Training and validation of a novel 4-miRNA ratio model (MiCaP) for prediction of postoperative outcome in prostate cancer patients.

Background: New molecular biomarkers for prostate cancer (PC) prognosis are urgently needed. Ratio-based models are attractive, as they require no additional normalization. Here, we train and independently validate a novel 4-miRNA prognostic ratio model for PC. Patients and methods: By genome-wide miRNA expression profiling of PC tissue samples from 123 men who underwent radical prostatectomy (RP) (PCA123, training cohort), we identified six top candidate prognostic miRNAs and systematically tested their ability to predict postoperative biochemical recurrence (BCR). The best miRNA-based prognostic ratio model (MiCaP) was validated in two independent cohorts (PCA352 and PCA476) including >800 RP patients in total. Clinical end points were BCR and prostate cancer-specific survival (CSS). The prognostic potential of MiCaP was assessed by univariate and multivariate Cox-regression analyses and Kaplan-Meier analyses. Results: We identified a 4-miRNA ratio model, MiCaP (miR-23a-3p×miR-10b-5p)/(miR-133a×miR-374b-5p), that predicted time to BCR independently of routine clinicopathologic variables in the training cohort (PCA123) and was successfully validated in two independent RP cohorts. In addition, MiCaP was a significant predictor of CSS in univariate analysis [HR 3.35 (95% CI 1.34 - 8.35), P = 0.0096] and in multivariate analysis [HR 2.43 (95% CI 1.45-4.07), P = 0.0210]. As proof-of-principle, we also analyzed MiCaP in plasma samples from 111 RP patients. A high MiCaP score in plasma was significantly associated with BCR (P = 0.0036, Kaplan-Meier analysis). Limitations include low mortality rates (CSS: 5.4%). Conclusions: We identified a novel 4-miRNA ratio model (MiCaP) with significant independent prognostic value in three RP cohorts, indicating promising potential to improve PC risk stratification.

Training-related improvements in musculoskeletal health and balance: a 13-week pilot study of female cancer survivors.

Cancer survivors often experience poor post-treatment musculoskeletal health. This study examined the feasibility of combined aerobic and resistant training (CART) for improving strength, skeletal health and balance. Cancer survivors (n = 24) were identified by convenience sampling in Los Angeles County with 11 survivors consenting to 13 weeks of CART. Pre- and post-intervention assessments of bone mineral density (BMD), strength, flexibility and biomarker analysis were performed. Paired t-test analysis suggested increases in lower and upper body strength. The average T-score for BMD at the femoral neck improved from -1.46 to -1.36 and whole body BMD improved from -1.65 to -1.55. From baseline to follow-up, participants also displayed decreases in sway velocity on the eyes open (7%) and eyes closed (27%) conditions. Improvement in lower body strength was associated with increases in lean body mass (LBM) (r = 0.721) and an inverse association was observed between sway velocity and LBM (r = 0.838). Age and time since last treatment were related with biomarkers of anabolic growth (IGF-1, IGFbp-3) and bone (DPD, BAP). In summary, observed physiological changes were consistent with functional improvements, suggesting that isometric and dynamic exercise prescription may reduce the risk for falls and fall-related fractures among survivors.

A solid target system with remote handling of irradiated targets for PET cyclotrons.

A solid target system was developed for a PET cyclotron. The system is compatible with many different target materials in the form of foils and electroplated/sputtered targets which makes it useful for production of a wide variety of different PET radionuclides. The target material is manually loaded into the system. Remote handling of irradiated target material is managed with a pneumatic piston and a vacuum technique which allows the targets to be dropped into a shielded transport container. To test the target performance, proton irradiations (12.8 MeV, 45 µA) of monoisotopic yttrium foils (0.64 mm, direct water cooling) were performed to produce 89Zr. The yields were 2200±200 MBq (1 h, n=13) and 6300±65 MBq (3 h, n=3).

Prognostic significance of aberrantly silenced ANPEP expression in prostate cancer.

