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Drug elimination interactions: analysis using a mathematical model.

A mathematical model was developed to analyze the elimination kinetics of drug interactions in the rat. The model is based on physiological blood flow rates and organ weights and includes Michaelis-Menten equations for enzymatic processes which are involved in the elimination of the drug; competitive inhibition interactions are computed for shared pathways. Using data from the single drugs, the model can simulate the results of experiments of the acute warfarin-BSP interactions in rats.

Animals↗

A DeFries and Fulker regression model for genetic nonadditivity.

Parameter estimates from the DeFries and Fulker [(DF) Behav. Genet. 15:462-473, 1985] regression method can be greater than unity or less than zero. This occurs when the monozygotic correlation is greater than twice the dizygotic correlation. Sensible values can be obtained in these cases by fitting a constrained DF model that estimates genetic and nonshared environmental variance components only. In this article I demonstrate that the original Df model yields positively biased heritability estimates and negatively biased estimates of shared environmentality when data are significantly influenced by genetic nonadditivity. The magnitude of the bias is algebraically expressed. I then describe a simple regression equation that provides unbiased estimates of the standardized additive and dominance genetic variance components. Results of a study of 6 million twin pairs from the Monte Carlo Twin Registry demonstrate that the DF additive and dominance genetic parameter estimates are virtually identical to those obtained by maximum-likelihood procedures. Finally, I derive the expectations for the constrained DF model and show that the genetic parameter estimates from this model are negatively biased estimates of broad-sense heritability.

Genes, Dominant↗

Defense Simulation Internet: next generation information highway.

The Department of Defense has been engaged in the Defense Modeling and Simulation Initiative (DMSI) to provide advanced distributed simulation warfighters in geographically distributed localities. Lessons learned from the Defense Simulation Internet (DSI) concerning architecture, standards, protocols, interoperability, information sharing, and distributed data bases are equally applicable to telemedicine. Much of the vision and objectives of the DMSI are easily translated into the vision for world wide telemedicine.

Computer Communication Networks↗

Application of VPN technique in the construction of public health information system.

Data communication and sharing of five level network of Public Health Information System, i.e. nation, province, district (city), county, and town, as far as to the countryside level were described, and how to apply the three solutions, i.e. Access VPN, Intranet VPN, and Extranet VPN of VPN technique to achieve the appropriation of the public network was also presented.

China↗

On-going on-farm microevolutionary processes in neighbouring cowpea landraces revealed by molecular markers.

A knowledge of existing levels of diversity is fundamental for planning in situ (on-farm) conservation activities. Three neighbouring cowpea landraces (LRs) currently cultivated in central Italy were studied by amplified fragment length polymorphism (AFLP) and selectively amplified microsatellite polymorphic locus (SAMPL) markers to determine the distribution of genetic variation within and among them. The three LRs studied, although relatively similar, are highly different from one another as shown by the significance of the Fisher exact test for the genic differentiation and the absence of genotype sharing among them. Data obtained from the AFLP and SAMPL markers separately and their combined data revealed a relatively high level of diversity still present within the LRs. The more efficient SAMPL technique was better at discriminating between the plants than the AFLP markers. The three LRs studied appear to be structured as a metapopulation in which a substantial differentiation is maintained at the subpopulation level. A complex interaction of factors (drift, LR isolation, farmer selection, migration within LRs) explains the observed pattern of diversity. The results suggest that the best strategy for maintaining diversity in the area is to preserve each of the LRs observed on the farms from which it came.

Breeding↗

Improving the performance of Drug and Therapeutics Committees in hospitals--a quasi-experimental study in Laos.

