Parvovirus B19 uptake is a highly selective process controlled by VP1u, a novel determinant of viral tropism

The VP1 unique region (VP1u) of human parvovirus B19 (B19V) is the immunodominant part of the viral capsid. Originally inaccessible, the VP1u becomes exposed upon primary attachment to the globoside receptor. To study the function of the exposed VP1u in B19V uptake, we expressed this region as a recombinant protein. Here, we report that purified recombinant VP1u binds and is internalized in UT7/Epo cells. By means of truncations and specific antibodies, we identified the most N-terminal amino acid residues of VP1u as the essential region for binding and internalization. Furthermore, the recombinant VP1u was able to block B19V uptake, suggesting that the protein and the virus undertake the same internalization pathway. Assays with different erythroid and nonerythroid cell lines showed that the N-terminal VP1u binding was restricted to a few cell lines of the erythroid lineage, which were also the only cells that allowed B19V internalization and infection. These results together indicate that the N-terminal region of VP1u is responsible for the internalization of the virus and that the interacting receptor is restricted to B19V-susceptible cells. The highly selective uptake mechanism represents a novel determinant of the tropism and pathogenesis of B19V.

Reducing CT radiation dose with iterative reconstruction algorithms: the influence of scan and reconstruction parameters on image quality and CTDIvol

OBJECTIVES In this phantom CT study, we investigated whether images reconstructed using filtered back projection (FBP) and iterative reconstruction (IR) with reduced tube voltage and current have equivalent quality. We evaluated the effects of different acquisition and reconstruction parameter settings on image quality and radiation doses. Additionally, patient CT studies were evaluated to confirm our phantom results. METHODS Helical and axial 256 multi-slice computed tomography scans of the phantom (Catphan(®)) were performed with varying tube voltages (80-140kV) and currents (30-200mAs). 198 phantom data sets were reconstructed applying FBP and IR with increasing iterations, and soft and sharp kernels. Further, 25 chest and abdomen CT scans, performed with high and low exposure per patient, were reconstructed with IR and FBP. Two independent observers evaluated image quality and radiation doses of both phantom and patient scans. RESULTS In phantom scans, noise reduction was significantly improved using IR with increasing iterations, independent from tissue, scan-mode, tube-voltage, current, and kernel. IR did not affect high-contrast resolution. Low-contrast resolution was also not negatively affected, but improved in scans with doses <5mGy, although object detectability generally decreased with the lowering of exposure. At comparable image quality levels, CTDIvol was reduced by 26-50% using IR. In patients, applying IR vs. FBP resulted in good to excellent image quality, while tube voltage and current settings could be significantly decreased. CONCLUSIONS Our phantom experiments demonstrate that image quality levels of FBP reconstructions can also be achieved at lower tube voltages and tube currents when applying IR. Our findings could be confirmed in patients revealing the potential of IR to significantly reduce CT radiation doses.

Feasible Dose Reduction in Routine Chest Computed Tomography Maintaining Constant Image Quality Using the Last Three Scanner Generations: From Filtered Back Projection to Sinogram-affirmed Iterative Reconstruction and Impact of the Novel Fully Integrated Detector Design Minimizing Electronic Noise

OBJECTIVE The aim of the present study was to evaluate a dose reduction in contrast-enhanced chest computed tomography (CT) by comparing the three latest generations of Siemens CT scanners used in clinical practice. We analyzed the amount of radiation used with filtered back projection (FBP) and an iterative reconstruction (IR) algorithm to yield the same image quality. Furthermore, the influence on the radiation dose of the most recent integrated circuit detector (ICD; Stellar detector, Siemens Healthcare, Erlangen, Germany) was investigated. MATERIALS AND METHODS 136 Patients were included. Scan parameters were set to a thorax routine: SOMATOM Sensation 64 (FBP), SOMATOM Definition Flash (IR), and SOMATOM Definition Edge (ICD and IR). Tube current was set constantly to the reference level of 100 mA automated tube current modulation using reference milliamperes. Care kV was used on the Flash and Edge scanner, while tube potential was individually selected between 100 and 140 kVp by the medical technologists at the SOMATOM Sensation. Quality assessment was performed on soft-tissue kernel reconstruction. Dose was represented by the dose length product. RESULTS Dose-length product (DLP) with FBP for the average chest CT was 308 mGy*cm ± 99.6. In contrast, the DLP for the chest CT with IR algorithm was 196.8 mGy*cm ± 68.8 (P = 0.0001). Further decline in dose can be noted with IR and the ICD: DLP: 166.4 mGy*cm ± 54.5 (P = 0.033). The dose reduction compared to FBP was 36.1% with IR and 45.6% with IR/ICD. Signal-to-noise ratio (SNR) was favorable in the aorta, bone, and soft tissue for IR/ICD in combination compared to FBP (the P values ranged from 0.003 to 0.048). Overall contrast-to-noise ratio (CNR) improved with declining DLP. CONCLUSION The most recent technical developments, namely IR in combination with integrated circuit detectors, can significantly lower radiation dose in chest CT examinations.

