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PubMed2003

Advances in pain therapeutics.

Recent work in defining molecular targets for neuropathic pain has been plentiful and varied. Three novel targets have received much attention recently: N-methyl-D-aspartate receptor subtypes such as the glycine and NR2B sites, and the tetrodotoxin-resistant voltage-gated sodium channel (Na(v) 1.8; SNS/PN3). Preclinical data have been encouraging as a number of selective NR2B and glycine site antagonists have shown efficacy in animal models. Selective Na(v) 1.8 channel blockers have yet to emerge; however, strong genetic evidence and data from non-selective Na channel blockers indicate that this target too may hold much promise.

Anesthetics, Local↗
PubMed2005

Choosing appropriate substitution models for the phylogenetic analysis of protein-coding sequences.

Although phylogenetic inference of protein-coding sequences continues to dominate the literature, few analyses incorporate evolutionary models that consider the genetic code. This problem is exacerbated by the exclusion of codon-based models from commonly employed model selection techniques, presumably due to the computational cost associated with codon models. We investigated an efficient alternative to standard nucleotide substitution models, in which codon position (CP) is incorporated into the model. We determined the most appropriate model for alignments of 177 RNA virus genes and 106 yeast genes, using 11 substitution models including one codon model and four CP models. The majority of analyzed gene alignments are best described by CP substitution models, rather than by standard nucleotide models, and without the computational cost of full codon models. These results have significant implications for phylogenetic inference of coding sequences as they make it clear that substitution models incorporating CPs not only are a computationally realistic alternative to standard models but may also frequently be statistically superior.

Classification↗
PubMedDate not supplied

Validation of the structure for the "Clinical Assessment of Confusion-A".

The Clinical Assessment of Confusion-A (CAC-A) is an observational checklist developed for practicing nurses to measure the presence and level of confusion in hospitalized adults. In a previous study, the following dimensions were found using principal factor analysis: cognition, general behavior, motor activity, orientation, psychotic/neurotic behavior, and two uninterpretable factors. A replication study was conducted to evaluate the validity of a statistically derived model for confusion suggested by the CAC-A. Data from a sample of 566 nurses were analyzed. Three theoretically justified statistical models for the structure of confusion were estimated and compared using a model selection approach to covariance structures analysis: a single-factor unidimensional model, an orthogonal six-factor model, and an oblique six-factor model similar to the structure suggested in the development study. The oblique six-factor model provided the best fit in the predictive sense and was the most satisfactory from a theoretical perspective.

Adult↗
PubMed1992

Avoiding "Cloudcuckooland" in ethics committee case review: matching models to issues and concerns.

... The special concerns of families, patients, and caregivers are inevitably interwoven among the difficult ethical issues that ethics committees confront when they review individual cases. Certain of these ethical issues and special concerns can be addressed more effectively by the use of one particular case review model. This means that no one model for case review is suited to address every ethically difficult patient care situation. When one case review model is used exclusively by an ethics committee, some issues and concerns will not be resolved effectively. This difficulty cannot be ameliorated by switching to another exclusive model. To do so would be to trade an Athens for a "Cloudcuckooland." The case review model selected by ethics committees must vary from case to case. The model that is chosen should be geared to resolve the ethical issues central to that situation and the special concerns of patient, family, and caregivers. An examination of the three received models [the committee as a whole, teams, and individual members or consultants] will show that each is particularly suited to resolve certain kinds of ethical issues and special concerns. Because of this, ethics committees should develop a method for choosing the most appropriate model for reviewing specific cases.

Bioethical Issues↗
PubMed2002

Roughness-dependent friction force of the tarsal claw system in the beetle Pachnoda marginata (Coleoptera, Scarabaeidae).

