In traditional free-form deformation (FFD) based registration, a B-spline basis function is commonly utilized to build the transformation model. As the B-spline order increases, the corresponding B-spline function becomes smoother. However, the higher-order B-spline has a larger support region, which means higher computational cost. For a given D-dimensional nth-order B-spline, an mth-order B-spline where (m < or = n) has (m +1/n + 1)D times lower computational complexity. Generally, the third-order B-spline is regarded as keeping a good balance between smoothness and computation time. A lower-order function is seldom used to construct the deformation field for registration since it is less smooth. In this research, we investigated whether lower-order B-spline functions can be utilized for efficient registration, by using a novel stochastic perturbation technique in combination with a postponed smoothing technique to higher B-spline order. Experiments were performed with 3D lung and brain scans, demonstrating that the lower-order B-spline FFD in combination with the proposed perturbation and postponed smoothing techniques even results in better accuracy and smoothness than the traditional third-order B-spline registration, while substantially reducing computational costs.
In peripheral lymphocytes, the transcription factors (TFs) NF-?B, NFAT, and AP-1 are the prime targets of signals that emerge from immune receptors. Upon activation, these TFs induce gene networks that orchestrate the growth, expansion, and effector function of peripheral lymphocytes. NFAT and NF-?B factors share several properties, such as a similar mode of induction and architecture in their DNA-binding domain, and there is a subgroup of ?B-like DNA promoter motifs that are bound by both types of TFs. However, unlike NFAT and AP-1 factors that interact and collaborate in binding to DNA, NFAT, and NF-?B seem neither to interact nor to collaborate. We show here that NF-?B1/p50 and c-Rel, the most prominent NF-?B proteins in BCR-induced splenic B cells, control the induction of NFATc1/?A, a prominent short NFATc1 isoform. In part, this is mediated through two composite ?B/NFAT-binding sites in the inducible Nfatc1 P1 promoter that directs the induction of NFATc1/?A by BCR signals. In concert with coreceptor signals that induce NF-?B factors, BCR signaling induces a persistent generation of NFATc1/?A. These data suggest a tight connection between NFATc1 and NF-?B induction in B lymphocytes contributing to the effector function of peripheral B cells.
Treatments like radiotherapy and focused ultrasound in the abdomen require accurate motion tracking, in order to optimize dosage delivery to the target and minimize damage to critical structures and healthy tissues around the target. 4D ultrasound is a promising modality for motion tracking during such treatments. In this study, the authors evaluate the accuracy of motion tracking in the liver based on deformable registration of 4D ultrasound images.
Because hypoperfusion of brain tissue precedes atrophy in dementia, the detection of dementia may be advanced by the use of perfusion information. Such information can be obtained noninvasively with arterial spin labeling (ASL), a relatively new MR technique quantifying cerebral blood flow (CBF). Using ASL and structural MRI, we evaluated diagnostic classification in 32 prospectively included presenile early stage dementia patients and 32 healthy controls. Patients were suspected of Alzheimer's disease (AD) or frontotemporal dementia. Classification was based on CBF as perfusion marker, gray matter (GM) volume as atrophy marker, and their combination. These markers were each examined using six feature extraction methods: a voxel-wise method and a region of interest (ROI)-wise approach using five ROI-sets in the GM. These ROI-sets ranged in number from 72 brain regions to a single ROI for the entire supratentorial brain. Classification was performed with a linear support vector machine classifier. For validation of the classification method on the basis of GM features, a reference dataset from the AD Neuroimaging Initiative database was used consisting of AD patients and healthy controls. In our early stage dementia population, the voxelwise feature-extraction approach achieved more accurate results (area under the curve (AUC) range?=?86?-?91%) than all other approaches (AUC?=?57?-?84%). Used in isolation, CBF quantified with ASL was a good diagnostic marker for dementia. However, our findings indicated only little added diagnostic value when combining ASL with the structural MRI data (AUC?=?91%), which did not significantly improve over accuracy of structural MRI atrophy marker by itself.
Maturation of high-affinity B lymphocytes is precisely controlled during the germinal center reaction. This is dependent on CD4(+)CXCR5(+) follicular helper T cells (TFH) and inhibited by CD4(+)CXCR5(+)Foxp3(+) follicular regulatory T cells (TFR). Because NFAT2 was found to be highly expressed and activated in follicular T cells, we addressed its function herein. Unexpectedly, ablation of NFAT2 in T cells caused an augmented GC reaction upon immunization. Consistently, however, TFR cells were clearly reduced in the follicular T cell population due to impaired homing to B cell follicles. This was TFR-intrinsic because only in these cells NFAT2 was essential to up-regulate CXCR5. The physiological relevance for humoral (auto-)immunity was corroborated by exacerbated lupuslike disease in the presence of NFAT2-deficient TFR cells.
Takotsubo cardiomyopathy (TC) is characterized by the abrupt onset of cardiac dysfunction, with transient apical and midventricular hypo-/akinesia with a compensatory hypercontractility of the remaining segments. The clinical presentation appears to be similar to acute myocardial infarction (AMI). However, the myocardial dysfunction is reversible.
To assess (1) whether normal and degenerated menisci exhibit different T1GD on delayed gadolinium-enhanced MRI of the meniscus (dGEMRIM), (2) the reproducibility of dGEMRIM and (3) the correlation between meniscus and cartilage T1GD in knee osteoarthritis (OA) patients.