The fusion protein of wild-type canine distemper virus is a major determinant of persistent infection.

The wild-type A75/17 canine distemper virus (CDV) strain induces a persistent infection in the central nervous system but infects cell lines very inefficiently. In contrast, the genetically more distant Onderstepoort CDV vaccine strain (OP-CDV) induces extensive syncytia formation. Here, we investigated the roles of wild-type fusion (F(WT)) and attachment (H(WT)) proteins in Vero cells expressing, or not, the canine SLAM receptor by transfection experiments and by studying recombinants viruses expressing different combinations of wild-type and OP-CDV glycoproteins. We show that low fusogenicity is not due to a defect of the envelope proteins to reach the cell surface and that H(WT) determines persistent infection in a receptor-dependent manner, emphasizing the role of SLAM as a potent enhancer of fusogenicity. However, importantly, F(WT) reduced cell-to-cell fusion independently of the cell surface receptor, thus demonstrating that the fusion protein of the neurovirulent A75/17-CDV strain plays a key role in determining persistent infection.

Impact of Hybrid Iterative Reconstruction on Agatston Coronary Artery Calcium Scores in Comparison to Filtered Back Projection in Native Cardiac CT

PURPOSE To investigate whether the effects of hybrid iterative reconstruction (HIR) on coronary artery calcium (CAC) measurements using the Agatston score lead to changes in assignment of patients to cardiovascular risk groups compared to filtered back projection (FBP). MATERIALS AND METHODS 68 patients (mean age 61.5 years; 48 male; 20 female) underwent prospectively ECG-gated, non-enhanced, cardiac 256-MSCT for coronary calcium scoring. Scanning parameters were as follows: Tube voltage, 120 kV; Mean tube current time-product 63.67 mAs (50 - 150 mAs); collimation, 2 × 128 × 0.625 mm. Images were reconstructed with FBP and with HIR at all levels (L1 to L7). Two independent readers measured Agatston scores of all reconstructions and assigned patients to cardiovascular risk groups. Scores of HIR and FBP reconstructions were correlated (Spearman). Interobserver agreement and variability was assessed with ĸ-statistics and Bland-Altmann-Plots. RESULTS Agatston scores of HIR reconstructions were closely correlated with FBP reconstructions (L1, R = 0.9996; L2, R = 0.9995; L3, R = 0.9991; L4, R = 0.986; L5, R = 0.9986; L6, R = 0.9987; and L7, R = 0.9986). In comparison to FBP, HIR led to reduced Agatston scores between 97 % (L1) and 87.4 % (L7) of the FBP values. Using HIR iterations L1 - L3, all patients were assigned to identical risk groups as after FPB reconstruction. In 5.4 % of patients the risk group after HIR with the maximum iteration level was different from the group after FBP reconstruction. CONCLUSION There was an excellent correlation of Agatston scores after HIR and FBP with identical risk group assignment at levels 1 - 3 for all patients. Hence it appears that the application of HIR in routine calcium scoring does not entail any disadvantages. Thus, future studies are needed to demonstrate whether HIR is a reliable method for reducing radiation dose in coronary calcium scoring.

Metal Artifact Reduction in Pelvic Computed Tomography With Hip Prostheses: Comparison of Virtual Monoenergetic Extrapolations From Dual-Energy Computed Tomography and an Iterative Metal Artifact Reduction Algorithm in a Phantom Study.

