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1.
Neurocrit Care ; 32(2): 575-585, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31346935

RESUMO

BACKGROUND: Animal models of stroke play a crucial role in determining the pathophysiology of stroke progression and assessment of any new therapeutic approaches. Transient middle cerebral artery occlusion (tMCAo) in rodent models are the most common site-specific type of ischemia because of their relevance to the clinical setting. Compared with the intraluminal filament technique for inducing tMCAo, the transfemoral approach using endovascular wires is relatively a new technique METHODS: Here we present the use of commercially available wires used for neuro-endovascular surgical procedures to induce tMCAo in rats via a transfemoral approach. We used male Wistar rats in four groups to assess the effect of occlusion time (1 vs. 2 hours) and the wire type (PT2 TM 0.014″ vs. TransendTM EX, 0.014″, Boston Scientific, MA, USA). Infarct volume, edema, neurological deficits, and pro-inflammatory/anti-inflammatory blood biomarkers were used as outcome measures. RESULTS: We observed a significant effect of the wire type on the infarct volume (p value = 0.0096) where infarcts were slightly larger in the PT2 wiregroups. However, the occlusion time had no significant effect on infarct volume, even though the interaction between wire-type * occlusion-time was significant (p value = 0.024). Also, the amount of edema and blood pro-inflammatory/anti-inflammatory biomarkers were not statistically different among the wire-type and occlusion-time groups. CONCLUSIONS: The choice of appropriate endovascular wire should probably be the focus of the study design instead of the occlusion time when planning an experiment. The transfemoral approach using endovascular wires for inducing tMCAo in rats provides a more consistent outcome with fewer complications compared with suture filament models.


Assuntos
Encéfalo/patologia , Modelos Animais de Doenças , Procedimentos Endovasculares/métodos , Infarto da Artéria Cerebral Média , Ratos , Animais , Circulação Cerebrovascular , Procedimentos Endovasculares/instrumentação , Artéria Femoral , Masculino , Ratos Wistar
2.
J Pediatr Hematol Oncol ; 41(1): e34-e37, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29432310

RESUMO

Congenital brain tumors are rare, representing <2% of all childhood brain tumors. Of these, ependymoblastoma is a profoundly aggressive embryonal brain tumor that is included in the diagnostic entity known as an embryonal tumor with multilayered rosettes. This report of a congenital ependymoblastoma diagnosed at birth aims to highlight how much remains unknown about embryonal tumor with multilayered rosettes and the devastating prognosis of this condition. Despite recent advancements made in identifying molecular targets for therapy, this tumor continues to have a high rate of recurrence with few successful treatment options, especially when diagnosed in the newborn period.


Assuntos
Neoplasias Encefálicas/congênito , Neoplasias Encefálicas/diagnóstico por imagem , Tumores Neuroectodérmicos Primitivos/congênito , Tumores Neuroectodérmicos Primitivos/diagnóstico por imagem , Adulto , Neoplasias Encefálicas/patologia , Feminino , Humanos , Recém-Nascido , Tumores Neuroectodérmicos Primitivos/patologia , Gravidez
3.
J Ultrasound Med ; 37(12): 2925-2933, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29689641

RESUMO

OBJECTIVES: To assess the feasibility of inducing different severities of shock wave (SW)-induced traumatic brain injury (TBI) using lithotripsy. METHODS: Wistar rats (n = 36) were divided into 2 groups: group 1 (n = 20) received 5 SW pulses, and group 2 (n = 16) received 15 SWs pulses. The SW pulses were delivered to the right side of the frontal cortex. Neurologic and behavioral assessments (Garcia test, beam walking, rotarod, and elevated plus maze) were performed at the baseline and at 3, 6, 24, 72, and 168 hours after injury. At day 7 after injury (168 hours), we performed cerebral angiography to assess the presence of cerebral vasospasm and vascular damage due to SW-induced TBI. At the conclusion of the study, the animals were euthanized to assess damage to brain tissue using an overall histologic severity score. RESULTS: The Garcia score was significantly higher, and the anxiety index (based on the elevated plus maze) was significantly lower in group 1 compared to group 2 (P < .05). The anxiety index for group 1 returned to the baseline level in a fast nonlinear fashion, whereas the anxiety index for group 2 followed a distinct slow linear reduction. Cerebral angiograms revealed a more severe vasospasm for the animals in group 2 compared to group 1 (P = .027). We observed a statistically significant difference in the overall histologic severity scores between the groups. The median (interquartile range) overall histologic severity scores for groups 1 and 2 were 3.0 (2.75) and 6.5 (6.0), respectively (P = .023). CONCLUSIONS: We have successfully established different SW-induced TBI severities in our SW-induced TBI model by delivering different numbers of SW pulses to brain tissue.


