Restoration of high-frequency glucose-entrained insulin oscillations in obese subjects with type 2 diabetes after biliopancreatic diversion.

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/m2), 9 obese NGT patients (BMI 51.1±12.7 kg/m2), and 9 obese T2D patients (BMI 56.8±11.6 kg/m2). 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/m2 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 ß-cell glucose sensing.

(99m)Tc-labeled aminosilane-coated iron oxide nanoparticles for molecular imaging of ανß3-mediated tumor expression and feasibility for hyperthermia treatment.

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 ανß3-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.

Real-time tumor ablation simulation based on the dynamic mode decomposition method.

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.

Investigation of realistic PET simulations incorporating tumor patient's specificity using anthropomorphic models: creation of an oncology database.

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/.

Automatic quantitative analysis of in-stent restenosis using FD-OCT in vivo intra-arterial imaging.

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.

PDE5 inhibition against acute renal ischemia reperfusion injury in rats: does vardenafil offer protection?

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.

Biological evaluation of an ornithine-modified (99m)Tc-labeled RGD peptide as an angiogenesis imaging agent.

INTRODUCTION: Radiolabeled RGD peptides that specifically target integrin α(ν)ß(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)ß(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.

Emerging technologies for image guidance and device navigation in interventional radiology.

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.

A dose point kernel database using GATE Monte Carlo simulation toolkit for nuclear medicine applications: comparison with other Monte Carlo codes.

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.

Hysterosalpingography using a flat panel unit: evaluation and optimization of ovarian radiation dose.

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.

Automatic vessel lumen segmentation and stent strut detection in intravascular optical coherence tomography.

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.

Tacrolimus and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors: An interaction study in CYP3A5 non-expressors, renal transplant recipients.

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.

Investigation of clinical interaction between omeprazole and tacrolimus in CYP3A5 non-expressors, renal transplant recipients.

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.

Factors affecting the long-term response to tacrolimus in renal transplant patients: pharmacokinetic and pharmacogenetic approach.

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.

Background adjustment of cDNA microarray images by Maximum Entropy distributions.

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%.

In vivo small animal imaging: current status and future prospects.

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.

Segmentation of complementary DNA microarray images by wavelet-based Markov random field model.

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).

Complementary DNA microarray image processing based on the fuzzy gaussian mixture model.

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.

Thrombin promotes arteriogenesis and hemodynamic recovery in a rabbit hindlimb ischemia model.

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.

Bayesian clustering of flow cytometry data for the diagnosis of B-chronic lymphocytic leukemia.

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.