Topographic hub maps of the human structural neocortical network

Hubs within the neocortical structural network determined by graph theoretical analysis play a crucial role in brain function. We mapped neocortical hubs topographically, using a sample population of 63 young adults. Subjects were imaged with high resolution structural and diffusion weighted magnetic resonance imaging techniques. Multiple network configurations were then constructed per subject, using random parcellations to define the nodes and using fibre tractography to determine the connectivity between the nodes. The networks were analysed with graph theoretical measures. Our results give reference maps of hub distribution measured with betweenness centrality and node degree. The loci of the hubs correspond with key areas from known overlapping cognitive networks. Several hubs were asymmetrically organized across hemispheres. Furthermore, females have hubs with higher betweenness centrality and males have hubs with higher node degree. Female networks have higher small-world indices

SWI-informed diffusion tensor tractography

Introduction In diffusion tensor tractography (DTT), white matter structure is inferred in vivo by reconstructing fiber tracts from diffusion weighted images (DWI). Recently [1], white matter structure has also been shown at 7T using susceptibility weighted imaging (SWI) [2]. Most notably, SWI shows excellent contrast between the highly myelinated optic radiation (OR) and the surrounding white matter [3]. Because DTT attempts to reconstruct tracts from voxels orders of magnitude larger than the underlying substrate, it suffers from partial volume effects in voxels that contain multiple or incoherently oriented tracts, resulting in false positive and false negative tracts. Tractography might therefore benefit from the combination of the diffusion tensor with the white matter contrasts in SWI which can be obtained at a much higher resolution. We have adapted a DTT algorithm to include the structure tensor [4] of the SWI magnitude in order to improve tractography in locations where DWI and SWI provide complementary information. Methods DWI (3T; 32-ch coil; twice-refocused spin echo EPI; 61+7 gradient directions; b=1000 s/mm2; TR=8300 ms; TE=95 ms; matrix size=110x110; FOV=220x220 mm; slice thickness=2.0 mm; number of slices=64) and SWI (7T; 8-ch coil; sagittal orientation; TR=36 ms; TE=25 ms; flip angle=15°; matrix size=448x336; FOV=224x168 mm; slice thickness=0.5 mm; number of slices=208; BW=120 Hz/px; acquisition time=20 min) were recorded from a healthy volunteer. The DWI mean b0 image and SWI were bias field corrected and then coregistered with FSL using the normalized mutual information algorithm and weighting volumes. The diffusion tensor and structure tensor fields were reconstructed from the DWI and SWI volumes, respectively. The structure tensor was calculated as the partial derivatives [dxx,dxy,dxz; dyx,dyy,dyz; dzx,dzy,dzz] of the SWI magnitude and every structure tensor component was smoothed (FWHM = 2.5 mm). Tractography was performed using Camino (PICo; 5000 iterations; curvature threshold = 80º; FA threshold = 0.10; step size = 0.50 mm). The structure tensor information was incorporated by requiring that the tracking direction be in the plane orthogonal to the first eigenvector of the structure tensor (ST ϵ1). This plane is assumed to be aligned to the direction of the tract that causes the intensity variation. The tracking direction within this plane is determined as the projection of the diffusion tensor onto the plane. To avoid adapted tracking directions where the structure tensor was non-informative, it was used only if the first eigenvalue of the structure tensor (ST λ1) > 100. For evaluating the performance, seeds were placed in the OR posterior to the point where it merged with the splenium of the corpus callosum (SCC). Waypoints were created anterior to the split in both the OR and SCC. Fractions of streamlines crossing these waypoints were extracted for both DTT and SWI-informed DTT. Results and Discussion Although the main tracts were similar for both DTT and SWI-informed DTT, the algorithms often showed very different branching patterns and more subtle differences in the course of the tracts. Examples are provided in Fig 1&2. In Fig 1 a putatively more accurate tracking of the OR using SWI-informed DTT compared to DTT is shown after seeding in the posterior OR. The seed at the merging of the OR and the SCC resulted in markedly different results for DTT and SWI-informed DTT (Fig 2). Frontal branches emerged for SWI-informed DTT, but not for DTT. A presumably non-veridical split is seen in the SCC for SWI-informed DTT (black arrow), where the structure tensor seems to cause a bias towards the borders of the tract. Fractions of streamlines entering OR/SCC were 0.026 for DTT vs. 0.336 for SWI-informed DTT. Conclusions A modification of a method was proposed to overcome some limitations of diffusion tensor tractography. It was shown that the contrast within the white matter in susceptibility weighted images can provide additional information for tractography algorithms, leading to increased sensitivity at specific locations. To have an unambiguous validation of the findings of SWI-informed DTT, an ex vivo validation of white matter connectivity has to be performed. We have shown that SWI-informed DTT reveals white matter fiber tracts that were not found using standard DTT