This paper studies slide-resisting forces generated by claws in the free-walking beetle Pachnoda marginata (Coleoptera, Scarabaeoidea) with emphasis on the relationship between the dimension of the claw tip and the substrate texture. To evaluate the force range by which the claw can interact with a substrate, forces generated by the freely moving legs were measured using a load cell force transducer. To obtain information about material properties of the claw, its mechanical strength was tested in a fracture experiment, and the internal structure of the fractured claw material was studied by scanning electron microscopy. The bending stress of the claw was evaluated as 143.4-684.2 MPa, depending on the cross-section model selected. Data from these different approaches led us to propose a model explaining the saturation of friction force with increased texture roughness. The forces are determined by the relative size of the surface roughness R(a) (or an average particle diameter) and the diameter of the claw tip. When surface roughness is much bigger than the claw tip diameter, the beetle can grasp surface irregularities and generate a high degree of attachment due to mechanical interlocking with substrate texture. When R(a) is lower than or comparable to the claw tip diameter, the frictional properties of the contact between claw and substrate particles play a key role in the generation of the friction force.

Animals↗
PubMed2004

Generalisability in economic evaluation studies in healthcare: a review and case studies.

OBJECTIVES: To review, and to develop further, the methods used to assess and to increase the generalisability of economic evaluation studies. DATA SOURCES: Electronic databases. REVIEW METHODS: Methodological studies relating to economic evaluation in healthcare were searched. This included electronic searches of a range of databases, including PREMEDLINE, MEDLINE, EMBASE and EconLit, and manual searches of key journals. The case studies of a decision analytic model involved highlighting specific features of previously published economic studies related to generalisability and location-related variability. The case-study involving the secondary analysis of cost-effectiveness analyses was based on the secondary analysis of three economic studies using data from randomised trials. RESULTS: The factor most frequently cited as generating variability in economic results between locations was the unit costs associated with particular resources. In the context of studies based on the analysis of patient-level data, regression analysis has been advocated as a means of looking at variability in economic results across locations. These methods have generally accepted that some components of resource use and outcomes are exchangeable across locations. Recent studies have also explored, in cost-effectiveness analysis, the use of tests of heterogeneity similar to those used in clinical evaluation in trials. The decision analytic model has been the main means by which cost-effectiveness has been adapted from trial to non-trial locations. Most models have focused on changes to the cost side of the analysis, but it is clear that the effectiveness side may also need to be adapted between locations. There have been weaknesses in some aspects of the reporting in applied cost-effectiveness studies. These may limit decision-makers' ability to judge the relevance of a study to their specific situations. The case study demonstrated the potential value of multilevel modelling (MLM). Where clustering exists by location (e.g. centre or country), MLM can facilitate correct estimates of the uncertainty in cost-effectiveness results, and also a means of estimating location-specific cost-effectiveness. The review of applied economic studies based on decision analytic models showed that few studies were explicit about their target decision-maker(s)/jurisdictions. The studies in the review generally made more effort to ensure that their cost inputs were specific to their target jurisdiction than their effectiveness parameters. Standard sensitivity analysis was the main way of dealing with uncertainty in the models, although few studies looked explicitly at variability between locations. The modelling case study illustrated how effectiveness and cost data can be made location-specific. In particular, on the effectiveness side, the example showed the separation of location-specific baseline events and pooled estimates of relative treatment effect, where the latter are assumed exchangeable across locations. CONCLUSIONS: A large number of factors are mentioned in the literature that might be expected to generate variation in the cost-effectiveness of healthcare interventions across locations. Several papers have demonstrated differences in the volume and cost of resource use between locations, but few studies have looked at variability in outcomes. In applied trial-based cost-effectiveness studies, few studies provide sufficient evidence for decision-makers to establish the relevance or to adjust the results of the study to their location of interest. Very few studies utilised statistical methods formally to assess the variability in results between locations. In applied economic studies based on decision models, most studies either stated their target decision-maker/jurisdiction or provided sufficient information from which this could be inferred. There was a greater tendency to ensure that cost inputs were specific to the target jurisdiction than clinical parameters. Methods to assess generalisability and variability in economic evaluation studies have been discussed extensively in the literature relating to both trial-based and modelling studies. Regression-based methods are likely to offer a systematic approach to quantifying variability in patient-level data. In particular, MLM has the potential to facilitate estimates of cost-effectiveness, which both reflect the variation in costs and outcomes between locations and also enable the consistency of cost-effectiveness estimates between locations to be assessed directly. Decision analytic models will retain an important role in adapting the results of cost-effectiveness studies between locations. Recommendations for further research include: the development of methods of evidence synthesis which model the exchangeability of data across locations and allow for the additional uncertainty in this process; assessment of alternative approaches to specifying multilevel models to the analysis of cost-effectiveness data alongside multilocation randomised trials; identification of a range of appropriate covariates relating to locations (e.g. hospitals) in multilevel models; and further assessment of the role of econometric methods (e.g. selection models) for cost-effectiveness analysis alongside observational datasets, and to increase the generalisability of randomised trials.