Assuntos
Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/etiologia , Litotripsia/efeitos adversos , Animais , Comportamento Animal , Encéfalo/diagnóstico por imagem , Angiografia Cerebral , Modelos Animais de Doenças , Estudos de Viabilidade , Litotripsia/métodos , Masculino , Ratos Wistar , Índice de Gravidade de Doença , Vasoespasmo Intracraniano/diagnóstico por imagem , Vasoespasmo Intracraniano/etiologia
4.
J Neurotrauma ; 40(13-14): 1481-1494, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36869619

RESUMO

Abstract Traumatic brain injury (TBI) continues to be a major cause of death and disability worldwide. This study assessed the effectiveness of non-invasive vagus nerve stimulation (nVNS) in reducing brain lesion volume and improving neurobehavioral performance in a rat model of TBI. Animals were randomized into three experimental groups: (1) TBI with sham stimulation treatment (Control), (2) TBI treated with five lower doses (2-min) nVNS, and (3) TBI treated with five higher doses (2 × 2-min) nVNS. We used the gammaCore nVNS device to deliver stimulations. Magnetic resonance imaging studies were performed 1 and 7 days post-injury to confirm lesion volume. We observed smaller brain lesion volume in the lower dose nVNS group compared with the control group on days 1 and 7. The lesion volume for the higher dose nVNS group was significantly smaller than either the lower dose nVNS or the control groups on days 1 and 7 post-injury. The apparent diffusion coefficient differences between the ipsilateral and contralateral hemispheres on day 1 were significantly smaller for the higher dose (2 × 2 min) nVNS group than for the control group. Voxel-based morphometry analysis revealed an increase in the ipsilateral cortical volume in the control group caused by tissue deformation and swelling. On day 1, these abnormal volume changes were 13% and 55% smaller in the lower dose and higher dose nVNS groups, respectively, compared with the control group. By day 7, nVNS dampened cortical volume loss by 35% and 89% in the lower dose and higher dose nVNS groups, respectively, compared with the control group. Rotarod, beam walking, and anxiety performances were significantly improved in the higher-dose nVNS group on day 1 compared with the control group. The anxiety indices were also improved on day 7 post-injury compared with the control and the lower-dose nVNS groups. In conclusion, the higher dose nVNS (five 2 × 2-min stimulations) reduced brain lesion volume to a level that further refined the role of nVNS therapy for the acute treatment of TBI. Should nVNS prove effective in additional pre-clinical TBI models and later in clinical settings, it would have an enormous impact on the clinical practice of TBI in both civilian and military settings, as it can easily be adopted into routine clinical practice.


Assuntos
Lesões Encefálicas Traumáticas , Estimulação do Nervo Vago , Ratos , Animais , Estimulação do Nervo Vago/métodos , Método Duplo-Cego , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/terapia , Encéfalo/diagnóstico por imagem
5.
Brain ; 134(Pt 5): 1506-18, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21596774