OBJECTIVE The aim of this study was to directly compare metal artifact reduction (MAR) of virtual monoenergetic extrapolations (VMEs) from dual-energy computed tomography (CT) with iterative MAR (iMAR) from single energy in pelvic CT with hip prostheses. MATERIALS AND METHODS A human pelvis phantom with unilateral or bilateral metal inserts of different material (steel and titanium) was scanned with third-generation dual-source CT using single (120 kVp) and dual-energy (100/150 kVp) at similar radiation dose (CT dose index, 7.15 mGy). Three image series for each phantom configuration were reconstructed: uncorrected, VME, and iMAR. Two independent, blinded radiologists assessed image quality quantitatively (noise and attenuation) and subjectively (5-point Likert scale). Intraclass correlation coefficients (ICCs) and Cohen κ were calculated to evaluate interreader agreements. Repeated measures analysis of variance and Friedman test were used to compare quantitative and qualitative image quality. Post hoc testing was performed using a corrected (Bonferroni) P < 0.017. RESULTS Agreements between readers were high for noise (all, ICC ≥ 0.975) and attenuation (all, ICC ≥ 0.986); agreements for qualitative assessment were good to perfect (all, κ ≥ 0.678). Compared with uncorrected images, VME showed significant noise reduction in the phantom with titanium only (P < 0.017), and iMAR showed significantly lower noise in all regions and phantom configurations (all, P < 0.017). In all phantom configurations, deviations of attenuation were smallest in images reconstructed with iMAR. For VME, there was a tendency toward higher subjective image quality in phantoms with titanium compared with uncorrected images, however, without reaching statistical significance (P > 0.017). Subjective image quality was rated significantly higher for images reconstructed with iMAR than for uncorrected images in all phantom configurations (all, P < 0.017). CONCLUSIONS Iterative MAR showed better MAR capabilities than VME in settings with bilateral hip prosthesis or unilateral steel prosthesis. In settings with unilateral hip prosthesis made of titanium, VME and iMAR performed similarly well.

Shadow Profit Maximization and a Generalized Measure of Inefficiency

Determining the profit maximizing input-output bundle of a firm requires data on prices. This paper shows how endogenously determined shadow prices can be used in place of actual prices to obtain the optimal input-output bundle where the firm.s shadow profit is maximized. This approach amounts to an application of the Weak Axiom of Profit Maximization (WAPM) formulated by Varian (1984) based on shadow prices rather than actual prices. At these prices the shadow profit of a firm is zero. Thus, the maximum profit that could have been attained at some other input-output bundle is a measure of the inefficiency of the firm. Because the benchmark input-output bundle is always an observed bundle from the data, it can be determined without having to solve any elaborate programming problem. An empirical application to U.S. airlines data illustrates the proposed methodology.

Planning and implementation efficacy as a determinant of health risk communication outcomes: Case studies of the U.S. Public Health Service (PHS)

This study was conducted under the auspices of the Subcommittee on Risk Communication and Education of the Committee to Coordinate Environmental Health and Related Programs (CCEHRP) to determine how Public Health Service (PHS) agencies are communicating information about health risk, what factors contributed to effective communication efforts, and what specific principles, strategies, and practices best promote more effective health risk communication outcomes.^ Member agencies of the Subcommittee submitted examples of health risk communication activities or decisions they perceived to be effective and some examples of cases they thought had not been as effective as desired. Of the 10 case studies received, 7 were submitted as examples of effective health risk communication, and 3, as examples of less effective communication.^ Information contained in the 10 case studies describing the respective agencies' health risk communication strategies and practices was compared with EPA's Seven Cardinal Rules of Risk Communication, since similar rules were not found in any PHS agency. EPA's rules are: (1) Accept and involve the public as a legitimate partner. (2) Plan carefully and evaluate your efforts. (3) Listen to the public's specific concerns. (4) Be honest, frank, and open. (5) Coordinate and collaborate with other credible sources. (6) Meet the needs of the media. (7) Speak clearly and with compassion.^ On the basis of case studies analysis, the Subcommittee, in their attempts to design and implement effective health risk communication campaigns, identified a number of areas for improvement among the agencies. First, PHS agencies should consider developing a focus specific to health risk communication (i.e., office or specialty resource). Second, create a set of generally accepted practices and guidelines for effective implementation and evaluation of PHS health risk communication activities and products. Third, organize interagency initiatives aimed at increasing awareness and visibility of health risk communication issues and trends within and between PHS agencies.^ PHS agencies identified some specific implementation strategies the CCEHRP might consider pursuing to address the major recommendations. Implementation strategies common to PHS agencies emerged in the following five areas: (1) program development, (2) building partnerships, (3) developing training, (4) expanding information technologies, and (5) conducting research and evaluation. ^

