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PubMed2000

EGFRvIII as a promising target for antibody-based brain tumor therapy.

Cell surface receptors are attractive candidates for targeted therapy of cancer. Growth factors and their receptors play important roles in the regulation of cell division, development, and differentiation. Among those, the epidermal growth factor receptor (EGFR) was the first identified to be amplified and/or rearranged in malignant gliomas. The most common rearranged form, EGFR type III variant (EGFRvIII), has a deletion in its extracellular domain that results in the formation of a new, tumor-specific target found in glioblastoma multiforme, as well as in breast, ovarian, prostate, and lung carcinomas. Monoclonal antibodies have been developed with specific activity against this mutant receptor. These antibodies are internalized into the cell after receptor binding. Specific antibodies, either unarmed or armed with cytotoxic agents, including radioisotopes and toxins, have shown a promising role for EGFRvIII as a target for brain tumor therapy.

Animals↗
PubMed2006

Variability in hospital-based brain death guidelines in Canada.

PURPOSE: Variability has been reported in the practices to determine death by neurological criteria for adults and children. The objective of this study was to determine if this variability exists in the Canadian context. METHODS: A cross-sectional survey of the Canadian intensive care units (ICUs) involved in the care of potential organ donors, and Canadian organ procurement organizations (OPOs) was undertaken. We contacted the medical directors of these units and asked them to provide their guidelines for the neurological determination of death (NDD). A framework, which identifies key diagnostic criteria for NDD, was used to assess the content of all study documents. RESULTS: With a response rate of 68%, we found that key diagnostic criteria for NDD were incorporated inconsistently in the guidelines from Canadian ICUs and OPOs. Areas of concern include omissions in: the testing of brainstem reflexes; components of the apnea test; indications for the use of supplementary testing; wait intervals prior to performing the first NDD examination; the definition of NDD; and potential confounding factors. In addition, inconsistencies were found pertaining to wait intervals required between examinations and the legal timing of death. CONCLUSION: These findings reinforce the need to standardize the practice of the neurological determination of death in Canadian centres, which has the potential to reduce practice variation. Clear medical standards for NDD augment the quality, rigour and credibility of this determination.

Adult↗
PubMed2001

Comparison of visual and ROI-based brain tumour grading using 18F-FDG PET: ROC analyses.

Several studies have suggested that the use of simple visual interpretation criteria for the investigation of brain tumours by positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET) might be similarly or even more accurate than quantitative or semi-quantitative approaches. We investigated this hypothesis by comparing the accuracy of FDG-PET brain tumour grading using a proposed six-step visual grading scale (VGS; applied by three independent observers unaware of the clinical history and the results of histopathology) and three different region of interest (ROI) ratios (maximal tumour uptake compared with contralateral tissue [Tu/Tis], grey matter [Tu/GM] and white matter [Tu/WM]). The patient population comprised 47 patients suffering from 17 benign (7 gliomas of grade II, 10 non-gliomatous tumours) and 30 malignant (23 gliomas of grade III-IV, 7 non-gliomatous tumours) tumours. The VGS results were highly correlated with the different ROI ratios (R=0.91 for Tu/GM, R=0.82 for Tu/WM, and R=0.79 for Tu/Tis), and high inter-observer agreement was achieved (kappa=0.63, 0.76 and 0.81 for the three observers). The mean ROI ratios and VGS readings of gliomatous and non-gliomatous lesions were not significantly different. For all measures, high-grade lesions showed significantly higher FDG uptake than low-grade lesions (P<0.005 to P<0.0001, depending on the measure used). Nominal logistic regressions and receiver operating characteristic (ROC) analyses were used to calculate cut-off values to differentiate low- from high-grade lesions. The predicted (by ROC) diagnostic sensitivity/specificity of the different tests (cut-off ratios shown in parentheses) were: Tu/GM: 0.87/0.85 (0.7), Tu/WM: 0.93/0.80 (1.3). Tu/Tis: 0.80/0.80 (0.8) and VGS: 0.84/0.95 (uptake < GM, but >> WM). The VGS yielded the highest Az (+/-SE) value (i.e. area under the ROC curve as a measure of predicted accuracy), 0.97+/-0.03, which showed a strong tendency towards being significantly greater than the Az of Tu/Tis (0.88+/-0.06; P=0.06). Tu/GM (0.92+/-0.04) and Tu/WM (0.91+/-0.05) reached intermediate Az values (not significantly different from any other value). We conclude that the VGS represents a measure at least as accurate as the Tu/GM and Tu/WM ratios. The Tu/Tis ratio is less valid owing to the high dependence on the location of the lesion. Depending on the investigator's experience and the structure of the lesions, the easily used VGS might be the most favourable grading criterion.