Coronary Disease↗
PubMed2002

Behavioral, morphologic, and electroencephalographic evaluation of seizures induced by intrahippocampal microinjection of pilocarpine.

PURPOSE: We studied, by means of video-EEG and neo-Timm histochemistry, the behavioral, electrophysiologic, and structural characteristics of seizures induced by intrahippocampal microinjection of pilocarpine (HIP-PILO), a selective model of temporal lobe epilepsy (TLE). METHODS: We investigated the behavioral and electrophysiologic (hippocampus and amygdala EEG) evaluation of status epilepticus (SE) induced by HIP-PILO and the consequent spontaneous recurrent seizures (SRSs). We evaluated hippocampal structural rearrangements after SE by means of neo-Timm staining. RESULTS: HIP-PILO induced SE in 17 (71%) of 24 animals. Although three animals displayed spontaneous remission of SE (not used in analysis) before the established SE duration (90 min), none of those undergoing SE died. Of SE animals, 10 (71%) of 14 had SRSs. All animals with SE had clear-cut mossy fiber sprouting (MFS) in the inner molecular layer of the dentate gyrus and epileptiform activity in hippocampus and amygdala. CONCLUSIONS: HIP-PILO rats displayed SE, SRS, MFS, and limbic epileptiform activity, without animal loss after SE. Thus, our data support this as a selective and efficient model of TLE.

Animals↗
PubMed1999

"Quasi-REML" correlation estimates between production and health traits in the presence of selection and confounding: a simulation study.

Performance of the "quasi-REML" method for estimating correlations between a continuous trait and a categorical trait, and between two categorical traits, was studied with Monte Carlo simulations. Three continuous, correlated traits were simulated for identical populations and three scenarios with either no selection, selection for one moderately heritable trait (Trait 1, h2 = .25), and selection for the same trait plus confounding between sires and management groups. The "true" environmental correlations between Traits 2 (h2 = .10) and 3 (h2 = .05) were always of the same absolute size (.20), but further data scenarios were generated by setting the sign of environmental correlation to either positive or negative. Observations for Traits 2 and 3 were then reassigned to binomial categories to simulate health or reproductive traits with incidences of 15 and 5%, respectively. Genetic correlations (r(g12), r(g13), and r(g23) and environmental correlations (r(e12), r(e13), and r(e23)) were estimated for the underlying continuous scale (REML) and the visible categorical scales ("quasi-REML") with linear multiple-trait sire and animal models. Contrary to theory, practically all "quasi-REML" genetic correlations were underestimated to some extent with the sire and animal models. Selection inflated this negative bias for sire model estimates, and the sign of r(e23) noticeably affected r(g23) estimates for the animal model, with greater bias and SD for estimates when the "true" r(e23) was positive. Transformed "quasi-REML" environmental correlations between a continuous and a categorical trait were estimated with good efficiency and little bias, and corresponding correlations between two categorical traits were systematically overestimated. Confounding between sires and contemporary groups negatively affected all correlation estimates on the underlying and the visible scales, especially for sire model "quasi-REML" estimates of genetic correlation. Selection, data structure, and the (co)variance structure influences how well correlations involving categorical traits are estimated with "quasi-REML" methods.

