Predicting adverse side effects of drugs

<p>Abstract</p> <p>Background</p> <p>Studies of toxicity and unintended side effects can lead to improved drug safety and efficacy. One promising form of study comes from molecular systems biology in the form of "systems pharmacology". Systems pharmacology combines data from clinical observation and molecular biology. This approach is new, however, and there are few examples of how it can practically predict adverse reactions (ADRs) from an experimental drug with acceptable accuracy.</p> <p>Results</p> <p>We have developed a new and practical computational framework to accurately predict ADRs of trial drugs. We combine clinical observation data with drug target data, protein-protein interaction (PPI) networks, and gene ontology (GO) annotations. We use cardiotoxicity, one of the major causes for drug withdrawals, as a case study to demonstrate the power of the framework. Our results show that an <it>in silico </it>model built on this framework can achieve a satisfactory cardiotoxicity ADR prediction performance (median AUC = 0.771, Accuracy = 0.675, Sensitivity = 0.632, and Specificity = 0.789). Our results also demonstrate the significance of incorporating prior knowledge, including gene networks and gene annotations, to improve future ADR assessments.</p> <p>Conclusions</p> <p>Biomolecular network and gene annotation information can significantly improve the predictive accuracy of ADR of drugs under development. The use of PPI networks can increase prediction specificity and the use of GO annotations can increase prediction sensitivity. Using cardiotoxicity as an example, we are able to further identify cardiotoxicity-related proteins among drug target expanding PPI networks. The systems pharmacology approach that we developed in this study can be generally applicable to all future developmental drug ADR assessments and predictions.</p

The Marketing Mix and Service Quality in Relation to Their Impacts on Customer Satisfaction: A Study of Fast Food Chains in Taiwan

The major objective of this dissertation is to explore the relationship between marketing mix/service quality and customer satisfaction in fast food chains in Taiwan. A mathematical relationship was sought to identify whether (a) marketing strategies developed from 4P (product, price, promotion and place) are related to customer satisfaction. (b) service quality developed from DINESERV (Stevens, Knutson, and Patton, 1995), the restaurant service quality measuring tool, is related to customer satisfaction, and (c) consumer satisfaction towards marketing and service of fast food chains differ by gender, age, education, occupation and income groups. The survey questionnaire included the main fast food industry determinants to customer satisfaction proposed by past research and the modified DINESERV instrument. A sample of one hundred and sixty four participants was used to collect data by visiting selected fast food restaurants. The results identified significant positive correlations between marketing mix/service quality and customer satisfaction. Results were inconclusive in the influence of demographics on the relationship between marketing mix/service quality and customer satisfaction. It appeared that customers among different groups of gender, age, education, occupation, and income only had significant differences on certain variables, such as food package design, food taste, food freshness, clean rest rooms, etc. Therefore, a conclusion was drawn that customers in Taiwan generally shared the evaluations and expectations towards the marketing mix and service quality of fast food chains

Effects of condensed tannins from Leucaena on methane reduction, rumen fermentation and populations of methaogens and protozoa in vitro

Different levels of purified condensed tannins (CT) extracted from Leucaena leucocephala hybrid-Rendang (LLR) were investigated for their effects on CH4 production, rumen fermentation parameters such as pH, dry matter (DM) degradability, N disappearance and volatile fatty acid (VFA) concentrations, as well as on populations of rumen methanogenic archaea and protozoa in vitro. Purified CT concentrations of 0 (control), 10, 15, 20, 25 and 30 mg, and 500 mg of oven dried guinea grass (Panicum maximum) with 40 ml of buffered rumen fluid were incubated for 24 h using an in vitro gas production procedure. Total gas (ml/g DM) decreased at a decreasing rate (linear P < 0.01; quadratic P < 0.05) with increased levels of CT inclusion. CH4 production (ml/g DM) decreased at a decreasing rate (linear P < 0.01; quadratic P < 0.01) with increasing levels of CT. Total VFA concentration (mmol/L) decreased at a decreasing rate (linear P < 0.01; quadratic P < 0.01) with increasing CT inclusions. In vitro DM degradation and N disappearance declined linearly (P < 0.01) with increasing levels of CT. Estimates of rumen methanogenic archaea and protozoa populations using microbiological methods and real-time PCR assay showed linear reductions in total methanogens (P < 0.01) and total protozoa (P < 0.01) with increasing levels of CT. Methanogens in the order Methanobacteriales also declined, but with quadratic and cubic aspects. Results suggest that CT from LLR at a relatively low level of 15 mg of CT/500 mg DM reduce CH4 production by 47%, with only 7% reduction in degradation of feed DM. However, higher CT inclusions, while further reducing CH4 emissions, have substantive negative effects on DM digestibility