Adolescent↗
PubMed2000

Behavioral evidence for brain-based ability factors in visuospatial information processing.

The present study examined possible parallels between the structure of human visuospatial abilities and the organization of the neural systems. Forty-eight participants were tested on seven speeded visuospatial tasks. Three of these tasks were constructed so as to rely primarily on known ventral stream functions and four were constructed so as to rely primarily on known dorsal stream functions. Both sets of tasks spanned approximately the same range of difficulty as indexed by both the speed and accuracy of decision making. Factor analysis of response times on the seven tasks revealed only two significant factors. The putative ventral stream tasks all loaded heavily on one factor (mean loading=0.843) but only weakly on the other factor (mean loading=0.222); the putative dorsal stream tasks showed the opposite pattern in that they all loaded heavily on the second factor (mean loading=0.828) but only weakly on the first factor (mean loading=0.229). These findings are consistent with the hypothesis that human visuospatial abilities can be classified using categories based on the specializations of underlying neural structures and systems.

Adult↗
PubMed2007

Targeting the cerebrovascular large neutral amino acid transporter (LAT1) isoform using a novel disulfide-based brain drug delivery system.

We describe a novel strategy to achieve high affinity recognition for the specific, cerebrovascular large neutral amino acid transporter (LAT1) isoform by covalent coupling of small molecules to the amino acid, L-cysteine (L-Cys). L-Cys (as the carrier) was covalently attached via a disulfide bond to either 6-mercaptopurine or 2-methyl-1-propanethiol (IBM) to form the brain-targeted drug delivery systems (BTDS). BTDS were designed for high affinity recognition by LAT1 at the cerebrovasculature. Using an in situ rat brain perfusion technique, competition between BTDS and the radiotracer [14C]L-Leu demonstrated significant inhibition of [14C]L-Leu brain uptake. BTDS possess affinity for cerebrovascular LAT1 in many distinct brain compartments, and the recognition of BTDS by LAT1 is influenced by hydrophobicity of the side-chain in BTDS. Thus, the BTDS strategy may be utilized for rapid shuttling of various neuropharmaceuticals into brain.

Algorithms↗
PubMed1999

Frequency component selection for an EEG-based brain to computer interface.

A new communication channel for severely handicapped people could be opened with a direct brain to computer interface (BCI). Such a system classifies electrical brain signals online. In a series of training sessions, where electroencephalograph (EEG) signals are recorded on the intact scalp, a classifier is trained to discriminate a limited number of different brain states. In a subsequent series of feedback sessions, where the subject is confronted with the classification results, the subject tries to reduce the number of misclassifications. In this study the relevance of different spectral components is analyzed: 1) on the training sessions to select optimal frequency bands for the feedback sessions and 2) on the feedback sessions to monitor changes.

Adult↗
PubMed2006

Electrocorticography-based brain computer interface--the Seattle experience.

Electrocorticography (ECoG) has been demonstrated to be an effective modality as a platform for brain-computer interfaces (BCIs). Through our experience with ten subjects, we further demonstrate evidence to support the power and flexibility of this signal for BCI usage. In a subset of four patients, closed-loop BCI experiments were attempted with the patient receiving online feedback that consisted of one-dimensional cursor movement controlled by ECoG features that had shown correlation with various real and imagined motor and speech tasks. All four achieved control, with final target accuracies between 73%-100%. We assess the methods for achieving control and the manner in which enhancing online control can be accomplished by rescreening during online tasks. Additionally, we assess the relevant issues of the current experimental paradigm in light of their clinical constraints.

