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Background: Minimal glucose infusions are known to entrain insulin oscillations in patients with normal glucose tolerance (NGT) but not in patients with type 2 diabetes (T2D)., Objectives: To investigate whether weight loss after a version of biliopancreatic diversion (BPD) can restore the glucose entrainment of high-frequency insulin oscillations in morbidly obese NGT or T2D patients., Setting: University Hospital, Greece., Methods: We prospectively studied 9 NGT controls (body mass index [BMI] 23.3±1.6 kg/m 2 ), 9 obese NGT patients (BMI 51.1±12.7 kg/m 2 ), and 9 obese T2D patients (BMI 56.8±11.6 kg/m 2 ). Patients were studied before and 1.5 years after BPD. Insulin was sampled every minute for 90 minutes. Glucose (6 mg/kg weight) was infused every 10 minutes for 1 minute. Regularity of insulin pulses was estimated by autocorrelation analysis, spectral analysis, approximate entropy/sample entropy (ApEn/SampEn), and insulin pulsatility by deconvolution analysis., Results: Postoperatively, glucose and insulin concentrations of NGT and T2D patients decreased to control levels and BMI to 31.3±6.3 for NGT patients and 34.9±9.9 kg/m 2 for T2D patients. Preoperatively, glucose entrainment was absent in all T2D and in 4 NGT patients as assessed with spectral analysis and in 8 and 4, respectively, as assessed with autocorrelation and deconvolution analysis. Postoperatively, it was restored to normal in all patients. ApEn/SampEn decreased significantly only in the T2D group postoperatively., Conclusion: BPD restores the glucose entrainment of high-frequency insulin oscillations in obese NGT and T2D patients after marked weight loss and normalizes glucose levels and insulin sensitivity, thus demonstrating recovery of β-cell glucose sensing., (Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Neuroendocrine tumours (NETs) belong to a relatively rare class of neoplasms. Nonetheless, their prevalence has increased significantly during the last decades. Peptide receptor radionuclide therapy (PRRT) is a relatively new treatment approach for inoperable or metastasised NETs. The therapeutic effect is based on the binding of radiolabelled somatostatin analogue peptides with NETs' somatostatin receptors, resulting in internal irradiation of tumours. Pre-therapeutic patient-specific dosimetry is essential to ensure that a treatment course has high levels of safety and efficacy. This paper reviews the methods applied for PRRT dosimetry, as well as the dosimetric results presented in the literature. Focus is given on data concerning the therapeutic somatostatin analogue radiopeptides (111)In-[DTPA(0),D-Phe(1)]-octreotide ((111)In-DTPA-octreotide), (90)Y-[DOTA(0),Tyr(3)]-octreotide ((90)Y-DOTATOC) and (177)Lu-[DOTA(0),Tyr(3),Thr(8)]-octreotide ((177)Lu-DOTATATE). Following the Medical Internal Radiation Dose (MIRD) Committee formalism, dosimetric analysis demonstrates large interpatient variability in tumour and organ uptake, with kidneys and bone marrow being the critical organs. The results are dependent on the image acquisition and processing protocol, as well as the dosimetric imaging radiopharmaceutical.

The aim of the present study is to examine the importance of using measures to predict the risk of inducing secondary malignancies in association with the clinical effectiveness of treatment plans in terms of tumor control and normal tissue complication probabilities. This is achieved by using radiobiologic parameters and measures, which may provide a closer association between clinical outcome and treatment delivery. Overall, 4 patients having been treated for lung cancer were examined. For each of them, 3 treatment plans were developed based on the helical tomotherapy (HT), multileaf collimator-based intensity modulated radiation therapy (IMRT), and 3-dimensional conformal radiation therapy (CRT) modalities. The different plans were evaluated using the complication-free tumor control probability (p+), the overall probability of injury (pI), the overall probability of control/benefit (pB), and the biologically effective uniform dose (D¯¯). These radiobiologic measures were used to develop dose-response curves (p-D¯¯ diagram), which can help to evaluate different treatment plans when used in conjunction with standard dosimetric criteria. The risks for secondary malignancies in the heart and the contralateral lung were calculated for the 3 radiation modalities based on the corresponding dose-volume histograms (DVHs) of each patient. Regarding the overall evaluation of the different radiation modalities based on the p+ index, the average values of the HT, IMRT, and CRT are 67.3%, 61.2%, and 68.2%, respectively. The corresponding average values of pB are 75.6%, 70.5%, and 71.0%, respectively, whereas the average values of pI are 8.3%, 9.3%, and 2.8%, respectively. Among the organs at risk (OARs), lungs show the highest probabilities for complications, which are 7.1%, 8.0%, and 1.3% for the HT, IMRT, and CRT modalities, respectively. Similarly, the biologically effective prescription doses (DB¯¯) for the HT, IMRT, and CRT modalities are 64.0, 60.9, and 60.8Gy, respectively. Regarding the risk for secondary cancer, for the heart, the lowest average risk is produced by IMRT (0.10%) compared with the HT (0.17%) and CRT (0.12%) modalities, whereas the 3 radiation modalities show almost equivalent results regarding the contralateral lung (0.8% for HT, 0.9% for IMRT, and 0.9% for CRT). The use of radiobiologic parameters in the evaluation of different treatment plans and estimation of their expected clinical outcome is shown to provide very useful clinical information. The radiobiologic analysis of the response probabilities showed that different radiation modalities appear to be more effective in different patient geometries and target sizes and locations. Furthermore, there is not a clear pattern between the plans that appear to be more effective for the treatment and the risk of secondary malignancy. It seems that radiobiologically based treatment planning taking into account the risk of secondary cancer can be established as an effective clinical tool for a more clinically relevant treatment optimization., (Copyright © 2014 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Hypothesis: Dual-modality imaging agents, such as radiolabeled iron oxide nanoparticles (IO-NPs), are promising candidates for cancer diagnosis and therapy. We developed and evaluated aminosilane coated Fe3O4 (10±2nm) as a tumor imaging agent in nuclear medicine through 3-aminopropyltriethoxysilane (APTES) functionalization. We evaluated this multimeric system of targeted (99m)Tc-labeled nanoparticles (NPs) conjugated with a new RGD derivate (cRGDfK-Orn3-CGG), characterized as NPs-RGD as a potential thermal therapy delivery vehicle., Experiments: Transmission Electron Microscopy (TEM) and spectroscopy techniques were used to characterize the IO-NPs indicating their functionalization with peptides. Radiolabeled IO-NPs (targeted, non-targeted) were evaluated with regard to their radiochemical, radiobiological and imaging characteristics. In vivo studies were performed in normal and ανβ3-positive tumor (U87MG glioblastoma) bearing mice. We also demonstrated that this system could reach ablative temperatures in vivo., Findings: Both radiolabeled IO-NPs were obtained in high radiochemical yield (>98%) and proved stable in vitro. The in vivo studies for both IO-NPs have shown significant liver and spleen uptake at all examined time points in normal and U87MG glioblastoma tumor-bearing mice, due to their colloidal nature. We have confirmed through in vivo biodistribution studies that the non-targeted (99m)Tc-NPs poorly internalized in the tumor, while the targeted (99m)Tc-NPs-RGD, present 9-fold higher tumor accumulation at 1h p.i. Accumulation of both IO-NPs in other organs was negligible. Blocking experiments indicated target specificity for integrin receptors in U87MG glioblastoma cells. The preliminary in vivo study of applied alternating magnetic field showed that the induced hyperthermia is feasible due to the aid of IO-NPs., (Copyright © 2014 Elsevier Inc. All rights reserved.)