RESUMO

Hippocampal sclerosis is a relatively common neuropathological finding (∼10% of individuals over the age of 85 years) characterized by cell loss and gliosis in the hippocampus that is not explained by Alzheimer's disease. Hippocampal sclerosis pathology can be associated with different underlying causes, and we refer to hippocampal sclerosis in the aged brain as hippocampal sclerosis associated with ageing. Much remains unknown about hippocampal sclerosis associated with ageing. We combined three different large autopsy cohorts: University of Kentucky Alzheimer's Disease Centre, the Nun Study and the Georgia Centenarian Study to obtain a pool of 1110 patients, all of whom were evaluated neuropathologically at the University of Kentucky. We focused on the subset of cases with neuropathology-confirmed hippocampal sclerosis (n=106). For individuals aged≥95 years at death (n=179 in our sample), each year of life beyond the age of 95 years correlated with increased prevalence of hippocampal sclerosis pathology and decreased prevalence of 'definite' Alzheimer's disease pathology. Aberrant TAR DNA protein 43 immunohistochemistry was seen in 89.9% of hippocampal sclerosis positive patients compared with 9.7% of hippocampal sclerosis negative patients. TAR DNA protein 43 immunohistochemistry can be used to demonstrate that the disease is usually bilateral even when hippocampal sclerosis pathology is not obvious by haematoxylin and eosin stains. TAR DNA protein 43 immunohistochemistry was negative on brain sections from younger individuals (n=10) after hippocampectomy due to seizures, who had pathologically confirmed hippocampal sclerosis. There was no association between cases with hippocampal sclerosis associated with ageing and apolipoprotein E genotype. Age of death and clinical features of hippocampal sclerosis associated with ageing (with or without aberrant TAR DNA protein 43) were distinct from previously published cases of frontotemporal lobar degeneration TAR DNA protein 43. To help sharpen our ability to discriminate patients with hippocampal sclerosis associated with ageing clinically, the longitudinal cognitive profile of 43 patients with hippocampal sclerosis associated with ageing was compared with the profiles of 75 controls matched for age, gender, education level and apolipoprotein E genotype. These individuals were followed from intake assessment, with 8.2 (average) longitudinal cognitive assessments. A neuropsychological profile with relatively high-verbal fluency but low word list recall distinguished the hippocampal sclerosis associated with ageing group at intake (P<0.015) and also 5.5-6.5 years before death (P<0.005). This may provide a first step in clinical differentiation of hippocampal sclerosis associated with ageing versus pure Alzheimer's disease in their earliest stages. In summary, in the largest series of autopsy-verified patients with hippocampal sclerosis to date, we characterized the clinical and pathological features associated with hippocampal sclerosis associated with ageing.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/mortalidade , Estudos de Coortes , Proteínas de Ligação a DNA/metabolismo , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Testes Neuropsicológicos , Esclerose/etiologia , Esclerose/mortalidade , Esclerose/patologia
6.
Neurology ; 98(11): e1114-e1123, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35121669

RESUMO

BACKGROUND AND OBJECTIVES: Little is known about the effect of education or other indicators of cognitive reserve on the rate of reversion from mild cognitive impairment (MCI) to normal cognition (NC) or the relative rate (RR) of reversion from MCI to NC vs progression from MCI to dementia. Our objectives were to (1) estimate transition rates from MCI to NC and dementia and (2) determine the effect of age, APOE, and indicators of cognitive reserve on the RR of reversion vs progression using multistate Markov modeling. METHODS: We estimated instantaneous transition rates between NC, MCI, and dementia after accounting for transition to death across up to 12 assessments in the Nun Study, a cohort study of religious sisters aged 75+ years. We estimated RRs of reversion vs progression for age, APOE, and potential cognitive reserve indicators: education, academic performance (high school grades), and written language skills (idea density, grammatical complexity). RESULTS: Of the 619 participants, 472 were assessed with MCI during the study period. Of these 472, 143 (30.3%) experienced at least one reverse transition to NC, and 120 of the 143 (83.9%) never developed dementia (mean follow-up = 8.6 years). In models adjusted for age group and APOE, higher levels of education more than doubled the RR ratio of reversion vs progression. Novel cognitive reserve indicators were significantly associated with a higher adjusted RR of reversion vs progression (higher vs lower levels for English grades: RR ratio = 1.83; idea density: RR ratio = 3.93; and grammatical complexity: RR ratio = 5.78). DISCUSSION: Knowledge of frequent reversion from MCI to NC may alleviate concerns of inevitable cognitive decline in those with MCI. Identification of characteristics predicting the rate of reversion from MCI to NC vs progression from MCI to dementia may guide population-level interventions targeting these characteristics to prevent or postpone MCI and dementia. Research on cognitive trajectories would benefit from incorporating predictors of reverse transitions and competing events, such as death, into statistical modeling. These results may inform the design and interpretation of MCI clinical trials, given that a substantial proportion of participants may experience improvement without intervention.