BACKGROUND: Novel biomarkers for prostate cancer (PC) are urgently needed. This study investigates the expression, epigenetic regulation, and prognostic potential of ANPEP in PC. METHODS: Aminopeptidase N (APN; encoded by ANPEP) expression was analysed by immunohistochemistry using tissue microarrays representing 267 radical prostatectomy (RP) and 111 conservatively treated (CT) PC patients. Clinical end points were recurrence-free survival (RFS) and cancer-specific survival (CSS), respectively. The ANPEP promoter methylation levels were determined by bisulphite sequencing or MethyLight analysis in 278 nonmalignant and PC tissue samples, and in cell lines. RESULTS: The APN expression was significantly downregulated in PC compared with nonmalignant prostate tissue samples. Aberrant promoter hypermethylation was frequently observed in PC tissue samples, and 5-aza-2'-deoxycytidine induced ANPEP expression in three hypermethylated prostate cell lines, suggesting epigenetic silencing. Negative APN immunoreactivity was significantly associated with short RFS and short CSS in the RP and CT cohort, respectively, independently of routine clinicopathological predictors. Combining APN with a known angiogenesis marker (vascular endothelial growth factor or microvessel density) improved risk prediction significantly in both cohorts. CONCLUSION: Our results suggest negative APN immunoreactivity as a new independent adverse prognostic factor for patients with clinically localised PC and, furthermore, that epigenetic mechanisms are involved in silencing of ANPEP in PC.

Melatonin induces transcriptional regulation of Bim by FoxO3a in HepG2 cells.

BACKGROUND: Melatonin induces apoptosis in many different cancer cell lines, including hepatocellular carcinoma cells. However, the responsible pathways have not been clearly elucidated. A member of the forkhead transcription factors' family, FoxO3a, has been implicated in the expression of the proapoptotic protein Bim (a Bcl-2-interacting mediator of cell death). In this study, we used human HepG2 liver cancer cells as an in vitro model to investigate whether melatonin treatment induces Bim through regulation by the transcription factor FoxO3a. METHODS: Cytotoxicity of melatonin was compared in HepG2 hepatoblastoma cells and primary human hepatocytes. Proapoptotic Bim expression was analysed by reverse transcriptase-polymerase chain reaction and western blot. Reporter gene assays and chromatin immunoprecipitation assays were performed to analyse whether FoxO3a transactivates the Bim promoter. Small interfering RNA (siRNA) was used to study the role of FoxO3a in Bim expression. Immunofluorescence was performed to analyse FoxO3a localisation in HepG2 cells. RESULTS: Melatonin treatment induces apoptosis in HepG2 cells, but not in primary human hepatocytes. The proapoptotic effect was mediated by increased expression of the BH3-only protein Bim. During melatonin treatment, we observed increased transcriptional activity of the forkhead-responsive element and could demonstrate that FoxO3a binds to a specific sequence within the Bim promoter. Furthermore, melatonin reduced phosphorylation of FoxO3a at Thr(32) and Ser(253), and induced its increased nuclear localisation. Moreover, silencing experiments with FoxO3a siRNA prevented Bim upregulation. CONCLUSION: This study shows that melatonin can induce apoptosis in HepG2 hepatocarcinoma cells through the upregulation of proapoptotic Bim mediated by nuclear translocation and activation of the transcription factor FoxO3a.

The human Lgl polarity gene, Hugl-2, induces MET and suppresses Snail tumorigenesis.

