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At least 1,243 records · Page 69Linked to original sources
PubMed1997

A comparison of outcome from febrile neutropenic episodes in children compared with adults: results from four EORTC studies. International Antimicrobial Therapy Cooperative Group (IATCG) of the European Organization for Research and Treatment of Cancer (EORTC).

The object of this study was to determine whether there were any differences between the 'typical' child with fever and neutropenia and their adult counterpart with regard to infection type and outcome, by analysis of 3080 patients, including 759 children < 18 years of age and 2321 adults. These represented patients randomized in previous trials, between 1986 and 1994, which compared empirical antibiotic regimens for fever in neutropenic patients. There were fewer childhood acute myeloid leukaemia patients than adults but more acute lymphoblastic leukaemia cases and more with solid tumours undergoing intensive myelosuppressive therapy. The children were less likely to be undergoing first induction therapy but the relative incidence of patients receiving relapse schedules or maintenance therapies were not significantly different in the two age groups. Children less frequently had a defined site of infection than adults and where they had a defined site there were more upper respiratory tract but fewer lung infections. There was a similar low incidence of shock at presentation in the two groups but the children's median neutrophil count was lower, and their median duration of granulocytopenia before the trial was shorter. The incidence of bacteraemia was similar, but clinically documented infection was less frequent and fever of unknown origin consequently more common in children. Children developed more streptococcal bacteraemias and fewer staphylococcal bacteraemias than adults (P=0.003) but the relative incidence of various gram-negative species was similar (P=0.57). In general, the children had a better overall success rate and lower mortality than adults. Death from infection was only 1% in children versus 4% in adults (P=0.001), and time to defervescence was shorter in children. In the younger age group, univariate logistic regression models showed high temperature, prolonged neutropenia before the trial and shock as prognostic indicators for the presence of bacteraemia. Solid tumour patients were significantly less likely to have a bacteraemia. Multivariate analysis confirmed the independent prognostic value of these indicators. Using the logistic equation of the selected model, the overall discriminant ability was poor. However, it was possible to identify a small subgroup without shock or high fever and with a short prior duration of neutropenia which carries a particularly low risk of bacteraemia, who could be considered for early discharge, monotherapy and shortened courses of antibodies, in prospective trials.

Acute Disease↗
PubMedDate not supplied

Non-Th2 regulatory T-cell control of Th1 autoimmunity.

The Th1/Th2 concept brought an attractive explanation of the active self tolerance which appears to control the onset of pathogenic autoimmunity. New data coming from various independent horizons indicate that self immunoregulation could also depend to a large extent on non-Th2 cells. Original data derived from the day-3-thymectomy model, selective T-cell lymphocytopenia and nonobese diabetic mice are discussed in an effort to analyze similarities and differences in phenotype (CD25, CD62L and CD45RB) and cytokine pattern (notably interleukin (IL)-4, IL-10 and transforming growth factor (TGF)beta) of regulatory cells involved in these models. The relationship of these cells with Th3, Tr1 and natural killer (NK) T cells are also discussed. The hypothesis is proposed that CD25 CD62L T cells mediate the physiologic regulation of self regulation whereas Th2 and Th3 cells are essentially induced following sensitization against autoantigens.

Antigens↗
PubMed2003

Binomial regression with misclassification.

Motivated by a study of human papillomavirus infection in women, we present a Bayesian binomial regression analysis in which the response is subject to an unconstrained misclassification process. Our iterative approach provides inferences for the parameters that describe the relationships of the covariates with the response and for the misclassification probabilities. Furthermore, our approach applies to any meaningful generalized linear model, making model selection possible. Finally, it is straightforward to extend it to multinomial settings.

Bayes Theorem↗
PubMed2005

Bioactivation of an anorganic bone matrix by P-15 peptide for the promotion of early bone formation.