Animal Husbandry↗
PubMed2005

A composite-likelihood approach for detecting directional selection from DNA sequence data.

We present a novel composite-likelihood-ratio test (CLRT) for detecting genes and genomic regions that are subject to recurrent natural selection (either positive or negative). The method uses the likelihood functions of Hartl et al. (1994) for inference in a Wright-Fisher genic selection model and corrects for nonindependence among sites by application of coalescent simulations with recombination. Here, we (1) characterize the distribution of the CLRT statistic (Lambda) as a function of the population recombination rate (R=4Ner); (2) explore the effects of bias in estimation of R on the size (type I error) of the CLRT; (3) explore the robustness of the model to population growth, bottlenecks, and migration; (4) explore the power of the CLRT under varying levels of mutation, selection, and recombination; (5) explore the discriminatory power of the test in distinguishing negative selection from population growth; and (6) evaluate the performance of maximum composite-likelihood estimation (MCLE) of the selection coefficient. We find that the test has excellent power to detect weak negative selection and moderate power to detect positive selection. Moreover, the test is quite robust to bias in the estimate of local recombination rate, but not to certain demographic scenarios such as population growth or a recent bottleneck. Last, we demonstrate that the MCLE of the selection parameter has little bias for weak negative selection and has downward bias for positively selected mutations.

Base Sequence↗
PubMed1991

Levels of selection, evolution of sex in RNA viruses, and the origin of life.

Multi-component RNA viruses have genomes that are segmented into two or more RNA molecules. A viral particle carries only one RNA molecule. Reproduction of a particle requires complementation by particles carrying other segments of the genome. Complementation is achieved when a group of particles co-infects the same host cell and forms a co-infection group. I have previously proposed the hypothesis that multi-component reproduction evolved in RNA viruses as a form of sex. Multi-component viruses may need sex because, like all RNA viruses, they have very high mutation rates. On the other hand, Nee (1987, J. molec. Biol. 25, 277-281.) has proposed the hypothesis that multi-component genomes evolved because smaller RNA molecules are favored by selection on RNAs within a host cell. Nee (1989, J. theor. Biol. 138, 407-412.) also claimed that selection on RNAs alone can account for the evolution of multi-component viruses. He criticized the viral sex hypothesis because, in his view, co-infection groups are not units of selection and are too transient to be engaged in sex. These two hypotheses were further examined through population genetic models. Three evolutionary agents are assumed to operate in the models. Selection on co-infection groups favors retention of the genome on one large RNA molecule because larger RNAs require less complementation. Selection on RNAs favor segmentation of the viral genome into smaller RNAs, which are replicated and encapsidated more rapidly. Mutation pressure also favors smaller molecules because those molecules are smaller targets for deleterious mutations. Analysis of the models shows that (when parameter values argued to be biologically realistic are used) selection on co-infection groups is necessary for the evolutionary persistence of multi-component viruses. Without selection on co-infections groups to oppose mutation pressure and selection on RNAs, a population of multi-component viruses is displaced by a population of parasitic viral RNAs that are replication and encapsidation specialists. These results support arguments that co-infection groups are units of selection in multi-component viruses. Both mutation pressure and selection on RNAs may be responsible for the evolution of genome segmentation in multi-component viruses because there is good evidence documenting the action of both in RNA viruses.(ABSTRACT TRUNCATED AT 400 WORDS)

Biological Evolution↗
PubMedDate not supplied

The amplitude and phase responses of the firing rates of some motoneuron models.