Lethal giant larvae proteins have key roles in regulating polarity in a variety of cell types and function as tumour suppressors. A transcriptional programme initiated by aberrant Snail expression transforms epithelial cells to potentially aggressive cancer cells. Although progress in defining the molecular determinants of this programme has been made, we have little knowledge as to how the Snail-induced phenotype can be suppressed. In our studies we identified the human lethal giant larvae homologue 2, Hugl-2, (Llgl2/Lgl2) polarity gene as downregulated by Snail. Snail binds E-boxes in the Hugl-2 promoter and represses Hugl-2 expression, whereas removal of the E-boxes releases Hugl-2 from Snail repression. We demonstrate that inducing Hugl-2 in cells with constitutive Snail expression reverses the phenotype including changes in morphology, motility, tumour growth and dissemination in vivo, and expression of epithelial markers. Hugl-2 expression reduced the nuclear localization of Snail and thus binding of Snail to its target promoters. Our results placing Hugl-2 within the Snail network as well as its ability to suppress Snail carcinogenesis identifies Hugl-2 as a target molecule driving cascades, which may have preventative and therapeutic promise to minimize cancer progression.

Violence among female stalkers.

BACKGROUND: Female stalkers account for 10-25% of all stalking cases, yet little is known about risk factors for female stalking violence. This study identifies risk factors for female stalking violence and contrasts these with risk factors for male stalking violence. METHOD: Seventy-one female and 479 male stalkers presenting to police in Sweden and a specialist stalking clinic in Australia were investigated. Univariate comparisons of behaviour by gender, and comparisons between violent and non-violent female stalkers, were undertaken. Logistic regression was then used to develop a predictive model for stalking violence based on demographic, offence and clinical characteristics. RESULTS: Rates of violence were not significantly different between genders (31% of males and 23% of females). For both men and women, violence was associated with a combination of a prior intimate relationship with the victim, threats and approach behaviour. This model produced receiver operating characteristic (ROC) curves with area under the curve (AUC)=0.80 for female stalkers and AUC=0.78 for male stalkers. The most notable gender difference was significantly higher rates of personality disorder among women. High rates of psychotic disorder were found in both genders. Stalking violence was directly related to psychotic symptoms for a small number of women. CONCLUSIONS: Similar risk factors generally predict stalking violence between genders, providing initial support for a similar approach to risk assessment for all stalkers. The most notable gender difference was the prevalence of personality and psychotic disorders among female stalkers, supporting an argument for routine psychiatric assessment of women charged with stalking.

Antibacterial activity of chemically defined chitosans: influence of molecular weight, degree of acetylation and test organism.

Chitosans, polysaccharides obtained from the exoskeleton of crustaceans, have been shown to exert antibacterial activity in vitro and their use as a food preservative is of growing interest. However, beyond a consensus that chitosan appears to disrupt the bacterial cell membrane, published data are inconsistent on the chemical characteristics that confer the antibacterial activity of chitosan. While most authors agree that the net charge density of the polymer (reflected in the fraction of positively charged amino groups at the C-2 position of the glucosamine unit) is an important factor in antibacterial activity, conflicting data have been reported on the effect of molecular weight and on the susceptibility among different bacterial species to chitosan. Therefore, we prepared batches of water-soluble hydrochloride salts of chitosans with weight average molecular weights (M(w)) of 2-224kDa and degree of acetylation of 0.16 and 0.48. Their antibacterial activity was evaluated using tube inhibition assays and membrane integrity assays (N-Phenyl-1-naphthylamine fluorescence and potassium release) against Bacillus cereus, Escherichia coli, Salmonella Typhimurium and three lipopolysaccharide mutants of E. coli and S. Typhimurium. Chitosans with lower degree of acetylation (F(A)=0.16) were more active than the more acetylated chitosans (F(A)=0.48). No trends in antibacterial action related to increasing or decreasing M(w) were observed although one of the chitosans (M(w) 28.4kDa, F(A)=0.16) was more active than the other chitosans, inhibiting growth and permeabilizing the membrane of all the test strains included. The test strains varied in their susceptibility to the different chitosans with wild type S. Typhimurium more resistant than the wild type E. coli. Salmonellae lipopolysaccharide mutants were more susceptible than the matched wild type strain. Our results show that the chitosan preparation details are critically important in identifying the antibacterial features that target different test organisms.