A meshless numerical method is proposed for the solution of the transient bioheat equation in two and three dimensions. The Pennes bioheat equation is extended in order to incorporate water evaporation, tissue damage, and temperature-dependent tissue properties during tumor ablation. The conductivity of the tissue is not assumed constant but is treated as a local function to simulate local variability due to the existence of usually unclear interfacing of healthy and pathological segments. In this way, one avoids the need for accurate identification of the boundaries between pathological and healthy regions, which is a typical problem in medical practice, and sidesteps, evidently, the corresponding mathematical treatment of such boundaries, which is usually a tedious procedure with some inevitable degree of approximation. The numerical results of the new method for test applications of the bioheat transfer equation are validated against analytical predictions and predictions of other numerical methods. 3D simulations are presented that involve the modeling of tumor ablation and account for metabolic heat generation, blood perfusion, and heat ablation using realistic values for the various parameters. An evaluation of the effective medium approximation to homogenize conductivity fields for use with the bioheat equation is also provided., (Copyright © 2014 John Wiley & Sons, Ltd.)

Purpose: The dynamic mode decomposition (DMD) method is used to provide a reliable forecasting of tumor ablation treatment simulation in real time, which is quite needed in medical practice. To achieve this, an extended Pennes bioheat model must be employed, taking into account both the water evaporation phenomenon and the tissue damage during tumor ablation., Methods: A meshless point collocation solver is used for the numerical solution of the governing equations. The results obtained are used by the DMD method for forecasting the numerical solution faster than the meshless solver. The procedure is first validated against analytical and numerical predictions for simple problems. The DMD method is then applied to three-dimensional simulations that involve modeling of tumor ablation and account for metabolic heat generation, blood perfusion, and heat ablation using realistic values for the various parameters., Results: The present method offers very fast numerical solution to bioheat transfer, which is of clinical significance in medical practice. It also sidesteps the mathematical treatment of boundaries between tumor and healthy tissue, which is usually a tedious procedure with some inevitable degree of approximation. The DMD method provides excellent predictions of the temperature profile in tumors and in the healthy parts of the tissue, for linear and nonlinear thermal properties of the tissue., Conclusions: The low computational cost renders the use of DMD suitable for in situ real time tumor ablation simulations without sacrificing accuracy. In such a way, the tumor ablation treatment planning is feasible using just a personal computer thanks to the simplicity of the numerical procedure used. The geometrical data can be provided directly by medical image modalities used in everyday practice.

Purpose: The GATE Monte Carlo simulation toolkit is used for the implementation of realistic PET simulations incorporating tumor heterogeneous activity distributions. The reconstructed patient images include noise from the acquisition process, imaging system's performance restrictions and have limited spatial resolution. For those reasons, the measured intensity cannot be simply introduced in GATE simulations, to reproduce clinical data. Investigation of the heterogeneity distribution within tumors applying partial volume correction (PVC) algorithms was assessed. The purpose of the present study was to create a simulated oncology database based on clinical data with realistic intratumor uptake heterogeneity properties., Methods: PET/CT data of seven oncology patients were used in order to create a realistic tumor database investigating the heterogeneity activity distribution of the simulated tumors. The anthropomorphic models (NURBS based cardiac torso and Zubal phantoms) were adapted to the CT data of each patient, and the activity distribution was extracted from the respective PET data. The patient-specific models were simulated with the Monte Carlo Geant4 application for tomography emission (GATE) in three different levels for each case: (a) using homogeneous activity within the tumor, (b) using heterogeneous activity distribution in every voxel within the tumor as it was extracted from the PET image, and (c) using heterogeneous activity distribution corresponding to the clinical image following PVC. The three different types of simulated data in each case were reconstructed with two iterations and filtered with a 3D Gaussian postfilter, in order to simulate the intratumor heterogeneous uptake. Heterogeneity in all generated images was quantified using textural feature derived parameters in 3D according to the ground truth of the simulation, and compared to clinical measurements. Finally, profiles were plotted in central slices of the tumors, across lines with heterogeneous activity distribution for visual assessment., Results: The accuracy of the simulated database was assessed against the original clinical images. The PVC simulated images matched the clinical ones best. Local, regional, and global features extracted from the PVC simulated images were closest to the clinical measurements, with the exception of the size zone variability and the mean intensity values, where heterogeneous tumors showed better reproducibility. The profiles on PVC simulated tumors after postfiltering seemed to represent the more realistic heterogeneous regions with respect to the clinical reference., Conclusions: In this study, the authors investigated the input activity map heterogeneity in the GATE simulations of tumors with heterogeneous activity distribution. The most realistic heterogeneous tumors were obtained by inserting PVC activity distributions from the clinical image into the activity map of the simulation. Partial volume effect (PVE) can play a crucial role in the quantification of heterogeneity within tumors and have an important impact on applications such as patient follow-up during treatment and assessment of tumor response to therapy. The development of such a database incorporating patient anatomical and functional variability can be used to evaluate new image processing or analysis algorithms, while providing control of the ground truth, which is not available when dealing with clinical datasets. The database includes all images used and generated in this study, as well as the sinograms and the attenuation phantoms for further investigation. It is freely available to the interested reader of the journal at http://www.med.upatras.gr/oncobase/.

Purpose: To evaluate the effect of vardenafil on renal function after renal ischemia-reperfusion (IR) injury (IRI) in a rat model., Materials and Methods: Seventy-one Wistar rats were divided into 7 groups including (1) a vehicle-treated group, (2) a vehicle pretreated-IR group, (3-6) vardenafil pretreated-IR groups in doses of 0.02, 0.2, 2 and 20 μg/kg, respectively, (7) a group of IR followed by treatment with 2 μg/kg of vardenafil. Vardenafil or vehicle solution was administered one hour before unilateral nephrectomy and the induction of 45 min of ischemia on the contralateral kidney by clamping of renal pedicle. Four hours of reperfusion were allowed after renal ischemia. Studied parameters were serum creatinine, fractional excretion of sodium (FENa), and histological evaluation of renal specimens. In addition, renal tissue cGMP levels, ERK1/2 phosphorylation as well as renal function by renal scintigraphy were also evaluated., Results: Administration of vardenafil before the induction of ischemia resulted in a significant reduction in creatinine and FENa levels as well as in less histological lesions observed in treated kidneys in comparison with the vehicle-treated group. The underlying mechanism of cytoprotection was cGMP depended and involved the phosphorylation of ERK proteins. Renal scintigraphy confirmed that PDE5 inhibition attenuates renal IRI., Conclusions: Vardenafil attenuates renal IRI. Based on similar results from relevant studies on other PDE-5 inhibitors in renal and cardiac IRI, it can be assumed that all PDE-5 inhibitors share a common mechanism of cytoprotection.

Purpose: A new segmentation technique is implemented for automatic lumen area extraction and stent strut detection in intravascular optical coherence tomography (OCT) images for the purpose of quantitative analysis of in-stent restenosis (ISR). In addition, a user-friendly graphical user interface (GUI) is developed based on the employed algorithm toward clinical use., Methods: Four clinical datasets of frequency-domain OCT scans of the human femoral artery were analyzed. First, a segmentation method based on fuzzy C means (FCM) clustering and wavelet transform (WT) was applied toward inner luminal contour extraction. Subsequently, stent strut positions were detected by utilizing metrics derived from the local maxima of the wavelet transform into the FCM membership function., Results: The inner lumen contour and the position of stent strut were extracted with high precision. Compared to manual segmentation by an expert physician, the automatic lumen contour delineation had an average overlap value of 0.917 ± 0.065 for all OCT images included in the study. The strut detection procedure achieved an overall accuracy of 93.80% and successfully identified 9.57 ± 0.5 struts for every OCT image. Processing time was confined to approximately 2.5 s per OCT frame., Conclusions: A new fast and robust automatic segmentation technique combining FCM and WT for lumen border extraction and strut detection in intravascular OCT images was designed and implemented. The proposed algorithm integrated in a GUI represents a step forward toward the employment of automated quantitative analysis of ISR in clinical practice.