BACKGROUND AND OBJECTIVES: Drug and Therapeutics Committees (DTCs), which are essential for ensuring the rational use of drugs (RUD) in hospitals, have recently been established in Laos. Sub-optimal performance had been reported. The aims of this study were to determine those factors in the working environment that relate to DTC performance in Lao hospitals and evaluate whether DTC performance could be improved through an educational intervention utilizing auditing and feedback targeted towards DTC members. METHODS: This was a quasi-experimental (before and after) study. Two central and seven provincial hospitals and the DTC members from these hospitals participated in the study. Performance of the DTCs was assessed by means of specifically developed indicators on structure and process combined with indicators for RUD and adherence to Standard Treatment Guidelines (STG). Data were collected for a 3-month period at baseline and for three consecutive periods thereafter. The results of the first three data collections were shared and discussed with the DTC members during feedback sessions. The DTC members were also interviewed in order to identify factors they thought may have an impact on DTC performance. RESULTS: Following the intervention, there was a significant improvement in the overall score for DTC performance (p<0.001) and, in particular, in general activity and feedback and drug information to staff. The STG scores also improved (p<0.01). Interviews indicated that one negative factor was the experience of the DTC members being overloaded with other work, resulting in DTC meetings being held irregularly and drawing poor attendance. CONCLUSION: Continuous self-monitoring of performance by means of indicators, followed by feedback discussions, is suggested the means of improving the work of the DTC.

Communicable Diseases↗

Variability, recombination, and mosaic evolution of the barley BARE-1 retrotransposon.

BARE-1 is a highly abundant, copia-like, LTR (long terminal repeat) retrotransposon in the genus Hordeum. The LTRs provide the promoter, terminator, and polyadenylation signals necessary for the replicational life cycle of retrotransposons. We have examined the variability and evolution of BARE-1-like elements, focusing on the LTRs. Three groups were found, corresponding to each of the Hordeum genome types analyzed, which predate the divergence of these types. The most variable LTR regions are tandem repeats near the 3' end and the promoter. In barley (H. vulgare L.), two main classes of LTR promoters were defined, corresponding to BARE-1 and to a new class we call BARE-2. These can be considered as families within the group I BARE elements. Although less abundant in cultivated barley than is BARE-1, BARE-2 is transcriptionally active in leaves and calli. A sequenced BARE-2 has more than 99% similar LTRs and perfect terminal direct repeats (TDRs), indicating it is a recent insertion, but the coding region, especially gag, is disrupted by frameshifts and stop codons. BARE-2 appears to be a chimeric element resulting from retrotransposon recombination by strand switching during replication, with LTRs and 5'UTR more similar to BARE-1 and the rest more similar to Wis-2. We provide evidence as well for another form of recombination, where LTR-LTR recombination has generated tandem multimeric BARE-1 elements in which internal coding domains are interspersed with shared LTRs. The data indicate that recombination contributes to the complexity and plasticity of retroelement evolution in plant genomes.

Base Sequence↗

Navigation and image-guided HBP surgery: a review and preview.

Image-guided surgery and navigation have resulted from convergent developments in radiology, teletransmission, and computer science. Patient selection and preoperative planning in hepatobiliary-pancreatic (HBP) surgery rely on preoperative imaging. The operative procedure is finally led by the fusion of additional information gained by the palpating hand and intraoperative ultrasound. Despite advances in reducing morbidity and mortality, decisions are often hardly quantifiable and are restricted to super-specialists in HBP surgery. New developments in computed tomography (CT) and magnetic resonance imaging (MRI) technology have led to the possibility of the volumetric prediction of liver resections. These data can be shared via telemedicine and used for simulation and training. Three-dimensional (3D) reconstructions have led to a better topologic understanding of tumor-vascular tree relations in the individual patient. With the increasing use of ablative procedures and laparoscopy, intraoperative imaging and navigation will hold increasing significance for the HBP surgeon. Flat screen monitors adjacent to the surgical field present computer-generated 3D virtual liver resection proposals which can be transferred into the real liver. The main obstacles in HBP navigation are the flexibility and mobility of the target organ. Intrahepatic and surface markers seem to be mandatory for computer-navigated surgery. The first feasibility studies are promising.

Bile Ducts↗

Stereotactic statistical imaging analysis of the brain using the easy Z-score imaging system for sharing a normal database.

Statistical brain imaging analysis has good objectivity and reproducibility. In Japan, statistical parametric mapping (SPM) and three-dimensional stereotactic surface projections (3D-SSP) are used nationwide as statistical imaging analysis with standard brain coordinates. They often help to interpret brain single photon emission computed tomography (SPECT) images by avoiding possible pitfalls (e.g., effects of aging, atrophy) with which clinicians are unfamiliar. However, this type of analysis presents a problem: statistical processing requires many normal subject images. The easy Z-score imaging system (eZIS) is one of the statistical analysis methods that uses SPM processing in normalization and smoothing, and it has the function of image conversion leading to statistical analysis without a control database. Therefore, statistical analysis can be used in clinical practice by sharing a prepared normal database. By unifying the image quality by processing a shared database, this program has great potential for sharing patient imaging data in many hospitals. It is expected that the eZIS will help perform detailed analysis in many functional diseases in collaborative studies. This article describes the interpretation of brain SPECT images and suggests the usefulness and potential of eZIS.