Effects of natto extract on endothelial injury in a rat model

Vascular endothelial damage has been found to be associated with thrombus formation, which is considered to be a risk factor for cardiovascular disease. A diet of natto leads to a low prevalence of cardiovascular disease. The aim of the present study was to investigate the effects of natto extract on vascular endothelia damage with exposure to laser irradiation. Endothelial damage both in vitro and in vivo was induced by irradiation of rose bengal using a DPSS green laser. Cell viability was determined by MTS assay, and the intimal thickening was verified by a histological approach. The antioxidant content of natto extract was determined for the free radical scavenging activity. Endothelial cells were injured in the presence of rose bengal irradiated in a dose-dependent manner. Natto extract exhibits high levels of antioxidant activity compared with purified natto kinase. Apoptosis of laser-injured endothelial cells was significantly reduced in the presence of natto extract. Both the natto extract and natto kinase suppressed intimal thickening in rats with endothelial injury. The present findings suggest that natto extract suppresses vessel thickening as a synergic effect attributed to its antioxidant and anti-apoptosis properties

Differentiation of Foot-and-Mouth Disease-Infected pigs from Vaccinated Pigs Using Antibody-Detecting Sandwich ELISA

The presence of serum antibodies for nonstructural proteins of the foot-and-mouth disease virus (FMDV) can differentiate FMDV-infected animals from vaccinated animals. In this study, a sandwich ELISA was developed for rapid detection of the foot-and-mouth disease (FMD) antibodies; it was based on an Escherichia coli-expressed, highly conserved region of the 3ABC nonstructural protein of the FMDV O/TW/99 strain and a monoclonal antibody derived from the expressed protein. The diagnostic sensitivity of the assay was 98.4%, and the diagnostic specificity was 100% for naïve and vaccinated pigs; the detection ability of the assay was comparable those of the PrioCHECK and UBI kits. There was 97.5, 93.4 and 66.6% agreement between the results obtained from our ELISA and those obtained from the PrioCHECK, UBI and CHEKIT kits, respectively. The kappa statistics were 0.95, 0.87 and 0.37, respectively. Moreover, antibodies for nonstructural proteins of the serotypes A, C, Asia 1, SAT 1, SAT 2 and SAT 3 were also detected in bovine sera. Furthermore, the absence of cross-reactions generated by different antibody titers against the swine vesicular disease virus and vesicular stomatitis virus (VSV) was also highlighted in this assay's specificit

Audio-video Synchronization with Arbitrary, Non-periodic Video Sources

The latency between audio and video streams of a device is usually measured using stock test videos. Although the use of stock test videos eases analysis, the test video differs materially from real-world videos, which tend to be far more diverse in content and encoding schemes, resulting in laborious experimental setup and inaccurate synchronization. This disclosure describes techniques to measure the latency between the audio and video streams of a given device using arbitrary, real-world, audio-visual footage (test video). Characteristic video and audio frames and their differences in timestamps (characteristic durations) are identified within the test video. The test video is played by the device-under-test while being recorded by a high-precision video camera. Characteristic durations of the recorded footage are determined. The differences in characteristic durations between the test and the recorded videos are statistically analyzed to determine the AV asynchrony of the device-under-test

Effect of condensed tannins on bovine rumen protist diversity based on 18S rRNA gene sequences

Molecular diversity of protists from bovine rumen fluid incubated with condensed tannins of Leucaena leucocephala hybrid-Rendang at 20 mg/500 mg dry matter (treatment) or without condensed tannins (control) was investigated using 18S rRNA gene library. Clones from the control library were distributed within nine genera, but clones from the condensed tannin treatment clone library were related to only six genera. Diversity estimators such as abundance-based coverage estimation and Chao1 showed significant differences between the two libraries, although no differences were found based on Shannon–Weaver index and Libshuff