OBJECTIVE:Overexpression of the drug transporter P-glycoprotein (P-gp) is thought to be involved in drug-resistance in epilepsy by extrusion of antiepileptic drugs (AEDs). We used positron emission tomography (PET) and the P-gp substrate radiotracer (R)-[11 C]verapamil (VPM) together with the third-generation P-gp inhibitor tariquidar (TQD) to evaluate P-gp function in individuals with drug-resistant epileptogenic developmental lesions. METHODS:Twelve healthy controls (7 male, median age 45, range 35-55 years), and two patients with epileptogenic developmental lesions (2 male, aged 24 and 62 years) underwent VPM-PET scans before and 60 minutes after a 30-minute infusion of 2 and 3 mg/kg TQD. The influx rate constant, VPM-K1 , was estimated from the first 10 minutes of dynamic data using a single-tissue compartment model with a VPM plasma input function. Statistical parametric mapping (SPM) analysis was used to compare individual patients with the healthy controls. RESULTS:At baseline, SPM voxel-based analysis revealed significantly lower uptake of VPM corresponding to the area of the epileptogenic developmental lesion compared to 12 healthy controls (P < .048). This was accentuated following P-gp inhibition with TQD. After TQD, the uptake of VPM was significantly lower in the area of the epileptogenic developmental lesion compared to controls (P < .002). SIGNIFICANCE:This study provides further evidence of P-gp overactivity in patients with drug-resistant epilepsy, irrespective of the type of lesion. Identifying P-gp overactivity as an underlying contributor to drug-resistance in individual patients will enable novel treatment strategies aimed at overcoming or reversing P-gp overactivity.

Purpose: To directly compare HRRT (high resolution brain) and HR+ (standard wholebody) PET only scanners for quantitative brain studies using three tracers with vastly different tracer distributions. Procedures: Healthy volunteers underwent successive scans on HR+ and HRRT scanners (in random order) using either (R)-[C]verapamil (n=6), [C]raclopride (n=7) or [C]flumazenil (n=7). For all tracers metabolite-corrected plasma input functions were generated. Results: After resolution matching, HRRT derived kinetic parameter values correlated well with those of HR+ for all tracers (intra-class correlation coefficients ≥0.78), having a good absolute interscanner test-retest variability (≤15%). However, systematic differences can be seen for HRRT derived kinetic parameter values (range: -13 to +15%). Conclusion: Quantification of kinetic parameters based on plasma input models leads to comparable results when spatial resolution between HRRT and HR+ data is matched. When using reference tissue models differences remain that are likely caused by differences in attenuation and scatter corrections and/or image reconstruction.

This study was conducted to directly compare the high-resolution research tomograph (HRRT) (high-resolution brain) and HR+ (standard whole-body) positron emission tomography (PET) only scanners for quantitative brain studies using three tracers with vastly different tracer distributions.

BACKGROUND:Studies in rodent models of epilepsy suggest that multidrug efflux transporters at the blood-brain barrier, such as P-glycoprotein, might contribute to pharmacoresistance by reducing target-site concentrations of antiepileptic drugs. We assessed P-glycoprotein activity in vivo in patients with temporal lobe epilepsy. METHODS:We selected 16 patients with pharmacoresistant temporal lobe epilepsy who had seizures despite treatment with at least two antiepileptic drugs, eight patients who had been seizure-free on antiepileptic drugs for at least a year after 3 or more years of active temporal lobe epilepsy, and 17 healthy controls. All participants had a baseline PET scan with the P-glycoprotein substrate (R)-[(11)C]verapamil. Pharmacoresistant patients and healthy controls then received a 30-min infusion of the P-glycoprotein-inhibitor tariquidar followed by another (R)-[(11)C]verapamil PET scan 60 min later. Seizure-free patients had a second scan on the same day, but without tariquidar infusion. Voxel-by-voxel, we calculated the (R)-[(11)C]verapamil plasma-to-brain transport rate constant, K1 (mL/min/cm(3)). Low baseline K1 and attenuated K1 increases after tariquidar correspond to high P-glycoprotein activity. FINDINGS:Between October, 2008, and November, 2011, we completed (R)-[(11)C]verapamil PET studies in 14 pharmacoresistant patients, eight seizure-free patients, and 13 healthy controls. Voxel-based analysis revealed that pharmacoresistant patients had lower baseline K1, corresponding to higher baseline P-glycoprotein activity, than seizure-free patients in ipsilateral amygdala (0·031 vs 0·036 mL/min/cm(3); p=0·014), bilateral parahippocampus (0·032 vs 0·037; p<0·0001), fusiform gyrus (0·036 vs 0·041; p<0·0001), inferior temporal gyrus (0·035 vs 0·041; p<0·0001), and middle temporal gyrus (0·038 vs 0·044; p<0·0001). Higher P-glycoprotein activity was associated with higher seizure frequency in whole-brain grey matter (p=0·016) and the hippocampus (p=0·029). In healthy controls, we noted a 56·8% increase of whole-brain K1 after 2 mg/kg tariquidar, and 57·9% for 3 mg/kg; in patients with pharmacoresistant temporal lobe epilepsy, whole-brain K1 increased by only 21·9% for 2 mg/kg and 42·6% after 3 mg/kg. This difference in tariquidar response was most pronounced in the sclerotic hippocampus (mean 24·5% increase in patients vs mean 65% increase in healthy controls, p<0·0001). INTERPRETATION:Our results support the hypothesis that there is an association between P-glycoprotein overactivity in some regions of the brain and pharmacoresistance in temporal lobe epilepsy. If this relation is confirmed, and P-glycoprotein can be identified as a contributor to pharmacoresistance, overcoming P-glycoprotein overactivity could be investigated as a potential treatment strategy. FUNDING:EU-FP7 programme (EURIPIDES number 201380).