Introduction: Radiolabeled RGD peptides that specifically target integrin α(ν)β(3) have great potential in early tumor detection through noninvasive monitoring of tumor angiogenesis. Based on previous findings of our group on radiopeptides containing positively charged aminoacids, we developed a new cyclic cRGDfK derivative, c(RGDfK)-(Orn)(3)-CGG. This new peptide availing the polar linker (Orn)(3) and the (99m)Tc-chelating moiety CGG (Cys-Gly-Gly) is appropriately designed for (99m)Tc-labeling, as well as consequent conjugation onto nanoparticles., Methods: A tumor imaging agent, c(RGDfK)-(Orn)(3)-[CGG-(99m)Tc], is evaluated with regard to its radiochemical, radiobiological and imaging characteristics., Results: The complex c(RGDfK)-(Orn)(3)-[CGG-(99m)Tc] was obtained in high radiochemical yield (>98%) and was stable in vitro and ex vivo. It presented identical to the respective, fully analytically characterized (185/187)Re complex retention time in RP-HPLC. In contrary to other RGD derivatives, we showed that the new radiopeptide exhibits kidney uptake and urine excretion due to the ornithine linker. High tumor uptake (3.87±0.48% ID/g at 60 min p.i.) was observed and was maintained relatively high even at 24 h p.i. (1.83±0.05 % ID/g), thus providing well-defined scintigraphic imaging. Accumulation in other organs was negligible. Blocking experiments indicated target specificity for integrin receptors in U87MG glioblastoma cells., Conclusion: Due to its relatively high tumor uptake, renal elimination and negligible abdominal localization, the new (99m)Tc-RGD peptide is considered promising in the field of imaging α(ν)β(3)-positive tumors. However, the preparation of multifunctional SPECT/MRI contrast agents (RGD-conjugated nanoparticles) for dual modality imaging of integrin expressing tumors should be further investigated., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Recent developments in image-guidance and device navigation, along with emerging robotic technologies, are rapidly transforming the landscape of interventional radiology (IR). Future state-of-the-art IR procedures may include real-time three-dimensional imaging that is capable of visualizing the target organ, interventional tools, and surrounding anatomy with high spatial and temporal resolution. Remote device actuation is becoming a reality with the introduction of novel magnetic-field enabled instruments and remote robotic steering systems. Robots offer several degrees of freedom and unprecedented accuracy, stability, and dexterity during device navigation, propulsion, and actuation. Optimization of tracking and navigation of interventional tools inside the human body will be critical in converting IR suites into the minimally invasive operating theaters of the future with increased safety and unsurpassed therapeutic efficacy. In the not too distant future, individual image guidance modalities and device tracking methods could merge into autonomous, multimodality, multiparametric platforms that offer real-time data of anatomy, morphology, function, and metabolism along with on-the-fly computational modeling and remote robotic actuation. The authors provide a concise overview of the latest developments in image guidance and device navigation, while critically envisioning what the future might hold for 2020 IR procedures.

Purpose: GATE is a Monte Carlo simulation toolkit based on the Geant4 package, widely used for many medical physics applications, including SPECT and PET image simulation and more recently CT image simulation and patient dosimetry. The purpose of the current study was to calculate dose point kernels (DPKs) using GATE, compare them against reference data, and finally produce a complete dataset of the total DPKs for the most commonly used radionuclides in nuclear medicine., Methods: Patient-specific absorbed dose calculations can be carried out using Monte Carlo simulations. The latest version of GATE extends its applications to Radiotherapy and Dosimetry. Comparison of the proposed method for the generation of DPKs was performed for (a) monoenergetic electron sources, with energies ranging from 10 keV to 10 MeV, (b) beta emitting isotopes, e.g., (177)Lu, (90)Y, and (32)P, and (c) gamma emitting isotopes, e.g., (111)In, (131)I, (125)I, and (99m)Tc. Point isotropic sources were simulated at the center of a sphere phantom, and the absorbed dose was stored in concentric spherical shells around the source. Evaluation was performed with already published studies for different Monte Carlo codes namely MCNP, EGS, FLUKA, ETRAN, GEPTS, and PENELOPE. A complete dataset of total DPKs was generated for water (equivalent to soft tissue), bone, and lung. This dataset takes into account all the major components of radiation interactions for the selected isotopes, including the absorbed dose from emitted electrons, photons, and all secondary particles generated from the electromagnetic interactions., Results: GATE comparison provided reliable results in all cases (monoenergetic electrons, beta emitting isotopes, and photon emitting isotopes). The observed differences between GATE and other codes are less than 10% and comparable to the discrepancies observed among other packages. The produced DPKs are in very good agreement with the already published data, which allowed us to produce a unique DPKs dataset using GATE. The dataset contains the total DPKs for (67)Ga, (68)Ga, (90)Y, (99m)Tc, (111)In, (123)I, (124)I, (125)I, (131)I, (153)Sm, (177)Lu (186)Re, and (188)Re generated in water, bone, and lung., Conclusions: In this study, the authors have checked GATE's reliability for absorbed dose calculation when transporting different kind of particles, which indicates its robustness for dosimetry applications. A novel dataset of DPKs is provided, which can be applied in patient-specific dosimetry using analytical point kernel convolution algorithms.

Purpose: The aim of the present study was the evaluation and optimization of radiation dose to the ovaries (D) in hysterosalpingography (HSG)., Methods: The study included a phantom study and a clinical one. In the phantom study, we evaluated imaging results for different geometrical setups and irradiation conditions. In the clinical study, 34 women were assigned into three different fluoroscopy modes and D was estimated with direct cervical TLD measurements., Results: In the phantom study, we used a source-to-image-distance (SID) of 110 cm and a field diagonal of 48 cm, and thus decreased air KERMA rate (KR) by 19% and 70%, respectively, for beam filtration: 4 mm Al and 0.9 mm Cu (Low dose). The least radiation exposure was accomplished by using the 3.75 pps fluoroscopy mode in conjunction with beam filtration: Low dose. In the clinical study, D normalized to 50 s of fluoroscopy time with a 3.75 pps fluoroscopy mode reached a value of 0.45 ± 0.04 mGy. Observers' evaluation of diagnostic image quality did not significantly differ for the three different modes of acquisition that were compared., Conclusions: Digital spot radiographs could be omitted in modern flat panel systems during HSG. Fluoroscopy image acquisitions in a modern flat panel unit at 3.75 pps and a beam filtration of 4 mm Al and 0.9 mm Cu demonstrate acceptable image quality with an average D equal to 0.45 mGy. This value is lower compared to the studied literature. For these reasons, the proposed method may be recommended for routine HSG examination in order to limit radiation exposure to the ovaries.

Purpose: Optical coherence tomography (OCT) is a catheter-based imaging method that employs near-infrared light to produce high-resolution cross-sectional intravascular images. The authors propose a segmentation technique for automatic lumen area extraction and stent strut detection in intravascular OCT images for the purpose of quantitative analysis of neointimal hyperplasia (NIH)., Methods: A clinical dataset of frequency-domain OCT scans of the human femoral artery was analyzed. First, a segmentation method based on the Markov random field (MRF) model was employed for lumen area identification. Second, textural and edge information derived from local intensity distribution and continuous wavelet transform (CWT) analysis were integrated to extract the inner luminal contour. Finally, the stent strut positions were detected via the introduction of each strut wavelet response across scales into a feature extraction and classification scheme in order to optimize the strut position detection., Results: The inner lumen contour and the position of stent strut were extracted with very high accuracy. Compared with manual segmentation by an expert vascular physician the automatic segmentation had an average overlap value of 0.937 ± 0.045 for all OCT images included in the study. The strut detection accuracy had an area under the curve (AUC) value of 0.95, together with sensitivity and specificity average values of 0.91 and 0.96, respectively., Conclusions: A robust automatic segmentation technique integrating textural and edge information for vessel lumen border extraction and strut detection in intravascular OCT images was designed and presented. The proposed algorithm may be employed for automated quantitative morphological analysis of in-stent neointimal hyperplasia.