Assuntos
Disfunção Cognitiva , Reserva Cognitiva , Demência , Idoso , Cognição , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Estudos de Coortes , Demência/diagnóstico , Demência/psicologia , Progressão da Doença , Humanos , Testes Neuropsicológicos
7.
Surg Neurol Int ; 13: 404, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36324951

RESUMO

Background: The awake craniotomy (AC) procedure allows for safe and maximal resection of brain tumors from highly eloquent regions. However, geriatric patients are often viewed as poor candidates for AC due to age and medical comorbidities. Frailty assessments gauge physiological reserve for surgery and are valuable tools for preoperative decision-making. Here, we present a novel case illustrating how frailty scoring enabled an elderly but otherwise healthy female to undergo successful AC for tumor resection. Case Description: A 92-year-old right-handed female with history of hypertension and basal cell skin cancer presented with a 1-month history of progressive aphasia and was found to have a ring-enhancing left frontoparietal mass abutting the rolandic cortex concerning for malignant neoplasm. Frailty scoring with the recalibrated risk analysis index (RAI-C) tool revealed a score of 30 (of 81) indicating low surgical risk. The patient and family were counseled appropriately that, despite advanced chronological age, a low frailty score predicts favorable surgical outcomes. The patient underwent left-sided AC for resection of tumor and experienced immediate improvement of speech intraoperatively. After surgery, the patient was neurologically intact and had an unremarkable postoperative course with significant improvements from preoperatively baseline at follow-up. Conclusion: To the best of our knowledge, this case represents the oldest patient to undergo successful AC for brain tumor resection. Nonfrail patients over 90 years of age with the proper indications may tolerate cranial surgery. Frailty scoring is a powerful tool for preoperative risk assessment in the geriatric neurosurgery population.

8.
Genes (Basel) ; 12(12)2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34946809

RESUMO

BACKGROUND: Signaling pathways mediated by microRNAs (miRNAs) have been identified as one of the mechanisms that regulate stroke progression and recovery. Recent investigations using stroke patient blood and cerebrospinal fluid (CSF) demonstrated disease-specific alterations in miRNA expression. In this study, for the first time, we investigated miRNA expression signatures in freshly removed human stroke brain tissue. METHODS: Human brain samples were obtained during craniectomy and brain tissue resection in severe stroke patients with life-threatening brain swelling. The tissue samples were subjected to histopathological and immunofluorescence microscopy evaluation, next generation miRNA sequencing (NGS), and bioinformatic analysis. RESULTS: miRNA NGS analysis detected 34 miRNAs with significantly aberrant expression in stroke tissue, as compared to non-stroke samples. Of these miRNAs, 19 were previously identified in stroke patient blood and CSF, while dysregulation of 15 miRNAs was newly detected in this study. miRNA direct target gene analysis and bioinformatics approach demonstrated a strong association of the identified miRNAs with stroke-related biological processes and signaling pathways. CONCLUSIONS: Dysregulated miRNAs detected in our study could be regarded as potential candidates for biomarkers and/or targets for therapeutic intervention. The results described herein further our understanding of the molecular basis of stroke and provide valuable information for the future functional studies in the experimental models of stroke.


Assuntos
Encéfalo/metabolismo , MicroRNAs/metabolismo , Acidente Vascular Cerebral/metabolismo , Encéfalo/cirurgia , Biologia Computacional/métodos , Craniectomia Descompressiva/métodos , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Transdução de Sinais/genética , Acidente Vascular Cerebral/cirurgia
10.
AJR Am J Roentgenol ; 193(1): 192-206, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19542414

RESUMO

OBJECTIVE: Toxic leukoencephalopathy may present acutely or subacutely with symmetrically reduced diffusion in the periventricular and supraventricular white matter, hereafter referred to as periventricular white matter. This entity may reverse both on imaging and clinically. However, a gathering together of the heterogeneous causes of this disorder as seen on MRI with diffusion-weighted imaging (DWI) and an analysis of their likelihood to reverse has not yet been performed. Our goals were to gather causes of acute or subacute toxic leukoencephalopathy that can present with reduced diffusion of periventricular white matter in order to promote recognition of this entity, to evaluate whether DWI with apparent diffusion coefficient (ADC) values can predict the extent of chronic FLAIR abnormality (imaging reversibility), and to evaluate whether DWI can predict the clinical outcome (clinical reversibility). MATERIALS AND METHODS: Two neuroradiologists retrospectively reviewed the MRI examinations of 39 patients with acute symptoms and reduced diffusion of periventricular white matter. The reviewers then scored the extent of abnormality on DWI and FLAIR. ADC ratios of affected white matter versus the unaffected periventricular white matter were obtained. Each patient's clinical records were reviewed to determine the cause and clinical outcome. Histology findings were available in three patients. Correlations were calculated between the initial MRI markers and both the clinical course and the follow-up extent on FLAIR using Spearman's correlation coefficient. RESULTS: Of the initial 39 patients, seven were excluded because of a nontoxic cause (hypoxic-ischemic encephalopathy [HIE] or congenital genetic disorders) or because of technical errors. In the remaining 32 patients, no correlation was noted between any of the initial MRI markers (percentage of ADC reduction, DWI extent, or FLAIR extent) with the clinical outcome. Three patients had histologic correlation. However, moderate correlation was seen between the extent of abnormality on initial FLAIR and the extent on follow-up FLAIR (r = 0.441, p = 0.047). Of the 13 patients who underwent repeat MRI at 21 days or longer, the reduced diffusion resolved in all but one. Significant differences were noted between ADC values in affected white matter versus unaffected periventricular white matter on initial (p < 0.0001) but not on follow-up MRI (p = 0.13), and in affected white matter on initial versus follow-up (p = 0.0014) in those individuals who underwent repeat imaging on the same magnet (n = 9), confirming resolution of the DWI abnormalities. CONCLUSION: Acute toxic leukoencephalopathy with reduced diffusion may be clinically reversible and radiologically reversible on DWI, and may also be reversible, but to a lesser degree, on FLAIR MRI. None of the imaging markers measured in this study appears to correlate with clinical outcome, which underscores the necessity for prompt recognition of this entity. Alerting the clinician to this potentially reversible syndrome can facilitate treatment and removal of the offending agent in the early stages.


Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Interpretação de Imagem Assistida por Computador/métodos , Leucoencefalite Hemorrágica Aguda/diagnóstico , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Remissão Espontânea , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
11.
Biochim Biophys Acta ; 1772(7): 797-803, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17560088

RESUMO

The incorporation of radioactive alpha tocopherol by various brain regions of wild type and apolipoprotein E (apoE)-deficient mice was investigated. Labeled tocopherol was injected into the lateral cerebral ventricles of 11 weeks old, male mice. Radioactive cholesterol injected simultaneously was used as an internal standard to account for experimental variability. Most areas of the brain of apoE-deficient mice took up less of alpha tocopherol per mg of protein than wild type animals. However, specific activity of alpha tocopherol was higher in cerebellum, pons, hypothalamus, midbrain and cerebral cortex in apoE-deficient brains than the wild type. This could be due to (a) the lower levels of alpha tocopherol in apoE-deficient brain and (b) reductions in the clearance and transport of tocopherol (possibly mediated by apoE). Tocopherol uptake by hippocampus was unusual since it was lower in apoE deficiency whether the data were expressed as specific activity or per mg of protein. Nearly all of the injected alpha tocopherol remained unchanged in the brains of both apoE-deficient and wild type animals suggesting low turnover. Overall, the current data reinforce the hypothesis that apoE is a key protein involved with the transport and/or retention of alpha tocopherol in brain.


Assuntos
Apolipoproteínas E/deficiência , Encéfalo/metabolismo , alfa-Tocoferol/farmacocinética , Animais , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , alfa-Tocoferol/administração & dosagem
12.
J Neurotrauma ; 35(1): 187-194, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28922962

RESUMO

We present a longitudinal study of cerebral metabolism using [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in a rat model of shockwave-induced traumatic brain injury (SW-TBI). Anesthetized rats received 5 or 10 SW pulses to the right anterior lateral or dorsal frontal regions using SW lithotripsy. Animals were scanned for FDG uptake at baseline, 3 h post-injury, and 3 days post-injury, using a small animal PET/computed tomography (CT) scanner. FDG uptake at all time-points was quantified as the ratio of brain activity relative to peripheral activity in the left ventricle (LV) in the heart (Abrain/ALV) for the entire brain, each hemisphere, and four cortices (motor, cingulate, somatosensory, and retrosplenial). The mixed-designed models analysis of variance (ANOVA) for the hemispheric and global FDG uptake ratio showed a significant effect of the time-of-scan (p = 0.038) and measured region (p = 6.12e-09). We also observed a significant effect of the time-of-scan (p = 0.046) and measured region (p = 2.28e-09) for the FDG uptake ratio in four cortical regions. None of the measurements (global or local) showed a significant effect for the number of SW pulses (5 or 10) or SW location (lateral or dorsal frontal regions). Our data suggest that SW-TBI causes hypermetabolism on the impact side of the rat brain at 3 h post-injury compared with the baseline measurements. However, the increase in FDG uptake by day 3 post-injury was not significant. Further studies on post-TBI metabolic changes are needed to understand better the pathophysiology of the injury.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Fluordesoxiglucose F18/metabolismo , Animais , Lesões Encefálicas Traumáticas/patologia , Modelos Animais de Doenças , Ondas de Choque de Alta Energia/efeitos adversos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/metabolismo , Ratos , Ratos Wistar
13.
J Neuropathol Exp Neurol ; 77(12): 1115-1121, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30295777