Nonrigid image registration is an important, but time-consuming task in medical image analysis. In typical neuroimaging studies, multiple image registrations are performed, i.e., for atlas-based segmentation or template construction. Faster image registration routines would therefore be beneficial. In this paper we explore acceleration of the image registration package elastix by a combination of several techniques: (i) parallelization on the CPU, to speed up the cost function derivative calculation; (ii) parallelization on the GPU building on and extending the OpenCL framework from ITKv4, to speed up the Gaussian pyramid computation and the image resampling step; (iii) exploitation of certain properties of the B-spline transformation model; (iv) further software optimizations. The accelerated registration tool is employed in a study on diagnostic classification of Alzheimer's disease and cognitively normal controls based on T1-weighted MRI. We selected 299 participants from the publicly available Alzheimer's Disease Neuroimaging Initiative database. Classification is performed with a support vector machine based on gray matter volumes as a marker for atrophy. We evaluated two types of strategies (voxel-wise and region-wise) that heavily rely on nonrigid image registration. Parallelization and optimization resulted in an acceleration factor of 4-5x on an 8-core machine. Using OpenCL a speedup factor of 2 was realized for computation of the Gaussian pyramids, and 15-60 for the resampling step, for larger images. The voxel-wise and the region-wise classification methods had an area under the receiver operator characteristic curve of 88 and 90%, respectively, both for standard and accelerated registration. We conclude that the image registration package elastix was substantially accelerated, with nearly identical results to the non-optimized version. The new functionality will become available in the next release of elastix as open source under the BSD license.
After allogeneic stem cell transplantation (SCT), a reliable diagnosis of acute graft versus host disease (aGvHD) is essential for an early and successful treatment. It is the aim of this analysis to assess intestinal aGvHD by magnetic resonance imaging (MRI).
Atherosclerotic plaque composition can indicate plaque vulnerability. We segment atherosclerotic plaque components from the carotid artery on a combination of in vivo MRI and CT-angiography (CTA) data using supervised voxelwise classification. In contrast to previous studies the ground truth for training is directly obtained from 3D registration with histology for fibrous and lipid-rich necrotic tissue, and with ?CT for calcification. This registration does, however, not provide accurate voxelwise correspondence. We therefore evaluate three approaches that incorporate uncertainty in the ground truth used for training: I) soft labels are created by Gaussian blurring of the original binary histology segmentations to reduce weights at the boundaries between components, and are weighted by the estimated registration accuracy of the histology and in vivo imaging data (measured by overlap), II) samples are weighted by the local contour distance of the lumen and outer wall between histology and in vivo data, and III) 10% of each class is rejected by Gaussian outlier rejection. Classification was evaluated on the relative volumes (% of tissue type in the vessel wall) for calcified, fibrous and lipid-rich necrotic tissue, using linear discriminant (LDC) and support vector machine (SVM) classification. In addition, the combination of MRI and CTA data was compared to using only one imaging modality. Best results were obtained by LDC and outlier rejection: the volume error per vessel was 0.9±1.0% for calcification, 12.7±7.6% for fibrous and 12.1±8.1% for necrotic tissue, with Spearman rank correlation coefficients of 0.91 (calcification), 0.80 (fibrous) and 0.81 (necrotic). While segmentation using only MRI features yielded low accuracy for calcification, and segmentation using only CTA features yielded low accuracy for necrotic tissue, the combination of features from MRI and CTA gave good results for all studied components.
In lymphocytes, the three NFAT factors NFATc1 (also designated as NFAT2), NFATc2 (NFAT1), and NFATc3 (NFAT4 or NFATx) are expressed and are the targets of immune receptor signals, which lead to a rapid rise of intracellular Ca(++), the activation of phosphatase calcineurin, and to the activation of cytosolic NFATc proteins. In addition to rapid activation of NFAT factors, immune receptor signals lead to accumulation of the short NFATc1/?A isoform in lymphocytes which controls their proliferation and survival. In this mini-review, we summarize our current knowledge on the structure and transcription of the Nfatc1 gene in lymphocytes, which is controlled by two promoters, two poly A addition sites and a remote downstream enhancer. The Nfatc1 gene resembles numerous primary response genes (PRGs) induced by LPS in macrophages. Similar to the PRG promoters, the Nfatc1 promoter region is organized in CpG islands, forms DNase I hypersensitive sites, and is marked by histone tail modifications before induction. By studying gene induction in lymphocytes in detail, it will be important to elucidate whether the properties of the Nfatc1 induction are not only typical for the Nfatc1 gene but also for other transcription factor genes expressed in lymphocytes.
N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels that play an important role in neuronal development, plasticity, and excitotoxicity. NMDAR antagonists are neuroprotective in animal models of neuronal diseases, and the NMDAR open-channel blocker memantine is used to treat Alzheimers disease. In view of the clinical application of these pharmaceuticals and the reported expression of NMDARs in immune cells, we analyzed the drugs effects on T-cell function. NMDAR antagonists inhibited antigen-specific T-cell proliferation and cytotoxicity of T cells and the migration of the cells towards chemokines. These activities correlated with a reduction in TCR-induced Ca(2+)-mobilization and nuclear localization of NFATc1, and they attenuated the activation of Erk1/2 and Akt. In the presence of antagonists, Th1 effector cells produced less IL-2 and IFN-?, whereas Th2 cells produced more IL-10 and IL-13. However, in NMDAR knock-out mice the presumptive expression of functional NMDARs in wild-type T cells was inconclusive. Instead, inhibition of NMDAR antagonists on the conductivity of Kv1.3 and KCa3.1 potassium channels was found. Hence, NMDAR antagonists are potent immunosuppressants with therapeutic potential in the treatment of immune diseases, but their effects on T cells have to be considered in that Kv1.3 and KCa3.1 channels are their major effectors.
There is increasing evidence that epicardial fat (i.e., adipose tissue contained within the pericardium) plays an important role in the development of cardiovascular disease. Obtaining the epicardial fat volume from routinely performed non-enhanced cardiac CT scans is therefore of clinical interest. The purpose of this work is to investigate the feasibility of automatic pericardium segmentation and subsequent quantification of epicardial fat on non-enhanced cardiac CT scans.