Objectives: Atherosclerosis is a significant factor affecting long-term outcome in renal transplant recipients. Studies have been conducted to determine the pharmacogenomic pathways involved in statin efficacy, efficiency, and adverse effect likelihood. However, little is known about the influence of statins on tacrolimus kinetics. The aim of this study was to investigate possible pharmacological interactions between tacrolimus and statins in CYP3A5 non-expressors, renal transplant recipients., Materials and Methods: Twenty-four patients, treated with tacrolimus (n=24), methylprednisolone (n=24), and mycophenolate mofetil (n=19)/azathioprine (n=1)/everolimus (n=4), participated in the study. After an observation time of 112±36 days, statins, namely, atorvastatin (n=12), simvastatin (n=8), pravastatin (n=2), or fluvastatin (n=2), were administered for additional 101±34 days. DNA was extracted from whole blood sample and polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for CYP3A5 genotyping. Student's t-test and Mann-Whitney test were used to test the significance of difference in variables that passed or did not pass Kolmogorov's normality test, respectively., Results: No statistically significant difference was observed in tacrolimus daily dose, concentration, concentration/dose ratio, and volume of distribution before and during the administration of statins. Statistically significant decrease in serum cholesterol was observed after initiation of statins. Renal and hepatic function remained unchanged and no skeletal muscle abnormalities were reported., Conclusions: The results of this study show that tacrolimus and statins do not interact in terms of efficacy, efficiency, and adverse effect likelihood. No significant clinical interaction or effect was observed, even with the use of atorvastatin or simvastatin, which are metabolized by CYP3A4 such as tacrolimus.

The use of small animal models in basic and preclinical sciences constitutes an integral part of testing new pharmaceutical agents prior to commercial translation to clinical practice. Whole-body small animal imaging is a particularly elegant and cost-effective experimental platform for the timely validation and commercialization of novel agents from the bench to the bedside. Biomedical imaging is now listed along with genomics, proteomics, and metabolomics as an integral part of biological and medical sciences. Miniaturized versions of clinical diagnostic modalities, including but not limited to microcomputed tomography, micromagnetic resonance tomography, microsingle-photon-emission tomography, micropositron-emission tomography, optical imaging, digital angiography, and ultrasound, have all greatly improved our investigative abilities to longitudinally study various experimental models of human disease in mice and rodents. After an exhaustive literature search, the authors present a concise and critical review of in vivo small animal imaging, focusing on currently available modalities as well as emerging imaging technologies on one side and molecularly targeted contrast agents on the other. Aforementioned scientific topics are analyzed in the context of cancer angiogenesis and innovative antiangiogenic strategies under-the-way to the clinic. Proposed hybrid approaches for diagnosis and targeted site-specific therapy are highlighted to offer an intriguing glimpse of the future.

Many empirical studies have demonstrated the exquisite sensitivity of both traditional and novel statistical and machine intelligence algorithms to the method of background adjustment used to analyze microarray datasets. In this paper we develop a statistical framework that approaches background adjustment as a classic stochastic inverse problem, whose noise characteristics are given in terms of Maximum Entropy distributions. We derive analytic closed form approximations to the combined problem of estimating the magnitude of the background in microarray images and adjusting for its presence. The proposed method reduces standardized measures of log expression variability across replicates in situations of known differential and non-differential gene expression without increasing the bias. Additionally, it results in computationally efficient procedures for estimation and learning based on sufficient statistics and can filter out spot measures with intensities that are numerically close to the background level resulting in a noise reduction of about 7%., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: As proton pump inhibitors share CYP3A4 enzyme with tacrolimus for their hepatic elimination, they potentially affect its pharmacokinetics, most prominently in patients with CYP2C19 or CYP3A5 gene mutations. Our aim was to investigate the impact of omeprazole on tacrolimus pharmacokinetics in CYP3A5 non-expressors, kidney transplant recipients., Methods: Twelve patients (five males/seven females) were observed for 175 +/- 92.05 days. Omeprazole (20 mg pos) was administrated for 75.83 +/- 45.17 days. Immunosuppressant regimen consisted of tacrolimus (n = 12), methylprednisolone (n = 10), mycophenolate mofetil (n = 11), azathioprine (n = 1), and everolimus (n = 2). Patient's body weight, coadministered drugs, and tacrolimus trough levels were monitored. Aspartate and alanine aminotransferase, gamma-glutamyltransferase, and bilirubin were used for evaluating hepatic function. Tacrolimus kinetics were estimated with daily dose, concentration, dose adjusted concentration, and volume of distribution with and without coadministration of omeprazole. CYP3A5 genotyping was performed with PCR followed by restriction fragment length polymorphism analysis. Statistical analysis was performed with Prism 4 software (GraphPad Software, Inc)., Results: No statistically significant difference was observed in tacrolimus kinetics and hepatic function during coadministration of omeprazole., Conclusion: Our results let us propose that there is no need for more frequent therapeutic drug monitoring of tacrolimus when coadministrated with omeprazole in CYP3A5 nonexpressors, though prospective studies with more patients and longer observation period are needed to confirm these findings.

Background: The aim of our study was to determine the impact of CYP3A5*1 and CYP3A5*3 on the kinetics of tacrolimus in renal transplant recipients., Material and Methods: Forty kidney recipients were selected to participate. Maintenance scheme consisted of tacrolimus, a purine inhibitor and a steroid. CYP3A5 genotyping was performed with PCR and RFLP. Pharmacokinetic model was developed with Linear Regression and General Linear Model repeated measures approach. The impact of sex, CYP3A5*1 allele, age at transplantation, hepatic and renal function on tacrolimus kinetics was examined., Results: The frequency of CYP3A5*3/*3 and CYP3A5*1/*3 genotype was 35/40 and 5/40, respectively. No CYP3A5*1/*1 was detected. CYP3A5*1 variant was associated with significant lower TAC dose adjusted concentration at 3, 6, 12 and 36 months after transplantation. Hepatic and renal function showed a significant effect on tacrolimus dose adjusted concentration 3 months after transplantation (p=0.000 and 0.028, respectively). Sex did not show a significant impact on tacrolimus kinetics. Carriers of CYP3A5*1 allele had lower predicted measures for tacrolimus dose adjusted concentration and higher predicted measures for volume of distribution., Conclusion: We proved that CYP3A5*1 carriers need higher tacrolimus dose than CYP3A5*3 homozygotes to achieve the target blood concentration.

A wavelet-based modification of the Markov random field (WMRF) model is proposed for segmenting complementary DNA (cDNA) microarray images. For evaluation purposes, five simulated and a set of five real microarray images were used. The one-level stationary wavelet transform (SWT) of each microarray image was used to form two images, a denoised image, using hard thresholding filter, and a magnitude image, from the amplitudes of the horizontal and vertical components of SWT. Elements from these two images were suitably combined to form the WMRF model for segmenting spots from their background. The WMRF was compared against the conventional MRF and the Fuzzy C means (FCM) algorithms on simulated and real microarray images and their performances were evaluated by means of the segmentation matching factor (SMF) and the coefficient of determination (r2). Additionally, the WMRF was compared against the SPOT and SCANALYZE, and performances were evaluated by the mean absolute error (MAE) and the coefficient of variation (CV). The WMRF performed more accurately than the MRF and FCM (SMF: 92.66, 92.15, and 89.22, r2 : 0.92, 0.90, and 0.84, respectively) and achieved higher reproducibility than the MRF, SPOT, and SCANALYZE (MAE: 497, 1215, 1180, and 503, CV: 0.88, 1.15, 0.93, and 0.90, respectively).

