Encefálicas/induzido quimicamente , Carcinógenos/toxicidade , Cricetinae , Dietilnitrosamina/toxicidade , Feminino , Masculino , Troca Materno-Fetal , Meningioma/induzido quimicamente , Meningioma/patologia , Meningioma/veterinária , Mesocricetus , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Doenças dos Roedores/induzido quimicamenteRESUMO
This report describes the morphologic, ultrastructural, and immunophenotypic features of a nodular ganglioneuroblastoma in the jejunum of a 13-month-old Holstein-Friesian heifer. On histologic examination, the mass was composed of clusters of neuroblasts and isolated ganglionic neurons in abundant neurophilic matrix that was surrounded by scanty Schwannian stroma. On ultrastructure examination, the large ganglionic neuron-like cells had unmyelinated neurites. Most ganglionic neuron-like tumor cells expressed neurofilament, neuron-specific enolase, chromogranin A, and S-100, whereas the Schwann-cell-like stromal cells expressed S-100 and vimentin. Both brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase-B (Trk-B) were expressed in ganglionic neuron-like tumor cells, which suggested the activation or reactivation of an embryonic autocrine BDNF/Trk-B pathway that could have prolonged cell survival and promoted differentiation with neurite formation.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/análise , Doenças dos Bovinos/enzimologia , Ganglioneuroblastoma/veterinária , Neoplasias do Jejuno/veterinária , Proteínas do Tecido Nervoso/metabolismo , Proteínas Quinases/metabolismo , Animais , Bovinos , Feminino , Ganglioneuroblastoma/enzimologia , Neoplasias do Jejuno/patologia , Jejuno/patologiaRESUMO
UNLABELLED: The growth of a cholesteatoma requires angioneogenesis in the connective tissue of the perimatrix. Angioneogenesis is also needed for wound healing as a host response to tissue injury. Normal wound repair is conducted through a wide number of growth factors. Basic fibroblast growth factor (b-FGF) plays a pivotal role in wound repair. This cytokine exerts its effects through stimulation of a wide range of target cells. B-FGF is chemotactic and mitogenic for fibroblasts, endothelial cells and keratinocytes. In addition, b-FGF can stimulate the production of collagenase and plasminogen activators to enhance fibroblast proliferation and angioneogenesis. Its necessity for normal wound repair has been confirmed by several workers. METHOD: In order to demonstrate angioneogenesis in the cholesteatoma perimatrix the distribution of b-FGF as the pivotal cytokine of the process was investigated in the perimatrix of 18 cholesteatoma specimens. RESULTS: B-FGF could be observed in 12 of 18 specimens (66%) in close approximation to histological signs of inflammation and wound healing. Areas with b-FGF also exhibited proliferation of the covering squamous epithelium. Cholesteatoma matrix tissue without inflammation or any sign of wound healing did not express b-FGF (6 of 18). CONCLUSION: Histological changes and distribution pattern of b-FGF in the perimatrix of cholesteatoma in the present study indicate that the perimatrix cells and substances of the wound healing cascade may play an important role in cholesteatoma development, angiogenesis and growth.
Assuntos
Colesteatoma da Orelha Média/patologia , Matriz Extracelular/patologia , Fator 2 de Crescimento de Fibroblastos/análise , Orelha Média/irrigação sanguínea , Orelha Média/patologia , Epitélio/patologia , Humanos , Técnicas Imunoenzimáticas , Neovascularização Patológica/patologia , Cicatrização/fisiologiaRESUMO
Granulocyte-colony-stimulating factor (G-CSF) is a hematopoietic cytokine that regulates the differentiation of myeloid progenitors and the function of mature neutrophils. It is produced in vitro by monocytes/macrophages, mesothelial cells, fibroblasts and endothelial cells after appropriate induction by inflammatory mediators like IL-1 and TNF. Normal as well as tumorous glial cells can also be induced to produce CSFs in vitro. However, little is yet known about the in vivo expression of G-CSF as a mediator in inflammation and malignancy within the human central nervous system. The aim of the present study was to investigate by immunostaining the expression of the G-CSF protein within non-tumorous and tumorous glial tissues, and primitive neuroectodermal tumors. Using the murine monoclonal anti-G-CSF TM 82/60 antibody, we found high G-CSF expression in astrocytoma WHO grades I and II and reactive brain tissue, low expression in astrocytoma WHO grade III, and none in glioblastoma, oligodendroglioma WHO grades II and III, and medulloblastoma. In consecutive sections of the tissue samples, G-CSF protein was localized in GFAP-positive glial cells, but not in macrophages/microglial cells, which expressed HLA-DR, detected by the antibody CR3/43. Computer-assisted microdensitometric evaluation of the intensity of immunostaining for G-CSF and statistic analysis of the data revealed significant differences between the diagnostic entities studied (p < 0.0001). We conclude that in vivo expression of G-CSF is a characteristic of reactive as well as tumorous astrocytes, with the latter losing this feature at higher degrees of dedifferentiation.