Multiresolution strategies are commonly used in the nonrigid registration to avoid local minima in the optimization space. Generally, a step-by-step hierarchical approach is adopted, in which the registration starts on a level with reduced complexity (downsampled images, global transformations), then continuing to levels with increased complexity, until the finest level is reached. In this paper, we propose two alternative multiresolution strategies for both the data and transformation models, in which different resolution levels are considered simultaneously instead of subsequently. Through combining the different strategies for data and transformation, we systematically define 3 × 3 multiresolution schemes, including both existing and novel methods. Experiments on 10 pairs of computed tomography lung data sets showed that the best performing strategy resulted in a reduction of the upper quartile of the mean target registration error from 2 to 1.5 mm, compared with the conventionally hierarchical multiresolution method, while achieving smoother deformations. Experiments with intersubject registration of 18 3D T1-weighted MRI brain scans confirmed that simultaneous multiresolution strategies produce more accurate registration results (median of mean overlap increased from 0.55 to 0.57) and smoother deformation fields than the traditionally hierarchical method. Evaluation of robustness indicated that the largest differences in accuracy between methods are observed for structures with a relatively large initial misalignment.
Few studies have evaluated granulocyte colony-stimulating factor (G-CSF) priming in elderly patients with intensively treated acute myeloid leukemia (AML), and no data are available for genetically defined AML subgroups. We provide long-term results (median follow-up 7.6 years) of a randomized trial in which 183 patients (median age 67 years) received G-CSF prior to (G-CSF priming) or after two cycles of induction chemotherapy. CR rates with G-CSF priming and G-CSF post-chemotherapy were comparable (57 vs. 67 %, p?=?0.153), with overall survival (OS) probabilities of 14 vs. 17 % at 10 years. Induction mortality was significantly higher with G-CSF priming (23 vs. 10 %, p?=?0.015), primarily in normal karyotype (NK) AML. In this subgroup, a trend for better relapse-free survival (RFS) was observed with G-CSF priming (44 vs. 22 % at 10 years, p?=?0.074) but did not translate into an OS benefit. G-CSF priming had no impact on AML with FLT3-ITD and NPM mutations and did not improve outcome in patients with adverse cytogenetics. In a landmark analysis, late consolidation with autologous stem cell transplantation or a second consolidation cycle significantly improved RFS compared with one consolidation cycle (21.0 vs. 12.8 months, p?=?0.046). Future studies on G-CSF priming should be restricted to NK AML and used only in post-remission therapy.
Anatomical alignment in neuroimaging studies is of such importance that considerable effort is put into improving the registration used to establish spatial correspondence. Tract-based spatial statistics (TBSS) is a popular method for comparing diffusion characteristics across subjects. TBSS establishes spatial correspondence using a combination of nonlinear registration and a "skeleton projection" that may break topological consistency of the transformed brain images. We therefore investigated feasibility of replacing the two-stage registration-projection procedure in TBSS with a single, regularized, high-dimensional registration. To optimize registration parameters and to evaluate registration performance in diffusion MRI, we designed an evaluation framework that uses native space probabilistic tractography for 23 white matter tracts, and quantifies tract similarity across subjects in standard space. We optimized parameters for two registration algorithms on two diffusion datasets of different quality. We investigated reproducibility of the evaluation framework, and of the optimized registration algorithms. Next, we compared registration performance of the regularized registration methods and TBSS. Finally, feasibility and effect of incorporating the improved registration in TBSS were evaluated in an example study. The evaluation framework was highly reproducible for both algorithms (R(2) 0.993; 0.931). The optimal registration parameters depended on the quality of the dataset in a graded and predictable manner. At optimal parameters, both algorithms outperformed the registration of TBSS, showing feasibility of adopting such approaches in TBSS. This was further confirmed in the example experiment.
It is unknown whether white matter lesions (WML) develop abruptly in previously normal brain areas, or whether tissue changes are already present before WML become apparent on MRI. We therefore investigated whether development of WML is preceded by quantifiable changes in normal-appearing white matter (NAWM).
A method for registering preoperative 3D+t coronary CTA with intraoperative monoplane 2D+t X-ray angiography images is proposed to improve image guidance during minimally invasive coronary interventions. The method uses a patient-specific dynamic coronary model, which is derived from the CTA scan by centerline extraction and motion estimation. The dynamic coronary model is registered with the 2D+t X-ray sequence, considering multiple X-ray time points concurrently, while taking breathing induced motion into account. Evaluation was performed on 26 datasets of 17 patients by comparing projected model centerlines with manually annotated centerlines in the X-ray images. The proposed 3D+t/2D+t registration method performed better than a 3D/2D registration method with respect to the accuracy and especially the robustness of the registration. Registration with a median error of 1.47 mm was achieved.
NFAT transcription factors control the proliferation and survival of peripheral lymphocytes. We have reported previously that the short isoform NFATc1/?A whose generation is induced by immune receptor stimulation supports the proliferation and inhibits the activation-induced cell death of peripheral T and B cells. We will show in this study that in novel bacterial artificial chromosome transgenic mice that express EGFP under the control of entire Nfatc1 locus the Nfatc1/Egfp transgene is expressed as early as in double-negative thymocytes and in nonstimulated peripheral T and B cells. Upon immune receptor stimulation, Nfatc1/Egfp expression is elevated in B, Th1, and Th2 cells, but only weakly in T regulatory, Th9, and Th17 cells in vitro whose generation is affected by TGF?. In naive lymphocytes, persistent immune receptor signals led to a 3-5 increase in NFATc1/?A RNA levels during primary and secondary stimulation, but a much stronger induction was observed at the protein level. Whereas anti-CD3(+)CD28 stimulation of primary T cells induces both NFATc1/?A and their proliferation and survival, anti-IgM stimulation of B cells induces NFATc1/?A and proliferation, but activation-induced cell death after 3-d incubation in vitro. The anti-IgM-mediated activation-induced cell death induction of B cells in vitro is suppressed by anti-CD40-, LPS-, and CpG-mediated signals. In addition to inducing NF-?B factors, together with anti-IgM, these signals also support the generation of NFATc1/?A. According to these data and the architecture of its promoter region, the Nfatc1 gene resembles a primary response gene whose induction is affected at the posttranscriptional level.