Dosimetry in patients with B-cell lymphoma treated with [(90)Y]ibritumomab tiuxetan or [(131)I]tositumomab.

Radioimmunotherapy involves the use of radiolabeled monoclonal antibodies (MAbs) to treat malignancy. The therapeutic effect is determined by the radiopharmaceutical, the radiation absorbed dose and previous treatments. There are currently two approved radiopharmaceuticals for the treatment of B-cell lymphoma - the (90)Y-labeled ibritumomab and the (131)I-labeled tositumomab. Both are directed against CD20, albeit not against the same epitope. This paper summarizes current results of dose-responses for normal tissues and tumours of [(131)I]tositumomab and [(90)Y]ibritumomab tiuxetan, discusses them in the context of dosimetry methods used and highlights the assumptions being made in the different dosimetry methodologies. Moreover, we wish to point at the possibility of performing low-cost therapy bremsstrahlung imaging for [(90)Y]ibritumomab tiuxetan to confirm biodistribution, and possibly also for dosimetric calculations.

Regional cerebral metabolic rate (positron emission tomography) during inhalation of nitrous oxide 50% in humans.

BACKGROUND: Recent studies in man have shown that cerebral blood flow increases during inhalation of nitrous oxide (N2O), a finding which is believed to be a result of an increased cerebral metabolic rate (CMR). However, this has not previously been evaluated in man. METHODS: Regional CMR(glu) (rCMR(glu)) was measured three dimensionally with positron emission tomography (PET) after injection of 2-(18F)fluoro-2-deoxy-D-glucose in 10 spontaneously breathing men (mean age 31 yr) inhaling either N2O 50% in O2 30% or O2 30% in N2. RESULTS: Global CMR(glu) in young men was 27 (3) micromol 100 g(-1) min(-1) [mean (SD)]. Inhalation of N2O 50% did not change global CMR(glu) [30 (5) micromol 100 g(-1) min(-1)] significantly, but it changed the distribution of the metabolism in the brain (P<0.0001 analysis of variance). Compared with inhalation of O2 30% in N2, N2O 50% inhalation increased the metabolism in the basal ganglia [14 (17)%, P<0.05] and thalamus [22 (23) %, P<0.05]. There was a prolonged metabolic effect of N2O inhalation seen on a succeeding PET scan with oxygen-enriched air (P<0.0001) performed 1 h after the N2O administration. CONCLUSIONS: Inhalation of N2O 50% did not change global CMR(glu), but the metabolism increased in central brain structures, an effect that was still present 1 h after discontinuation of N2O.

Rat testis as a radiobiological in vivo model for radionuclides.

The radiobiological effect of intracellularly localised radionuclides emitting low energy electrons (Auger electrons) has received much attention. Most in vivo studies reported have been performed in the mouse testis. We have investigated the rat testis as an in vivo radiobiological model, with sperm-head survival, testis weight loss and also alteration in the blood plasma hormone levels of FSH and LH as radiobiological endpoints. Validation of the rat testis model was evaluated by using mean absorbed doses of up to 10 Gy from intratesticularly (i.t.) injected (111)In oxine or local X-ray irradiation. Biokinetics of the i.t. injected radionuclide was analysed by scintillation camera imaging and used in the absorbed dose estimation. By the analysis of the autoradiographs, the activity distribution was revealed. Cell fractionation showed (111)In to be mainly associated with the cell nuclei. External irradiations were monitored by thermoluminescence dosimeters. The sperm-head survival was the most sensitive radiobiological parameter correlated to the mean absorbed dose, with a D(37) of 2.3 Gy for (111)In oxine and 1.3 Gy for X rays. The levels of plasma pituitary gonadal hormones FSH and LH were elevated for absorbed doses >7.7 Gy. This investigation shows that the radiobiological model based on the rat testis has several advantages compared with the previously commonly used mouse testis model. The model is appropriate for further investigations of basic phenomena such as radiation geometry, intracellular kinetics and heterogeneity, crucial for an understanding of the biological effect of low-energy electrons.

