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J. Hugh Webb, Winchell McK. Craig and James W. Kernohan

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Jason G. Mandell, Jack W. Langelaan, Andrew G. Webb and Steven J. Schiff

OBJECT

Accurate edge tracing segmentation remains an incompletely solved problem in brain image analysis. The authors propose a novel algorithm using a particle filter to follow the boundary of the brain in the style often used in autonomous air and ground vehicle navigation. Their goals were to create a versatile tool to segment brain and fluid in MRI and CT images of the developing brain, lay the foundation for an intelligent automated edge tracker that is modality independent, and segment normative data from MRI that can be applied to both MRI and CT.

METHODS

Simulated MRI data sets were used to train and evaluate the particle filter segmentation algorithm. The method was then applied to produce normative growth curves for children and adolescents from 0 to 18 years of age for brain and fluid from MR images from the National Institutes of Health pediatric database and these data were compared to historical results. The authors further adapted this method for use with CT images of pediatric hydrocephalus and compared the results with hand-segmented data.

RESULTS

Segmentation of simulated MRI data with varied levels of noise (0%–9%) and spatial inhomogeneity (0%–40%) resulted in percent errors ranging from 0.06% to 5.38% for brain volume and 2.45% to 22.3% for fluid volume. The authors used this tool to create normal brain and CSF growth curves from MR images. The calculated growth curves showed excellent consistency with historical data. Additionally, compared with manual segmentation the particle filter accurately segmented brain and fluid volumes from CT scans of 5 pediatric patients with hydrocephalus (p < 0.001).

CONCLUSIONS

The authors have produced the first normative brain and CSF growth curves for children and adolescents 0–18 years of age. In addition, this study includes the first use of a particle filter as an edge tracker in image segmentation and offers a semiautomatic method to segment both pediatric and adult brain data from MR and CT images. The particle filter has the potential to be further automated toward a clinical rather than research tool with both of these modalities. Because of its modality independence, it has the capability to allow CT to be a more effective diagnostic tool for neurological disorders, a task of substantial importance in emergency settings and in developing countries where CT is often the only available method of brain imaging.

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Jeffrey J. Laurent, K. Michael Webb, Elisa J. Beres, Kevin McGee, Jinzhong Li, Bert van Rietbergen and Gregory A. Helm

Object. Fusion procedures in the lumbar spine have been performed in the US since 1911. Since that time, the indications and techniques for spinal fusion have evolved. Despite technical advancements, spinal fusion remains a major operation, and fusion nonunion rates of up to 35% are still reported. In this study, the authors were able to induce intertransverse process fusions in immune-competent New Zealand White rabbits by percutaneous administration of an adenoviral vector containing the bone morphogenetic protein (BMP-6) gene (Ad-BMP-6). The results represent an important step forward in finding new methods to increase the success and decrease the morbidity associated with spinal fusion.

Methods. Five New Zealand White rabbits were used. Injection of the adenoviral construct was performed at multiple levels (bilaterally) in each animal while using fluoroscopic guidance. Injection consisted of either Ad-BMP-6 or Ad—β-galactosidase (β-gal) (control). Because multiple levels were injected, each animal served as an internal control. The animals underwent postinjection computerized tomography (CT) scanning at 7 and 14 weeks. After undergoing final CT scanning, the animals were killed and the spines were harvested. The fusion sites were analyzed by gross inspection, histopathological methods, and micro—CT studies.

Conclusions. The results of this study show that an anatomically precise fusion can be accomplished by percutaneous administration of gene therapy. The next step in these studies will be extension of the technique to nonhuman primates and eventually to human clinical studies.

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Ann-Shung Lieu, Jin Zhong Li, Donna J. Webb, Gerald R. Hankins, Shen-long Howng and Gregory A. Helm

Object

Promotion of the repair and regeneration of damaged adult neurons is a major goal of neurological science. In this study, the effects of G protein–coupled receptor kinase interacting protein 1 (GIT1) overexpression in human neuron cells were tested in human neuronal cells by using an adenoviral vector.

Methods

A recombinant GIT1 and enhanced green fluorescent protein (EGFP) adenoviral vector (AdGIT1) was created by using a standard viral construction procedure. Human neuronal (NT2N) cells, which had been derived from an NT2 human teratocarcinoma cell line, were used in this experiment. Immunocytochemical methods were applied to identify NT2N cells with neural features and to probe the relationship among signaling proteins. Several biological activities were assessed, including neural spine formation, cell migration, and the levels of expression of growth-associated protein–43 (GAP-43) and active Cdc42. The number of cells with spine formation and the number of migrated cells were significantly higher in the AdGIT1-treated group of NT2N cells than in untreated (control) NT2N cells or in AdEGFP-treated NT2N cells. The levels of GAP-43 and active Cdc42 expression were significantly higher in the AdGIT1-treated group than that in the other two cell groups.

Conclusions

The results of this study demonstrate that GIT1 overexpression has the potential to promote neural spine formation and cell migration in human neuronal cells. At the same time, the increased level of GAP-43 in GIT1-overexpressed cells indicates that GIT1 may have the potential to improve growth and regeneration of damaged axons. The GIT1–β-PIX–Cdc42–PAK pathway may play an important role in neuronal outgrowth.

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Jason G. Mandell, Thomas Neuberger, Corina S. Drapaca, Andrew G. Webb and Steven J. Schiff

Object

Hydrocephalus has traditionally been quantified by linear measures of ventricular size, with adjunct use of cortical mantle thickness. However, clinical outcome depends on cognitive function, which is more directly related to brain volume than these previous measures. The authors sought to quantify the dynamics of brain and ventricular volume growth in normal compared with hydrocephalic mice.