Centrosomes play important roles in the maintenance of genetic stability and centrosomal aberrations are a hallmark of cancer. Deregulation of centriole duplication leads to supernumerary centrosomes, sister chromatid missegregation and could result in chromosomal instability (CIN) and aneuploidy. CIN is a common feature in at least 45% of patients with myelodysplastic syndromes (MDS). Therefore, we sought to investigate the centrosomal status and its role for development of CIN in bone marrow (BM) cells of MDS patients. BM cells of 34 MDS patients were examined cytogenetically. Furthermore, cells were immunostained with a centrosome-specific antibody to pericentrin to analyze the centrosomal status. Umbilical cord blood specimens and BM cells of healthy persons (n = 11 and n = 4) served as controls. In addition, the protein expression of the protease separase responsible for genetic stability was examined by western blot analysis. Centrosome abnormalities were detected in 10% (range, 4-17%) of cells of MDS samples, but in only 2% (range, 0-4%) of cells of healthy controls. Normal karyotypes were found in control cells and in BM cells of 16/34 MDS patients. The incidence of centrosomal alterations was higher in BM cells of patients with cytogenetic alterations (mean, 12%) compared to BM cells of patients without cytogenetic changes (mean, 7%). Our results indicate that centrosome alterations are a common and early detectable feature in MDS patients and may contribute to the acquisition of chromosomal aberrations. We assume that centrosome defects could be involved in disease progression and may serve as a future prognostic marker.
Viscosupplementation with hyaluronic acid (HA) of osteoarthritic (OA) knee joints has a well-established positive effect on clinical symptoms. This effect, however, is only temporary and the working mechanism of HA injections is not clear. It was suggested that HA might have disease modifying properties because of its beneficial effect on cartilage sulphated glycosaminoglycan (sGAG) content. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) is a highly reproducible, non-invasive surrogate measure for sGAG content and hence composition of cartilage. The aim of this study was to assess whether improvement in cartilage structural composition is detected using dGEMRIC 14 weeks after 3 weekly injections with HA in patients with early-stage knee OA.
Histology sections provide accurate information on atherosclerotic plaque composition, and are used in various applications. To our knowledge, no automated systems for plaque component segmentation in histology sections currently exist.
Dienogest offers pharmacological advantages for the effective treatment of endometriosis and for use in contraception and hormone replacement therapy. This pharmacodynamic study investigated the ovulation-inhibiting effects of dienogest monotherapy in healthy women. Dienogest was administered at 0.5, 1, 2, or 3 mg daily for up to 72 days to women aged 18 to 35 years (n = 102). Ovarian activity was assessed pretreatment and during 2 treatment periods (days 0-36 and days 37-72) by the Hoogland score, based on follicle size and serum estradiol and progesterone levels. Additional hormonal parameters and endometrial thickness were assessed. Hoogland scoring indicated ovulation in all women pretreatment, decreasing to 3 of 21, 1 of 23, 0 of 20, and 0 of 23 women in the 0.5-, 1-, 2-, and 3-mg groups, respectively (per-protocol set). Maximum serum estradiol concentrations were similar to pretreatment levels in the 0.5- or 1-mg group and decreased moderately (within physiologic levels) in the 2- or 3-mg group. Endometrial thickness was reduced by all dienogest doses. Hormonal changes during follow-up indicated resumption of ovulation in most women, shortly after treatment cessation. Dienogest ?2 mg daily provides moderate suppression of estradiol production and reliable ovulation inhibition, which reverses rapidly after treatment cessation.
Accurate automated brain structure segmentation methods facilitate the analysis of large-scale neuroimaging studies. This work describes a novel method for brain structure segmentation in magnetic resonance images that combines information about a structures location and appearance. The spatial model is implemented by registering multiple atlas images to the target image and creating a spatial probability map. The structures appearance is modeled by a classifier based on Gaussian scale-space features. These components are combined with a regularization term in a Bayesian framework that is globally optimized using graph cuts. The incorporation of the appearance model enables the method to segment structures with complex intensity distributions and increases its robustness against errors in the spatial model. The method is tested in cross-validation experiments on two datasets acquired with different magnetic resonance sequences, in which the hippocampus and cerebellum were segmented by an expert. Furthermore, the method is compared to two other segmentation techniques that were applied to the same data. Results show that the atlas- and appearance-based method produces accurate results with mean Dice similarity indices of 0.95 for the cerebellum, and 0.87 for the hippocampus. This was comparable to or better than the other methods, whereas the proposed technique is more widely applicable and robust.
Tagged magnetic resonance imaging (tMRI) is a well-known noninvasive method for studying regional heart dynamics. It offers great potential for quantitative analysis of a variety of kine(ma)tic parameters, but its clinical use has so far been limited, in part due to the lack of robustness and accuracy of existing tag tracking algorithms in dealing with low (and intrinsically time-varying) image quality. In this paper, we evaluate the performance of four frequently used concepts found in the literature (optical flow, harmonic phase (HARP) magnetic resonance imaging, active contour fitting, and non-rigid image registration) for cardiac motion analysis in 2D tMRI image sequences, using both synthetic image data (with ground truth) and real data from preclinical (small animal) and clinical (human) studies. In addition we propose a new probabilistic method for tag tracking that serves as a complementary step to existing methods. The new method is based on a Bayesian estimation framework, implemented by means of reversible jump Markov chain Monte Carlo (MCMC) methods, and combines information about the heart dynamics, the imaging process, and tag appearance. The experimental results demonstrate that the new method improves the performance of even the best of the four previous methods. Yielding higher consistency, accuracy, and intrinsic tag reliability assessment, the proposed method allows for improved analysis of cardiac motion.