The objective of this paper was to investigate the segmentation ability of the fuzzy Gaussian mixture model (FGMM) clustering algorithm, applied on complementary DNA (cDNA) images. Following a standard established procedure, a simulated microarray image of 1600 cells, each containing one spot, was produced. For further evaluation of the algorithm, three real microarray images were also used, each containing 6400 spots. For the task of locating spot borders and surrounding background (BG) in each cell, an automatic gridding process was developed and applied on microarray images. The FGMM and the Gaussian mixture model (GMM) algorithms were applied to each cell with the purpose of discriminating foreground (FG) from BG. The segmentation abilities of both algorithms were evaluated by means of the segmentation matching factor, coefficient of determination, and concordance correlation, in respect to the actual classes (FG-BG pixels) of the simulated spots. Pairwise correlation and mean absolute error of the real images among replicates were also calculated. The FGMM was found to perform better and with equal processing time, as compared to the GMM, rendering the FGMM algorithm an efficient alternative for segmenting cDNA microarray images.

In the rapidly advancing field of flow cytometry, methodologies facilitating automated clinical decision support are increasingly needed. In the case of B-chronic lymphocytic leukemia (B-CLL), discrimination of the various subpopulations of blood cells is an important task. In this work, our objective is to provide a useful paradigm of computer-based assistance in the domain of flow-cytometric data analysis by proposing a Bayesian methodology for flow cytometry clustering. Using Bayesian clustering, we replicate a series of (unsupervised) data clustering tasks, usually performed manually by the expert. The proposed methodology is able to incorporate the expert's knowledge, as prior information to data-driven statistical learning methods, in a simple and efficient way. We observe almost optimal clustering results, with respect to the expert's gold standard. The model is flexible enough to identify correctly non canonical clustering structures, despite the presence of various abnormalities and heterogeneities in data; it offers an advantage over other types of approaches that apply hierarchical or distance-based concepts.

Background: Compared with angiogenesis, arteriogenesis is a distinct process based on the remodeling and maturation of pre-existing arterioles into large conductance arteries. Therapeutic angiogenesis has been proposed as a potential treatment for ischemic atherosclerotic diseases. Since a variety of angiogenic factors have been tested with inconsistent so far clinical results, the challenge remains in identifying the factor(s) that will stimulate functional neovascularization. Thrombin has been reported to play a pivotal role in the initiation of angiogenesis by regulating and organizing a network of angiogenic mediators. Also, it was recently demonstrated that thrombin is a potent anti-apoptotic factor for endothelial cells, providing evidence on a potential role of thrombin in vascular protection and maintenance of vessel integrity. Based on these observations, we hypothesized that thrombin may promote the development of mature functional blood vessels., Methods: Seventy-four (n=74) rabbits underwent bilateral femoral artery surgical excision. On the 20th postsurgical day increasing doses of VEGF or bFGF or thrombin were injected in one ischemic limb per rabbit and an equal volume of normal saline to the contralateral control limbs. Quantification of newly developed collateral vessels (diameter >500 mum) was performed by transauricular intra-arterial subtraction angiography. Computerized quantitative analysis of collateral vessels in angiography images was based on the concept of multiscale structural tensor. Perfusion analysis of an in vivo dynamic computed tomography study was performed to investigate hemodynamic recovery of the distal ischemic limbs. Tissue perfusion analysis was performed with the semiquantitative slope methodology, which focuses on the first-pass arterial phase., Results: A single administration of thrombin exhibited a dose-dependent increase of arteriogenic outcome. Thrombin at 5000 IU induced a 30.2 +/- 7.4% (P < 0.05) increase of total collateral area and length. Both VEGF and bFGF were without any significant effect at the concentrations used. Functional estimation of limb perfusion showed a statistically significant increase of blood flow recovery only for thrombin. The semiquantitative slope method perfusion score differed significantly in the 5000 IU thrombin treated limbs (5.7 +/- 0.3 vs 5.0 +/- 0.3 in control ischemic limbs; P < .05), and was not significantly inferior from the score of normal nonoperated limbs (6.5 +/- 0.3) suggesting a trend towards hemodynamic recovery of distal limb perfusion., Conclusions: In a rabbit hindlimb ischemia model, thrombin promoted the formation of large collateral vessels and improved the perfusion of distal ischemic tissue. These results provide new insights in understanding the involvement of thrombin in vascular formation and point to a novel role of thrombin in arteriogenesis.

The purpose of our study was to develop a user-independent computerized tool for the automated segmentation and quantitative assessment of in vivo-acquired digital subtraction angiography (DSA) images. Vessel enhancement was accomplished based on the concept of image structural tensor. The developed software was tested on a series of DSA images acquired from one animal and two human angiogenesis models. Its performance was evaluated against manually segmented images. A receiver's operating characteristic curve was obtained for every image with regard to the different percentages of the image histogram. The area under the mean curve was 0.89 for the experimental angiogenesis model and 0.76 and 0.86 for the two clinical angiogenesis models. The coordinates of the operating point were 8.3% false positive rate and 92.8% true positive rate for the experimental model. Correspondingly for clinical angiogenesis models, the coordinates were 8.6% false positive rate and 89.2% true positive rate and 9.8% false positive rate and 93.8% true positive rate, respectively. A new user-friendly tool for the analysis of vascular networks in DSA images was developed that can be easily used in either experimental or clinical studies. Its main characteristics are robustness and fast and automatic execution.

Molecular imaging (MI) constitutes a recently developed approach of imaging, where modalities and agents have been reinvented and used in novel combinations in order to expose and measure biologic processes occurring at molecular and cellular levels. It is an approach that bridges the gap between modalities acquiring data from high (e.g., computed tomography, magnetic resonance imaging, and positron-emitting isotopes) and low (e.g., PCR, microarrays) levels of a biological organization. While data integration methodologies will lead to improved diagnostic and prognostic performance, interdisciplinary collaboration, triggered by MI, will result in a better perception of the underlying biological mechanisms. Toward the development of a unifying theory describing these mechanisms, medical physicists can formulate new hypotheses, provide the physical constraints bounding them, and consequently design appropriate experiments. Their new scientific and working environment calls for interventions in their syllabi to educate scientists with enhanced capabilities for holistic views and synthesis.

The present study reports on computational fluid dynamics in the case of severe renal artery stenosis (RAS). An anatomically realistic model of a renal artery was reconstructed from CT scans, and used to conduct CFD simulations of blood flow across RAS. The recently developed shear stress transport (SST) turbulence model was pivotally applied in the simulation of blood flow in the region of interest. Blood flow was studied in vivo under the presence of RAS and subsequently in simulated cases before the development of RAS, and after endovascular stent implantation. The pressure gradients in the RAS case were many orders of magnitude larger than in the healthy case. The presence of RAS increased flow resistance, which led to considerably lower blood flow rates. A simulated stent in place of the RAS decreased the flow resistance at levels proportional to, and even lower than, the simulated healthy case without the RAS. The wall shear stresses, differential pressure profiles, and net forces exerted on the surface of the atherosclerotic plaque at peak pulse were shown to be of relevant high distinctiveness, so as to be considered potential indicators of hemodynamically significant RAS.

Background: The integration of biomedical information is essential for tackling medical problems. We describe a data model in the domain of flow cytometry (FC) allowing for massive management, analysis and integration with other laboratory and clinical information. The paper is concerned with the proper translation of the Flow Cytometry Standard (FCS) into a relational database schema, in a way that facilitates end users at either doing research on FC or studying specific cases of patients undergone FC analysis, Results: The proposed database schema provides integration of data originating from diverse acquisition settings, organized in a way that allows syntactically simple queries that provide results significantly faster than the conventional implementations of the FCS standard. The proposed schema can potentially achieve up to 8 orders of magnitude reduction in query complexity and up to 2 orders of magnitude reduction in response time for data originating from flow cytometers that record 256 colours. This is mainly achieved by managing to maintain an almost constant number of data-mining procedures regardless of the size and complexity of the stored information., Conclusion: It is evident that using single-file data storage standards for the design of databases without any structural transformations significantly limits the flexibility of databases. Analysis of the requirements of a specific domain for integration and massive data processing can provide the necessary schema modifications that will unlock the additional functionality of a relational database.