Cerebral Cortex↗
PubMed2006

Long-term changes of functional MRI-based brain function, behavioral status, and histopathology after transient focal cerebral ischemia in rats.

BACKGROUND AND PURPOSE: The relation between recovery of brain function and neurological status after clinical and experimental cerebral ischemia is incompletely characterized. We assessed the evolution of ischemic injury, behavioral status, and brain activity at acute to chronic periods after transient middle cerebral artery occlusion (tMCAO) in rats. METHODS: Male Sprague-Dawley rats were subjected to 20-minute tMCAO (n=10) or sham operation (n=10). Sensorimotor behavioral testing and multimodal (diffusion, perfusion, T2, and functional) MRI, as well as postmortem hematoxylin-eosin staining, were performed before and up to 21 days after tMCAO. MRI and histological parameters were evaluated in 5 regions of interest within the sensorimotor network. Diffusion, perfusion, and T2 lesion volumes were calculated according to previously established viability thresholds. RESULTS: Diffusion and perfusion lesions were present during occlusion but disappeared completely and permanently within 30 minutes after reperfusion, with no T2 lesions seen. Functional MRI and behavioral deficits did not normalize until 1 and 21 days after tMCAO, respectively. Histology demonstrated selective neuronal cell death at 7 and 21 days after reperfusion. CONCLUSIONS: Twenty-minute tMCAO produced distinct changes on multimodal MRI, histology, and behavioral parameters acutely and chronically. Normal findings on MRI after transient ischemia may not indicate normal tissue status, as behavioral and histological anomalies remain. Behavioral dysfunction persisting long after the recovery of MRI parameters may relate to the subtle neuronal damage seen on histology. Together, these results may help explain unremitting neurological deficits in stroke or transient ischemic attack patients with normal MRI findings.

Animals↗
PubMed2000

Endocytosis and transcytosis of an immunoliposome-based brain drug delivery system.

Immunoliposomes conjugated with the OX26 monoclonal antibody to the rat transferrin receptor can be used for brain delivery of small molecules. In the present study the uptake of OX26-immunoliposomes by target cells as well as their transcytosis across the blood-brain barrier was investigated. Microscopy of RG2 rat glioma cells incubated with fluorescence labeled OX26-immunoliposomes revealed intracellular co-localization of liposomal cargo, the liposomal membrane bilayer and the OX26 monoclonal antibody. The distinct particulate staining pattern was indicative for accumulation of OX26-immunoliposomes within endosomal or lysosomal compartments. Prolonged incubations demonstrated endosomal release of the liposomal cargo propidium iodide to the cytoplasm. A maximum of 50% of propidium iodide was released from the endosomal compartment after 24 hours of incubation. Transcytosis was studied using an in vitro model of the blood-brain barrier consisting of immortalized RBE4 rat brain endothelial cells. OX26-immunoliposomes did permeate across the RBE4 cell monolayer and showed a permeability coefficient of P(app) = 1.6 x 10(-5) ml/s. Transport was inhibited at low temperature, by competition with free OX26 or by exchanging the OX26 monoclonal antibody for an unspecific isotype antibody. Transcytosis of OX26-immunolipsomes was confirmed in vivo by the brain perfusion and capillary depletion technique. OX26-immunoliposomes were detected within the post-vascular compartment of brain parenchyma (PS product = 2.4 microl/g/min.) and were not associated with the brain microvasculature.

Animals↗
PubMed1983

[Giant brain-base aneurysm--manifested by psychotic symptoms].

An extensive aneurysm in two lobes simulated schizophrenic behavior for six months in a 55-year old man. Headaches, neurological symptoms, unconsciousness and computed tomography led to the diagnosis of a frontobasal tumor. The patient died several days later on hematocephalus internus and constriction of the cerebellum in the foramen occipitale magnum, followed by aneurysm wall dissection. This case shows the necessity of complementing computed tomography with angiography and all other possible tests for exogenous causes of psychotic symptoms.

Autopsy↗