Superior localisation and imaging of radiolabelled monoclonal antibody E48 F(ab')2 fragment in xenografts of human squamous cell carcinoma of the head and neck and of the vulva as compared to monoclonal antibody E48 IgG.

Monoclonal antibody (MAb) E48 and its F(ab')2 fragment, radiolabelled with 131I, were tested for tumour localisation and imaging in nude mice bearing a squamous cell carcinoma xenograft line derived from a head and neck carcinoma (HNX-HN) or from a vulva carcinoma (VX-A431). MAb IgG or F(ab')2 fragments were injected in parallel and at day 1, 2, 3 and 6 or 7, mice were either scanned with a gamma camera or dissected for determination of isotope biodistribution. In HNX-HN bearing mice, E48 IgG as well as F(ab')2 showed highly specific localisation in tumour tissue. The mean tumour uptake (n = 4) expressed as the percentage of the injected dose per gram of tumour tissue (percentage ID/g) of IgG was 11.9% at day 1 and increased to 14.6% at day 6 whereas percentage ID/g of F(ab')2 was 7.2% at day 1 and decreased during subsequent days. Tumour to blood ratios (T/B) at day 1 were 1.2 for IgG and 13.6 for F(ab')2 and reached a maximum at day 6 with values of 6.4 and 54.2 respectively. In VX-A431 bearing mice, only E48 F(ab')2 showed preferential localisation in tumour tissue. At day 1, Percentage ID/g of IgG was 3.7 and T/B was 0.3, while percentage ID/g of F(ab')2 was 2.4 and T/B was 3.2. Percentage ID/g decreased after day 1 while T/B increased. In these experiments no preferential localisation of either isotype matched 125I-labelled control IgG or F(ab')2 was observed. In F(ab')2 injected HNX-HN bearing mice as well as VX-A431 bearing mice, tumours could be visualised at day 1 and 2 without any appreciable background activity. With MAb IgG this was also possible in HNX-HN bearing mice (but not in VX-A431 bearing mice) but only at day 3 and 6. These findings suggest that the superior tumour to non-tumour ratios render the E48 F(ab')2 fragment more qualified for specific targeting of radioisotopes to tumour xenografts in this experimental setting

Quantification of fibrous cap thickness in intracoronary optical coherence tomography with a contour segmentation method based on dynamic programming

OBJECTIVES: Fibrous cap thickness is the most critical component of plaque stability. Therefore, in vivo quantification of cap thickness could yield valuable information for estimating the risk of plaque rupture. In the context of preoperative planning and perioperative decision making, intracoronary optical coherence tomography imaging can provide a very detailed characterization of the arterial wall structure. However, visual interpretation of the images is laborious, subject to variability, and therefore not always sufficiently reliable for immediate decision of treatment. METHODS: A novel semiautomatic segmentation method to quantify coronary fibrous cap thickness in optical coherence tomography is introduced. To cope with the most challenging issue when estimating cap thickness (namely the diffuse appearance of the anatomical abluminal interface to be detected), the proposed method is based on a robust dynamic programming framework using a geometrical a priori. To determine the optimal parameter settings, a training phase was conducted on 10 patients. RESULTS: Validated on a dataset of 179 images from 21 patients, the present framework could successfully extract the fibrous cap contours. When assessing minimal cap thickness, segmentation results from the proposed method were in good agreement with the reference tracings performed by a medical expert (mean absolute error and standard deviation of [Formula: see text] ) and were similar to inter-observer reproducibility ([Formula: see text] , R = .74), while being significantly faster and fully reproducible. CONCLUSION: The proposed framework demonstrated promising performances and could potentially be used for online identification of high-risk plaques

Radioimmunotherapy of human head and neck squamous cell carcinoma xenografts with 131I-labelled monoclonal antibody E48 IgG.

