Characterization of Spatiooral Cardiac Action Potential Variability at Baseline and under ß-Adrenergic Stimulation by Combined Unscented Kalman Filter and Double Greedy Dimension Reduction

Objective: Elevated spatiooral variability of human ventricular repolarization has been related to increased risk for ventricular arrhythmias and sudden cardiac death, particularly under ß-adrenergic stimulation (ß-AS). This work presents a methodology for theoretical characterization of temporal and spatial repolarization variability at baseline conditions and in response to ß-AS. For any measured voltage trace, the proposed methodology estimates the parameters and state variables of an underlying human ventricular action potential (AP) model by combining Double Greedy Dimension Reduction (DGDR) with automatic selection of biomarkers and the Unscented Kalman Filter (UKF). Such theoretical characterization can facilitate subsequent characterization of underlying variability mechanisms. Material and Methods: Given an AP trace, initial estimates for the ionic conductances in a stochastic version of the baseline human ventricular O'Hara et al. model were obtained by DGDR. Those estimates served to initialize and update model parameter estimates by the UKF method based on formulation of an associated nonlinear state-space representation and joint estimation of model parameters and state variables. Similarly, ß-AS-induced phosphorylation levels of cellular substrates were estimated by the DGDR-UKF methodology. Performance was tested by building an experimentally-calibrated population of virtual cells, from which synthetic AP traces were generated for baseline and ß-AS conditions. Results: The combined DGDR-UKF methodology led to 25% reduction in the error associated with estimation of ionic current conductances at baseline conditions and phosphorylation levels under ß-AS with respect to individual DGDR and UKF methods. This improvement was not at the expense of higher computational load, which was diminished by 90% with respect to the individual UKF method. Both temporal and spatial AP variability of repolarization were accurately characterized by the DGDR-UKF methodology. Conclusions: A combined DGDR-UKF methodology is proposed for parameter and state variable estimation of human ventricular cell models from available AP traces at baseline and under ß-AS. This methodology improves the estimation performance and reduces the convergence time with respect to individual DGDR and UKF methods and renders a suitable approach for computational characterization of spatiooral repolarization variability to be used for ascertainment of variability mechanisms and its relation to arrhythmogenesis

Protoporphyrin IX enhancement by 5-aminolaevulinic acid peptide derivatives and the effect of RNA silencing on intracellular metabolism

Intracellular generation of the photosensitiser, protoporphyrin IX, from a series of dipeptide derivatives of the haem precursor, 5-aminolaevulinic acid (ALA), was investigated in transformed PAM212 murine keratinocytes, together with studies of their intracellular metabolism. Porphyrin production was substantially increased compared with equimolar ALA using N-acetyl terminated phenylalanyl, leucinyl and methionyl ALA methyl ester derivatives in the following order: Ac-L-phenylalanyl-ALA-Me, Ac-L-methionyl-ALA-Me and Ac-L-leucinyl-ALA-Me. The enhanced porphyrin production was in good correlation with improved photocytotoxicity, with no intrinsic dark toxicity apparent. However, phenylalanyl derivatives without the acetyl/acyl group at the N terminus induced significantly less porphyrin, and the replacement of the acetyl group by a benzyloxycarbonyl group resulted in no porphyrin production. Porphyrin production was reduced in the presence of class-specific protease inhibitors, namely serine protease inhibitors. Using siRNA knockdown of acylpeptide hydrolase (ACPH) protein expression, we showed the involvement of ACPH, a member of the prolyl oligopeptidase family of serine peptidases, in the hydrolytic cleavage of ALA from the peptide derivatives. In conclusion, ALA peptide derivatives are capable of delivering ALA efficiently to cells and enhancing porphyrin synthesis and photocytotoxicity; however, the N-terminus state, whether free or substituted, plays an important role in determining the biological efficacy of ALA peptide derivatives

Identification of nursing assessment models/tools validated in clinical practice for use with diverse ethno-cultural groups: an integrative review of the literature

<p>Abstract</p> <p>Background</p> <p>High income nations are currently exhibiting increasing ethno-cultural diversity which may present challenges for nursing practice. We performed an integrative review of literature published in North America and Europe between 1990 and 2007, to map the state of knowledge and to identify nursing assessment tools/models which are have an associated research or empirical perspective in relation to ethno-cultural dimensions of nursing care.</p> <p>Methods</p> <p>Data was retrieved from a wide variety of sources, including key electronic bibliographic databases covering research in biomedical fields, nursing and allied health, and culture, e.g. CINAHL, MEDline, PUBmed, Cochrane library, PsycINFO, Web of Science, and HAPI. We used the Critical Appraisal Skills Programme tools for quality assessment. We applied Torraco's definition and method of an integrative review that aims to create new knowledge and perspectives on a given phenomena. To add methodological rigor with respect to the search strategy and other key review components we also used the principles established by the Centre for Reviews and Dissemination.</p> <p>Results</p> <p>Thirteen thousand and thirteen articles were retrieved, from which 53 full papers were assessed for inclusion. Eight papers met the inclusion criteria, describing research on a total of eight ethno-cultural assessment tools/models. The tools/models are described and synthesized.</p> <p>Conclusions</p> <p>While many ethno-cultural assessment tools exist to guide nursing practice, few are informed by research perspectives. An increased focus on the efficiency and effectiveness of health services, patient safety, and risk management, means that provision of culturally responsive and competent health services will inevitably become paramount.</p