Expression of Hugl-1 is strongly reduced in malignant melanoma.

The human gene Hugl-1 (Llgl/Lgl1) has significant homology to the Drosophila tumor suppressor gene lethal(2)giant larvae (lgl). The lgl gene codes for a cortical cytoskeleton protein, Lgl, that is involved in maintaining cell polarity and epithelial integrity. We speculate that Hugl-1 might play a role in epithelial-mesenchymal transition (EMT) and that loss of Hugl-1 expression plays a role in the development or progression of malignant melanoma. Thus, we evaluated melanoma cell lines and tissue samples of malignant melanoma for loss of Hugl-1 transcription. We found that Hugl-1 was downregulated or lost in all cell lines and in most of the tumor samples analysed, and that these losses were associated with advanced stage of the disease. Reduced Hugl-1 expression occurred as early as in primary tumors detected by both immunohistochemical and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Functional assays with stable Hugl-1-transfected cell lines revealed that Hugl-1 expression increased cell adhesion and decreased cell migration. Further, downregulation of MMP2 and MMP14 (MT1-MMP) and re-expression of E-cadherin was found in the Hugl-1-expressing cell clones supporting a role of Hugl-1 in EMT. Our studies thus indicate that loss of Hugl-1 expression contributes to melanoma progression.

Histone deacetylase inhibition by valproic acid down-regulates c-FLIP/CASH and sensitizes hepatoma cells towards CD95- and TRAIL receptor-mediated apoptosis and chemotherapy.

Hepatocellular carcinoma (HCC) is highly resistant to chemotherapy, leading to a poor prognosis of advanced disease. Inhibitors of histone deacetylase (HDACi) induce re-differentiation in tumor cells and thereby re-establish sensitivity towards apoptotic stimuli. HDACi are entering the clinical stage of tumor treatment, and several substances are currently being tested in clinical trials to prove their efficacy in the treatment of leukemias and solid tumors. In this study, we investigated the impact of the HDACi valproic acid (VA) on TRAIL- and CD95-mediated apoptosis in hepatoma cells, as well as its sensitizing effect on a chemotherapeutic agent. Treatment of HepG2 cells with VA increased sensitivity to CD95-mediated apoptosis (4% apoptosis vs. 42%), and treatment with epirubicin (74% vs. 90% viability). Caspase-3 activity was significantly enhanced in cells treated with VA plus anti-CD95 antibodies compared to cells treated with antibodies alone. In parallel, VA strongly augmented the effect of TNF-related apoptosis-inducing ligand (TRAIL or Apo2 ligand) on HepG2 cells (10% vs. 58% apoptosis). VA induced down-regulation of cellular FLICE-inhibitory protein (c-FLIP/CASH, also known as Casper/iFLICE/FLAME-1/CLARP/MRIT/usurpin), providing a possible molecular mechanism underlying the increased sensitivity towards cell death-mediated apoptosis. HDAC inhibitors are a promising class for the treatment of leukemias. In addition, among other class members, VA deserves further evaluation as a treatment option for patients with advanced HCC.

Development of educational image databases and e-books for medical physics training.

Medical physics education and training requires the use of extensive imaging material and specific explanations. These requirements provide an excellent background for application of e-Learning. The EU projects Consortia EMERALD and EMIT developed five volumes of such materials, now used in 65 countries. EMERALD developed e-Learning materials in three areas of medical physics (X-ray diagnostic radiology, nuclear medicine and radiotherapy). EMIT developed e-Learning materials in two further areas: ultrasound and magnetic resonance imaging. This paper describes the development of these e-Learning materials (consisting of e-books and educational image databases). The e-books include tasks helping studying of various equipment and methods. The text of these PDF e-books is hyperlinked with respective images. The e-books are used through the readers' own Internet browser. Each Image Database (IDB) includes a browser, which displays hundreds of images of equipment, block diagrams and graphs, image quality examples, artefacts, etc. Both the e-books and IDB are engraved on five separate CD-ROMs. Demo of these materials can be taken from www.emerald2.net.