Monoclonal antibody (MAb) E48 reacts with a 22 kD antigen exclusively expressed in squamous and transitional epithelia and their neoplastic counterparts. Radiolabelled with 99mTc, MAb E48 is capable of targeting metastatic and recurrent disease in patients with head and neck cancer. In this study, the capacity of 131I-labelled MAb E48 to eradicate xenografts of human squamous cell carcinoma of the head and neck (HNSCC) in nude mice was examined. Experimental groups received a single i.v. bolus injection of 400 microCi MAb E48 IgG (number of mice (n = 6, number of tumours (t) = 9) or 800 microCi MAb E48 IgG (n) = 5,t = 7), whereas control groups received either diluent (n = 3,t = 5), unlabelled MAb E48 IgG (n = 4,t = 5) or 800 microCi 131I-labelled isotype-matched control MAb (n = 6,t = 9). A 4.1-fold increase in the median tumour volume doubling time and regression of two out of ten tumours (20%) was observed in mice treated with 400 microCi. In mice treated with 800 microCi. In mice treated with 800 microCi, two out of seven tumours (29%) showed complete remission without regrowth during follow-up (greater than 3 months). Median tumour volume doubling time in the remaining five tumours was increased 7.8-fold. No antitumour effects were observed in mice injected with diluent, unlabelled MAb E48 or 131I-labelled control MAb. In the same xenograft model, chemotherapy with doxorubicin, 5-fluorouracil, cisplatin, bleomycin, methotrexate or 2',2'-difluorodeoxycytidine yielded a less profound effect on tumour volume doubling time. Increases in tumour volume doubling time with these chemotherapeutic agents were 4, 2.2, 2.1, 1.7, 0, and 2.6 respectively. Moreover, no cures were observed with any of these chemotherapeutic agents. From the tissue distribution of 800 microCi MAb E48, the absorbed cumulative radiation doses of tumour and various organs were calculated using the trapezoid integration method for the area under the curve. To tumour xenografts, 12,170 cGy was delivered, blood received 2,984 cGy, whereas in every other tissue the accumulated dose was less than 6% of the dose delivered to tumour. These data, describing the first radiolabelled MAb with therapeutic efficacy against HNSCC, suggest radioimmunotherapy with MAb E48 to be a potential therapeutic modality for the treatment of head and neck cancer

Enhanced therapeutic efficacy of 5'deoxy-5-fluorouridine in 5-fluorouracil resistant head and neck tumours in relation to 5-fluorouracil metabolising enzymes.

