ADME/Tox (absorption, distribution, metabolism, elimination and toxicity) technology is traditionally associated as a tool in the drug discovery process which is often used to predict the efficiency of drug adsorption, distribution, metabolic pathways, and elimination. For the past four years we have been involved in an effort to evaluate readily available Food and Drug Administration (FDA) consumer drug profiles and pharmacological data. Portable Document Format (PDF) data from drug profiles available on the FDA Drug Information website were used to create a searchable FDA Consumer Drug Database© using Bio-Rad's KnowItAll® platform which includes ADME/Tox in silico predictors. 14 pertinent pharmaceutical and pharmacological properties were collected for 75 structurally diverse consumer prescription drugs, and for several drugs, not all properties were completely populated. The major objective of this investigation was to validate the platforms prediction models for plasma protein binding (PPB) and bioavailability (BIO).

Shannon entropy is a powerful tool in image analysis, but its reliable computation from image data faces an inherent dimensionality problem that calls for a low-dimensional and closed form model for the pixel value distributions. The most promising such models are Markovian, however, the conventional Markov random field is hampered by noncausality and its causal versions are also not free of difficulties. For example, the Markov mesh random field has its own limitations due to the strong diagonal dependency in its local neighboring system. A new model, named quadrilateral Markov random field (QMRF) is introduced in this paper in order to overcome these limitations. A property of QMRF with neighboring size of 2 is then used to decompose an image prior into a product of 2-D joint pdfs in which they are estimated using a joint histogram under the homogeneity assumption. In addition, the paper includes an extension of the introduced method to the computation of image spatial mutual information. Comparisons on synthesized images as well as two applications with real images are presented to motivate the developments in this paper and demonstrate the advantages in the performance of the introduced method over the existing ones.

We present MEMLET (MATLAB-enabled maximum-likelihood estimation tool), a simple-to-use and powerful program for utilizing maximum-likelihood estimation (MLE) for parameter estimation from data produced by single-molecule and other biophysical experiments. The program is written in MATLAB and includes a graphical user interface, making it simple to integrate into the existing workflows of many users without requiring programming knowledge. We give a comparison of MLE and other fitting techniques (e.g., histograms and cumulative frequency distributions), showing how MLE often outperforms other fitting methods. The program includes a variety of features. 1) MEMLET fits probability density functions (PDFs) for many common distributions (exponential, multiexponential, Gaussian, etc.), as well as user-specified PDFs without the need for binning. 2) It can take into account experimental limits on the size of the shortest or longest detectable event (i.e., instrument "dead time") when fitting to PDFs. The proper modification of the PDFs occurs automatically in the program and greatly increases the accuracy of fitting the rates and relative amplitudes in multicomponent exponential fits. 3) MEMLET offers model testing (i.e., single-exponential versus double-exponential) using the log-likelihood ratio technique, which shows whether additional fitting parameters are statistically justifiable. 4) Global fitting can be used to fit data sets from multiple experiments to a common model. 5) Confidence intervals can be determined via bootstrapping utilizing parallel computation to increase performance. Easy-to-follow tutorials show how these features can be used. This program packages all of these techniques into a simple-to-use and well-documented interface to increase the accessibility of MLE fitting.

Theoretical work suggests that if the interpulse intervals ( IPIs ) of motor unit action potential trains ( MUAPTs ) are independently and normally distributed, then spectral analysis of the electromyogram could be a useful tool for studying rate modulation by virtue of the presence of a peak in the power spectrum at the average firing frequency of all active motor units. It is shown in this paper that IPIs need not be normally distributed, specifically that the results are very much the same if the IPIs are distributed according to a Gamma probability density function ( PDF ). Simulation of the electromyogram based on this theory proved the applicability of the method. Experimental results obtained for the masseter, biceps brachii and first dorsal interosseus (FDI) muscles, however, were in disagreement with both theory and simulation except for the biceps muscle at force levels up to 20% of the maximal force and for the masseter and FDI muscles in 1 out of 5 subjects. This indicates that the models for MUAPTs hitherto used might not be generally correct. Apart from this discrepancy, our results reveal differences between masseter and FDI muscles on the one hand and the biceps brachii on the other, which indicate that motor unit synchronisation is much more pronounced in the latter muscle.