Background and Purpose: Recent reports concerning coronary, carotid, and femoral vasculature have proposed the use of drug-eluting metal stents (MS) to improve clinical and angiographic outcomes. Based on these reports, we used paclitaxel-eluting MS within an animal renal artery lumen and compared the results with those using a bare-metal stent., Materials and Methods: The experimental model in this study was the female pig renal artery. Ten pigs with weights ranging from 25 to 30 kg were used. Twenty stents were placed, two in each animal. The MS placement was randomly performed in either the right or left renal artery of each animal. In 10 arteries, a 3.5 x 18 mm R-stent (group A) was placed; in the remaining 10 arteries, a 3 x 32 mm paclitaxel-eluting coronary stent (T-stent, group B) was inserted. Patency was estimated with the use of digital subtraction angiography, CT angiography, and virtual endoscopy at 24 hours and 1 month poststent placement., Results: The positioning of the MS was successful in all cases. The initial angiographic result was maintained 24 hours after the intervention. No stent migration was seen, except for one paclitaxel stent that was acutely occluded. The one-month patency rate, as demonstrated by angiography, CT angiography, and virtual endoscopy, was 70% (8 arteries) in group A and 90% (9 arteries) in group B. The thickness of the endothelium and of the muscular coat was statistically significantly less in group B compared with group A (P = 0.0352 and P = 0.0046, respectively)., Conclusion: These preliminary experimental study results suggest that the paclitaxel-eluting MS is more efficient than the bare-metal stent when used within the pig renal artery. Further experimental and clinical studies are necessary to validate our preliminary encouraging results.

Background: Vasospasm is a major cause of ischemic neurological deficits developing after subarachnoid hemorrhage. The goal was to identify hemodynamic changes and the presence of clinical vasospasm in patients suffering from subarachnoid hemorrhage secondary to ruptured intracranial aneurysms., Material/methods: Pre- and postoperative serial transcranial cerebral oximetry and transcranial doppler sonography (TCD) examinations were performed in 75 patients operated for aneurysmal subarachnoid hemorrhage., Results: No significant difference (p=0.14) was found in the levels of regional oxygen saturation (rSO2) between patients with vasospasm and those without. In patients who developed clinical vasospasm, the blood flow velocity values were significantly higher compared with those who did not (127.5+/-2.7 versus 92.5+/-1.2 cm/sec, p<0.001). In six patients with clinical vasospasm and low TCCO measurements, the use of triple-H therapy led to oxygen saturation increment and clinical improvement., Conclusions: Transcranial cerebral oximetry seems to be of limited value for the detection of vasospasm in patients with subarachnoid hemorrhage. However, it may be useful in estimating the clinical impact of triple-H therapy in such patients.

Purpose: We report our long-term experience with the management of benign ureteroileal anastomotic strictures using self-expandable metal stents., Materials and Methods: A total of 16 male and 2 female patients with a mean+/-SD age of 72+/-7 years (range 66 to 78) with benign fibrotic strictures at the site of ureteroileal anastomosis underwent implantation of self-expandable metal stents with a nominal diameter of 6 to 8 mm. A total of 24 ureteroileal conduits were treated. The external nephrostomy tubes were removed after fluoroscopic validation of ureteral patency. Patients were followed with blood biochemistry, ultrasonography, urography and/or virtual endoscopy. Retrograde external-internal catheter insertion through the cutaneous stoma was performed in cases of recalcitrant stricture., Results: The technical success rate of ureteroileal stricture crossing and stenting was 100% (24 of 24 cases). Mean followup was 21 months (range 7 to 50). The clinical success rate during the immediate post-stenting period was 70.8% (17 of 24 cases). The 1 and 4-year primary patency rates were 37.8% and 22.7%, respectively. Secondary interventions included repeat balloon dilation in 15 ureters, of which 8 also underwent subsequent coaxial stent placement. The 1 and 4-year secondary patency rates were 64.8% and 56.7%, respectively. Except in 2 patients who died external-internal Double-J catheters continued to be inserted retrograde in 6 ureteroileal conduits. They are periodically exchanged to prevent mucous inspissation and stent encrustation., Conclusions: Metal stents served as the definitive treatment for stricture in more than half of the cases, whereas in the remainder the stents allowed the uncomplicated and regular exchange of Double-J catheters in retrograde fashion. This combined, less invasive treatment for ureteroileal anastomotic strictures may help patients avoid surgical revision and preserve quality of life.

Pulmonary artery sling is frequently accompanied by tracheal anomalies other than local compression, including focal/segmental or extensive stenosis (ring-sling complex). Recent advances in computed tomography technology, such as multidetector computed tomography with 3-dimensional imaging (3-D) and virtual bronchoscopy (VB), offer important and accurate information of the entire tracheobronchial tree. We report on the value of 3-D imaging and VB in the preoperative assessment of a 4-year-old child with pulmonary artery sling and long segment tracheal stenosis owing to complete cartilaginous rings; we suggest that 3-D imaging and VB are important contributions in this assessment.

Background: We evaluated the ability of 3D-CT and virtual bronchoscopy to estimate trachea stenosis in comparison to conventional axial CT and fiberoptic bronchoscopy, with a view to assist thoracic surgeons in depicting the anatomical characteristics of tracheal strictures., Methods: Spiral CT was performed in 16 patients with suspected tracheal stenoses and in 5 normal subjects. Tracheal stenoses due to an endoluminal neoplasm were detected in 13 patients, whilst post-intubation tracheal stricture was observed in the other 3 patients. Multiplanar reformatting (MPR), volume rendering techniques (VRT) and virtual endoscopy (VE) for trachea evaluation were applied and findings were compared to axial CT and fiberoptic bronchoscopy. The accuracy of the procedure in describing the localization and degree of stenosis was tested by two radiologists in a blinded controlled trial., Results: The imaging modalities tested showed the same stenoses as the ones detected by flexible bronchoscopy and achieved accurate and non-invasive morphological characterization of the strictures, as well as additional information about the extraluminal extent of the disease. No statistically significant difference was observed between the bronchoscopic findings and the results of axial CT estimations (P = 1.0). No statistically significant differences were observed between bronchoscopic findings and the MPR, VRT and VE image evaluations (P = 0.705, 0.414 and 0.414 respectively)., Conclusion: CT and computed generated images may provide a high fidelity, noninvasive and reproducible evaluation of the trachea compared to bronchoscopy. They may play a role in assessment of airway patency distal to high-grade stenoses, and represent a reliable alternative method for patients not amenable to conventional bronchoscopy.

Objective: The purpose of the present study is to compare the standard bare metal stents (BMS) with the Paclitaxel-Drug Eluting Stent (DES) in the ureter of a pig model., Materials and Methods: We report on an experimental study with ten female pigs weighing between 25 and 30 kg. The stents were randomly placed in either the right or left ureter in each of 10 study animals, for a total of 20 stented ureters. Ten ureters were stented with an R-Stent (Orbus Medical Technologies, Hoevelaken Netherlands), and ten with a Paclitaxel-Eluting Coronary Stent (Boston Scientific, Natick, MA, USA). Patency was measured by radiograph of the nephrostomy tract, intravenous urography and virtual endoscopy at 24 hours and 21 days after the initial procedure, respectively., Results: Free flow of urine through the stents into the bladder was documented in all stented ureters 24 hours after stent insertion by radiograph of the nephrostomy tract. At the 21 day follow-up examination, 5 R-Stents were found to be completely occluded and two partially stenosed, whereas no occluded stent was detected in the Paclitaxel-DES group. Pathology examination of the stents at 21 days follow-up showed that the obstructed R-Stents generated severe inflammation with metaplasia of the urothelium. The Paclitaxel-Eluting MS generated a mild inflammatory response within the ureteral lumen at the site of the stent, without hindering ureteral patency. R-stents proved to develop more hyperplasia compared to the Paclitaxel-Eluting MS., Conclusions: Paclitaxel-DES, when compared with the standard R- Stent BMS, generated less inflammation and/or hyperplasia of the surrounding tissues, thus maintaining ureteral patency. Long-term animal trials are required to further validate our results.