This animal experiment compared the regenerative processes within defined bony defects of the porcine skull after delivery of routinely utilized bone graft materials: anorganic bone matrix (ABM) and an identical ABM carrying the cell binding peptide P-15. Particulated autogenous bone was used as a control group. The chosen porcine model guaranteed the transferability of the obtained results to clinical practice. A total observation period of 6 months was defined. The bone samples were examined microradiographically and histologically at 8 specific times. Sufficient osseointegration and osseoconduction could be demonstrated for both anorganic bone minerals. However, in the selected model significantly higher mineralization rates (p = 0.0286) were found in the microradiographic image at 12 weeks after application of the bioactive form. The histological examination confirmed this accelerating effect on bone formation starting at day 3. At the end of the study after 6 months, the mineralization values had equalized in both study groups. For the first time, the material was demonstrated to be suitable as a bone substitute material for the treatment of larger bony defects in a large animal model. The P-15 sequence accelerated the process of bone formation on the surface of the anorganic bone matrix as early as 3 days but was not traced over the whole term of the study.

Animals↗
PubMed2002

Model choice in gene mapping: what and why.

The choice of an appropriate genetic model describing the genetic architecture underlying a character of interest is an inherent part of the gene mapping studies of human and other living organisms. The genetic model specifies the statistical parameters for the number of genes, their positions, and the types and magnitudes of their contributions to the phenotype. There are many considerations involved in model formulation (choice) ranging from the assumptions concerning the data, the role of environment, and the number of oligogenes (or quantitative trait loci) influencing the trait behavior. There are several model selection procedures and criteria under specific sampling designs in the genetic literature. These approaches often have their origin in computer science or in general statistical theory. Our aim here is to give an overview of the most popular statistical criteria and to present principles behind them. Bayesian model averaging is suggested as a robust alternative for such methods.

Animals↗
PubMed2003

3D-Jury: a simple approach to improve protein structure predictions.

MOTIVATION: Consensus structure prediction methods (meta-predictors) have higher accuracy than individual structure prediction algorithms (their components). The goal for the development of the 3D-Jury system is to create a simple but powerful procedure for generating meta-predictions using variable sets of models obtained from diverse sources. The resulting protocol should help to improve the quality of structural annotations of novel proteins. RESULTS: The 3D-Jury system generates meta-predictions from sets of models created using variable methods. It is not necessary to know prior characteristics of the methods. The system is able to utilize immediately new components (additional prediction providers). The accuracy of the system is comparable with other well-tuned prediction servers. The algorithm resembles methods of selecting models generated using ab initio folding simulations. It is simple and offers a portable solution to improve the accuracy of other protein structure prediction protocols. AVAILABILITY: The 3D-Jury system is available via the Structure Prediction Meta Server (http://BioInfo.PL/Meta/) to the academic community. SUPPLEMENTARY INFORMATION: 3D-Jury is coupled to the continuous online server evaluation program, LiveBench (http://BioInfo.PL/LiveBench/)

Algorithms↗
PubMed2004

Mechanisms of nonsteroidal anti-inflammatory drug-induced gastrointestinal injury and repair: a window of opportunity for cyclooxygenase-inhibiting nitric oxide donors.

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause damage in the upper gastrointestinal (GI) tract by impairing the ability of the mucosa to resist and respond to injury. Many of these effects of NSAIDs can be attributed to their ability to suppress mucosal prostaglandin synthesis. Selective inhibitors of cyclooxygenase (COX)-2 are less likely to disrupt mucosal defence and do not interfere with platelet aggregation. Thus, their use is associated with a reduced incidence of serious GI adverse events; however, a significant risk of such events still persists. At least in animal models, selective COX-2 inhibitors interfere with ulcer healing to the same extent as conventional NSAIDs. In contrast, COX-inhibiting nitric oxide donors (CINODs) produce anti-inflammatory and analgesic effects comparable or superior to those of NSAIDs, but with greatly reduced GI toxicity. Unlike NSAIDs and selective COX-2 inhibitors, CINODs do not interfere with ulcer healing. Moreover, because CINODs suppress the activity of both COX-1 and COX-2, they do not share with selective COX-2 inhibitors the lack of cardioprotection afforded by significant suppression of platelet aggregation. Because of their safety profile, CINODs may be particularly useful for long term prevention applications, such as for colon cancer, cardiovascular disease and Alzheimer's disease.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

The influence of cholesterol 3-sulphate on phase behaviour and hydrocarbon order in model membrane systems.