Four human head and neck xenograft (HNX) tumour lines grown in nude mice and two murine colon carcinomas (Colon 26 and 38) were tested for their sensitivity to 5-fluorouracil (5-FU) and its prodrug 5'deoxy-5-fluorouridine (Doxifluridine, 5'd-FUR). 5-FU sensitivity at the maximum tolerated dose (MTD) showed the following pattern; HNX-DU less than HNX-KE = HNX-E = HNX-G less than Colon 26 much less than Colon 38. The sensitivity pattern to 5'd-FUR was: HNX-DU less than HNX-G less than HNX-E less than HNX-KE less than Colon 38 less than Colon 26. For HNX-KE, HNX-E and Colon 26 an increase in therapeutic efficacy was observed with 5'd-FUR as compared to 5-FU; Colon 38 was as sensitive to 5'd-FUR as to 5-FU. Plasma pharmacokinetics of 5'd-FUR and 5-FU were comparable in normal and nude mice. Metabolism of 5-FU and 5'd-FUR was studied in the tumours. Conversion of 5'd-FUR to 5-FU was highest in Colon 26 and 15-20 times lower in HNX-DU, HNX-KE and Colon 38. The Km for 5'd-FUR in all tumours was 1-2 mM. Further anabolism of 5-FU to fluorouridine (FUR) was 5-10 times higher than that of 5-FU to FUR in HNX tumours and 3 times in the colon tumours. 5-FU conversion to FUMP via FUR had the following pattern: Colon 26 much greater than HNX-DU greater than HNX-G greater than HNX-E greater than HNX-KE much greater than Colon 38; of 5-FU to FdUMP via FUdR: Colon 26 greater than HNX-DU = HNX-KE greater than HNX-E greater than HNX-G = Colon 38; and that of 5-FU to FUMP catalysed by orotate phosphoribosyl transferase (OPRT); Colon 26 greater than or equal to Colon 38 greater than HNX-KE greater than HNX-E = HNX-DU = HNX-G. Only those tumours with a relatively high activity of OPRT were sensitive to 5'd-FUR. Colon 26, which has a very high rate of pyrimidine nucleoside phosphorylase, showed a relatively high increase in the therapeutic efficacy. It is concluded that a low rate of pyrimidine nucleoside phosphorylase is enough to convert 5'd-FUR to 5-FU; further anabolism of 5-FU catalysed by OPRT may be limiting and explain the differential sensitivity

A novel method to perform morphological measurements on three-dimensional (3D) models of the calcaneus based on computed tomography (CT)-imaging

Background: While current preoperative and postoperative assessment of the fractured and surgically reconstructed calcaneus relies on computed tomography (CT)-imaging, there are no established methods to quantify calcaneus morphology on CT-images. This study aims to develop a semi-automated method for morphological measurements of the calcaneus on three-dimensional (3D) models derived from CT-imaging. Methods: Using CT data, 3D models were created from healthy, fractured, and surgically reconstructed calcanei. Böhler's angle (BA) and Critical angle of Gissane (CAG) were measured on conventional lateral radiographs and corresponding 3D CT reconstructions using a novel point-based method with semiautomatic landmark placement by three observers. Intraobserver and interobserver reliability scores were calculated using intra-class correlation coefficient (ICC). In addition, consensus among observers was calculated for a maximal allowable discrepancy of 5 and 10 degrees for both methods. Results: Imaging data from 119 feet were obtained (40 healthy, 39 fractured, 40 reconstructed). Semiautomated measurements on 3D models of BA and CAG showed excellent reliability (ICC: 0.87-1.00). The manual measurements on conventional radiographs had a poor-to-excellent reliability (ICC: 0.22-0.96). In addition, the percentage of consensus among observers was much higher for the 3D method when compared to conventional two-dimensional (2D) measurements. Conclusions: The proposed method enables reliable and reproducible quantification of calcaneus morphology in 3D models of healthy, fractured and reconstructed calcanei.</p

A novel method to perform morphological measurements on three-dimensional (3D) models of the calcaneus based on computed tomography (CT)-imaging

Background: While current preoperative and postoperative assessment of the fractured and surgically reconstructed calcaneus relies on computed tomography (CT)-imaging, there are no established methods to quantify calcaneus morphology on CT-images. This study aims to develop a semi-automated method for morphological measurements of the calcaneus on three-dimensional (3D) models derived from CT-imaging. Methods: Using CT data, 3D models were created from healthy, fractured, and surgically reconstructed calcanei. Böhler's angle (BA) and Critical angle of Gissane (CAG) were measured on conventional lateral radiographs and corresponding 3D CT reconstructions using a novel point-based method with semiautomatic landmark placement by three observers. Intraobserver and interobserver reliability scores were calculated using intra-class correlation coefficient (ICC). In addition, consensus among observers was calculated for a maximal allowable discrepancy of 5 and 10 degrees for both methods. Results: Imaging data from 119 feet were obtained (40 healthy, 39 fractured, 40 reconstructed). Semiautomated measurements on 3D models of BA and CAG showed excellent reliability (ICC: 0.87-1.00). The manual measurements on conventional radiographs had a poor-to-excellent reliability (ICC: 0.22-0.96). In addition, the percentage of consensus among observers was much higher for the 3D method when compared to conventional two-dimensional (2D) measurements. Conclusions: The proposed method enables reliable and reproducible quantification of calcaneus morphology in 3D models of healthy, fractured and reconstructed calcanei.</p