Aging↗

Task allocation and the balancing of task demands in the multi-man-machine system--some case studies.

Various forms of team organisation are described. These are based on the concepts of vertical and horizontal structure. Task factors of complexity and organisation are introduced and their relationships with various forms of multiman-machine system are discussed. Experimental work is briefly described and then two case study analyses of operational systems are presented. The first, an examination of airport air traffic control, illustrates how a multiman system can be reorganised to yield a more balanced distribution of task demands. The second, a study of an ambulance control room, shows the implications for team organisation of a shared computer data-base. These case studies demonstrate that the concepts developed in the laboratory context can be applied to operational multiman-machine systems.

Journal Article↗

OASYS: a computerized auditing system for orthopaedic surgery.

Medical auditing based on individual diagnoses or specific therapies is well established. Auditing of all medical activity has an expanding role in quality assurance and research. In an attempt to overcome the limitations of existing auditing systems, a fundamentally different, flexible, high quality and easily accessible orthopaedic auditing system has been developed. This records a description of each component of patients' orthopaedic diagnoses, records treatment and complications, produces discharge letters and surgical log books and allows flexible and comprehensive audits. It has been in use in an orthopaedic service since January 1990 and has been successful in identifying problems and monitoring the effectiveness of changes. It is anticipated that the system will become more widely used and provide the basis for a 'user group' which will share the accumulated data and further development costs.

Adult↗

Human movement analysis using stereophotogrammetry. Part 1: theoretical background.

This paper sets the stage for a series of reviews dealing with the problems associated with the reconstruction and analysis of in vivo skeletal system kinematics using optoelectronic stereophotogrammetric data. Instantaneous bone position and orientation and joint kinematic variable estimations are addressed in the framework of rigid body mechanics. The conceptual background to these exercises is discussed. Focus is placed on the experimental and analytical problem of merging the information relative to movement and that relative to the morphology of the anatomical body parts of interest. The various global and local frames that may be used in this context are defined. Common anatomical and mathematical conventions that can be used to describe joint kinematics are illustrated in a comparative fashion. The authors believe that an effort to systematize the different theoretical and experimental approaches to the problems involved and related nomenclatures, as currently reported in the literature, is needed to facilitate data and knowledge sharing, and to provide renewed momentum for the advancement of human movement analysis.

Biomechanical Phenomena↗

TFinder: A Python Web Tool for Predicting Transcription Factor Binding Sites.

Transcription is a key cell process that consists of synthesizing several copies of RNA from a gene DNA sequence. This process is highly regulated and closely linked to the ability of transcription factors to bind specifically to DNA. TFinder is an easy-to-use Python web portal allowing the identification of Individual Motifs (IM) such as Transcription Factor Binding Sites (TFBS). Using the NCBI API, TFinder extracts either promoter or gene terminal regulatory regions, through a simple query of NCBI gene name or ID. It enables simultaneous analysis across five different species for an unlimited number of genes. TFinder searches for Individual Motifs in different formats, including IUPAC codes and JASPAR entries. Moreover, TFinder also allows de novo generations of a Position Weight Matrix (PWM) and the use of already established PWM. Finally, the data are provided in a tabular and a graph format showing the relevance and the P-value of the Individual Motifs found as well as their location relative to the Transcription Start Site (TSS) or the terminal region of the gene. The results are then sent by email to users facilitating the subsequent data analysis and sharing. TFinder is written in Python and freely available on GitHub under the MIT license: https://github.com/Jumitti/TFinder. It can be accessed as a web application implemented in Streamlit at https://tfinder-ipmc.streamlit.app. Resources are available on Streamlit "Resources" tab. TFINDER strength is that it relies on an all-in-one intuitive tool allowing users inexperienced with bioinformatics tools to retrieve gene regulatory regions sequences in multiple species and to search for individual motifs in a huge number of genes.