Chlamydia trachomatis is an obligate intracellular bacterium responsible for a number of health problems, including sexually transmitted infection in humans. We recently discovered that C. trachomatis infection in cell culture is highly susceptible to inhibitors of peptide deformylase, an enzyme that removes the N-formyl group from newly synthesized polypeptides. In this study, one of the deformylase inhibitors, GM6001, was tested for potential antichlamydial activity using a murine genital C. muridarum infection model. Topical application of GM6001 significantly reduced C. muridarum loading in BALB/c mice that were vaginally infected with the pathogen. In striking contrast, growth of the probiotic Lactobacillus plantarum is strongly resistant to the PDF inhibitor. GM6001 demonstrated no detectable toxicity against host cells. On the basis of these data and our previous observations, we conclude that further evaluation of PDF inhibitors for prevention and treatment of sexually transmitted chlamydial infection is warranted.

In cohort studies, variables are measured repeatedly and can be considered as trajectories. A classic way to work with trajectories is to cluster them in order to detect the existence of homogeneous patterns of evolution. Since cohort studies usually measure a large number of variables, it might be interesting to study the joint evolution of several variables (also called joint-variable trajectories). To date, the only way to cluster joint-trajectories is to cluster each trajectory independently, then to cross the partitions obtained. This approach is unsatisfactory because it does not take into account a possible co-evolution of variable-trajectories. KmL3D is an R package that implements a version of k-means dedicated to clustering joint-trajectories. It provides facilities for the management of missing values, offers several quality criteria and its graphic interface helps the user to select the best partition. KmL3D can work with any number of joint-variable trajectories. In the restricted case of two joint trajectories, it proposes 3D tools to visualize the partitioning and then export 3D dynamic rotating-graphs to PDF format.

The absence of inferior vena cava (IVC) is one among infrequent subtypes of IVC abnormalities that are rarely seen in general population. The absence of IVC involves either that of entire IVC or that of infrarenal segment. These two entities are relatively similar but their etiopathogeneses are still controversial. The absence of the entire IVC is thought to be a result of an embryologic disorder, whereas perinatal thrombosis is hypothesised to lead to the development of absent infrarenal IVC, thus the latter is a developmental disorder and the former occurs due to embryologic disorder. We report an adult man with renal-infrarenal absence of IVC, as well as missing common iliac veins. He clinically presented with extensive varicose collateral circulation on the thoracoabdominal wall, right varicocele and severe varices on lower limbs. Calcifications of adrenal glands indicate a hematologic disorder during perinatal period. The etiopathogenesis of this unusual abnormality is emphasized in this case report (Fig. 5, Ref. 10). Full Text (Free, PDF) www.bmj.sk.

1. A method is described for the isolation of hexokinase from baker's yeast. The method is based mainly on fractionation with alcohol and results See PDF for Structure in a 30-fold increase in specific activity. The final product could be crystallized from ammonium sulfate without change in specific activity. 2. The enzyme catalyzes a transfer of phosphate from adenosinetriphosphate to glucose, fructose, or mannose, the relative rates with these three sugars being 1:1.4:0.3. 3. With glucose as substrate, the turnover number for the crystalline enzyme is 13,000 moles of substrate per 10(5) gm. of protein per minute at 30 degrees and pH 7.5. The temperature coefficient (Q(10 degrees )) between 0 and 30 degrees is 1.9. 4. Magnesium ions are necessary for the activity, the dissociation constant for the Mg(++) -protein complex being 2.6 x 10(-3). Fluoride in concentrations as high as 0.125 M has no inhibitory effect on the enzyme when the Mg(++) and orthophosphate concentrations are 6.5 x 10(-3)M and 1 x 10(-3)M, respectively. 5. The crystalline enzyme shows a loss in activity when highly diluted. This loss in activity can be prevented by diluting in the presence of small amounts of other proteins. Of the various protective proteins tested, insulin was the most effective, providing complete protection in a concentration of 6 micrograms per cc.; with serum albumin, a concentration of 60 micrograms per cc. was necessary. Thiol compounds (cysteine, glutathione) exerted no protective action. 6. The inactivation of the crystalline enzyme on incubation with trypsin can be prevented to a marked degree by the presence of glucose. The instability of crude preparations of yeast hexokinase may be attributed to the presence of proteolytic enzymes, since glucose or fructose has a remarkable protective effect on such preparations.