Carbonic Acid Pretreatment of Biomass

This project sought to address six objectives, outlined below. The objectives were met through the completion of ten tasks. 1) Solidify the theoretical understanding of the binary CO2/H2O system at reaction temperatures and pressures. The thermodynamics of pH prediction have been improved to include a more rigorous treatment of non-ideal gas phases. However it was found that experimental attempts to confirm theoretical pH predictions were still off by a factor of about 1.8 pH units. Arrhenius experiments were carried out and the activation energy for carbonic acid appears to be substantially similar to sulfuric acid. Titration experiments have not yet confirmed or quantified the buffering or acid suppression effects of carbonic acid on biomass. 2) Modify the carbonic acid pretreatment severity function to include the effect of endogenous acid formation and carbonate buffering, if necessary. It was found that the existing severity functions serve adequately to account for endogenous acid production and carbonate effects. 3) Quantify the production of soluble carbohydrates at different reaction conditions and severity. Results show that carbonic acid has little effect on increasing soluble carbohydrate concentrations for pretreated aspen wood, compared to pretreatment with water alone. This appears to be connected to the release of endogenous acids by the substrate. A less acidic substrate such as corn stover would derive benefit from the use of carbonic acid. 4) Quantify the production of microbial inhibitors at selected reaction conditions and severity. It was found that the release of inhibitors was correlated to reaction severity and that carbonic acid did not appear to increase or decrease inhibition compared to pretreatment with water alone. 5) Assess the reactivity to enzymatic hydrolysis of material pretreated at selected reaction conditions and severity. Enzymatic hydrolysis rates increased with severity, but no advantage was detected for the use of carbonic acid compared to water alone. 6) Determine optimal conditions for carbonic acid pretreatment of aspen wood. Optimal severities appeared to be in the mid range tested. ASPEN-Plus modeling and economic analysis of the process indicate that the process could be cost competitive with sulfuric acid if the concentration of solids in the pretreatment is maintained very high (~50%). Lower solids concentrations result in larger reactors that become expensive to construct for high pressure applications

Retinal OCT speckle as a biomarker for glaucoma diagnosis and staging

This paper presents a novel image analysis strategy that increases the potential of macular Optical Coherence Tomography (OCT) by using speckle features as biomarkers in different stages of glaucoma. A large pool of features (480) were computed for a subset of macular OCT volumes of the Leuven eye study cohort. The dataset contained 258 subjects that were divided into four groups based on their glaucoma severity: Healthy (56), Mild (94), Moderate (48), and Severe (60). The OCT speckle features were categorized as statistical properties, statistical distributions, contrast, spatial gray-level dependence matrices, and frequency domain features. The averaged thicknesses of ten retinal layers were also collected. Kruskal-Wallis H test and multivariable regression models were used to infer the most significant features related to glaucoma severity classification and to the correlation with visual field mean deviation. Four features were selected as being the most relevant: the ganglion cell layer (GCL) and the inner plexiform layer (IPL) thicknesses, and two OCT speckle features, the data skewness computed on the retinal nerve fiber layer (RNFL) and the scale parameter (a) of the generalized gamma distribution fitted to the GCL data. Based on a significance level of 0.05, the regression models revealed that RNFL skewness exhibited the highest significance among the features considered for glaucoma severity staging (p-values of 8.6×10-6 for the logistic model and 2.8×10-7 for the linear model). Furthermore, it demonstrated a strong negative correlation with the visual field mean deviation (ρ=-0.64). The post hoc analysis revealed that, when distinguishing healthy controls from glaucoma subjects, GCL thickness is the most relevant feature (p-value of 8.7×10-5). Conversely, when comparing the Mild versus Moderate stages of glaucoma, RNFL skewness emerged as the only feature exhibiting statistical significance (p-value = 0.001). This work shows that macular OCT speckle contains information that is currently not used in clinical practice, and not only complements structural measurements (thickness) but also has a potential for glaucoma staging