Dosimetry at 28 keV synchrotron radiation for cell irradiations.

Accurate dosimetry is a prerequisite for reliable comparisons between radiobiological irradiation experiments. Parameters affecting the determination of absorbed dose to cells in the shape of a small cell pellet in a centrifuge tube, irradiated by 28 keV mono-energetic photons from a synchrotron, were investigated. Thermoluminescent dosimeter (TLD), diode and ion chambers were utilized to monitor the irradiations. The distribution of the absorbed dose and such parameters as scatter, attenuation and interface dosimetry in the target, which influence the dose, were studied. A method for inter-calibrations of two different calibration sources by using TLD and TLD readers is given. Characteristics of the TLD, that is, fading, supralinearity, energy response, self-attenuation and mini-dosimetry were considered for the dosimetry. A method for correcting photon fluence attenuation in cylindrical TLDs is presented. The study shows that the absorbed dose to cells irradiated at low photon energy at a synchrotron irradiation facility can, using accurate dosimetry protocol, be correctly and reproducibly determined.

Calibration of a radioactive ink-based stack phantom and its applications in nuclear medicine.

This paper describes a stack phantom useful for imaging complex activity distributions. It is based on images printed with radioactive ink using a commercial ink-jet printer. The application for the phantom is in the evaluation of planar and SPECT scintillation camera images and for validation of Monte Carlo simulated images. The accuracy in generating the activity distributions on paper sheets is especially important. Here we describe the calibration procedure for the ink-jet printer. The goal of the printer calibration is to find the relationship between the digital image count (voxel grey level) and its corresponding activity on the paper sheets (radioactivity). The relationship between the voxel grey level and the radioactivity on the paper sheets (measured by scanning technique and well counter) was found to be logarithmic, and a 3rd degree polynomial was found to fit the relationship. The distribution of radioactivity in the ink cartridge was investigated by pinhole SPECT. The distribution of (99m)Tc solution was found to be homogeneous in the ink solution. Experimental studies were done directly on Monte Carlo simulated heart images from the NCAT phantom. The result showed that the simulated images are similar to the images measured using the ink-jet technique. This stack phantom could be a promising solution with an advantage that the exact geometry generated in Monte Carlo could be imitated in the phantom. The phantom is a very flexible device and clearly much more versatile than conventional phantoms which have a fixed geometry and spatial limitation.

Preparation and characterisation of fluorescent chitosans using 9-anthraldehyde as fluorophore.

Chitosans with chemical composition ranging from a fraction of N-acetylated units (F(A)) of 0.01 to 0.61 were used to prepare fluorescence labelled chitosans by reductive amination with 9-anthraldehyde. Fluorescent chitosans with a low theoretical degree of substitution (DS, 0.001-1%) were prepared, and the actual DS of the products were determined by UV and (1)H NMR spectroscopy. The fluorescence excitation and emission spectra of the chitosan with F(A) of 0.09 and DS 1% showed an excitation maximum at 254 nm and an emission maximum at 413 nm. The intrinsic viscosities ([eta]) of the fluorescent chitosans were compared to those of the original chitosans, showing that the derivatisation procedure lead only to a negligible decrease in [eta]. The conformation of these fluorescent chitosans with very low DS-values is not altered and they can conveniently be directly quantified by UV or fluorescence spectroscopy.

Screening of chitosans and conditions for bacterial flocculation.