Transcription Factors↗

Genome-scale evolution and phylodynamics of swine influenza A viruses in China: a genomic epidemiology study.

BACKGROUND: Pigs are recognised as crucial intermediate hosts for the emergence of influenza viruses of pandemic potential. As the largest pork-producing nation, China hosts a complex ecosystem of swine influenza viruses (SIVs). We aimed to investigate the evolutionary processes, spatiotemporal dynamics, and biological characteristics of SIVs in China. METHODS: From Jan 15, 2016, to Dec 22, 2020, we collected nasal swabs from pigs at eight abattoirs and 16 swine farms in the Guangdong, Henan, and Shandong provinces of China, as part of SIV surveillance. SIVs were detected with RT-PCR. Positive samples underwent viral isolation and genome sequencing. We analysed evolution and spatiotemporal dynamics using the whole genomes of isolated SIVs, as well as genome sequences of SIV isolates from human infections worldwide retrieved from the Global Initiative on Sharing All Influenza Data and GenBank Flu databases up to April 28, 2024. Viral sequences without a sample collection area or date were excluded from the analysis. Viral receptor-binding properties and in-vitro replication of strains isolated in this study were evaluated with a solid-phase binding assay and various cell lines, including Madin-Darby canine kidney cells, porcine alveolar macrophages, primary porcine trachea epithelial cells, human bronchial epithelioid, and human lung adenocarcinoma epithelial (A549) cells. Viral replication and transmission studies were conducted in 33 guinea pigs and 13 pigs. Additionally, we collected serum samples from pig farm workers and members of the general public recruited by the Third Affiliated Hospital of Sun Yat-sen University between Feb 28 and May 11, 2023, to detect specific antibodies against Eurasian avian-like A(H1) and human-like A(H3N2) SIVs using the haemagglutination inhibition assay. FINDINGS: 23 (1&#xb7;3%) of 1818 nasal swabs collected in abattoirs had SIVs; 22 (0&#xb7;9%) of 2375 swabs from swine farms had SIVs. Further viral isolation yielded 39 strains of SIV. We identified 534 A(H1N1), 69 A(H1N2), and 92 A(H3N2) SIVs, representing 20 genotypes within the Eurasian avian-like lineage, 14 within the classical swine A(H1) lineage, and 16 within the human-like A(H3N2) lineage. The introduction of the A(H1N1)pdm/09 virus significantly influenced the internal gene pool of SIVs, enhancing genotypic diversity in China. Notably, the Eurasian avian-like A(H1), classical swine A(H1), and human-like A(H3N2) lineages showed human-mediated spread over long distances between provinces, with the Eurasian avian-like A(H1) lineage showing the most prevalent spread pathways. Eurasian avian-like A(H1) SIVs showed a preference for binding to sialic acid &#x3b1;-2,6 glycan receptors, predominantly found in humans, resulting in an increased production of progeny viruses in human airway epithelial cells, as well as effective transmission and infectivity among guinea pigs and pigs. Among 54 eligible serum samples collected from pig farm workers (24 from slaughterhouses and 30 from swine farms), 23 (43%) were seropositive for Eurasian avian-like A(H1) SIVs and 46 (85%) for human-like A(H3N2) SIVs. Among 100 eligible samples from members of the general public, 14 (14%) were seropositive for Eurasian avian-like A(H1) SIVs and 85 (85%) for human-like A(H3N2) SIVs. INTERPRETATION: This study elucidates the evolutionary processes and spatiotemporal patterns of SIVs, highlighting potential risks to public health. These findings are crucial for informing public health interventions that aim to prevent future SIV epidemics in China and other countries worldwide. FUNDING: Scientific Innovation Strategy-Construction of High-Level Academy of Agriculture Science-Distinguished Scholar (R2020PY-JC001).

Animals↗

Improved posthypoxic recovery in vitro on treatment with drugs used for secondary stroke prevention.