The natural function of the C-C chemokine receptor type 5 (CCR5) is poorly understood. A 32 base pair deletion in the CCR5 gene (CCR5-delta32) located on chromosome 3 results in a non-functional protein. It is supposed that this deletion causes an alteration in T-cell response to inflammation. For example, the presence of the CCR5-delta32 allele in recipients of allografts constitutes as an independent and protective factor associated with a decreased risk of graft-versus-host disease (GVHD) and graft rejection. However, the mechanism of this beneficial effect of the deletion regarding GVHD is unknown. In this survey we searched for a CCR5-delta32 associated regulation of critical genes involved in the immune response and the development of GVHD.
Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with non-syndromic cleft lip with or without cleft palate (NSCL/P), and other previous studies showed distinctly differing facial distance measurements when comparing unaffected relatives of NSCL/P patients with normal controls. Here, we test the hypothesis that genetic loci involved in NSCL/P also influence normal variation in facial morphology. We tested 11 SNPs from 10 genomic regions previously showing replicated evidence of association with NSCL/P for association with normal variation of nose width and bizygomatic distance in two cohorts from Germany (N=529) and the Netherlands (N=2497). The two most significant associations found were between nose width and SNP rs1258763 near the GREM1 gene in the German cohort (P=6 × 10(-4)), and between bizygomatic distance and SNP rs987525 at 8q24.21 near the CCDC26 gene (P=0.017) in the Dutch sample. A genetic prediction model explained 2% of phenotype variation in nose width in the German and 0.5% of bizygomatic distance variation in the Dutch cohort. Although preliminary, our data provide a first link between genetic loci involved in a pathological facial trait such as NSCL/P and variation of normal facial morphology. Moreover, we present a first approach for understanding the genetic basis of human facial appearance, a highly intriguing trait with implications on clinical practice, clinical genetics, forensic intelligence, social interactions and personal identity.
EMPIRE10 (Evaluation of Methods for Pulmonary Image REgistration 2010) is a public platform for fair and meaningful comparison of registration algorithms which are applied to a database of intrapatient thoracic CT image pairs. Evaluation of nonrigid registration techniques is a nontrivial task. This is compounded by the fact that researchers typically test only on their own data, which varies widely. For this reason, reliable assessment and comparison of different registration algorithms has been virtually impossible in the past. In this work we present the results of the launch phase of EMPIRE10, which comprised the comprehensive evaluation and comparison of 20 individual algorithms from leading academic and industrial research groups. All algorithms are applied to the same set of 30 thoracic CT pairs. Algorithm settings and parameters are chosen by researchers expert in the configuration of their own method and the evaluation is independent, using the same criteria for all participants. All results are published on the EMPIRE10 website (http://empire10.isi.uu.nl). The challenge remains ongoing and open to new participants. Full results from 24 algorithms have been published at the time of writing. This paper details the organization of the challenge, the data and evaluation methods and the outcome of the initial launch with 20 algorithms. The gain in knowledge and future work are discussed.
It has been hypothesized that white matter lesions at different locations may have different etiology and clinical consequences. Several approaches for the quantification of local white matter lesion load have been proposed in the literature, most of which rely on a distinction between lesions in a periventricular region close to the ventricles and a subcortical zone further away. In this work we present a novel automated method for local white matter lesion volume quantification in magnetic resonance images. The method segments and measures the white matter lesion volume in 43 regions defined by orientation and distance to the ventricles, which allows a more spatially detailed study of lesion load. The potential of the method was demonstrated by analyzing the effect of blood pressure on the regional white matter lesion volume in 490 elderly subjects taken from a longitudinal population study. The method was also compared to two commonly used techniques to assess the periventricular and subcortical lesion load. The main finding was that high blood pressure was primarily associated with lesion load in the vascular watershed area that forms the border between the periventricular and subcortical regions. It explains the associations found for both the periventricular and subcortical load computed for the same data, and that were reported in the literature. But the proposed method can localize the region of association with greater precision than techniques that distinguish between periventricular and subcortical lesions only.
Moesin is a member of the ERM (ezrin, radixin, moesin) family of cytoskeleton/membrane structure organizing and signal transduction proteins. Previously, we found an increased expression of moesin during HIV-1 infection. Moesin was also reported to be incorporated into HIV-1 virions. To analyze whether moesin is a host factor affecting the replication cycle of human immunodeficiency virus type 1 (HIV-1), we used small interfering RNAs (siRNAs) to evaluate the effect of moesin knockdown on HIV-1 replication in P4-CCR5?cells. Moesins knockdown did not affect the cell viability or cell phenotype. Interestingly, we observed a marked increase in viral replication, as demonstrated by enhanced HIV-1 RNA, p24 antigen, and ß-galactosidase reporter expression. Moesin-dependent enhancement of HIV-1 replication was confirmed in lymphocytic host cells (Jurkat). These results suggest an overall rather restrictive role of moesin for HIV-1 replication in host cells in vitro.
Brain-Computer interface technologies mean to create new communication channels between our mind and our environment, independent of the motor system, by detecting and classifying self regulation of local brain activity. BCIs can provide patients with severe paralysis a means to communicate and to live more independent lives. There has been a growing interest in using invasive recordings for BCI to improve the signal quality. This also potentially gives access to new control strategies previously inaccessible by non-invasive methods. However, before surgery, the best implantation site needs to be determined. The blood-oxygen-level dependent signal changes measured with fMRI have been shown to agree well spatially with those found with invasive electrodes, and are the best option for pre-surgical localization. We show, using real-time fMRI at 7T, that eye movement-independent visuospatial attention can be used as a reliable control strategy for BCIs. At this field strength even subtle signal changes can be detected in single trials thanks to the high contrast-to-noise ratio. A group of healthy subjects were instructed to move their attention between three (two peripheral and one central) spatial target regions while keeping their gaze fixated at the center. The activated regions were first located and thereafter the subjects were given real-time feedback based on the activity in these regions. All subjects managed to regulate local brain areas without training, which suggests that visuospatial attention is a promising new target for intracranial BCI. ECoG data recorded from one epilepsy patient showed that local changes in gamma-power can be used to separate the three classes.