Modulation of BCL-X$\sb{\rm L}$ is a critical determinant of c-myc induced apoptosis

The fine balance between proliferation and apoptosis plays a primary role in carcinogenesis. Proto-oncogenes that induce both proliferation and apoptosis provide a powerful inbuilt system to inhibit clonal expansion of cells with high proliferation rates. This provides a restraint to the development of neoplasms. C-myc expressing cells undergo apoptosis in low serum by an unknown mechanism. Several lines of evidence suggested that c-myc induces apoptosis by a transcriptional mechanism. However, the target genes of this program have not been fully defined. Protein synthesis inhibitors induce apoptosis in c-myc over-expressing cells at high serum levels suggesting that inhibition of synthesis of a survival factor may induce apoptosis. We show that the expression of c-myc directly correlates with an increase in the level of a survival protein, bcl-$\rm x\sb{L},$ and a decrease in the pro-apoptotic protein, bax, at both the protein and mRNA level. Furthermore, a significant decrease of the bcl-$\rm x\sb{L}$ protein levels is observed under low serum conditions. In order to investigate the mechanism of regulation of bcl-$\rm x\sb{L}$ and bax by c-myc, the bcl-x and bax promoters were cloned, sequenced and shown to contain c-myc binding sites. The chloramephenicol acetyl transferase (CAT) reporter assay was used to demonstrate activation of the bcl-x promoter by increasing levels of c-myc when co-transfected in COS cells. The bax promoter was also shown to be transrepressed in c-myc expressing cells. The role of bcl-$\rm x\sb{L}$ in apoptosis regulation in c-myc cell lines in normal and low serum was then investigated. Cells lines expressing c-myc and bcl-$\rm x\sb{L}$ were generated and were shown to be resistant to apoptosis induction in low serum. Furthermore, cell lines expressing c-myc, anti-sense bcl-$\rm x\sb{L}$ and $\beta$-galactosidase demonstrated significantly enhanced rates of apoptosis in high serum compared to c-myc Rat 1a cells. These findings suggest that c-myc activates a survival program involving bcl-$\rm x\sb{L}$ upregulation and bax downregulation. However, this survival signal is reduced under low serum conditions by the relative downregulation of bcl-$\rm x\sb{L}$ allowing for apoptosis to proceed. These data also directly demonstrates that downregulation in the level of bcl-$\rm x\sb{L}$ associated with low serum conditions is a critical determinant of c-myc induced apoptosis. ^

Mechanism of translationally coupled mRNA turnover mediated by c-fos protein-coding-region determinant

Proto-oncogene c-fos is a member of the class of early-response genes whose transient expression plays a crucial role in cell proliferation, differentiation, and apoptosis. Degradation of c- fos mRNA is an important mechanism for controlling c-fos expression. Rapid mRNA turnover mediated by the protein-coding-region determinant (mCRD) of the c-fos transcript illustrates a functional interplay between mRNA turnover and translation that coordinately influences the fate of cytoplasmic mRNA. It is suggested that mCRD communicates with the 3′ poly(A) tail via an mRNP complex comprising mCRD-associated proteins, which prevents deadenylation in the absence of translation. Ribosome transit as a result of translation is required to alter the conformation of the mRNP complex, thereby eliciting accelerated deadenylation and mRNA decay. To gain further insight into the mechanism of mCRD-mediated mRNA turnover, Unr was identified as an mCRD-binding protein, and its binding site within mCRD was characterized. Moreover, the functional role for Unr in mRNA decay was demonstrated. The result showed that elevation of Unr protein level in the cytoplasm led to inhibition of mRNA destabilization by mCRD. In addition, GST pull-down assay and immuno-precipitation analysis revealed that Unr interacted with PABP in an RNA-independent manner, which identified Unr as a novel PABP-interacting protein. Furthermore, the Unr interacting domain in PABP was characterized. In vivo mRNA decay experiments demonstrated a role for Unr-PABP interaction in mCRD-mediated mRNA decay. In conclusion, the findings of this study provide the first evidence that Unr plays a key role in mCRD-mediated mRNA decay. It is proposed that Unr is recruited by mCRD to initiate the formation of a dynamic mRNP complex for communicating with poly(A) tail through PABP. This unique mRNP complex may couple translation to mRNA decay, and perhaps to recruit the responsible nuclease for deadenylation. ^