Besides aspirin several new drugs for inhibition of platelet aggregation and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibition are used in secondary stroke prevention. Pharmacology and clinical effects, however, are not fully explained by current understanding of underlying mechanisms. Population spike amplitude (PSAP), an established marker of slice integrity, was measured during hypoxia and recovery thereof in hippocampal slices from control CD1 mice (25-35 g) and animals pretreated in vivo with a single i.p. injection of clopidogrel, ticlopidine, or atorvastatine at different time intervals and dosages. Posthypoxic recovery of PSAP was 20 +/- 35% in control CD1 mice. Upon pretreatment with clopidogrel (1-24 h, 0.5-2 mg/kg body weight) an increase up to 81 +/- 20% (p < 0.01 to control) was observed at 1h interval and 1mg/kg. Application of ticlopidine (1-24 h, 1-4 mg/kg body weight) resulted in an improvement of posthypoxic recovery to 61 +/- 41% (p < 0.05 to control) while administration of atorvastatine (1-24 h, 1-4 mg/kg body weight) caused an increase up to 87 +/- 31% (p < 0.01 to control) at 1h interval and 2 mg/kg. On application of these substances in vitro the NADH autofluorescence spectrum in hippocampal slices is blue-shifted suggesting an alteration of oxidative metabolism. The present data demonstrate a shared neuroprotective effect of agents known to inhibit platelets (acetylsalicylic acid, clopidogrel, and ticlopidine) and HMG-CoA reductase (atorvastatine). The time course of this neuroprotective action in the current experimental study (onset within an hour, duration of several hours in contrast to several days) resembles clinical practice in dosing these substances. We hypothesize that an increase of hypoxic tolerance resulting from mild mitochondrial inhibition by these substances is a principal constituent of the effectiveness of these drugs.

Action Potentials↗

Gene expression profiling: methodological challenges, results, and prospects for addiction research.

This review describes the current methods used to profile gene expression. These methods include microarrays, spotted arrays, serial analysis of gene expression (SAGE), and massive parallel signature sequencing (MPSS). Methodological and statistical problems in interpreting microarray and spotted array experiments are also discussed. Methods and formats such as minimum information about microarray experiments (MIAME) needed to share gene expression data are described. The last part of the review provides an overview of the application of gene-expression profiling technology to substance abuse research and discusses future directions.

Animals↗

Endoscopic scoring of late rectal mucosal damage after conformal radiotherapy for prostatic carcinoma.

PURPOSE: To describe rectal mucosal damage in an endoscopic study after conformal radiotherapy of prostate cancer and to correlate this with clinical outcome. MATERIALS AND METHODS: Flexible rectosigmoidoscopy was performed on 44 patients who voluntarily accepted the examination. The median follow-up was 29 months (20-41 months) after 3-D-planned conformal radiotherapy of prostate cancer (66 Gy at the ICRU Reference point, 2 Gy per fraction). To enable a systematic topographic description of endoscopic findings the rectum was divided into four sections. Additionally we differentiated between anterior, posterior, right and left lateral rectal wall. Due to the lack of an existing valid graduation system for radiation induced proctitis, we introduced a six-scaled rectoscopy score for describing and reporting endoscopic findings based on the standardization of the endoscopic terminology published by the ESGE (European Society for Gastrointestinal Endoscopy). Endoscopic findings were compared to the EORTC/RTOG morbidity score. In addition, since 3-D dose distribution of organs at risks was available, a correlation could be made between the location of the rectal lesions and the absorbed dose at that level. RESULTS: In general, endoscopic findings increased from the proximal rectum to the anorectal transition, as well as from the posterior to the anterior rectum wall. Telangiectasia grade 1 and 2 were observed at the whole circumference, only telangiectasia grade 3 were limited to the high dose region at the anterior rectum wall. Similar results were found for congested mucosa (reddening and edematous mucosa). Correlation with symptoms, 7/9 patients who suffered from intermittent rectal bleeding (EORTC/RTOG grade 2) had multiple telangiectasia grade 2-3 and/or congested mucosa grade 3 and microulcerations. However, the same extent of mucosal damage (rectoscopy score 2-3) was found in seven out of 35 patients who have never developed a period of macroscopic rectal bleeding. CONCLUSION: Rectoscopy offers the possibility of detecting signs of tissue dysfunction below the level of subjective symptoms. Systematic analytic examinations such as rectoscopy, in addition to clinical examinations, as already foreseen in the LENT-SOMA-score, will be necessary due to the fact that even telangiectatic lesions have been observed for asymptomatic patients. For the opportunity of sharing and comparing data collected from endoscopy after radiotherapy a graduation system as proposed based on a standardisation of the endoscopic terminology will be necessary.

Aged↗