Cholesterol 3-sulphate (CS) is a component of the intercellular lipid found in the uppermost layer of human epidermis (the 'stratum corneum') and is thought to play an important role in tissue cohesion. In this investigation we have compared the influence of cholesterol (CH) and CS on the gel-to-liquid crystalline phase behaviour, the polymorphic phase behaviour, and the hydrocarbon order profile in selected model membranes. It is shown that in sphingomyelin (SPM) systems, the presence of equimolar amounts of either CH or CS eliminates the gel-to-liquid crystalline transition as detected by calorimetry. Similarly, in 1-palmitoyl,2-oleoyl-phosphatidylethanolamine (POPE) dispersions containing a perdeuterated palmitoyl chain (POPE-d31), it is shown that both CH and CS exert an ordering effect as determined by 2H-NMR techniques, however, CS is less potent at temperatures both above and below that of the main transition for the native phospholipid. Alternatively, in mixed systems containing dioleoylphosphatidylethanolamine (DOPE) and SPM (DOPE/SPM, 6:1 mol/mol) CH promotes thermotropic L alpha-->HII phase transitions, whereas CS stabilizes the bilayer organization. These bilayer stabilization effects can be diminished by addition of Ca2+. These effects are consistent with a larger area per molecule of CS as compared to CH, presumably related to the presence of the negatively charged sulphate moiety of CS.

Cell Membrane↗
PubMed1999

The evolutionary ecology of dominance-recessivity.

An "adaptive dynamics" modelling approach to the evolution of dominance-recessivity is presented. In this approach, fitness derives from an explicit ecological scenario, and both evolutionary attractivity and invasibility of resident populations are examined. The ecology consists of a within-individual part representing a locus with regulated activity and a between-individual part that is a two-patch soft selection model. Evolutionary freedom is allowed at a single locus. The evolutionary analysis considers directed random walks on trait space, generated by repeated invasions of mutants. The phenotype of an individual is determined by allelic parameters. Mutations can have two effects: they either affect the affinity of the promoter sequence for transcription factors, or they affect the gene product. The dominance interaction between alleles derives from their promoter affinities. Additive genetics is evolutionarily unstable when selection and evolution maintain two alleles in the population. In such a situation, dominance interactions can become stationary and close to additive genetics or they continue to evolve at a very slow pace towards dominance-recessivity. The probability that a specific dominance interaction will evolve depends on the relative mutation rate of promoter compared to gene product and the distribution of mutational effect sizes. Either allele in the dimorphism can become dominant, and dominance-recessivity is always most likely to evolve. Evolution then approaches a population state where every phenotype has maximum viability in one of the two patches. When the within-individual part is replaced by a housekeeping locus that codes for a metabolic enzyme, evolution favours a population of two alleles under the same conditions as for a regulated locus. In the case of a housekeeping gene, however, the evolutionary dynamical system approaches a population state where the heterozygote and only one homozygote phenotype are equivalent to the optimum phenotypes in the two patches.

Alleles↗
PubMed2006

A new approach to modeling covariate effects and individualization in population pharmacokinetics-pharmacodynamics.

By combining Laplace's approximation and Monte Carlo methods to evaluate multiple integrals, this paper develops a new approach to estimation in nonlinear mixed effects models that are widely used in population pharmacokinetics and pharmacodynamics. Estimation here involves not only estimating the model parameters from Phase I and II studies but also using the fitted model to estimate the concentration versus time curve or the drug effects of a subject who has covariate information but sparse measurements. Because of its computational tractability, the proposed approach can model the covariate effects nonparametrically by using (i) regression splines or neural networks as basis functions and (ii) AIC or BIC for model selection. Its computational and statistical advantages are illustrated in simulation studies and in Phase I trials.