9th International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM) Location: Baltimore, MD Date: AUG 09-11, 2012

With large scale botnets emerging as one of the major current threats, the automatic detection of botnet traffic is of high importance for service providers and large campus network monitoring. Faced with high speed network connections, detecting botnets must be efficient and accurate. This paper proposes a novel approach for this task, where NetFlow related data is correlated and a host dependency model is leveraged for advanced data mining purposes. We extend the popular linkage analysis algorithm PageRank [27] with an additional clustering process in order to efficiently detect stealthy botnets using peer-to-peer communication infrastructures and not exhibiting large volumes of traffic. The key conceptual component in our approach is to analyze communication behavioral patterns and to infer potential botnet activities.

As part of a study to investigate early changes following exposure to aerosols of Mycobacterium tuberculosis (Mtb), 10 rhesus macaques (Macaca mulatta) were infected with high (731 colony forming units [cfu]), medium (70 cfu) or low (7 cfu) doses of Mtb, and tissues were examined at 2 and 3 weeks post infection (wpi). Clinical disease was not observed. Results of advanced imaging and pathological findings were compared with respect to the delivered dose and time post infection. Magnetic resonance imaging revealed lesions in the lungs at these early time points ex vivo immediately prior to detailed post-mortem examination in the absence of clinical disease. In animals exposed to high and medium doses of Mtb that were studied at 2 and 3 wpi, a range of lesions including small foci of mainly mononuclear cells, primarily macrophages (granulomatous lesions), as well as obvious granulomas, were observed microscopically in the lungs, including lymphatics and hilar lymph nodes. In the low-dose group at 3 weeks, small lesions were identified in the lung and hilar lymph nodes of one animal, and the remaining two animals in this group had lesions in either lung or hilar lymph node. Acid fast bacilli were demonstrated in the lung and lymph nodes in all animals that received high and medium doses, and the lymph nodes of two animals at the low dose. A dose-dependent effect was observed with increasing dose and time post infection. Furthermore, early dissemination of bacilli to the draining, hilar lymph nodes with concomitant granulomatous lesion formation was observed. By contributing to the recognition of early lesion development due to aerosol challenge of Mtb in the rhesus macaque, this study forms a basis for further investigation of early lesions and may inform the design of future vaccine and therapeutic studies involving early time points in this species.

Botnets are a major threat of the current Internet. Understanding the novel generation of botnets relying on peer-to-peer networks is crucial for mitigating this threat. Nowadays, botnet traffic is mixed with a huge volume of benign traffic due to almost ubiquitous high speed networks. Such networks can be monitored using IP flow records but their forensic analysis form the major computational bottleneck. We propose in this paper a distributed computing framework that leverages a host dependency model and an adapted PageRank [1] algorithm. We report experimental results from an open-source based Hadoop cluster [2] and highlight the performance benefits when using real network traces from an Internet operator.

Retrospective comparison of diagnostic quality of virtual monoenergetic images (VMI) and conventional images (CI) reconstructed from dual-layer detector CT (DLCT) regarding intraparenchymal hemorrhage (IPH) and hypodense parenchymal lesions (HPL) of the brain.58 patients underwent unenhanced DLCT of the head. CI and VMI ranging from 40 to 120 keV were reconstructed. Objective image quality was assessed using ROI-based measurements within IPH, HPL, grey matter, white matter and cerebrospinal fluid, from which contrast to noise ratio (CNR) was calculated. Two radiologists assessed IPH, HPL, artifacts and image noise on a 5-point Likert-scale. Statistical significance was determined using Wilcoxon rank sum test.In comparison to conventional images, CNR of HPL to white matter was significantly increased in VMI at 120 keV (p ≤ 0.01), whereas at 40 keV, CNR to grey matter was enhanced (p ≤ 0.0001). Contrary, CNR of IPH to white matter was increased at 40 keV (p ≤ 0.01), while CNR to grey matter was improved at 120 keV (p ≤ 0.01). Subjective readings confirmed best delineation of IPH within grey matter at 120 keV. Both readers detected four additional hyperdense lesions within white and one within grey matter at 40 keV.VMI obtained with DLCT can improve depiction of hypodense parenchymal lesions and intraparenchymal hemorrhage. The initial data show a great dependency on the type of pathology and on its location: hypodense lesions in white matter and hyperdense lesions in grey matter are better visualized in higher keV reconstructions, while hyperdense lesion in white matter and hypodense lesions in grey matter are better visualized at low keV values.