Computational Schemes for Optimizing Domains of Attraction in Dynamical Systems

In this paper, several computational schemes are presented for the optimal tuning of the global behavior of nonlinear dynamical sys- tems. Specifically, the maximization of the size of domains of attraction associated with invariants in parametrized dynamical sys- tems is addressed. Cell Mapping (CM) tech- niques are used to estimate the size of the domains, and such size is then maximized via different optimization tools. First, a ge- netic algorithm is tested whose performance shows to be good for determining global maxima at the expense of high computa- tional cost. Secondly, an iterative scheme based on a Stochastic Approximation proce- dure (the Kiefer-Wolfowitz algorithm) is eval- uated showing acceptable performance at low cost. Finally, several schemes combining neu- ral network based estimations and optimiza- tion procedures are addressed with promising results. The performance of the methods is illus- trated with two applications: first on the well-known van der Pol equation with stan- dard parametrization, and second the tuning of a controller for saturated systems.

Determinant factors to discriminate the body weight loss in overweight people

Introduction. Most studies have described how the weight loss is when different treatments are compared (1-3), while others have also compared the weight loss by sex (4), or have taken into account psychosocial (5) and lifestyle (6, 7) variables. However, no studies have examined the interaction of different variables and the importance of them in the weight loss. Objective. Create a model to discriminate the range of weight loss, determining the importance of each variable. Methods. 89 overweight people (BMI: 25-29.9 kg?m-2), aged from 18 to 50 years, participated in the study. Four types of treatments were randomly assigned: strength training (S), endurance training (E), strength and endurance training (SE), and control group (C). All participants followed a 25% calorie restriction diet. Two multivariate discriminant models including the variables age, sex, height, daily energy expenditure (EE), type of treatment (T), caloric restriction (CR), initial body weight (BW), initial fat mass (FM), initial muscle mass (MM) and initial bone mineral density (BMD) were performed having into account two groups: the first and fourth quartile of the % of weight loss in the first model; the groups above and below the mean of the % of weight loss in the second model. The discriminant models were built using the inclusion method in SPSS allowing us to find a function that could predict the body weight loss range that an overweight person could achieve in a 6 months weight loss intervention.Results. The first discriminant analysis predicted that a combination of the studied variables would discriminate between the two ranges of body weight loss with 81.4% of correct classification. The discriminant function obtained was (Wilks? Lambda=0.475, p=0.003): Discriminant score=-18.266-(0.060xage)- (1.282xsex[0=female;1=male])+(14.701xheight)+(0.002xEE)- (0.006xT[1=S;2=E;3=SE;4=C])-(0.047xCR)- (0.558xBW)+(0.475xFM)+(0.398xMM)+(3.499xBMD) The second discriminant model obtained would discriminate between the two groups of body weight loss with 74.4% of correct classification. The discriminant function obtained was (Wilks? Lambda=0.725, p=0.005): Discriminant score=-5.021-(0.052xage)- (0.543xsex[0=female;1=male])+(3.530xheight)+(0.001xEE)- (0.493xT[1=S;2=E;3=SE;4=C])+(0.003xCR)- (0.365xBW)+(0.368xFM)+(0.296xMM)+(4.034xBMD) Conclusion. The first developed model could predict the percentage of weight loss in the following way: if the discriminant score is close to 1.051, the range of weight loss will be from 7.44 to -4.64% and if it is close to - 1.003, the range will be from -11.03 to -25,00% of the initial body weight. With the second model if the discriminant score is close to 0.623 the body weight loss will be above -7.93% and if it is close to -0.595 will be below - 7.93% of the initial body weight. References. 1. Brochu M, et al. Resistance training does not contribute to improving the metabolic profile after a 6-month weight loss program in overweight and obese postmenopausal women. J Clin Endocrinol Metab. 2009 Sep;94(9):3226-33. 2. Del Corral P, et al. Effect of dietary adherence with or without exercise on weight loss: a mechanistic approach to a global problem. J Clin Endocrinol Metab. 2009 May;94(5):1602-7. 3. Larson-Meyer DE, et al. Caloric Restriction with or without Exercise: The Fitness vs. Fatness Debate. Med Sci Sports Exerc. 2010;42(1):152-9. 4. Hagan RD, et al. The effects of aerobic conditioning and/or caloric restriction in overweight men and women. Medicine & Science in Sports & Exercise. 1986;18(1):87-94. 5. Teixeira PJ, et al. Mediators of weight loss and weight loss maintenance in middle-aged women. Obesity (Silver Spring). 2010 Apr;18(4):725-35. 6. Bautista-Castano I, et al. Variables predictive of adherence to diet and physical activity recommendations in the treatment of obesity and overweight, in a group of Spanish subjects. Int J Obes Relat Metab Disord. 2004 May;28(5):697-705.

