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STUDY DESIGN: Experimental study. OBJECTIVES: The objective of this study was to establish a non-invasive model to produce pressure ulcers of varying severity in animals with spinal cord injury (SCI). SETTING: The study was conducted at the Johns Hopkins Hospital in Baltimore, Maryland, USA. METHODS: A mid-thoracic (T7-T9) left hemisection was performed on Sprague-Dawley rats. At 7 days post SCI, rats received varying degrees of pressure on the left posterior thigh region. Laser Doppler Flowmetry was used to record blood flow. Animals were killed 12 days after SCI. A cardiac puncture was performed for blood chemistry, and full-thickness tissue was harvested for histology. RESULTS: Doppler blood flow after SCI prior to pressure application was 237.808±16.175 PFUs at day 7. Following pressure application, there was a statistically significant decrease in blood flow in all pressure-applied groups in comparison with controls with a mean perfusion of 118.361±18.223 (P<0.001). White blood cell counts and creatine kinase for each group were statistically significant from the control group (P=0.0107 and P=0.0028, respectively). CONCLUSIONS: We have created a novel animal model of pressure ulcer formation in the setting of a SCI. Histological analysis revealed different stages of injury corresponding to the amount of pressure the animals were exposed to with decreased blood flow immediately after the insult along with a subsequent marked increase in blood flow the next day, conducive to an ischemia-reperfusion injury (IRI) and a possible inflammatory response following tissue injury. Following ischemia and hypoxia secondary to microcirculation impairment, free radicals generate lipid peroxidation, leading to ischemic tissue damage. Future studies should be aimed at measuring free radicals during this period of increased blood flow, following tissue ischemia.
Assuntos
Modelos Animais de Doenças , Úlcera por Pressão/etiologia , Traumatismos da Medula Espinal/complicações , Animais , Análise Química do Sangue , Creatina Quinase/sangue , Feminino , Fluxometria por Laser-Doppler , Contagem de Leucócitos , Pressão , Úlcera por Pressão/patologia , Úlcera por Pressão/fisiopatologia , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional , Traumatismos da Medula Espinal/fisiopatologia , Vértebras TorácicasRESUMO
BACKGROUND AND PURPOSE: Thin-section MR imaging through the posterior fossa is frequently used for trigeminal neuralgia. Typical heavily T2-weighted imaging methods yield high anatomic detail and contrast between CSF and neurovascular structures, but poor contrast between vessels and nerves. We hypothesized that the addition of gadolinium-based contrast material to 3D-constructive interference in steady-state imaging would improve the characterization of trigeminal compression. MATERIALS AND METHODS: Retrospective review of high-resolution MRIs was performed in patients without prior microvascular decompression. 3D-CISS imaging without contrast and with contrast for 81 patients with trigeminal neuralgia and 15 controls was intermixed and independently reviewed in a blinded fashion. Cisternal segments of both trigeminal nerves were assessed for the grade of neurovascular conflict, cross-sectional area, and degree of flattening. Data were correlated with symptom side and pain relief after microvascular decompression using the Fisher exact test, receiver operating curve analysis, and a paired t test. RESULTS: Contrast-enhanced CISS more than doubled the prevalence of the highest grade of neurovascular conflict (14.8% versus 33.3%, P = .001) and yielded significantly lower cross-sectional area (P = 8.6 × 10-6) and greater degree of flattening (P = .02) for advanced-grade neurovascular conflict on the symptoms side compared with non-contrast-enhanced CISS. Patients with complete pain relief after microvascular decompression had significantly lower cross-sectional area on contrast-enhanced CISS compared with non-contrast-enhanced CISS on preoperative imaging (P = 2.0 × 10-7). Performance based on receiver operating curve analysis was significantly improved for contrast-enhanced CISS compared with non-contrast-enhanced CISS. CONCLUSIONS: The addition of contrast material to 3D-CISS imaging improves the performance of identifying unilateral neurovascular compression for symptomatic trigeminal neuralgia and predicting outcomes after microvascular decompression.