Adult↗
PubMedDate not supplied

An accelerated procedure for recursive feature ranking on microarray data.

We describe a new wrapper algorithm for fast feature ranking in classification problems. The Entropy-based Recursive Feature Elimination (E-RFE) method eliminates chunks of uninteresting features according to the entropy of the weights distribution of a SVM classifier. With specific regard to DNA microarray datasets, the method is designed to support computationally intensive model selection in classification problems in which the number of features is much larger than the number of samples. We test E-RFE on synthetic and real data sets, comparing it with other SVM-based methods. The speed-up obtained with E-RFE supports predictive modeling on high dimensional microarray data.

Oligonucleotide Array Sequence Analysis↗
PubMed2003

Mapping multiple genetic loci associated with Ceratomyxa shasta resistance in Oncorhynchus mykiss.

Ceratomyxa shasta is enzootic to some rivers of the Pacific Northwest and California, and has caused extensive mortalities of salmonids, the only known host of the actinosporean stage of the pathogen. Mortalities from C. shasta are induced by severe inflammation and necrosis of the intestinal tract, and no therapeutants have been discovered for the treatment of ceratomyxosis. Inheritance studies by previous investigators suggested that C. shasta resistance is genetically controlled, but none have revealed the number and locations of gene regions associated with resistance. Here, we characterized differences in resistance among clonal lines, and used line crosses between clonal lines with resistance differences for a genetic analysis of C. shasta resistance in Oncorhynchus mykiss, following a short term in situ exposure to the pathogen. We found that Oregon State University (OSU) x Arlee (ARL) clonal hybrids were highly susceptible, while OSU x Clearwater (CW) hybrids were highly resistant to C. shasta. Doubled haploids, produced by androgenesis from an F1 hybrid between the OSU and CW lines, were evaluated for the co-segregation of molecular markers and resistance phenotype. Amplified fragment length polymorphic (AFLP) markers, used to construct a genetic linkage map in this cross, were tested for associations with resistance expressed as absolute survival (binary trait) and days to death (survival analysis). Segregation of the resistance phenotype suggested that the resistance was inherited as a single Mendelian locus, but the binary trait failed to map to a single genomic location. Markers identified in single-marker analyses were used in multiple-regression model selection, within both the linear regression and Cox proportional-hazards survival analysis frameworks, to determine the number and potential location of loci simultaneously contributing to variation in the survival phenotypes of doubled-haploid progeny. We found multiple genomic loci associated with C. shasta resistance through these models, confirming studies by previous investigators that suggested C. shasta resistance is polygenic.

Animals↗
PubMed2006

An innovative application of Bayesian disease mapping methods to patient safety research: a Canadian adverse medical event study.

Recently developed disease mapping and ecological regression methods have become important techniques in studies of disease epidemiology and in health services research. This increase in importance is partially a result of the development of Bayesian statistical methodologies that make it possible to study associations between health problems and risk factors at an aggregate (i.e. areal) level while taking into account such matters as unmeasured confounding and spatial relationships. In this paper we present a demonstration of the joint use of empirical Bayes (EB) and full Bayesian inferential techniques in a small area study of adverse medical events (also known as 'iatrogenic injury') in British Columbia, Canada. In particular, we illustrate a unified Bayesian hierarchical spatial modelling framework that enables simultaneous examinations of potential associations between adverse medical event occurrence and regional characteristics, age effects, residual variation and spatial autocorrelation. We propose an analytic strategy for complementary use of EB and FB inferential techniques for risk assessment and model selection, presenting an EB-FB combined approach that draws on the strengths of each method while minimizing inherent weaknesses. The work was motivated by the need to explore relatively efficient ways to analyse regional variations of health services outcomes and resource utilization when a considerable amount of statistical modelling and inference are required.

Adolescent↗
PubMed2003

Synthesis and biological evaluation of 2,4-diamino-6-(arylaminomethyl)pyrido[2,3-d]pyrimidines as inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase and as antiopportunistic infection and antitumor agents.