BACKGROUND

Methods like FBA and kinetic modeling are widely used to calculate fluxes in metabolic networks. For the analysis and understanding of simulation results and experimentally measured fluxes visualization software within the network context is indispensable.

RESULTS

We present Flux Viz, an open-source Cytoscape plug-in for the visualization of flux distributions in molecular interaction networks. FluxViz supports (i) import of networks in a variety of formats (SBML, GML, XGMML, SIF, BioPAX, PSI-MI) (ii) import of flux distributions as CSV, Cytoscape attributes or VAL files (iii) limitation of views to flux carrying reactions (flux subnetwork) or network attributes like localization (iv) export of generated views (SVG, EPS, PDF, BMP, PNG). Though FluxViz was primarily developed as tool for the visualization of fluxes in metabolic networks and the analysis of simulation results from FASIMU, a flexible software for batch flux-balance computation in large metabolic networks, it is not limited to biochemical reaction networks and FBA but can be applied to the visualization of arbitrary fluxes in arbitrary graphs.

BACKGROUND

The platform-independent program is an open-source project, freely available at http://sourceforge.net/projects/fluxvizplugin/ under GNU public license, including manual, tutorial and examples.

Governments use statutes, regulations, and policies, often in innovative ways, to promote health and safety. Organizations outside government, from private schools to major corporations, create rules on matters as diverse as tobacco use and paid sick leave. Very little of this activity is systematically tracked. Even as the rest of the health system is working to build, share, and use a wide range of health and social data, legal information largely remains trapped in text files and pdfs, excluded from the universe of usable data. This article makes the case for the practice of policy surveillance to help end the anomalous treatment of law in public health research and practice. Policy surveillance is the systematic, scientific collection and analysis of laws of public health significance. It meets several important needs. Scientific collection and coding of important laws and policies creates data suitable for use in rigorous evaluation studies. Policy surveillance addresses the chronic lack of readily accessible, nonpartisan information about status and trends in health legislation and policy. It provides the opportunity to build policy capacity in the public health workforce. We trace its emergence over the past fifty years, show its value, and identify major challenges ahead.

BACKGROUND

Conventional peritoneal dialysis fluids (PDFs) consist of ready-to-use solutions with an acidic pH. Sterilization of these fluids is known to generate high levels of glucose degradation products (GDPs). Although several neutral-pH, low-GDP PD solutions have been developed, none are commercially available in the United States. We analyzed pH and GDPs in Delflex Neutral pH (Fresenius Medical Care North America, Waltham, MA, USA), the first neutral-pH PDF to be approved by the US Food and Drug Administration.

METHODS

We evaluated whether patients (n = 26; age range: 18 - 78 years) could properly mix the Delflex Neutral pH PDF after standardized initial training. We further analyzed the concentrations of 10 different glucose degradation products in Delflex Neutral pH PDF and compared the results with similar analyses in other commercially available biocompatible PDFs.

