The surrogate scaffold method for quantifying molecular release kinetics from drug delivery systems

The accurate determination of kinetics of therapeutic release from drug delivery vehicles is an essential step in the optimized design of such systems for biomedical and pharmaceutical applications. Most methods in current use for quantifying therapeutic release rates are developed to provide consistency, reproducibility, and ease of usage in a laboratory setting. These methods, however, do not necessarily mirror the release conditions when the drug delivery system comes into contact with the target tissue environment during application. As a result, the findings from these studies provide only comparative guidelines about the drug delivery rates and duration. Successful optimization of a drug delivery system requires complete, and accurate, knowledge about the release profile over an extended period of time to determine the initial release rate—including burst release if present, the rate of change of the release kinetics, and the maximum duration of delivery at a minimum therapeutic concentration level. We have developed an indirect method for the quantification of release kinetics suitable for nanoparticle-based drug delivery systems that utilizes a hydrogel scaffold as a tissue surrogate to better emulate therapeutic delivery into a target tissue environment. Details of the method and its application to the release of an angiogenic peptide from a nanoparticle emulsion are provided in this communication.     

Engineering the xenobiotic substrate specificity of maize glutathione S-transferase I

Glutathione S-transferases (GSTs) are a heterogeneous family of enzymes that catalyse the conjugation of glutathione (GSH) to electrophilic sites on a variety of hydrophobic substrates. In the present study three amino acid residues (Trp12, Phe35 and Ile118) of the xenobiotic binding site (H-site) of maize GST I were altered in order to evaluate their contribution to substrate binding and catalysis. These residues are not conserved and hence may affect substrate specificity and/or product dissociation. The results demonstrate that these residues are important structural moieties that modulate an enzyme's catalytic efficiency and specificity. Phe35 and Ile118 also participate in k(cat) regulation by affecting the rate-limiting step of the catalytic reaction. The effect of temperature on the catalytic activity of the wild-type and mutant enzymes was also investigated. Biphasic Arrhenius and Eyring plots for the wild-type enzyme showed an apparent transition temperature at 35 degrees C, which seems to be the result of a change in the rate-limiting step of the catalytic reaction. Thermodynamic analysis of the activity data showed that the activation energy increases at low temperatures, whereas the entropy change seems to be the main determinant that contributes to the rate-limiting step at high temperatures.     

Evaluation of networks of randomized trials

Randomized trials may be designed and interpreted as single experiments or they may be seen in the context of other similar or relevant evidence. The amount and complexity of available randomized evidence vary for different topics. Systematic reviews may be useful in identifying gaps in the existing randomized evidence, pointing to discrepancies between trials, and planning future trials. A new, promising, but also very much debated extension of systematic reviews, mixed treatment comparison (MTC) meta-analysis, has become increasingly popular recently. MTC meta-analysis may have value in interpreting the available randomized evidence from networks of trials and can rank many different treatments, going beyond focusing on simple pairwise-comparisons. Nevertheless, the evaluation of networks also presents special challenges and caveats. In this article, we review the statistical methodology for MTC meta-analysis. We discuss the concept of inconsistency and methods that have been proposed to evaluate it as well as the methodological gaps that remain. We introduce the concepts of network geometry and asymmetry, and propose metrics for the evaluation of the asymmetry. Finally, we discuss the implications of inconsistency, network geometry and asymmetry in informing the planning of future trials.     

Fe(III)-humate complexes from Megalopolis peaty lignite: A novel eco-friendly fertilizer

Fe(III)-humate complexes were synthesized from Greek peaty lignite of the Megalopolis Basin. The preparation was carried out under mild and low-energy conditions producing a biodegradable, eco-friendly and effective material to substitute the synthetic chelates Fe-EDDHA, Fe-EDTA and Fe-DTPA. Due to both the existing expanded configuration of the humic substances (that make binding sites accessible to the metal ions) and the ionization of functional groups, alkaline environment facilitates the association between Fe(III) ions and the lignite-derived humic substances. UV-vis and IR spectra revealed coordination of the metal ions with the carboxylic and phenolic groups of the oxygen-rich humic substances. Fe(III)-humate complexes were proved stable in a wide pH range similar to Fe-EDDHA synthetic chelates. Furthermore, the presence of K⁺ and humic matter increases the agronomic value of this material establishing alternative applications for Megalopolis peaty lignite.     

Aryl diazonium functionalization of carbon nanohorns

Carbon nanohorns (CNHs) are a relatively new material within the family of elongated carbon nanostructures. A strategy for their solubilization is presented here. Aryl diazonium functionalization of CNHs has been achieved giving rise to soluble materials in common organic solvents as well as water. The modified CNHs have been characterized by complementary spectroscopic and microscopic means as well as thermal gravimetric analysis and dynamic light scattering measurements.     

Healthcare provider cultural competency: Development and initial validation of a patient report measure.