Purpose: To investigate distal embolism during endovascular procedures of the infra-aortic arteries by utilizing a commercial filter basket and unveil any correlation between the baseline clinical and procedural variables and the histopathological findings of the collected particles., Methods: In a prospective study, 48 patients (37 men; mean age 70.8+/-7.8 years, range 50- 83) underwent endoluminal therapy of infra-aortic lesions (stenosis >75% or occlusion; mean lesion length 52.2+/-38.0 mm) with standard endovascular procedures. A nitinol filter basket (n=50) was employed for distal protection. The collected particles were histopathologically analyzed. The harvested specimens were quantified after digital image post processing., Results: Procedural success of filter-protected revascularization was 93.8%. Three failures included 1 vasospasm, 1 distal embolus, and 1 side-branch occlusion. The total area of retrieved particles per basket was 2.76+/-6.49 mm(2) (range 0.0-40.3). Particles with a major axis >1 and >3 mm were detected in 29 (58.0%) and 6 (12.0%), respectively, of the examined filters. Collected particles consisted primarily of platelets and fibrin conglomerates, trapped erythrocytes, inflammatory cells, and extracellular matrix. Increased lesion length, increased reference vessel diameter, acute thromboses, and total occlusions were positively correlated with higher amounts of captured particles (p<0.05). Multivariate analysis incriminated declotting procedures as the only independent predictor of increased embolic burden (p<0.05)., Conclusion: The embolism phenomenon during infra-aortic interventions is frequent and underestimated. The liberated particles consisted primarily of atheromatous plaque elements and thrombus. The reported data might support the application of a protective filter basket in selected subsets of lesions with a riskier embolic profile and whenever declotting procedures are performed.

Technological breakthroughs have advanced the temporal and spatial resolutions of diagnostic imaging, and 3 dimensional (3-D) reconstruction techniques have been introduced into everyday clinical practice. Virtual endoscopy (VE) is a non-invasive technique that amplifies the perception of cross-sectional images in the 3-D space, providing precise spatial relationships of pathological regions and their surrounding structures. A variety of computer algorithms can be used to generate 3-D images, taking advantage of the information inherent in either spiral computed tomography or magnetic resonance imaging (MRI). VE images enable endoluminal navigation through hollow organs, thus simulating conventional endoscopy. Several clinical studies have validated the diagnostic utility of virtual cystoscopy, which has high sensitivity and specificity rates in the detection of bladder tumor. Published experience in the virtual exploration of the renal pelvis, ureter and urethra is encouraging but still scarce. VE is a safe, non-invasive method that could be applied in the long-term follow-up of patients with ureteropelvic junction obstruction, urinary bladder tumors and ureteral and/or urethral strictures. Its principal limitations are the inability to provide biopsy tissue specimens for histopathologic examination and the associated ionizing radiation hazards (unless MRI is used). However, in the case of endoluminal stenosis or obstruction, VE permits virtual endoluminal navigation both cephalad and caudal to the stenotic segment. To conclude, VE provides a less invasive method of evaluating the urinary tract, especially for clinicians who are less familiar with cross-sectional imaging than radiologists.

Our purpose was to describe a technique for simulating the surgical view of ruptured intracranial aneurysms, using volume-rendering techniques in spiral computed tomography (CT) angiography data. The 3D (three-dimensional) rendered images were assessed by a team consisted of four radiologists, one neurosurgeon and one medical physicist. The resultant 'surgical view' image was standardized in space using a three-dimensional coordinate system, which allowed for its reproduction in the operating theatre. The surgical views are a potentially useful tool for the surgical planning of intracranial aneurysms.

Introduction: Cerebral CT angiography (CTA) is an established method applied to both the detection and treatment planning of intracranial aneurysms. The aim of our study was to compare CTA and digital subtraction angiography (DSA) findings with the surgical results mainly in patients with acute SAH and to evaluate the clinical usefulness of CTA., Materials and Methods: During the last 2 years, 82 consecutive patients were admitted under clinical symptoms and signs suggestive of harboring an intracranial aneurysm. CT angiography performed immediately afterwards the plain CT, while DSA was performed within the first 48 h of admission. All aneurysms detected were confirmed during surgery or endovascular embolization. Repeat DSA was performed in all patients having both the initial CTA and the DSA 15 days after the onset of symptoms negative. CT angiograms and conventional angiographies were studied by a consensus of two radiologists for each technique, who performed aneurysm detection, morphological features characterization and evaluation of the technique., Results: Surgical or/and endovascular treatment was performed in 45 patients and 53 aneurysms were confirmed. Using 3D-CT angiography, we detected 47 aneurysms in 42 patients. Conventional angiography depicted 43 aneurysms in 39 patients. The sensitivity of CTA for the detection of all aneurysms versus surgery was 88.7%, the specificity 100%, the positive predictive value (PPV) 100%, the negative predictive value (NPV) 80.7% and the accuracy 92.3%. Accordingly, the sensitivity of DSA was 87.8%, the specificity 98%, the PPV 97.7%, the NPV 89.1% and the accuracy 92.9%. Considering aneurysms > or =3 mm, CTA showed a sensitivity ranging from 93.3 to 100%, equal to that of DSA., Conclusion: Cerebral CT angiography has an equal sensitivity to DSA in the detection of intracranial aneurysms >3 mm. It has also 100% detection rate in AcoA and MCA bifurcation aneurysms, while some locations, like posterior communicating artery aneurysms, remain problematic. The delineating features of each aneurysm are better depicted with CTA due to 3D visualization. The use of digital subtraction angiography as a diagnostic tool can be limited in equivocal cases.

Transcriptional repressors controlling the expression of cytokine genes have been implicated in a variety of physiological and pathological phenomena. An unknown repressor that binds to the distal NFAT element of the interleukin-2 (IL-2) gene promoter in naive T-helper lymphocytes has been implicated in autoimmune phenomena and has emerged as a potentially important factor controlling the latency of HIV-1. The aim of this paper was the identification of this repressor. We resorted to public microarray databases looking for DNA-binding proteins that are present in naïve resting T cells but are downregulated when the cells are activated. A Bayesian data mining statistical analysis uncovered 25 candidate factors. Of the 25, NFAT4 and the oncogene ets-2 bind to the common motif AAGGAG found in the HIV-1 LTR and IL-2 probes. Ets-2 binding site contains the three G's that have been shown to be important for binding of the unknown factor; hence, we considered it the likeliest candidate. Electrophoretic mobility shift assays confirmed cross-reactivity between the unknown repressor and anti-ets-2 antibodies, and cotransfection experiments demonstrated the direct involvement of Ets-2 in silencing the IL-2 promoter. Designing experiments for transcription factor analysis using microarrays and Bayesian statistical methodologies provides a novel way toward elucidation of gene control networks.

The present work aims to display the use of groupware as a tool for better management of the available resources (human, computing and imaging) within the University Hospital of Patras, Greece for the task of managing patients with postoperative residual brain tumour. Emphasis is given to the additional information that can be revealed and taken into account from novel image processing techniques, developed by our group, and the central role of the Medical Physicist in the groupware. Fused images, produced by the combination of CT, MR and SPECT representations of the brain, contain both anatomical and functional information and comprise a new representation of reality. Medical experts, unfamiliar with this new representation, form a groupware for the task of interpreting them and providing better services to the patient. Groupware procedures, facilitated by modern network technology, bring experts' tacit knowledge to the surface and facilitate its exchange.