RESULTS

All pH measurements (n = 288) in the delivered Delflex Neutral pH solution consistently fell within the labeled range of 7.0 ± 0.4. Analysis of mixing errors showed no significant impact on the pH results. Delflex Neutral pH, Balance (Fresenius Medical Care, Bad Homburg, Germany), BicaVera (Fresenius Medical Care), and Gambrosol Trio (Gambro Lundia AB, Lund, Sweden) exhibited similar low total GDP concentrations, with maximums in the 4.25% solutions of 88 μmol/L, 74 μmol/L, 74 μmol/L, and 79 μmol/L respectively; the concentration in Physioneal (Baxter Healthcare Corporation, Deerfield, IL, USA) was considerably higher at 263.26 μmol/L. The total GDP concentration in Extraneal (Baxter Healthcare Corporation) was 63 μmol/L, being thus slightly lower than the concentrations in the 4.25% glucose solutions, but higher than the concentrations in the 1.5% and 2.5% glucose solutions.

CONCLUSIONS

The new Delflex Neutral pH PDF consistently delivers neutral pH with minimal GDPs.

OBJECTIVE

Autoimmune thyroid diseases are frequent in patients with type 1 diabetes mellitus. The aim of our study was to determine the incidence of autoimmune thyroid diseases (AIT) in the different groups of patients with DM (DM type 1--classical form, DM type 1--subtype LADA, DM type 2) and compare the incidence of AIT among the groups as well as to the control group of non-diabetics. We also focused our attention on the factors that influence the risk of thyroid diseases incidence in diabetics.

METHODS

We examined 79 diabetics (38 women and 41 men, x = 55.4 +/- 2.8). Diabetic patients were divided into three groups. The control group consisted of 30 non-diabetics.

RESULTS

Chronic autoimmune thyroiditis was diagnosed in 8 (40%) patients in the first group, in 6 (50%) in the 2nd group of patients and finally in 20 (43%) patients with type 2 diabetes mellitus--3rd group. A significantly higher prevalence of chronic autoimmune thyroiditis was observed in female diabetics and in diabetics with positive family history of thyroid diseases.

CONCLUSIONS

Results of paper confirm an increased prevalence of chronic autoimmune thyroiditis in patients with all types of diabetes mellitus resulting in recommendation of careful follow-up of all diabetic patients for presence of thyroid autoimmunity (Tab. 5, Ref, 13). Full Text (Free, PDF) www.bmj.sk.

BACKGROUND

Exploring bioactive chemistry requires navigating between structures and data from a variety of text-based sources. While PubChem currently includes approximately 16 million document-extracted structures (15 million from patents) the extent of public inter-document and document-to-database links is still well below any estimated total, especially for journal articles. A major expansion in access to text-entombed chemistry is enabled by chemicalize.org. This on-line resource can process IUPAC names, SMILES, InChI strings, CAS numbers and drug names from pasted text, PDFs or URLs to generate structures, calculate properties and launch searches. Here, we explore its utility for answering questions related to chemical structures in documents and where these overlap with database records. These aspects are illustrated using a common theme of Dipeptidyl Peptidase 4 (DPPIV) inhibitors.

RESULTS

Full-text open URL sources facilitated the download of over 1400 structures from a DPPIV patent and the alignment of specific examples with IC50 data. Uploading the SMILES to PubChem revealed extensive linking to patents and papers, including prior submissions from chemicalize.org as submitting source. A DPPIV medicinal chemistry paper was completely extracted and structures were aligned to the activity results table, as well as linked to other documents via PubChem. In both cases, key structures with data were partitioned from common chemistry by dividing them into individual new PDFs for conversion. Over 500 structures were also extracted from a batch of PubMed abstracts related to DPPIV inhibition. The drug structures could be stepped through each text occurrence and included some converted MeSH-only IUPAC names not linked in PubChem. Performing set intersections proved effective for detecting compounds-in-common between documents and merged extractions.

CONCLUSIONS

This work demonstrates the utility of chemicalize.org for the exploration of chemical structure connectivity between documents and databases, including structure searches in PubChem, InChIKey searches in Google and the chemicalize.org archive. It has the flexibility to extract text from any internal, external or Web source. It synergizes with other open tools and the application is undergoing continued development. It should thus facilitate progress in medicinal chemistry, chemical biology and other bioactive chemistry domains.