A vertebrate motoneuron receives an enormous amount of synaptic activity from descending pathways, from spinal cord interneurons and directly from mechanoreceptor afferents. The intrinsic characteristics of the motoneuron will determine how its output spike train will encode the activities of all its inputs. Therefore, the essence of the intrinsic motoneuron characteristics should be well studied and modelled if the roles of the motoneuron as a processing or encoding element are to be well understood. Mathematical models of motoneurons have been described in the literature and tested mostly under static conditions. To increase the reality of the validation of such models, the objective of the present work is to test a few selected models described in the literature using sinusoidal injected current of different frequencies. The resulting frequency responses are compared with data available in the literature from cat type F motoneurons. Discrepancies between some of the models' responses and real motoneuron data suggest that improvements are needed in the modelling of the afterhyperpolarization mechanism.

Models, Neurological↗
PubMed1979

Experimental bone tumors as models of human bone tumors.

Experimental models of human bone tumors may be classified as causal, descriptive, and selective models. These models are useful for analyzing the morphology, biology, and therapy of human bone tumors. The application of these models, however, requires us to define clearly the questions to be answered and to consider the special features of experimental and human bone tumors. The suitability of experimental bone tumors as models can be determined only on the basis of a large amount of relevant experimental and clinical data.

Animals↗
PubMed1986

Parameterized multistate population dynamics and projections.

"This article reports progress on the development of a population projection process that emphasizes model selection over demographic accounting. Transparent multiregional/multistate population projections that rely on parameterized model schedules are illustrated [using data primarily from a number of developed countries, particularly Sweden], together with simple techniques that extrapolate the recent trends exhibited by the parameters of such schedules." The author notes that "the parameterized schedules condense the amount of demographic information, expressing it in a language and variables that are more readily understood by the users of the projections. In addition, they permit a concise specification of the expected temporal patterns of variation among these variables, and they allow a disaggregated focus on demographic change that otherwise would not be feasible."

Demography↗
PubMed2005

Active concept learning in image databases.

Concept learning in content-based image retrieval systems is a challenging task. This paper presents an active concept learning approach based on the mixture model to deal with the two basic aspects of a database system: the changing (image insertion or removal) nature of a database and user queries. To achieve concept learning, we a) propose a new user directed semi-supervised expectation-maximization algorithm for mixture parameter estimation, and b) develop a novel model selection method based on Bayesian analysis that evaluates the consistency of hypothesized models with the available information. The analysis of exploitation versus exploration in the search space helps to find the optimal model efficiently. Our concept knowledge transduction approach is able to deal with the cases of image insertion and query images being outside the database. The system handles the situation where users may mislabel images during relevance feedback. Experimental results on Corel database show the efficacy of our active concept learning approach and the improvement in retrieval performance by concept transduction.

Algorithms↗
PubMed2001

Similarity indices for spatial ecological data.

We present a method for assessing similarity between species maps of presence and absence or abundance that emphasizes global features while ignoring minor local dissimilarities. The method arranges sites into small groups, or cliques, and allows controlled changes to be made within cliques to reduce the influence of local discrepancies. Resulting measures of similarity are visually more satisfactory than traditional indices. We show that the similarity indices are useful for model selection by comparing observed spatial patterns with those predicted by different fitted models. Examples are provided for spatial distributions of oribatid mites (Acari, Oribatei), woodlarks (Lullula arborea), and red deer (Cervus elaphus).

Algorithms↗
PubMed2005

Countercurrent compartmental models describe hind limb skeletal muscle helium kinetics at resting and low blood flows in sheep.

AIMS: This study evaluated the relative importance of perfusion and diffusion mechanisms in compartmental models of blood : tissue helium exchange in a predominantly skeletal muscle tissue bed in the sheep hind limb. Helium has different physiochemical properties from previously studied gases and is a common diluent gas in underwater diving where decompression schedules are based on theoretical models of inert gas kinetics. METHODS: Helium kinetics across skeletal muscle were determined during and after 20 min of helium inhalation, at separate resting and low steady-states of femoral vein blood flow in six sheep under isoflurane anaesthesia. Helium concentrations in arterial and femoral vein blood were determined using gas chromatographic analysis and femoral vein blood flow was monitored continuously. Parameters and model selection criteria of various perfusion-limited or perfusion-diffusion compartmental models of skeletal muscle were estimated by simultaneous fitting of the models to the femoral vein helium concentrations for both blood flow states. RESULTS: A model comprising two parallel perfusion-limited compartment models fitted the data well but required a 51-fold difference in relative compartment perfusion that did not seem physiologically plausible. Models that allowed a countercurrent diffusion exchange of helium between arterial and venous vessels outside of the tissue compartments provided better overall fit of the data and credible parameter estimates. CONCLUSIONS: These results suggest a role of arterial-venous diffusion in blood : tissue helium equilibration in skeletal muscle.