Methods

Hydrocephalus was induced in 14-day-old C57BL/6 mice by percutaneous injection of kaolin into the cisterna magna. Nine hydrocephalic and 6 normal mice were serially imaged from age 2–12 weeks with a 14.1-T MR imaging unit. Total brain and ventricle volumes were calculated, and linear discriminant analysis was applied.

Results

Two very different patterns of response were seen in hydrocephalic mice compared with mice with normative growth. In one pattern (3 mice) brain growth was normal despite accumulation of CSF, and in the second pattern (6 mice) abnormal brain enlargement was accompanied by increased CSF volume along with parenchymal edema. In this latter pattern, spontaneous ventricular rupture led to normalization of brain volume, implying edema from transmantle pressure gradients. These 2 patterns of hydrocephalus were significantly discriminable using linear discriminant analysis (p < 0.01). In contrast, clinically relevant measurements of head circumference or frontal and occipital horn ratios were unable to discriminate between these patterns.

Conclusions

This study is, to the authors' knowledge, the first serial quantification of the growth of brain and ventricle volumes in normal versus hydrocephalic development. The authors' findings demonstrate the feasibility of constructing normative curves of brain and fluid growth as complements to normative head circumference curves. By measuring brain volumes, distinct patterns of brain growth and enlargement can be observed, which are more likely linked to cognitive development and clinical outcome than fluid volumes alone.

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Oliver D. Mrowczynski, Russell A. Payne, Alexandre J. Bourcier, Christine Y. Mau, Becky Slagle-Webb, Ganesh Shenoy, Achuthamangalam B. Madhankumar, Stephan B. Abramson, Darren Wolfe, Kimberly S. Harbaugh, Elias B. Rizk and James R. Connor

OBJECTIVE

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that harbor a high potential for metastasis and have a devastating prognosis. Combination chemoradiation aids in tumor control and decreases tumor recurrence but causes deleterious side effects and does not extend long-term survival. An effective treatment with limited toxicity and enhanced efficacy is critical for patients suffering from MPNSTs.

METHODS

The authors recently identified that interleukin-13 receptor alpha 2 (IL-13Rα2) is overexpressed on MPNSTs and could serve as a precision-based target for delivery of chemotherapeutic agents. In the work reported here, a recombinant fusion molecule consisting of a mutant human IL-13 targeting moiety and a point mutant variant of Pseudomonas exotoxin A (IL-13.E13 K-PE4E) was utilized to treat MPNST in vitro in cell culture and in an in vivo murine model.

RESULTS

IL-13.E13 K-PE4E had a potent cytotoxic effect on MPNST cells in vitro. Furthermore, intratumoral administration of IL-13.E13 K-PE4E to orthotopically implanted MPNSTs decreased tumor burden 6-fold and 11-fold in late-stage and early-stage MPNST models, respectively. IL-13.E13 K-PE4E treatment also increased survival by 23 days in the early-stage MPNST model.

CONCLUSIONS

The current MPNST treatment paradigm consists of 3 prongs: surgery, chemotherapy, and radiation, none of which, either singly or in combination, are curative or extend survival to a clinically meaningful degree. The results presented here provide the possibility of intratumoral therapy with a potent and highly tumor-specific cytotoxin as a fourth treatment prong with the potential to yield improved outcomes in patients with MPNSTs.

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Jason G. Mandell, Kenneth L. Hill, Dan T. D. Nguyen, Kevin W. Moser, Robert E. Harbaugh, James McInerney, Brian Kaaya Nsubuga, John K. Mugamba, Derek Johnson, Benjamin C. Warf, Warren Boling, Andrew G. Webb and Steven J. Schiff

OBJECT

The incidence of temporal lobe epilepsy (TLE) due to mesial temporal sclerosis (MTS) can be high in developing countries. Current diagnosis of MTS relies on structural MRI, which is generally unavailable in developing world settings. Given widespread effects on temporal lobe structure beyond hippocampal atrophy in TLE, the authors propose that CT volumetric analysis can be used in patient selection to help predict outcomes following resection.

METHODS

Ten pediatric patients received preoperative CT scans and temporal resections at the CURE Children's Hospital of Uganda. Engel classification of seizure control was determined 12 months postoperatively. Temporal lobe volumes were measured from CT and from normative MR images using the Cavalieri method. Whole brain and fluid volumes were measured using particle filter segmentation. Linear discrimination analysis (LDA) was used to classify seizure outcome by temporal lobe volumes and normalized brain volume.

RESULTS

Epilepsy patients showed normal to small brain volumes and small temporal lobes bilaterally. A multivariate measure of the volume of each temporal lobe separated patients who were seizure free (Engel Class IA) from those with incomplete seizure control (Engel Class IB/IIB) with LDA (p < 0.01). Temporal lobe volumes also separate normal subjects, patients with Engel Class IA outcomes, and patients with Class IB/IIB outcomes (p < 0.01). Additionally, the authors demonstrated that age-normalized whole brain volume, in combination with temporal lobe volumes, may further improve outcome prediction (p < 0.01).

CONCLUSIONS

This study shows strong evidence that temporal lobe and brain volume can be predictive of seizure outcome following temporal lobe resection, and that volumetric CT analysis of the temporal lobe may be feasible in lieu of structural MRI when the latter is unavailable. Furthermore, since the authors' methods are modality independent, these findings suggest that temporal lobe and normative brain volumes may further be useful in the selection of patients for temporal lobe resection when structural MRI is available.