Since its release in 2006, the US Food and Drug Administration (FDA) final improved format for prescription drug labeling has revamped the comprehensiveness of drug inserts, including chemotherapy drugs. The chemotherapy drug "packets", retrieved via the FDA website and other accredited drug information reporting agencies such as the Physician Drug Reference (PDR), are practically the only available unbiased summary of information. One objective is to impartially evaluate the reporting of useful pharmacokinetic parameters, in particular, Volume of Distribution (V(D)) and elimination half-life (t(1/2)), in randomly selected FDA approved chemotherapy drug inserts. The web-accessible portable document format (PDF) files for 30 randomly selected chemotherapy drugs are subjected to detailed search and the two parameters of interest are tabulated. The knowledge of the two parameters is essential in directing patient care as well as for clinical research and since the completeness of the core FDA recommendations has been found deficient, a detailed explanation of the impact of such deficiencies is provided.

OBJECTIVE

Multiple investigators have recently reported the use of yttrium-90 (90Y) bremsstrahlung single photon emission computed tomography (SPECT) imaging for the dosimetry of targeted radionuclide therapies. Because Monte Carlo (MC) simulations are useful for studying SPECT imaging, this study investigates the MC simulation of 90Y bremsstrahlung photons in SPECT. To overcome the computationally expensive simulation of electrons, the authors propose a fast way to simulate the emission of 90Y bremsstrahlung photons based on prerecorded bremsstrahlung photon probability density functions (PDFs).

METHODS

The accuracy of bremsstrahlung photon simulation is evaluated in two steps. First, the validity of the fast bremsstrahlung photon generator is checked. To that end, fast and analog simulations of photons emitted from a 90Y point source in a water phantom are compared. The same setup is then used to verify the accuracy of the bremsstrahlung photon simulations, comparing the results obtained with PDFs generated from both simulated and measured data to measurements. In both cases, the energy spectra and point spread functions of the photons detected in a scintillation camera are used.

RESULTS

Results show that the fast simulation method is responsible for a 5% overestimation of the low-energy fluence (below 75 keV) of the bremsstrahlung photons detected using a scintillation camera. The spatial distribution of the detected photons is, however, accurately reproduced with the fast method and a computational acceleration of approximately 17-fold is achieved. When measured PDFs are used in the simulations, the simulated energy spectrum of photons emitted from a point source of 90Y in a water phantom and detected in a scintillation camera closely approximates the measured spectrum. The PSF of the photons imaged in the 50-300 keV energy window is also accurately estimated with a 12.4% underestimation of the full width at half maximum and 4.5% underestimation of the full width at tenth maximum.

CONCLUSIONS

Despite its limited accuracy, the fast bremsstrahlung photon generator is well suited for the simulation of bremsstrahlung photons emitted in large homogeneous organs, such as the liver, and detected in a scintillation camera. The computational acceleration makes it very useful for future investigations of 90Y bremsstrahlung SPECT imaging.

BACKGROUND

Mesangial expansion is thought to be a major cause of diabetic nephropathy (DN). Platelet-derived growth factor (PDGF) plays an important role in the production of extracellular matrix proteins in renal diseases. The present study was designed to determine the expression of PDGF and PDF receptor (PDGFR) mRNA in the renal tissues of type 2 diabetic patients with DN.

METHODS

We examined open renal biopsies of 20 type 2 diabetic patients with DN, and 10 normal human kidneys (NHK). Histopathologically, the severity of DN was classified as grade I (DN I, n = 10; mild mesangial expansion) or grade II (DN II, n = 10; moderate mesangial expansion). We evaluated the expression and localization of PDGF-A, -B, and PDGFR-Alpha, -Beta using in situ hybridization, and quantified PDGF and PDGFR mRNA expression by counting all nuclei, and nuclei surrounded by PDGF-positive cytoplasm and PDGFR-positive cytoplasm, in at least ten randomly selected cross-sections of nonsclerotic glomeruli.