By studying mice in which the Nfatc1 gene was inactivated in bone marrow, spleen, or germinal center B cells, we show that NFATc1 supports the proliferation and suppresses the activation-induced cell death of splenic B cells upon B cell receptor (BCR) stimulation. BCR triggering leads to expression of NFATc1/?A, a short isoform of NFATc1, in splenic B cells. NFATc1 ablation impaired Ig class switch to IgG3 induced by T cell-independent type II antigens, as well as IgG3(+) plasmablast formation. Mice bearing NFATc1(-/-) B cells harbor twofold more interleukin 10-producing B cells. NFATc1(-/-) B cells suppress the synthesis of interferon-? by T cells in vitro, and these mice exhibit a mild clinical course of experimental autoimmune encephalomyelitis. In large part, the defective functions of NFATc1(-/-) B cells are caused by decreased BCR-induced Ca(2+) flux and calcineurin (Cn) activation. By affecting CD22, Rcan1, CnA, and NFATc1/?A expression, NFATc1 controls the Ca(2+)-dependent Cn-NFAT signaling network and, thereby, the fate of splenic B cells upon BCR stimulation.
Magnetic resonance imaging (MRI), together with histology, is widely used to diagnose and to monitor treatment in oncology. Spatial correspondence between these modalities provides information about the ability of MRI to characterize cancerous tissue. However, registration is complicated by deformations during pathological processing, and differences in scale and information content.
The AIO KRK-0104 randomized phase II trial investigated the efficacy and safety of cetuximab combined with capecitabine and irinotecan (CAPIRI) or capecitabine and oxaliplatin (CAPOX) in the first-line treatment of metastatic colorectal cancer (mCRC).
The intracellular signaling mechanisms underlying postnatal angiogenesis are incompletely understood. Herein we show that Grb-2-associated binder 1 (Gab1) plays a critical role in ischemic and VEGF-induced angiogenesis. Endothelium-specific Gab1 KO (EGKO) mice displayed impaired angiogenesis in the ischemic hindlimb despite normal induction of VEGF expression. Matrigel plugs with VEGF implanted in EGKO mice induced fewer capillaries than those in control mice. The vessels and endothelial cells (ECs) derived from EGKO mice were defective in vascular sprouting and tube formation induced by VEGF. Biochemical analyses revealed a substantial reduction of endothelial NOS (eNOS) activation in Gab1-deficient vessels and ECs following VEGF stimulation. Interestingly, the phosphorylation of Akt, an enzyme known to promote VEGF-induced eNOS activation, was increased in Gab1-deficient vessels and ECs whereas protein kinase A (PKA) activity was significantly decreased. Introduction of an active form of PKA rescued VEGF-induced eNOS activation and tube formation in EGKO ECs. Reexpression of WT or mutant Gab1 molecules in EGKO ECs revealed requirement of Gab1/Shp2 association for the activation of PKA and eNOS. Taken together, these results identify Gab1 as a critical upstream signaling component in VEGF-induced eNOS activation and tube formation, which is dependent on PKA. Of note, this pathway is conserved in primary human ECs for VEGF-induced eNOS activation and tube formation, suggesting considerable potential in treatment of human ischemic diseases.
The purpose of this paper is to present a methodology to estimate the carotid artery lumen centerlines in ultrasound (US) images obtained in a free-hand examination. Challenging aspects here are speckle noise in US images, artifacts, and the lack of contrast in the direction orthogonal to the US beam direction.
An accurate spatial relationship between 3D in-vivo carotid plaque and lumen imaging and histological cross sections is required to study the relationship between biomechanical parameters and atherosclerotic plaque components. We present and evaluate a fully three-dimensional approach for this registration problem, which accounts for deformations that occur during the processing of the specimens. By using additional imaging steps during tissue processing and semi-automated non-linear registration techniques, a 3D-reconstruction of the histology is obtained. The methodology was evaluated on five specimens obtained from patients, operated for severe atherosclerosis in the carotid bifurcation. In more than 80% of the histology slices, the quality of the semi-automated registration with computed tomography angiography (CTA) was equal to or better than the manual registration. The inter-observer variability was between one and two in-vivo CT voxels and was equal to the manual inter-observer variability. Our technique showed that the angles between the normals of the registered histology slices and the in-vivo CTA scan direction ranged 6-56 degrees , indicating that proper 3D-registration is crucial for establishing a correct spatial relation with in-vivo imaging modalities. This new 3D-reconstruction technique of atherosclerotic plaque tissue opens new avenues in the field of biomechanics as well as in the field of image processing, where it can be used for validation purposes of segmentation algorithms.
Thoracic computed tomography (CT) scans provide information about cardiovascular risk status. These scans are non-ECG synchronized, thus precise quantification of coronary calcifications is difficult. Aortic calcium scoring is less sensitive to cardiac motion, so it is an alternative to coronary calcium scoring as an indicator of cardiovascular risk. The authors developed and evaluated a computer-aided system for automatic detection and quantification of aortic calcifications in low-dose noncontrast-enhanced chest CT.
Medical image registration is an important task in medical image processing. It refers to the process of aligning data sets, possibly from different modalities (e.g., magnetic resonance and computed tomography), different time points (e.g., follow-up scans), and/or different subjects (in case of population studies). A large number of methods for image registration are described in the literature. Unfortunately, there is not one method that works for all applications. We have therefore developed elastix, a publicly available computer program for intensity-based medical image registration. The software consists of a collection of algorithms that are commonly used to solve medical image registration problems. The modular design of elastix allows the user to quickly configure, test, and compare different registration methods for a specific application. The command-line interface enables automated processing of large numbers of data sets, by means of scripting. The usage of elastix for comparing different registration methods is illustrated with three example experiments, in which individual components of the registration method are varied.