Objective: Health researchers have proposed that provider cultural competency may contribute to health disparities. Yet, this belief continues to lack empirical support, and this is due in part to measurement issues that have plagued the cultural competency construct. In the present research, we report on the development of a theoretically grounded, generally applicable, and patient report measure of provider cultural competency. Design: Samples of predominantly African American patients (N = 310) were recruited from three urban medical clinics to complete a survey about their relationship with their physician. Main Outcome Measures: We examined the factor structure, validity and other psychometric characteristics of a newly proposed patient report measure of provider cultural competency. Results: Psychometric analyses supported a tripartite model of cultural competency that was comprised of patient judgments of their physician's cultural knowledge, awareness, and skill. In addition, this result was replicated across multiple clinical contexts, while also demonstrating convergent and incremental validity when correlated with measures of trust, satisfaction and discrimination. Conclusion: This newly proposed measure addresses prior limitations in cultural competency measurement and may enhance future research by providing a standardized tool for use in multiple clinical and cultural contexts. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lactobacillus fermentum ACA-DC 179 displays probiotic potential in vitro and protects against trinitrobenzene sulfonic acid (TNBS)-induced colitis and Salmonella infection in murine models

Lactobacillus fermentum ACA-DC 179, Lactobacillus plantarum ACA-DC 287 and Streptococcus macedonicus ACA-DC 198 were studied for their probiotic potential. Firstly, strains were screened for antimicrobial activity towards a broad range of target strains, including lactic acid bacteria, food spoilage and pathogenic bacteria. L. fermentum ACA-DC 179 was active against five streptococci, including the two pathogenic strains Streptococcus oralis LMG 14532T and Streptococcus pneumoniae LMG 14545T. S. macedonicus ACA-DC 198 was active against the majority of the strains tested, including not only lactic acid bacteria but also many food spoilage or pathogenic species. The three potential probiotic strains were found to survive variably at pH 2.5 and were unaffected by bile salts. Only S. macedonicus ACA-DC 198 exhibited bile salt hydrolase activity, while none of the strains was haemolytic. Moreover, strains exhibited variable susceptibility towards commonly used antibiotics. L. plantarum ACA-DC 287 and S. macedonicus ACA-DC 198 induced the secretion of the pro-inflammatory cytokines IL-12, IFN-gamma and TNF-alpha by human peripheral blood mononuclear cells. Also elevated levels of the anti-inflammatory IL-10 were observed with L. fermentum ACA-DC 179. This strain consequently was found to significantly reduce colitis in a TNBS-induced colitis mouse model. Furthermore, L. fermentum ACA-DC 179 was successfully applied in an experimental Salmonella-infection mouse model. To conclude, strain L. fermentum ACA-DC 179 possesses desirable probiotic properties, such as antimicrobial activity and immunomodulation in vitro, which were confirmed in vivo by the use of animal models.     

Unveiling the Essential Role of Arkadia’s Non-RING Elements in the Ubiquitination Process

Arkadia is a positive regulator of the TGFβ-SMAD2/3 pathway, acting through its C-terminal RING-H2 domain and targeting for degradation of its negative regulators. Here we explore the role of regions outside the RING domain (non-RING elements) of Arkadia on the E2-E3 interaction. The contribution of the non-RING elements was addressed using Arkadia RING 68 aa and Arkadia 119 aa polypeptides. The highly conserved NRGA (asparagine-arginine-glycine-alanine) and TIER (threonine-isoleucine-glutamine-arginine) motifs within the 119 aa Arkadia polypeptide, have been shown to be required for pSMAD2/3 substrate recognition and ubiquitination in vivo. However, the role of the NRGA and TIER motifs in the enzymatic activity of Arkadia has not been addressed. Here, nuclear magnetic resonance interaction studies with the E2 enzyme, UBCH5B, C85S UBCH5B-Ub oxyester hydrolysis, and auto-ubiquitination assays were used to address the role of the non-RING elements in E2-E3 interaction and in the enzymatic activity of the RING. The results support that the non-RING elements including the NRGA and TIER motifs are required for E2-E3 recognition and interaction and for efficient auto-ubiquitination. Furthermore, while Arkadia isoform-2 and its close homologue Arkadia 2C are known to interact with free ubiquitin, the results here showed that Arkadia isoform-1 does not interact with free ubiquitin.     

Employee perceptions on the implementation of robotic manufacturing technology.

[Correction Notice: An erratum for this article was reported in Vol 71(3) of Journal of Applied Psychology (see record 2008-10743-001). Several crucial horizontal rules were omitted from Table 2. The corrected table appears in the erratum.] A review of the industrial robotics literature identified 4 areas of employee concern during the implementation of robots: general robotics orientation, job security, management concern, and expected changes. A principal factors analysis of a 58-item questionnaire generated to measure these dimensions extracted 4 factors that reproduced the a priori conceptual areas. Composite scales formed from items loading on these factors yielded acceptable reliabilities. A discriminant analysis using the scale scores indicated significant group differences among 316 manufacturing employees in 3 occupational classes—assembly line workers, job setters, and skilled trades. These results, corroborated by a content analysis of an open-ended question, show that low-skill workers reacted negatively toward the implementation of robots, perceiving them largely as threats to their job security. High-skill workers reacted more positively toward the robots and perceived the implementation as providing opportunities to expand their skills. (31 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Rule-based query personalization in digital libraries

Searching a digital library is typically a tedious task. A system can improve information access by building on knowledge about a user acquired in a user profile in order to customize information access both in terms of the information returned in response to a query (query personalization) as well as in terms of the presentation of the results (presentation personalization). In this paper, we focus on query personalization in digital libraries; in particular, we address structured queries involving metadata stored in relational databases. We describe the specification of user preferences at the level of a user profile and the process of query personalization with the use of query-rewriting rules.