RESULTS

In all glomeruli, PDGF and PDGFR mRNAs were expressed mainly in glomerular resident cells, predominantly glomerular mesangial and epithelial cells. The percentages of cells positive for PDGF-A and PDGFR-Alpha mRNA in DN were similar to those in NHK. In contrast, the percentages of PDGF-B and PDGFR-Beta mRNA-positive cells in DN were significantly higher than those in NHK, and were significantly higher in DN I than in DN II: The percentages of cells positive for PDGF-B correlated with the PDGFR-Beta mRNA level.

CONCLUSIONS

Our results suggest that the expression of PDGF-B and PDGFR-Beta is an important factor in histologically early glomerular lesions of DN. Mesangial expansion is thought to be a major cause of diabetic nephropathy (DN). Platelet-derived growth factor (PDGF) plays an important role in the production of extracellular matrix proteins in renal diseases. The present study was designed to determine the expression of PDGF and PDGF receptor (PDGFR) mRNA in the renal tissues of type 2 diabetic patients with DN.

Inhibitors of peptide deformylase (PDF) represent a new class of antibacterial agents with a novel mechanism of action. Mutations that inactivate formyl methionyl transferase (FMT), the enzyme that formylates initiator methionyl-tRNA, lead to an alternative initiation of protein synthesis that does not require deformylation and are the predominant cause of resistance to PDF inhibitors in Staphylococcus aureus. Here, we report that loss-of-function mutations in FMT impart pleiotropic effects that include a reduced growth rate, a nonhemolytic phenotype, and a drastic reduction in production of multiple extracellular proteins, including key virulence factors, such as α-hemolysin and Panton-Valentine leukocidin (PVL), that have been associated with S. aureus pathogenicity. Consequently, S. aureus FMT mutants are greatly attenuated in neutropenic and nonneutropenic murine pyelonephritis infection models and show very high survival rates compared with wild-type S. aureus. These newly discovered effects on extracellular virulence factor production demonstrate that FMT-null mutants have a more severe fitness cost than previously anticipated, leading to a substantial loss of pathogenicity and a restricted ability to produce an invasive infection.

Eutectics are a long known class of multi-component solids with important and useful applications in daily life. In comparison to other multi-component crystalline solids, such as salts, solid solutions, molecular complexes and cocrystals, eutectics are less studied in terms of molecular structure organization and bonding interactions. Classically, a eutectic is defined based on its low melting point compared to the individual components. In this article, we attempt to define eutectics not just based on thermal methods but from a structural organization view point, and discuss their microstructures and properties as organic materials vis-a-vis solid solutions and cocrystals. The X-ray crystal structure of a cocrystal is different from that of the individual components whereas the unit cell of a solid solution is similar to that of one of the components. Eutectics are closer to the latter species in that their crystalline arrangement is similar to the parent components but they are different with respect to the structural integrity. A solid solution possesses structural homogeneity throughout the structure (single phase) but a eutectic is a heterogeneous ensemble of individual components whose crystal structures are like discontinuous solid solutions (phase separated). Thus, a eutectic may be better defined as a conglomerate of solid solutions. A structural analysis of cocrystals, solid solutions and eutectics has led to an understanding that materials with strong adhesive (hetero) interactions between the unlike components will lead to cocrystals whereas those having stronger cohesive (homo/self) interactions will more often give rise to solid solutions (for similar structures of components) and eutectics (for different structures of components). We demonstrate that the same crystal engineering principles which have been profitably utilized for cocrystal design in the past decade can now be applied to make eutectics as novel composite materials, illustrated by stable eutectics of the hygroscopic salt of the anti-tuberculosis drug ethambutol as a case study. A current gap in the characterization of eutectic microstructure may be fulfilled through pair distribution function (PDF) analysis of X-ray diffraction data, which could be a rapid signature technique to differentiate eutectics from their components.