Analysis of donor chimerism is an important diagnostic tool to assess the risk of relapse after allogeneic stem cell transplantation, especially in patients lacking a specific marker suitable for monitoring of minimal residual disease. We prospectively investigated the predictive value of donor chimerism analyses in sorted CD34(+) peripheral blood cells in 90 patients with acute leukemia and myelodysplastic syndrome. The cumulative incidence of relapse after four years was significantly increased in cases with decreasing or incomplete CD34(+) donor chimerism (57% vs. 18%, p=0.0001). Multivariate analysis confirmed decreasing CD34(+) donor chimerism as an independent predictor of relapse and inferior survival. The interval between a decrease of CD34(+) chimerism of less than 80% and hematologic relapse was 61 days (range 0-567). Monitoring of CD34(+) donor chimerism in the peripheral blood allows prediction of imminent relapse after allogeneic stem cell transplantation even when a disease-specific marker is lacking.
Atlas-based segmentation is a powerful generic technique for automatic delineation of structures in volumetric images. Several studies have shown that multi-atlas segmentation methods outperform schemes that use only a single atlas, but running multiple registrations on volumetric data is time-consuming. Moreover, for many scans or regions within scans, a large number of atlases may not be required to achieve good segmentation performance and may even deteriorate the results. It would therefore be worthwhile to include the decision which and how many atlases to use for a particular target scan in the segmentation process. To this end, we propose two generally applicable multi-atlas segmentation methods, adaptive multi-atlas segmentation (AMAS) and adaptive local multi-atlas segmentation (ALMAS). AMAS automatically selects the most appropriate atlases for a target image and automatically stops registering atlases when no further improvement is expected. ALMAS takes this concept one step further by locally deciding how many and which atlases are needed to segment a target image. The methods employ a computationally cheap atlas selection strategy, an automatic stopping criterion, and a technique to locally inspect registration results and determine how much improvement can be expected from further registrations. AMAS and ALMAS were applied to segmentation of the heart in computed tomography scans of the chest and compared to a conventional multi-atlas method (MAS). The results show that ALMAS achieves the same performance as MAS at a much lower computational cost. When the available segmentation time is fixed, both AMAS and ALMAS perform significantly better than MAS. In addition, AMAS was applied to an online segmentation challenge for delineation of the caudate nucleus in brain MRI scans where it achieved the best score of all results submitted to date.
The aim of this study was to identify and to characterize a highly active anti-HIV ribozyme. Therefore, the genome of HIV-1 IIIb was screened for not yet addressed GUC triplets within highly conserved sequences. Here we report the in vitro characteristics and the antiviral activity of the fittest identified anti-HIV hammerhead ribozyme, targeting the 13th GUC triplet within the HIV-1 pol gene (HHPol13). Multiple turnover kinetics were determined in vitro and revealed very promising kinetic data: V(max) = 39 nM/minute, K(m) = 576 nM, k(cat) = 3.9/minute, and K(cat)/K(m) = 6.8/minute/microM. To analyze its antiviral activity the hammerhead ribozyme was expressed retrovirally in Hut78 cells followed by HIV-1 infection. The newly identified ribozyme conferred a long-term inhibition of HIV-1 replication until the end of the observation period at day 56. We were able to demonstrate that the antiviral activity was mainly due to a ribozyme effect combined with a limited antisense activity. Additionally, the effect of the identified ribozyme was compared with a retrovirally expressed siRNA directed against the same target in the HIV-1 pol gene. This siRNA (siPol13) showed no inhibition of HIV replication. In summary, the hammerhead ribozyme HHPol13 was demonstrated to confer superior cleavage and antiviral activity against HIV-1. These results suggest that even in the RNAi era ribozymes still have the potential as highly active antiviral agents.
Purpose of this study was the evaluation of the thoracic aortic wall thickness as a potential identifier of patients at increased risk for future cardiac events. Thoracic aortic wall thickness was measured with MDCT in 160 patients. The CT-scans were implemented as non-invasive coronary angiography studies. Relationships between aortic wall thickness, sex, age, major risk factors and atherosclerotic plaque burden of the coronary arteries were explored. Higher values of maximum aortic wall thickness of the descending aorta (women P = 0.02, men P = 0.01) were found in patients with coronary atherosclerosis, compared to patients with same gender but excluded atherosclerosis. Aortic wall thickness of the mid-portion of the descending aorta of 3.0 mm is associated with coronary artery disease (CAD) with a specificity of 96.6% (sensitivity 27.5%) and a positive predictive value (PPV) of 93.3%. For patients with two or more major risk factors and a maximum wall thickness of equal or more than 2.6 mm we found a PPV of 100%. We conclude that measurements of maximum wall thickness of the descending aorta are a potential tool for detecting patients with coronary atherosclerosis. The potential effect of combining measurements of aortic wall thickness at routine chest CT studies with a possible cardiovascular screening is substantial and merits further study.
Radiation therapy for cervical cancer can benefit from image registration in several ways, for example by studying the motion of organs, or by (partially) automating the delineation of the target volume and other structures of interest. In this paper, the registration of cervical data is addressed using mutual information (MI) of not only image intensity, but also features that describe local image structure. Three aspects of the registration are addressed to make this approach feasible. First, instead of relying on a histogram-based estimation of mutual information, which poses problems for a larger number of features, a graph-based implementation of alpha-mutual information (alpha-MI) is employed. Second, the analytical derivative of alpha-MI is derived. This makes it possible to use a stochastic gradient descent method to solve the registration problem, which is substantially faster than nonderivative-based methods. Third, the feature space is reduced by means of a principal component analysis, which also decreases the registration time. The proposed technique is compared to a standard approach, based on the mutual information of image intensity only. Experiments are performed on 93 T2-weighted MR clinical data sets acquired from 19 patients with cervical cancer. Several characteristics of the proposed algorithm are studied on a subset of 19 image pairs (one pair per patient). On the remaining data (36 image pairs, one or two pairs per patient) the median overlap is shown to improve significantly compared to standard MI from 0.85 to 0.86 for the clinical target volume (CTV, p = 2 x 10(-2)), from 0.75 to 0.81 for the bladder (p = 8 x 10(-6)), and from 0.76 to 0.77 for the rectum (p = 2 x 10(-4)). The registration error is improved at important tissue interfaces, such as that of the bladder with the CTV, and the interface of the rectum with the uterus and cervix.