Assuntos
Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Neuralgia do Trigêmeo/diagnóstico por imagem , Adulto , Idoso , Meios de Contraste , Feminino , Gadolínio , Humanos , Masculino , Cirurgia de Descompressão Microvascular , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Nervo Trigêmeo/diagnóstico por imagemRESUMO
BACKGROUND AND PURPOSE: Patients with trigeminal neuralgia often undergo trigeminal rhizotomy via radiofrequency thermocoagulation or glycerol injection for treatment of symptoms. To date, radiologic changes in patients with trigeminal neuralgia post-rhizotomy have not been described, to our knowledge. The aim of this study was to evaluate patients after trigeminal rhizotomy to characterize post-rhizotomy changes on 3D high-resolution MR imaging. MATERIALS AND METHODS: A retrospective review of trigeminal neuralgia protocol studies was performed in 26 patients after rhizotomy compared with 54 treatment-naïve subjects with trigeminal neuralgia. Examinations were reviewed independently by 2 neuroradiologists blinded to the side of symptoms and treatment history. The symmetry of Meckel's cave on constructive interference in steady-state and the presence of contrast enhancement within the trigeminal nerves on volumetric interpolated breath-hold examination images were assessed subjectively. The signal intensity of Meckel's cave was measured on coronal noncontrast constructive interference in steady-state imaging on each side. RESULTS: Post-rhizotomy changes included subjective clumping of nerve roots and/or decreased constructive interference in steady-state signal intensity within Meckel's cave, which was identified in 17/26 (65%) patients after rhizotomy and 3/54 (6%) treatment-naïve patients (P < .001). Constructive interference in steady-state signal intensity within Meckel's cave was, on average, 13% lower on the side of the rhizotomy in patients posttreatment compared with a 1% difference in controls (P < .001). Small regions of temporal encephalomalacia were noted in 8/26 (31%) patients after rhizotomy and 0/54 (0%) treatment-naïve patients (P < .001). CONCLUSIONS: Post-trigeminal rhizotomy findings frequently include nerve clumping and decreased constructive interference in steady-state signal intensity in Meckel's cave. Small areas of temporal lobe encephalomalacia are encountered less frequently.
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Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumors in adults. Uncontrolled proliferation and abnormal cell migration are two prominent spatially and temporally disassociated characteristics of GBMs. In this study, we investigated the role of the receptor tyrosine kinase EphB2 in controlling the proliferation/migration dichotomy of GBM. We studied EphB2 gain of function and loss of function in glioblastoma-derived stem-like neurospheres, whose in vivo growth pattern closely replicates human GBM. EphB2 expression stimulated GBM neurosphere cell migration and invasion, and inhibited neurosphere cell proliferation in vitro. In parallel, EphB2 silencing increased tumor cell proliferation and decreased tumor cell migration. EphB2 was found to increase tumor cell invasion in vivo using an internally controlled dual-fluorescent xenograft model. Xenografts derived from EphB2-overexpressing GBM neurospheres also showed decreased cellular proliferation. The non-receptor tyrosine kinase focal adhesion kinase (FAK) was found to be co-associated with and highly activated by EphB2 expression, and FAK activation facilitated focal adhesion formation, cytoskeleton structure change and cell migration in EphB2-expressing GBM neurosphere cells. Taken together, our findings indicate that EphB2 has pro-invasive and anti-proliferative actions in GBM stem-like neurospheres mediated, in part, by interactions between EphB2 receptors and FAK. These novel findings suggest that tumor cell invasion can be therapeutically targeted by inhibiting EphB2 signaling, and that optimal antitumor responses to EphB2 targeting may require concurrent use of anti-proliferative agents.
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Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Movimento Celular/fisiologia , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Receptor EphB2/metabolismo , Animais , Neoplasias Encefálicas/genética , Adesão Celular/genética , Adesão Celular/fisiologia , Processos de Crescimento Celular/genética , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/genética , Glioblastoma/enzimologia , Glioblastoma/genética , Humanos , Camundongos , Camundongos SCID , Invasividade Neoplásica , Receptor EphB2/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
It is necessary to understand mechanisms by which differentiating agents influence tumor-initiating cancer stem cells. Toward this end, we investigated the cellular and molecular responses of glioblastoma stem-like cells (GBM-SCs) to all-trans retinoic acid (RA). GBM-SCs were grown as non-adherent neurospheres in growth factor supplemented serum-free medium. RA treatment rapidly induced morphology changes, induced growth arrest at G1/G0 to S transition, decreased cyclin D1 expression and increased p27 expression. Immunofluorescence and western blot analysis indicated that RA induced the expression of lineage-specific differentiation markers Tuj1 and GFAP and reduced the expression of neural stem cell markers such as CD133, Msi-1, nestin and Sox-2. RA treatment dramatically decreased neurosphere-forming capacity, inhibited the ability of neurospheres to form colonies in soft agar and inhibited their capacity to propagate subcutaneous and intracranial xenografts. Expression microarray analysis identified â¼350 genes that were altered within 48 h of RA treatment. Affected pathways included retinoid signaling and metabolism, cell-cycle regulation, lineage determination, cell adhesion, cell-matrix interaction and cytoskeleton remodeling. Notch signaling was the most prominent of these RA-responsive pathways. Notch pathway downregulation was confirmed based on the downregulation of HES and HEY family members. Constitutive activation of Notch signaling with the Notch intracellular domain rescued GBM neurospheres from the RA-induced differentiation and stem cell depletion. Our findings identify mechanisms by which RA targets GBM-derived stem-like tumor-initiating cells and novel targets applicable to differentiation therapies for glioblastoma.