RESUMO

Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant CNS neoplasms that typically occur in children <2 years of age. These are characterized by high-grade histologic features and mutations of the INI1/SMARCB1 gene readily detected by loss of expression by immunohistochemistry. Among adults, the majority of AT/RTs occurs in the cerebral hemispheres. A small number of adult AT/RTs involving the sellar and suprasellar region reported in the literature suggest a distinct clinical course for this group. Here, we describe detailed clinical and genetic characterization of 5 adult patients with AT/RTs involving the sellar and suprasellar region, and provide a review of the available clinical and genetic features of 22 previously reported cases in order to help increase our understanding of this unusual entity.


Assuntos
Tumor Rabdoide/diagnóstico por imagem , Tumor Rabdoide/genética , Sela Túrcica/diagnóstico por imagem , Teratoma/diagnóstico por imagem , Teratoma/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Endocrinology ; 148(5): 2148-56, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17289849

RESUMO

Allopregnanolone (ALLO) and androsterone (ADT) are naturally occurring 3alpha-hydroxysteroids that act as positive allosteric regulators of gamma-aminobutyric acid type A receptors. In addition, ADT activates nuclear farnesoid X receptor and ALLO activates pregnane X receptor. At least with respect to gamma-aminobutyric acid type A receptors, the biological activity of ALLO and ADT depends on the 3alpha-hydroxyl group and is lost upon its conversion to either 3-ketosteroid or 3beta-hydroxyl epimer. Such strict structure-activity relationships suggest that the oxidation or epimerization of 3alpha-hydroxysteroids may serve as physiologically relevant mechanisms for the control of the local concentrations of bioactive 3alpha-hydroxysteroids. The exact enzymes responsible for the oxidation and epimerization of 3alpha-hydroxysteroids in vivo have not yet been identified, but our previous studies showed that microsomal nicotinamide adenine dinucleotide-dependent short-chain dehydrogenases/reductases (SDRs) with dual retinol/sterol dehydrogenase substrate specificity (RoDH-like group of SDRs) can oxidize and epimerize 3alpha-hydroxysteroids in vitro. Here, we present the first evidence that microsomal nicotinamide adenine dinucleotide-dependent 3alpha-hydroxysteroid dehydrogenase/epimerase activities are widely distributed in human tissues with the highest activity levels found in liver and testis and lower levels in lung, spleen, brain, kidney, and ovary. We demonstrate that RoDH-like SDRs contribute to the oxidation and epimerization of ALLO and ADT in living cells, and show that RoDH enzymes are expressed in tissues that have microsomal 3alpha-hydroxysteroid dehydrogenase/epimerase activities. Together, these results provide further support for the role of RoDH-like SDRs in human metabolism of 3alpha-hydroxysteroids and offer a new insight into the enzymology of ALLO and ADT inactivation.


Assuntos
3-alfa-Hidroxiesteroide Desidrogenase (B-Específica)/metabolismo , Hidroxiesteroides/metabolismo , Fígado/enzimologia , Microssomos/enzimologia , Testículo/enzimologia , 3-alfa-Hidroxiesteroide Desidrogenase (B-Específica)/genética , Encéfalo/enzimologia , Linhagem Celular , Ativação Enzimática , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Imuno-Histoquímica , Rim/citologia , Rim/enzimologia , Pulmão/enzimologia , Masculino , NAD/metabolismo , Ovário/enzimologia , Oxirredução , Baço/enzimologia , Transfecção
15.
J Neurosurg ; 107(6 Suppl): 500-3, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18154021