A series of 2,4-diamino-6-(arylaminomethyl)pyrido[2,3-d]pyrimidines were synthesized and evaluated as inhibitors of Pneumocystis carinii (pc), Toxoplasma gondii (tg), and rat liver (rl) dihydrofolate reductase (DHFR) and as inhibitors of the growth of tumor cell lines in culture. Compounds 4-15 were designed as part of a continuing effort to examine the effects of substitutions at the 5-position, in the two-atom bridge, and in the side chain phenyl ring on structure-activity/selectivity relationships of 2,4-diaminopyrido[2,3-d]pyrimidines against a variety of DHFRs. Reductive amination of the common intermediate 2,4-diaminopyrido[2,3-d]pyrimidine-6-carbonitrile 16 with the appropriate anilines afforded the target compounds 4-12. Nucleophilic substitution or reductive methylation afforded the N10-methyl target compounds 13-15. As predicted, compounds 4-15 were, in general, less potent against all three DHFRs compared to the corresponding 2,4-diamino-5-methyl analogues previously reported; however, the greater decrease in potency against rlDHFR compared to pcDHFR and tgDHFR resulted in appreciable selectivity toward pathogenic DHFRs from different pathogens. The 2',5'-dichloro analogue 8 showed selectivity ratios (IC(50) against rlDHFR/IC(50) against pcDHFR or tgDHFR) of 15.7 and 23 for pcDHFR and tgDHFR, respectively. Thus, the selectivity of 8 for pcDHFR is higher than the first line clinical agent trimethoprim (TMP). In a P. carinii cell culture study, analogue 8 exhibited 88% cell growth inhibition at a concentration of 10 muM and afforded marginal effects in an in vivo study in the T. gondii mouse model. Selected compounds were evaluated in the National Cancer Institute (NCI) in vitro preclinical antitumor screening program and inhibited the growth of tumor cells in culture at micromolar to submicromolar concentrations and were selected for evaluation in a NCI in vivo hollow fiber assay.

Animals↗
PubMed2001

A new paradigm for practice education.

This paper explores the complex nature of professional practice. It suggests that educating for all practice disciplines is about to undergo a paradigm shift whereby the value of practical education and experience will be better understood, more rigorously analyzed and integrated with propositional knowledge in the construction of personal professional knowledge and identity. It relates this cross disciplinary position to the present problems of skills deficits which are evident in nurses at the point of registration and demonstrates how routinization and internalization of process and tacit knowledge can create problems for students and newly qualified staff nurses. It also suggests how this can be addressed. It discusses the present culture of 'clinical education by default', unavailability of mentors and resources, and general lack of formal collaborative structures between education and service institutions and suggests that the present system cannot sustain the complex demands, expectations and pace of the clinical context and the evolution of nursing practice. Clinical credibility is an issue as is the current heavy clinical workload of staff nurse mentors, and several collaborative clinical education models are outlined which ensure that staff nurses or resident clinical educators are available and can make clinical teaching their priority. History and the present crisis in nursing suggest that there is a case for mandatory collaborative education/service structures to ensure adequate funding and to monitor the effectiveness of selected models so that staff nurse mentors can work with lecturer colleagues to articulate and teach the complexities of clinical practice through related research. It is predicted that this collaborative approach is capable of addressing both the skills deficits and the wider intellectual challenge of developing a new paradigm of practice education and providing an integrated base for continuing professional development.

Clinical Competence↗
PubMed1991

Lewontin and Kojima meet Fisher: linkage in a symmetric model of sex determination.

The effect of linkage and epistasis on the evolution of the sex-ratio is studied in a symmetric two-locus model of autosomal sex determination closely related to the symmetric viability model of R. C. Lewontin and K. Kojima. R. A. Fisher's expectation of an even sex ratio for autosomal sex determination by a single gene governs the dynamics when the loci are tightly linked. However, recombination may preclude optimization of the sex ratio just as occurs in viability selection models. Many of the evolutionary phenomena known for the symmetric viability model also occur here. In addition, we exhibit a series of new phenomena related to the presence of surfaces of even sex ratio.