Image registration of multimodality images is an essential task in numerous applications in three-dimensional medical image processing. Medical diagnosis can benefit from the complementary information in different modality images. Surface-based registration techniques, while still widely used, were succeeded by volume-based registration algorithms that appear to be theoretically advantageous in terms of reliability and accuracy. Several applications of such algorithms for the registration of CT-MRI, CT-PET, MRI-PET, and SPECT-MRI images have emerged in the literature, using local optimization techniques for the matching of images. Our purpose in this work is the development of automatic techniques for the registration of real CT and SPECT images, based on either surface- or volume-based algorithms. Optimization is achieved using genetic algorithms that are known for their robustness. The two techniques are compared against a well-established method, the Iterative Closest Point-ICP. The correlation coefficient was employed as an independent measure of spatial match, to produce unbiased results. The repeated measures ANOVA indicates the significant impact of the choice of registration method on the magnitude of the correlation (F = 4.968, p = 0.0396). The volume-based method achieves an average correlation coefficient value of 0.454 with a standard deviation of 0.0395, as opposed to an average of 0.380 with a standard deviation of 0.0603 achieved by the surface-based method and an average of 0.396 with a standard deviation equal to 0.0353 achieved by ICP. The volume-based technique performs significantly better compared to both ICP (p<0.05, Neuman Keuls test) and the surface-based technique (p<0.05, Neuman-Keuls test). Surface-based registration and ICP do not differ significantly in performance.

We report a case of ipsilateral double tracheal bronchi supplying a tracheal lobe in a 42-year-old man, who presented with a 10-year history of recurrent respiratory infections. Diagnosis was established by chest computed tomography (CCT), virtual endoscopy and bronchoscopy. Both bronchi were surgically resected along with the right upper lobe of the lung and the associated tracheal lobe. To our knowledge, this is the first report of ipsilateral double tracheal bronchi in the adult life to be diagnosed and treated on the basis of modern radiological techniques and especially virtual endoscopy findings.

The assessment of a head-injured patient's prognosis is a task that involves the evaluation of diverse sources of information. In this study we propose an analytical approach, using a Bayesian Network (BN), of combining the available evidence. The BN's structure and parameters are derived by learning techniques applied to a database (600 records) of seven clinical and laboratory findings. The BN produces quantitative estimations of the prognosis after 24 hours for head-injured patients in the outpatients department. Alternative models are compared and their performance is tested against the success rate of an expert neurosurgeon.

This work proposes the integration of computer-aided instruction systems in the curricula of medical education, and describes an intelligent tutoring system used for teaching Dermatology. The Dermatology Tutor uses a self-organized society of autonomous software agents which have different capabilities or roles. The society contains tutor, medical and information agents which participate in the tutoring process and collaborate through deliberation in order to achieve a tutoring task. The agents are built according to a BDI architecture, which implements the mental attitudes of beliefs (B), desires (D) and intentions (I). Each medical agent is a specialist in a medical field, while a tutoring agent, which implements a widely accepted dermatology teaching process, coordinates the overall operation of the system. Depending on the subject that is to be taught during any session, the tutoring agent forms teams of medical agents, which in turn use search agents to retrieve information. Although the presented multi-agent architecture is dedicated to teaching dermatology (since the tutor agent is specialized in Dermatology), it can be extended to other domains also with the incorporation of other tutor agents.

The present study concerns the construction and operation of a Bayesian analytical system, namely a Bayesian belief network (BBN) for the prognosis at 24 h of head-injured patients of the intensive care unit. The construction of a BBN incorporates the maintenance of a large database including all the critical variables corresponding to the specific clinical domain. This database is processed to provide the necessary libraries of conditional probability values. BBNs permit the combination of prognostic evidence in a cumulative manner and provide a quantitative measure of certainty in the final decision. The user views the changes at each step, thus being capable of deciding upon the necessary pieces of information in order to reach a certain belief threshold. The system produces results that are compatible with the opinions of medical experts regarding the prognosis of patients exhibiting certain patterns of clinical or laboratory data.

In the present paper, a nonlinear compartmental model for theophylline pharmacokinetics is developed. The analytical solution of the model, in parametric form, is derived under plateau conditions for plasma metabolite concentration. The parameters are obtained from plasma and urine data using best fitting techniques and their values are used in order to calculate maintenance intravenous infusion. Numerical simulation is then performed in order to compare the drug concentration obtained by our approach with that of alternative intravenous regimens. The differences argue for individualized dosage regimens, since theophylline is a drug with a narrow therapeutic window and its concentration at the active sites strongly depends on characteristic parameters of the patient's response. Our results show that it is possible to estimate the patients' parameters during the first 8 h after intravenous administration of the drug and these parameters can be used to design an individualized dosage regimen in patients receiving theophylline intravenously.

This preliminary nonrandomized study was conducted to evaluate the clinical usefulness of TATI and CYFRA 21-1 as tumor markers in head and neck squamous cell carcinoma. Serum levels of these markers were measured from 122 subjects of a tertiary-care university hospital, divided into four groups: (1) normal individuals and patients with (2) inflammatory pathology, (3) benign tumors and (4) squamous cell carcinoma of the head and neck. Serum samples were collected before and after treatment, with a mean follow-up period of 12 months. The cutoff level, sensitivity, specificity and likelihood ratio of a positive and negative test were: 21 microg/l, 66.6%, 93.75%, 10.6 and 0.35 for TATI; 3.3 microg/l, 28.5%, 95%, 5.7 and 0.75 for CYFRA 21-1, respectively. Both markers presented elevated mean values and statistically significant differences in the cancer patient group compared with the other groups. Significant differences were also observed between the stage of disease and tumor differentiation. TATI levels seem to relate positively to the course of disease during the follow-up period. Although CYFRA 21-1 values presented significant differences, the majority of them were under the cutoff level. We conclude that TATI seems to play a role in the clinical evaluation of head and neck squamous cell carcinoma, while the usefulness of CYFRA 21-1 is limited.

The value of the Auditory Brain Stem Response (ABR) in the assessment and detection of neurological disorders could be considerably enhanced if the normative standards of ABR characteristic parameters take into account all other systematic sources of variance. The present study attempts to take into account the influence of head size on latency and amplitude of the ABR components. We examined amplitude and latency as a function of head size in 40 normal male subjects (age 20-40 years). Significant negative correlation was found between amplitude and head radius. The experimental data were fitted using a theoretical curve of the potential on the surface of a three-concentric sphere model representing the human head. The fitted curve of amplitude versus radius can be applied to normative data in order to substantially reduce dispersion and consequently increase the diagnostic value of this parameter. Moreover, a substantial effect of radius on wave V latency was detected. Normalization of the latencies with reference to the head radius, assuming that the latter is proportional to the length of brain stem, resulted in a significant reduction in the standard deviation of these data as compared to the original.

Accumulating evidence suggests that vitiligo is a systemic disease affecting the entire pigmentary system and possibly the melanin-containing cellular elements of the nervous system. In the present paper we comparatively study the auditory brainstem response (ABR) of 30 patients with active vitiligo and 50 healthy human subjects in order to detect possible subclinical abnormalities of the auditory system in this disorder. Our findings reveal a statistically significant (p < 0.01) decrease of the I peak latency and a statistically significant (p < 0.01) increase of the I-III interpeak latency in the patients as compared to the controls. The decrease of the first peak latency may be due to a numerical decrease of active melanocytes in the inner ear which results in an impairment of the ion exchange between the endolymph and perilymph. The increase of the I-III interpeak latency may be explained in terms of an abnormal synaptic activity and transmission of the action potential from the auditory nerve to the superior olive.