BACKGROUND

The statistical measures commonly used to assess therapies for recurrent atrial arrhythmias (such as time to first recurrence) often assume a uniformly random pattern of arrhythmic events over time. However, the true temporal pattern of atrial arrhythmia recurrences is unknown. The aim of this study was to use linear and nonlinear analyses to characterize the temporal pattern of atrial arrhythmia recurrences in patients with implantable cardioverter defibrillators.

RESULTS

The time and date of atrial tachyarrhythmias recorded in 65 patients with combined atrial and ventricular defibrillators were used to construct a probability density function (PDF) and a model of a Poisson distribution of arrhythmic events for each patient. Average patient age was 66 +/- 10 years and follow-up was 7.8 +/- 4.8 months. A total of 10,759 episodes of atrial tachyarrhythmias were analyzed (range 43 to 618 episodes per patient). The PDF fit a power law distribution for all 65 patients, with an average r2 = 0.89 +/- 0.08. The PDF distribution differed significantly from the model Poisson distribution in 47 of 65 patients (P = 0.0002). Differences from the Poisson distribution were noted for patients both taking (30/43 patients; P < or = 0.015) and not taking (17/22 patients; P < or = 0.017) antiarrhythmic drugs. Median time between atrial arrhythmia detections for all 65 patients was 10.8 minutes.

CONCLUSIONS

In implantable cardioverter defibrillator patients, the temporal pattern of frequent recurrences of atrial tachyarrhythmias usually is characterized by a power law distribution. The unique statistical properties of this type of distribution should be considered in designing outcome measures for treatment of atrial tachyarrhythmias.

The antibacterial activity of NVP-<em>PDF</em>386 (VRC4887), a novel peptide deformylase (<em>PDF</em>) inhibitor, was tested against over 1000 recent clinical isolates collected during 2001 and 2002. The MIC(50/90) (mg/L) results for NVP-<em>PDF</em>386 (VRC4887) were: Staphylococcus aureus (SA) 0.5/1, coagulase-negative staphylococci (CoNS) 0.5/1, Streptococcus pneumoniae 0.25/0.5, other streptococci 0.25/0.5, enterococci 1/2, Moraxella catarrhalis 0.25/0.25, Haemophilus influenzae 8/32 and Enterobacteriaceae or non-fermentative Gram-negative bacilli >32/>32 mg/L. No differences in NVP-<em>PDF</em>386/(VRC4887) MIC distributions were observed between methicillin-resistant (MR) S. aureus and methicillin-susceptible (MS) S. aureus, MR-CoNS and MS-CoNS, penicillin-susceptible and non-susceptible streptococci, and macrolide-susceptible and -resistant strains. The potency of NVP-<em>PDF</em>386 (VRC4887) compared favourably with those of control compounds, including glycopeptides, oxazolidinones, a streptogramin combination and other agents with activity focused against Gram-positive cocci.

Clinical nonfunctional pituitary adenomas (NFAs) account for about 40% of pituitary adenomas with almost no clinically relevant hormonal symptoms. Increasing evidence shows that many microRNAs are involved in the development and progression of pituitary adenomas. MicroRNA-524-5p (miR-524-5p) has been reported to cause characteristic alterations in various tumors. However, the functional importance of miR-524-5p in NFAs remains unknown. The aim of this study was to explore the effects of overexpressing miR-524-5p on the proliferation, migration, invasion, and tumorigenicity of pituitary-derived folliculostellate (PDFS) cells using lentiviral transfection. Interestingly, the results showed that overexpressing miR-524-5p downregulated pituitary tumor-transforming gene 1 (PTTG1) binding factor (PBF) expression at both mRNA and protein levels and significantly attenuated cell proliferation, clonogenicity, migration, and invasion in vitro. Moreover, enhancing miR-524-5p blocked tumor growth in a nude mouse xenograft model in vivo. These findings suggest that miR-524-5p appears to play a critical role in the regulation of biological properties of PDFS cells, and may represent a potential therapeutic target for NFAs.