Animals↗
PubMed2002

Comparative morphometry of L4 vertebrae: comparison of large animal models for the human lumbar spine.

STUDY DESIGN: Anatomic analysis of L4 vertebral morphometry comparing specimens harvested from humans and five common large animal species. OBJECTIVE: To compare fundamental structural similarities and differences in the vertebral bodies of commonly used experimental animals relative to human vertebrae. SUMMARY OF BACKGROUND DATA: Animal models are commonly used for assessment of spine fusion, instrumentation techniques, and vertebral bone biology. Among the animals used, the lumbar vertebrae exhibit considerable anatomic variability. The goal of this study was to determine which of the animals commonly used for spine research is best suited as an anatomic model for the human lumbar spine. METHODS: Morphometric features of the L4 vertebrae of five common research animals were compared with those of the human L4 vertebrae. Mature canines, immature pigs, mature micropigs, mature dairy goats, and mature sheep were analyzed. These species were chosen because they are commonly selected research animals, and most research facilities do not need to be modified to use them. The samples included ten L4 vertebrae of each animal species and seven human L4 vertebrae. Each specimen was meticulously cleaned of all soft tissue. The measurements were grouped into vertebral body parameters, neural canal dimensions, and pedicle and facet morphometery. The mean of each anatomic measurement was compared using a single factor analysis of variance and a Scheffe's post hoc test, with 0.05 denoting significance. RESULTS: The human vertebral body was significantly wider and deeper in the anteroposterior plane than any of the animals studied. However, the mean vertebral body height of the sheep and goat significantly exceeded that of the human specimens. The mean pedicle angle of every animal species was significantly greater than that of the human. The mean pedicle width of the micropig and goat were significantly narrower than the human pedicles, and the dog specimens lacked a definable pedicle altogether. There was no significant difference in mean pedicle width between any of the remaining species and the human specimens. Facet tropism and radius of curvature of the sheep and goat specimens differed significantly from the remaining selections. CONCLUSIONS: When posterior pedicle instrumentation is part of a testing protocol, the increased pedicle angle and lack of vertebral body depth found in all animals studied must be kept in mind. In addition, when testing interbody cages designed to stabilize the spine and promote fusion, one must be aware of the decreased vertebral body depth and width in these animals, as compared with humans. Physeal defects in the immature pig may alter specific biomechanical results during failure or fatigue testing, or in basic studies of vertebral bone material properties. In all cases, instrumentation and hardware must be sized appropriately to the selected model to provide meaningful results.

Age Factors↗
PubMed1996

Concepts, properties, and applications of linear systems to describe distribution, identify input, and control endogenous substances and drugs in biological systems.

The response at time t (R(t)) of a (causal linear time invariant) system to an input A(t) is represented by: [equation: see text] where K(t) is called the unit impulse response function of the system, and the integration on the right side of the equation (above) is called the convolution (from the latin cum volvere: to interwine) of A(t) and K(t). The system described by this equation is at zero (initial conditions) when t = 0. Although it does not even begin to describe the incredible variety of possible responses of biological systems to inputs, this representation has large applicability in biology. One of the most frequently used applications is known as deconvolution: to deinterwine R(t) given a known K(t) (or A(t)) and observations of R(t), to obtain A(t) (or K(t)). In this paper attention is focused on a greater variety of aspects associated with the use of linear systems to describe biological systems. In particular I define causal linear time-invariant systems and their properties and review the most important classes of methods to solve the deconvolution problem, address. The problem of model selection, the problem of obtaining statistics and in particular confidence bands for the estimated A(t) (and K(t)), and the problem of deconvolution in a population context is also addressed, and so is the application of linear system analysis to determine fraction of input absorbed (bioavailability). A general model to do so in a multiinput-site linear system is presented. Finally the application of linear system analysis to control a biological system, and in particular to target a desired response level, is described, and a general method to do so is presented. Applications to simulated, endocrinology, and pharmacokinetics data are reported.

Bayes Theorem↗