Current monitoring of IP flow records is challenged by the required analysis of large volume of flow records. Finding essential information is equivalent to searching for a needle in a haystack. This analysis can reach from simple counting of basic flow level statistics to complex data mining techniques. Some key target objectives are for instance the identification of malicious traffic as well as tracking the cause of observed flow related events. This paper investigates the usage of link analysis based methods for ranking IP flow records. We leverage the well known HITS algorithm in the context of flow level dependency graphs. We assume a simple dependency model that can be build in the context of large scale IP flow record data. We apply our approach on several datasets, ranging from ISP captured flow records up to forensic packet captures from a real world intrusion.

The current study aimed to derive accurate esti­mates of regional cerebral blood flow (rCBF) from noisy dynamic [15O]H2O PET images acquired on the High Resolution Research Tomograph (HRRT), whilst retaining the high spatial resolution of this scanner (2–3 mm) in parametric images. We compared the PET autoradiographic and the generalised linear least squares (GLLS) methods to the non-linear least squares (NLLS) method for rCBF estimation. Six healthy volunteers underwent two [15O]H2O PET scans which included continuous arterial blood sampling. rCBF estimates were obtained from different methods of image reconstruction: 3DRP, OP-OSEM, and RM-OP-OSEM which includes a resolution model. A range of filters (3D Gaussian, 0–6 mm FWHM) were considered, as were a range of accumulation times (40–120 s) in the case of the autoradiogrpahic method. Whole-brain rCBF values were found to be relatively insensitive to the method of reconstruction and rCBF quantification. The average whole-brain gray matter (GM) rCBF for 3DRP reconstruction and NLLS was 0.44±0.03 mL min cm−3, in agreement with literature values. Similar values were obtained from other methods. For generation of parametric images using GLLS or the autoradiographic method, a filter of ≥4 mm was required in order to suppress noise in the PET images which can otherwise produce large biases in the rCBF estimates.

The corrosion behavior of electroplastic rolled (ER) AZ31 magnesium alloys subjected to high energy electric pulse treating (EPT) and conventional heat treating (CHT) respectively in 3.5%NaCl solution (mass fraction) were investigated using potentiodynamic polarization curves, electrochemical impedance spectroscopy (EIS), corrosion morphology observation and corrosion rate measurement. The results indicate that the corrosion resistance of the as-ER alloys is enhanced by EPT or CHT, which is attributed to complete recrystallization and lower dislocation density after treatments. Compared with CHT, the EPT process can increase mechanical properties of materials more significantly, but it is not good at the corrosion resistance improvement, which may result from more corrosion micro-cells caused by finer grains.

This paper considers the monitoring of large volumes of IP flow records, typically encountered on large ISP backbone/edge routers. The approach described in our paper aims to detect relevant flow records, where relevancy is related to overall traffic activity and associated applications. The core contribution of the paper consists in a dependency graph that leverages relationships between hosts, as well as flow-specific risk modeling. The risk model is constructed using well-known link analysis algorithms and application-specific signatures.

To study the corrosion property of an electroplastic rolled AZ31 magnesium alloy in comparison with that of the cold rolled one, the corrosion behavior of an AZ31 magnesium alloy subjected to cold rolling (CR) and electroplastic rolling (ER) respectively in the simulated sea water (3.5wt% NaCl) was systematically investigated using electrochemical techniques such as potentio-dynamic polarization curves, electrochemical impedance spectroscopy (EIS), corrosion morphology observation and corrosion rate measurements. The results show that, under the same deformation strain, corrosion resistance of the as-ER samples is enhanced to some extent compared with that of the as-CR specimens. This improvement in corrosion resistance is probably associated with the high ratio of recrystallization, the low dislocation density and stable corrosion film in the ER alloy.

The effect of electropulsing tension (ET) on the elongation to failure and microstructure of Mg–3Al–1Zn (AZ31) alloy was studied. It was found that electropulsing increased the elongation to failure dramatically at a high strain rate of 2.5×10−2s−1, compared with the non-ET sample. The mechanism for increasing the elongation was proposed mainly based on dynamic recrystallization (DRX). The results in this investigation indicated that an ideal improvement in plasticity and fine equiaxial grains were obtained at a low temperature and a high strain rate due to the coupling of the thermal and athermal effects of ET. It is different from conventional theories.