Chitosans with different chemical compositions and molecular weights have been evaluated as flocculants of Escherichia coli suspensions. The flocculation performance of chitosans at different conditions (pH, ionic strength) was followed by residual turbidity measurements. For precise comparison, the chitosan concentrations corresponding to 75% flocculated bacteria (x(75)) were calculated from a mathematical function fitted to the measured data. At all conditions, an increase in the fraction of acetylated units (F(A)) resulted in lower x(75) and thereby better flocculation efficiency. Especially the most acetylated chitosans (F(A) 0.49 and F(A) 0.62) were excellent flocculants. An increase in F(A) from 0.002 to 0.6 caused a 10-fold reduction in necessary concentrations, at both pH 5 and 6.8. pH was a rather insignificant factor in the range 4-7.4, further pH increase led to either increase of necessary doses at low F(A) or sudden ceasing of flocculation at high F(A). The chitosans flocculated in a broad range of molecular weights, although an increase in molecular weight was a favorable factor. Increase in ionic strength caused a severalfold reduction in x(75) for all chitosans and considerable broadening of flocculation intervals.

Reduced postnatal cerebral glucose metabolism measured by PET after asphyxia in near term fetal lambs.

The effects of fetal asphyxia on cerebral function and development, involve the transition from fetal to neonatal life. Changes in cerebral glucose metabolism may be an early postnatal indicator of fetal asphyxia. The objective is to develop an experimental lamb model involving the transition from fetal to neonatal life and to examine the effect of fetal asphyxia with cerebral hypoxic ischemia on early postnatal cerebral glucose metabolism. Fetal asphyxia was induced by total umbilical cord occlusion in eight near-term fetal lambs (134-138 days) with the ewe under isoflurane-opiate anesthesia. The mean occlusion time until cardiac arrest was 14.5 (4.2) min (SD). Lambs were immediately delivered and standardized resuscitation was instituted after 2 min asystole. At 4 hr postnatal age, [18-F]Fluoro-2-deoxy-glucose (18-FDG) was injected intravenously in eight asphyxiated lambs and in eight controls. Cerebral glucose metabolism was examined by positron emission tomography (PET). As a result the mean arterial blood pressure, acid-base values, blood glucose and serum lactate at 4 hr postnatal age did not differ significantly between lambs subjected to umbilical cord occlusion and controls. EEG was abnormal in all lambs subjected to cord occlusion and normal in the controls at 4 hr postnatal age. Global cerebral metabolic rate (CMRgl) as determined by PET was significantly lower in lambs subjected to cord occlusion mean/median (SD) 22.2/19.6 (8.4) micromol/min/100 g) than in controls mean/median (SD) 37.8/35.9 (6.1); P < 0.01). Global CMRgl is significantly reduced in newborn lambs 4 hr after fetal asphyxia induced by umbilical cord occlusion. A reduction in CMRgl is an early indicator of global hypoxic cerebral ischemia.

Registration of emission and transmission whole-body scintillation-camera images.

UNLABELLED: In this work, a method for registration of whole-body (WB) scintillation-camera images is presented. The primary motive for the development is to perform activity quantification using the conjugate view method on an image basis. Accurate image registration is required for sequential anterior and posterior scans, for serial emission images for analysis of the biokinetics, and for transmission and emission images for a pixel-based attenuation correction. METHODS: Registration is performed by maximization of the mutual information. The spatial transformation has been tailored for the registration of WB images and is composed of global and local transformations, including rigid, projective, and curved transformations. A coarse registration is first performed using cross-correlation and direct pixel scaling. Optimization is then performed in a sequence, beginning with the 2 legs independently, followed by the upper body and head. Evaluation is performed for clinical images of an (131)I-labeled monoclonal antibody and for Monte Carlo-simulated images. An anthropomorphic WB computer phantom, which has been especially modified to match the patient position during WB scanning, is used for the simulations. RESULTS: For simulated images, registration errors are within 1 pixel (<3.6 mm) for a sufficient image count level. Separate evaluation of the influence of noise shows that the errors increase below a total image count of approximately 10(5) (signal-to-noise ratio, approximately 4). For clinical evaluations, the deviations between point markers are 9 +/- 5 mm. CONCLUSION: An automatic registration method for WB images has been developed, which is applicable to emission-emission and transmission-emission registration. This method has been applied in more than 50 clinical studies and has shown to be robust and reliable.