From the clinical point of view, it is important to recognize residents level of expertise with regard to basic psychomotor skills. For that reason, surgeons and surgical organizations (e.g., Acreditation Council for Graduate Medical Education, ACGME) are calling for assessment tools that credential residents as technically competent. Currently, no method is universally accepted or recommended for classifying residents as "experienced," "intermediates," or "novices" according to their technical abilities. This study introduces a classification method for recognizing residents level of experience in laparoscopic surgery based on psychomotor laparoscopic skills alone.
Aneurysm morphodynamics is potentially relevant for assessing aneurysm rupture risk. A method is proposed for automated quantification and visualization of intracranial aneurysm morphodynamics from electrocardiogram (ECG)-gated computed tomography angiography (CTA) data.
To evaluate the effect of automated registration in delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) of the knee on the occurrence of movement artefacts on the T1 map and the reproducibility of region-of-interest (ROI)-based measurements.
Quantitative information about the geometry of the carotid artery bifurcation is relevant for investigating the onset and progression of atherosclerotic disease. This paper proposes an automatic approach for quantifying the carotid bifurcation angle, carotid area ratio, carotid bulb size and the vessel tortuosity from multispectral MRI. First, the internal and external carotid centerlines are determined by finding a minimum cost path between user-defined seed points where the local costs are based on medialness and intensity. The minimum cost path algorithm is iteratively applied after curved multi-planar reformatting to refine the centerline. Second, the carotid lumen is segmented using a topology preserving geodesic active contour which is initialized by the extracted centerlines and steered by the MR intensities. Third, the bifurcation angle and vessel tortuosity are automatically extracted from the segmented lumen. The methods for centerline tracking and lumen segmentation are evaluated by comparing their accuracy to the inter- and intra-observer variability on 48 datasets (96 carotid arteries) acquired as part of a longitudinal population study. The evaluation reveals that 94 of 96 carotid arteries are segmented successfully. The distance between the tracked centerlines and the reference standard (0.33 mm) is similar to the inter-observer variation (0.32 mm). The lumen segmentation accuracy (average DSC=0.89, average mean absolute surface distance=0.31 mm) is close to the inter-observer variation (average dice=0.92, average mean surface distance=0.23 mm). The correlation coefficient of manually and automaticly derived bifurcation angle, carotid proximal area ratio, carotid proximal bulb size and vessel totuosity quantifications are close to the correlation of these measures between observers. This demonstrates that the automated method can be used for replacing manual centerline annotation and manual contour drawing for lumen segmentation in MRIs data prior to quantifying the carotid bifurcation geometry.
AIO-PK0104 investigated two treatment strategies in advanced pancreatic cancer (PC): a reference sequence of gemcitabine/erlotinib followed by 2nd-line capecitabine was compared with a reverse experimental sequence of capecitabine/erlotinib followed by gemcitabine.
In effector T and B cells immune receptor signals induce within minutes a rise of intracellular Ca++, the activation of the phosphatase calcineurin and the translocation of NFAT transcription factors from cytosol to nucleus. In addition to this first wave of NFAT activation, in a second step the occurrence of NFATc1/?A, a short isoform of NFATc1, is strongly induced. Upon primary stimulation of lymphocytes the induction of NFATc1/?A takes place during the G1 phase of cell cycle. Due to an auto-regulatory feedback circuit high levels of NFATc1/?A are kept constant during persistent immune receptor stimulation. Contrary to NFATc2 and further NFATc proteins which dampen lymphocyte proliferation, induce anergy and enhance activation induced cell death (AICD), NFATc1/?A supports antigen-mediated proliferation and protects lymphocytes against rapid AICD. Whereas high concentrations of NFATc1/?A can also lead to apoptosis, in collaboration with NF-?B-inducing co-stimulatory signals they support the survival of mature lymphocytes in late phases after their activation. However, if dysregulated, NFATc1/?A appears to contribute to lymphoma genesis and - as we assume - to further disorders of the lymphoid system. While the molecular details of NFATc1/?A action and its contribution to lymphoid disorders have to be investigated, NFATc1/?A differs in its generation and function markedly from all the other NFAT proteins which are expressed in lymphoid cells. Therefore, it represents a prime target for causal therapies of immune disorders in future.
State of the art cardiac computed tomography (CT) enables the acquisition of imaging data of the heart over the entire cardiac cycle at concurrent high spatial and temporal resolution. However, in clinical practice, acquisition is increasingly limited to 3-D images. Estimating the shape of the cardiac structures throughout the entire cardiac cycle from a 3-D image is therefore useful in applications such as the alignment of preoperative computed tomography angiography (CTA) to intra-operative X-ray images for improved guidance in coronary interventions. We hypothesize that the motion of the heart is partially explained by its shape and therefore investigate the use of three regression methods for motion estimation from single-phase shape information. Quantitative evaluation on 150 4-D CTA images showed a small, but statistically significant, increase in the accuracy of the predicted shape sequences when using any of the regression methods, compared to shape-independent motion prediction by application of the mean motion. The best results were achieved using principal component regression resulting in point-to-point errors of 2.3±0.5 mm, compared to values of 2.7±0.6 mm for shape-independent motion estimation. Finally, we showed that this significant difference withstands small variations in important parameter settings of the landmarking procedure.
Myelodysplastic syndromes (MDS) are mainly a disease of the elderly. Commonly, MDS patients are treated in an outpatient setting making hematological/oncological private practices (PP) an important backbone in the management of MDS patients.
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