Administration, Inhalation↗
PubMed1998

Review article: Helicobacter species and in vivo models of gastrointestinal cancer.

Although gastric cancer is an uncommon spontaneous neoplasm of laboratory animal species, rodents, and to a lesser extent other animals, have been used in chemically induced gastric carcinogenesis studies for decades. The role of diet in preventing or promoting gastric cancer has also been addressed in animal models. With the discovery of Helicobacter pylori and its causative role in gastric disease in humans, several animal models have been described for Helicobacter spp.-induced gastric disease, and in selected models, development of gastric and hepatic cancer. This review has attempted to highlight salient features of Helicobacter models and how these observations may be interpreted in light of data obtained from chemical carcinogenesis and nutritional studies. Further insight into mechanisms of Helicobacter-induced cancer should evolve by combining and comparing relevant features of these in vivo models.

Adenocarcinoma↗
PubMed1996

The effect of ketoprofen creams on periodontal disease in rhesus monkeys.

Ketoprofen creams were evaluated for the treatment of periodontal disease in a placebo-controlled, double-blind study in the rhesus monkeys, Macaca mulatta. Two formulations containing ketoprofen (1%), with or without vitamin E, were evaluated against appropriate controls (8 monkeys per group). Two weeks prior to treatment, the animals received prophylaxis on only the left side of the mouth (spontaneous model). Selected teeth on the right side of the mouth were ligated (ligature model). The creams were administered to the gingiva once daily at a standard dose of 1.8 ml per monkey for 6 months. Clinical assessments were made 2 wk before initiation, at baseline and 1, 2, 3 and 6 months post-treatment. The clinical parameters included plaque formation, gingival redness, edema, bleeding on probing and Ramfjord Attachment Level measurements (RAL). Radiographs were taken at 2 wk before initiation, baseline and at 3 and 6 months post-treatment. Digital, subtraction radiography was used to measure vertical linear bone loss along the interproximal root surfaces of the left and right mandibular first molars. Gingival crevicular fluid (GCF) was collected for biochemical assays on PGE2, TxB2, LTB4, IL-1 beta and TNF alpha. There were no significant differences among groups with respect to gingival indices. Radiographic data demonstrated significant positive effects on bone activity in both groups treated with ketoprofen formulations with improvement over time in the ligature model (0.01 < or = p < or = 0.04). The placebo group exhibited bone loss of 1.96 +/- 0.48 and 1.40 +/- 0.56 mm per site at 3 and 6 months, respectively. The group treated with ketoprofen cream showed an apparent bone gain of 0.28 +/- 0.41 and 0.78 +/- 0.47 mm per site at 3 and 6 months, respectively. The group treated with ketoprofen cream containing vitamin E showed a mean bone loss of 0.41-0.48 mm per site at 3 months with improvement to an apparent bone gain of 0.31 +/- 0.44 mm per site at 6 months. The biochemical data demonstrated early and significant suppression of GCF-LTB4 by both ketoprofen formulations at 1 month, which preceded the significant suppression of GCF-PGE2 at 2 and 3 months in the ligature model (p < 0.003) and at 2 to 6 months in the spontaneous model (p < 0.02). We conclude that ketoprofen at 1% level in suitable topical vehicles can effectively inhibit GCF-LTB4 and GCF-PGE2 and positively alter alveolar bone activity in the ligature-induced model of periodontitis in the monkey.

Administration, Topical↗