Efficient methodologies for system matrix modelling in iterative image reconstruction for rotating high-resolution PET

A fully 3D iterative image reconstruction algorithm has been developed for high-resolution PET cameras composed of pixelated scintillator crystal arrays and rotating planar detectors, based on the ordered subsets approach. The associated system matrix is precalculated with Monte Carlo methods that incorporate physical effects not included in analytical models, such as positron range effects and interaction of the incident gammas with the scintillator material. Custom Monte Carlo methodologies have been developed and optimized for modelling of system matrices for fast iterative image reconstruction adapted to specific scanner geometries, without redundant calculations. According to the methodology proposed here, only one-eighth of the voxels within two central transaxial slices need to be modelled in detail. The rest of the system matrix elements can be obtained with the aid of axial symmetries and redundancies, as well as in-plane symmetries within transaxial slices. Sparse matrix techniques for the non-zero system matrix elements are employed, allowing for fast execution of the image reconstruction process. This 3D image reconstruction scheme has been compared in terms of image quality to a 2D fast implementation of the OSEM algorithm combined with Fourier rebinning approaches. This work confirms the superiority of fully 3D OSEM in terms of spatial resolution, contrast recovery and noise reduction as compared to conventional 2D approaches based on rebinning schemes. At the same time it demonstrates that fully 3D methodologies can be efficiently applied to the image reconstruction problem for high-resolution rotational PET cameras by applying accurate pre-calculated system models and taking advantage of the system's symmetries.

An approach to operational modal analysis using the expectation maximization algorithm

This paper presents the Expectation Maximization algorithm (EM) applied to operational modal analysis of structures. The EM algorithm is a general-purpose method for maximum likelihood estimation (MLE) that in this work is used to estimate state space models. As it is well known, the MLE enjoys some optimal properties from a statistical point of view, which make it very attractive in practice. However, the EM algorithm has two main drawbacks: its slow convergence and the dependence of the solution on the initial values used. This paper proposes two different strategies to choose initial values for the EM algorithm when used for operational modal analysis: to begin with the parameters estimated by Stochastic Subspace Identification method (SSI) and to start using random points. The effectiveness of the proposed identification method has been evaluated through numerical simulation and measured vibration data in the context of a benchmark problem. Modal parameters (natural frequencies, damping ratios and mode shapes) of the benchmark structure have been estimated using SSI and the EM algorithm. On the whole, the results show that the application of the EM algorithm starting from the solution given by SSI is very useful to identify the vibration modes of a structure, discarding the spurious modes that appear in high order models and discovering other hidden modes. Similar results are obtained using random starting values, although this strategy allows us to analyze the solution of several starting points what overcome the dependence on the initial values used.