RESUMO

Neurocutaneous melanosis (NM) coexisting with the Dandy-Walker complex (DWC) is a rare condition, with fewer than 15 cases reported in the literature. The authors present a case of an infant with NM and DWC suffering from progressive brainstem compression following ventriculoperitoneal (VP) shunt placement for hydrocephalus. This 1-year-old boy with congenital melanocytic nevi had met normal developmental milestones until the age of 11 months, when he began regressing in ambulation and language function. Intractable vomiting had developed 1 week later. Magnetic resonance (MR) imaging of the brain revealed DWC with hydrocephalus, and spinal MR images demonstrated a proliferative process within the meninges, consistent with NM. The patient underwent right frontal VP shunt placement resulting in immediate symptom relief, but 3 weeks later became irritable, increasingly lethargic, unable to pull to stand, and unable to tolerate solid food without choking. Due to these symptoms and intractable vomiting, the patient presented to the authors' institution. Brain MR imaging revealed a new-onset diffuse cystic process with anterior and posterior brainstem compression, marked kinking of the cervicomedullary junction, melanocyte pigmentation of the left temporal lobe, diffuse leptomeningeal enhancement, and no evidence of hydrocephalus. Consistent with these imaging findings, the degree of brainstem involvement upon gross visualization predictably deterred resection attempts beyond those necessary for biopsy. Pathological examination revealed diffuse melanocytosis, and the family decided not to pursue aggressive measures postoperatively. This report indicates the potential for rapid intracranial manifestation of diffuse melanocytosis in NM patients. Although the prognosis is poor, early neurosurgical involvement in these patients may provide tissue diagnosis and the potential for decompression if the process is caught early in its course.


Assuntos
Tronco Encefálico/patologia , Síndrome de Dandy-Walker/patologia , Hidrocefalia/complicações , Hidrocefalia/cirurgia , Melanose/patologia , Síndromes de Compressão Nervosa/etiologia , Síndromes de Compressão Nervosa/patologia , Síndromes Neurocutâneas/patologia , Complicações Pós-Operatórias/patologia , Derivação Ventriculoperitoneal/efeitos adversos , Síndrome de Dandy-Walker/complicações , Humanos , Lactente , Laminectomia , Imageamento por Ressonância Magnética , Masculino , Melanose/complicações , Melanose/cirurgia , Síndromes Neurocutâneas/complicações , Síndromes Neurocutâneas/cirurgia , Procedimentos Neurocirúrgicos , Prognóstico
16.
AJR Am J Roentgenol ; 189(4): 904-12, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17885064

RESUMO

OBJECTIVE: Posterior reversible encephalopathy syndrome (PRES) is classically characterized as symmetric parietooccipital edema but may occur in other distributions with varying imaging appearances. This study determines the incidence of atypical and typical regions of involvement and unusual imaging manifestations. MATERIALS AND METHODS: Seventy-six patients were eventually included as having confirmed PRES from 111 initially suspected cases, per imaging and clinical follow-up. Two neuroradiologists retrospectively reviewed each MR image. Standard sequences were unenhanced FLAIR and T1- and T2-weighted images in all patients, with diffusion-weighted imaging (n = 75) and contrast-enhanced T1-weighted imaging (n = 69) in most. The regions involved were recorded on the basis of FLAIR findings, and the presence of atypical imaging findings (contrast enhancement, restricted diffusion, hemorrhage) was correlated with the severity (extent) of hyperintensity or mass effect on FLAIR. RESULTS: The incidence of regions of involvement was parietooccipital, 98.7%; posterior frontal, 78.9%; temporal, 68.4%; thalamus, 30.3%; cerebellum, 34.2%; brainstem, 18.4%; and basal ganglia, 11.8%. The incidence of less common manifestations was enhancement, 37.7%; restricted diffusion, 17.3%; hemorrhage, 17.1%; and a newly described unilateral variant, 2.6%. Poor correlation was found between edema severity and enhancement (r = 0.072), restricted diffusion (r = 0.271), hemorrhage (r = 0.267), blood pressure (systolic, r = 0.13; diastolic, r = 0.02). Potentially new PRES causes included contrast-related anaphylaxis and alcohol withdrawal. CONCLUSION: This large series of PRES cases shows that atypical distributions and imaging manifestations of PRES have a higher incidence than commonly perceived, and atypical manifestations do not correlate well with the edema severity.