Identification and Characterisation of a Novel Acylpeptide Hydrolase from Sulfolobus Solfataricus: Structural and Functional Insights

A novel acylpeptide hydrolase, named APEH-3Ss, was isolated from the hypertermophilic archaeon Sulfolobus solfataricus. APEH is a member of the prolyl oligopeptidase family which catalyzes the removal of acetylated amino acid residues from the N terminus of oligopeptides. The purified enzyme shows a homotrimeric structure, unique among the associate partners of the APEH cluster and, in contrast to the archaeal APEHs which show both exo/endo peptidase activities, it appears to be a “true” aminopeptidase as exemplified by its mammalian counterparts, with which it shares a similar substrate specificity. Furthermore, a comparative study on the regulation of apeh gene expression, revealed a significant but divergent alteration in the expression pattern of apeh-3Ss and apehSs (the gene encoding the previously identified APEHSs from S. solfataricus), which is induced in response to various stressful growth conditions. Hence, both APEH enzymes can be defined as stress-regulated proteins which play a complementary role in enabling the survival of S. solfataricus cells under different conditions. These results provide new structural and functional insights into S. solfataricus APEH, offering a possible explanation for the multiplicity of this enzyme in Archaea

One-year seasonal survey of the chlorophyll photodegradation process in the northwestern Mediterranean Sea

Particulate samples from the water column were collected monthly from depths of 5-150 m, between May 1996 and March 1997, in the northwestern Mediterranean Sea (Ligurian Sea) as part of the DYFAMED project within the French JGOFS program. These samples were analyzed by gas chromatography-electron impact mass spectrometry for their phytol and 3-methylidene-3,7,11-trimethylhexadecan-1,2-diol (phytyldiol) content. The corresponding Chlorophyll Phytyl side chain Photodegradation Index, molar ratio of phytyldiol to phytol, was calculated and the mean amount of chlorophyll photodegraded within the euphotic zone estimated. Seasonal differences in the chlorophyll photodegradation process appear in the one-year study. The chlorophyll appeared more photodegraded in the surface water (generally more than 40% photodegraded at 5-10m) than at the deep chlorophyll maximum (DCM) (40-50m) observed in the summer stratified waters (about 20% photodegraded). This difference was attributed to the healthy state of the phytoplankton community (coincidence with the highest primary production levels) and to the lower intensity of irradiance at the DCM level. On the other hand, the bulk of the detrital chlorophyll (chlorophyll associated with phytodetritus, phaeopigments) undergoes photodegradation before it sinks out of the photic zone. However, in January (winter mixed water) the pigments exported towards the sea floor were less photodegraded. This is thought to result from a shorter period of residence of the pigments in the photic zone due to vertical convection and grazing activity of macrozooplankton (salps), which are producers of rapid sinking fecal pellets. (C) 2002 Elsevier Science Ltd. All rights reserved

Engineered protein coatings to improve the osseointegration of dental and orthopaedic implants

Here we present the design of an engineered, elastin-like protein (ELP) that is chemically modified to enable stable coatings on the surfaces of titanium-based dental and orthopaedic implants by novel photocrosslinking and solution processing steps. The ELP includes an extended RGD sequence to confer bio-signaling and an elastin-like sequence for mechanical stability. ELP thin films were fabricated on cpTi and Ti6A14V surfaces using scalable spin and dip coating processes with photoactive covalent cross linking through a carbene insertion mechanism. The coatings withstood procedures mimicking dental screw and hip replacement stem implantations, a key metric for clinical translation. They promoted rapid adhesion of MG63 osteoblast-like cells, with over 80% adhesion after 24 h, compared to 38% adhesion on uncoated Ti6A14V. MG63 cells produced significantly more mineralization on ELP coatings compared to uncoated Ti6A14V. Human bone marrow mesenchymal stem cells (hMSCs) had an earlier increase in alkaline phosphatase activity, indicating more rapid osteogenic differentiation and mineral deposition on adhesive ELP coatings. Rat tibia and femur in vivo studies demonstrated that cell -adhesive ELP-coated implants increased bone-implant contact area and interfacial strength after one week. These results suggest that ELP coatings withstand surgical implantation and promote rapid osseointegration, enabling earlier implant loading and potentially preventing micromotion that leads to aseptic loosening and premature implant failure