It has been proposed that populations of neurons process information in terms of probability density functions (PDFs) of analog variables. Such analog variables range, for example, from target luminance and depth on the sensory interface to eye position and joint angles on the motor output side. The requirement that analog variables must be processed leads inevitably to a probabilistic description, while the limited precision and lifetime of the neuronal processing units lead naturally to a population representation of information. We show how a time-dependent probability density rho(x; t) over variable x, residing in a specified function space of dimension D, may be decoded from the neuronal activities in a population as a linear combination of certain decoding functions phi(i)(x), with coefficients given by the N firing rates a(i)(t) (generally with D (< N). We show how the neuronal encoding process may be described by projecting a set of complementary encoding functions phi;(i)(x) on the probability density rho(x; t), and passing the result through a rectifying nonlinear activation function. We show how both encoders phi;(i)(x) and decoders phi(i)(x) may be determined by minimizing cost functions that quantify the inaccuracy of the representation. Expressing a given computation in terms of manipulation and transformation of probabilities, we show how this representation leads to a neural circuit that can carry out the required computation within a consistent Bayesian framework, with the synaptic weights being explicitly generated in terms of encoders, decoders, conditional probabilities, and priors.

OBJECTIVE

At hospital discharge, preterm infants may have low body stores of nutrients, deficient bone mineralization, and an accumulated energy deficit. This double-blind, randomized study evaluated the growth of premature infants with birth weights <1800 g who were fed a 22 kcal/fl oz nutrient-enriched postdischarge formula (PDF) or a 20 kcal/fl oz term-infant formula (TF) from hospital discharge to 12 months' corrected age (CA).

METHODS

Infants were randomized to PDF or TF a few days before hospital discharge with stratification by gender and birth weight (<1250 g or>>/=1250 g). The formulas were fed to 12 months' CA. Growth was evaluated using analysis of variance controlling for site, feeding, gender, and birth weight group. Interaction effects were also assessed. Secondary analyses included a repeated measures analysis and growth modeling.

RESULTS

One hundred twenty-five infants were randomized; 74 completed to 6 months' CA and 53 to 12 months' CA. PDF-fed infants weighed more than TF-fed infants at 1 and 2 months' CA, gained more weight from study day 1 to 1 and 2 months' CA, and were longer at 3 months' CA. There were significant interactions between feeding and birth weight group-among infants with birth weights <1250 g, those fed PDF weighed more at 6 months' CA, were longer at 6 months' CA, had larger head circumferences at term 1, 3, 6, and 12 months' CA, and gained more in head circumference from study day 1 to term and to 1 month CA. The repeated measures and growth modeling analyses confirmed the analysis of variance results. The PDF formula seemed to be of particular benefit for the growth of male infants. Infants fed the PDF consumed less formula and had higher protein intakes at several time points. Energy intakes, however, were not different.

CONCLUSIONS

Growth was improved in preterm infants fed a nutrient-enriched postdischarge formula after hospital discharge to 12 months' CA. Beneficial effects were most evident among infants with birth weights <1250 g, particularly for head circumference measurements.

We consider the task of solving the independent component analysis (ICA) problem x=As given observations x, with a constraint of nonnegativity of the source random vector s. We refer to this as nonnegative independent component analysis and we consider methods for solving this task. For independent sources with nonzero probability density function (pdf) p(s) down to s=0 it is sufficient to find the orthonormal rotation y=Wz of prewhitened sources z=Vx, which minimizes the mean squared error of the reconstruction of z from the rectified version y/sup +/ of y. We suggest some algorithms which perform this, both based on a nonlinear principal component analysis (PCA) approach and on a geodesic search method driven by differential geometry considerations. We demonstrate the operation of these algorithms on an image separation problem, which shows in particular the fast convergence of the rotation and geodesic methods and apply the approach to a musical audio analysis task.