Assuntos
Edema Encefálico/epidemiologia , Edema Encefálico/patologia , Imageamento por Ressonância Magnética/estatística & dados numéricos , Medição de Risco/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Fatores de Risco , Síndrome
17.
J Clin Neurosci ; 41: 75-77, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28291643

RESUMO

The optimal treatment of pituitary carcinomas (PC) is unknown. Treatment includes surgical resection, radiation, and more recently, temozolomide (TMZ). Pituitary adenomas have relatively high expression of vascular endothelial growth factor; therefore, bevacizumab, an antiangiogenic agent, has been used in a small number of aggressive or malignant pituitary tumors after recurrence. However, it has not been administered concurrently with other chemotherapeutic agents or combined with radiation therapy in PC. We present a 63-year-old man with an adrenocorticotropic hormone (ACTH)-secreting PC, causing visual loss. It was resected transsphenoidally. There were several notable factors placing the patient at high risk for recurrence including distant metastasis in the form of a pulmonary nodule. Morphologically, his tumor was a pituitary neoplasm with malignant histopathologic features. It had abundant mitotic figures and zones of necrosis. Six weeks post-surgery, the patient started concurrent chemoradiation, using combination therapy with TMZ and bevacizumab. TMZ was continued for 12 cycles in the adjuvant setting. The ACTH was effective as a serum-based tumor marker and normalized during treatment. The patient is alive, five years after diagnosis, with no recurrence to date. This is the first case of pituitary carcinoma treated successfully with concurrent chemoradiation therapy that combined TMZ and bevacizumab with a long-term follow up.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma/terapia , Quimiorradioterapia , Dacarbazina/análogos & derivados , Neoplasias Hipofisárias/terapia , Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab/administração & dosagem , Carcinoma/cirurgia , Dacarbazina/administração & dosagem , Dacarbazina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/cirurgia , Temozolomida
19.
Cell Rep ; 18(1): 23-31, 2017 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-28052252

RESUMO

While several studies link the cell-surface marker CD44 to cancer progression, conflicting results show both positive and negative correlations with increased CD44 levels. Here, we demonstrate that the survival outcomes of genetically induced glioma-bearing mice and of high-grade human glioma patients are biphasically correlated with CD44 level, with the poorest outcomes occurring at intermediate levels. Furthermore, the high-CD44-expressing mesenchymal subtype exhibited a positive trend of survival with increased CD44 level. Mouse cell migration rates in ex vivo brain slice cultures were also biphasically associated with CD44 level, with maximal migration corresponding to minimal survival. Cell simulations suggest that cell-substrate adhesiveness is sufficient to explain this biphasic migration. More generally, these results highlight the potential importance of non-monotonic relationships between survival and biomarkers associated with cancer progression.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Movimento Celular , Glioma/metabolismo , Glioma/patologia , Receptores de Hialuronatos/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Humanos , Camundongos Endogâmicos C57BL , Análise de Sobrevida , Transposases/metabolismo
20.
World J Virol ; 5(1): 31-7, 2016 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-26870672

RESUMO

AIM: To investigate the neuropathology of the brain in a rare case of remission following diagnosis of progressive multifocal leukoencephalopathy (PML). METHODS: Consent from the family for an autopsy was obtained, clinical records and radiograms were retrieved. A complete autopsy was performed, with brain examination after fixation and coronal sectioning at 1 cm intervals. Fourteen regions were collected for paraffin embedding and staining for microscopic analysis. Histologic sections were stained with Luxol blue, hematoxylin/eosin, and immunostained for myelin basic protein, neurofilament, SV40 T antigen and p53. The biopsy material was also retrieved and sections were stained with hematoxylin/eosin and immunostained for SV40 and p53. Sections were examined by American Board of Pathology certified pathologists and images captured digitally. RESULTS: Review of the clinical records was notable for a history of ulcerative colitis resulting in total colectomy in 1977 and a liver transplant in 1998 followed by immune-suppressive therapy. Neurological symptoms presented immediately, therefore a biopsy was obtained which was diagnosed as PML. Immunotherapy was adjusted and clinical improvement was noted. No subsequent progression was reported. Review of the biopsy demonstrated atypical astrocytes and enlarged hyperchromatic oligodendroglial cells consistent with JC virus infection. Strong SV40 and p53 staining was found in glial cells and regions of dense macrophage infiltration were present. On gross examination of the post-mortem brain, a lesion in the same site as the original biopsy in the cerebellum was identified but no other lesions in the brain were found. Microscopic analysis of this cerebellar lesion revealed a loss of myelin and axons, and evidence of axonal damage. This single burned-out lesion was equivocally positive for SV40 antigen with little p53 staining. Examination of thirteen other brain regions found no other occult sites. CONCLUSION: Our study reveals residual damage, rare macrophages or other inflammation and minimal evidence of persistent virus. This case demonstrates the possibility of complete remission of PML.

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