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PubMedDate not supplied

Accuracy of surface fit registration for PET and MR brain images using full and incomplete brain surfaces.

OBJECTIVE: The accuracy of a surface-fitting image registration technique has been investigated for matching [18F]fluorodeoxyglucose (FDG) and [15O]H2O PET brain images with MR images. Use of partial-brain surfaces (a single hemisphere or a limited number of slices) was investigated to simulate cases in which severe brain defects or limited axial field of view would preclude using the entire brain surface. MATERIALS AND METHODS: Three FDG and three H2O scans were performed on five volunteers, in addition to volume MR studies. Fiducial markers were placed on the subjects' scalps to provide references for registration accuracy. The registration procedure was applied to each PET-MR set, using the surfaces defined by locating the brain edge in multiple slices for each set. RESULTS: The surfaces fit well, with only 1% scaling necessary for the best fit. Errors in fiducial marker positions between MRI and transformed PET were < 2 mm in the transverse directions and < 4.5 mm in the axial direction. Fits based on the partial surfaces worked well and gave results very similar to the full-brain fits. CONCLUSION: The surface-fitting technique is accurate for FDG and H2O PET studies, even when part of the brain surface cannot be used.

Algorithms↗
PubMed2003

Role of Baseline pol Genotype in HIV-1 Fitness Evolution.

Viral fitness can be modified upon development of antiretroviral drug resistance, usually by selection of compensatory mutations. In this study, we have used HIV-1 isolates from individuals receiving a protease inhibitor (PI)-based regimen to analyze the impact of basal genetic background on viral fitness evolution. Paired plasma samples and HIV-1 isolates were obtained from 10 PI-naive HIV-infected individuals enrolled in 2 different studies of combination antiretroviral therapy. Genomic regions from pol and env were sequenced. Viral fitness was measured using growth competition experiments followed by heteroduplex tracking analysis. Baseline genotypic analyses of pol showed that 9 of 10 viruses had a different degree of secondary mutations in the protease gene at codons associated with PI resistance (i.e., 10I, 36I, 63P, 71T, and 77I). After 48 weeks of PI-based therapy, a strong correlation was observed between protease genetic divergence and viral fitness difference (r = 0.78, P = 0.03), but not with reverse transcription or Env divergence, suggesting that genotypic changes in the protease gene were driving HIV-1 evolution in these patients. As expected, an inverse correlation was observed between the number of protease and reverse transcription primary mutations and viral fitness (r = -0.65, P < 0.0001). However, our results suggest that the preexistence of secondary mutations in protease genetic background may have implications in HIV-1 fitness evolution and virologic response to antiretroviral therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Genetic variation for total fitness in Drosophila melanogaster.

We measured the heterozygous effects on net fitness of a sample of 12 wild-type third chromosomes in D. melanogaster. Effects on fitness were assessed by competing the wild-type chromosomes against balancer chromosomes, to prevent the production of recombinants. The measurements were carried out in the population cage environment in which the life history had been evolving, in an undisturbed population with overlapping generations, and replicated measurements were made on each chromosome to control for confounding effects such as mutation accumulation. We found significant variation among the wild type chromosomes in their additive genetic effect on net fitness. The system provides an opportunity to obtain an accurate estimate of the distribution of heterozygous effects on net fitness, the contribution of different fitness components including male mating success, and the role of intra-chromosomal epistasis in fitness variation.

Animals↗
PubMed2002

In vitro analysis of human immunodeficiency virus type 1 resistance to nevirapine and fitness determination of resistant variants.

Nevirapine-resistant variants were generated by serial passages in MT-2 cells in the presence of increasing drug concentrations. In passage 5, mutations V106A, Y181C and G190A were detected in the global population, associated with a 100-fold susceptibility decrease. Sequence analysis of biological clones obtained from passage 5 and subsequent passages showed that single mutants, detected in first passages, were progressively replaced in passage 15 by double mutants, correlating with a 500-fold increase in phenotypic resistance. Fitness determination of single mutants confirmed that, in the presence of nevirapine, every variant was more fit than wild-type with a fitness order Y181C>V106A>G190A>wild-type. Unexpectedly, in the absence of the drug, the Y181C resistant mutant was more fit than wild-type, with a fitness gradient Y181C>wild-type >G106A>or=V190A. Using a molecular clone in which the Y181C mutation was introduced by in vitro mutagenesis, the greater fitness of the Y181C mutant was confirmed in new competition cultures. These data exemplify the role of resistance mutations on virus phenotype but also on virus evolution leading, occasionally, to resistant variants fitter than the wild-type in the absence of the drug.

Adaptation, Physiological↗
PubMed2003

A novel TaqMan real-time PCR assay to estimate ex vivo human immunodeficiency virus type 1 fitness in the era of multi-target (pol and env) antiretroviral therapy.

Despite numerous studies on human immunodeficiency virus type 1 (HIV-1) fitness, many key conceptual and technical questions are still unsolved. For example, the proper system to determine virus fitness of HIV-1 is still unknown. In this study, an assay was developed to estimate HIV-1 fitness based on growth competition experiments and TaqMan real-time PCR. This novel technique was compared with several methods (i.e. virus growth kinetics, growth competition/heteroduplex-tracking analysis and single-cycle replication capacity assay) in order to analyse the impact of various genomic regions and overall genetic background on virus fitness. HIV-1 primary isolates and three different sets of recombinant viruses [i.e. recombinant clones carrying protease (PR), reverse transcriptase (RT) or the 3' end of Gag, PR and RT (3'Gag/PR/RT), sequences amplified by PCR from the same primary isolates)] were evaluated. Here, it is demonstrated that, in spite of intrinsic differences, both growth competition/TaqMan and single-cycle replication assays detected a significant reduction in HIV-1 fitness as a consequence of drug-resistant mutations in pol. However, this new assay, based on HIV-1 isolates, may be useful to quantify replicative fitness in viruses from patients treated simultaneously with antiretroviral drugs targeting different genomic regions of HIV-1 (e.g. pol and env).

Anti-HIV Agents↗
PubMed1999

A global goodness-of-fit statistic for Cox regression models.

In this paper, a global goodness-of-fit test statistic for a Cox regression model, which has an approximate chi-squared distribution when the model has been correctly specified, is proposed. Our goodness-of-fit statistic is global and has power to detect if interactions or higher order powers of covariates in the model are needed. The proposed statistic is similar to the Hosmer and Lemeshow (1980, Communications in Statistics A10, 1043-1069) goodness-of-fit statistic for binary data as well as Schoenfeld's (1980, Biometrika 67, 145-153) statistic for the Cox model. The methods are illustrated using data from a Mayo Clinic trial in primary billiary cirrhosis of the liver (Fleming and Harrington, 1991, Counting Processes and Survival Analysis), in which the outcome is the time until liver transplantation or death. The are 17 possible covariates. Two Cox proportional hazards models are fit to the data, and the proposed goodness-of-fit statistic is applied to the fitted models.

Biometry↗
PubMed2002

The ecology and genetics of fitness in Chlamydomonas. XII. Repeated sexual episodes increase rates of adaptation to novel environments.

We investigated the dynamics of adaptation of the unicellular chlorophyte Chlamydomonas reinhardtii to new and hostile conditions of growth provided by novel carbon substrates in the dark. The experiment was designed to contrast perennially asexual lines with lines that had experienced one or more sexual episodes. All lines were capable of adapting to the novel environment. The sexual lines, however, showed greater adaptation over the course of the experiment, especially in more complex environments. Moreover, the effect of sex on adaptation increased with the number of successive sexual episodes. The time-course of adaptation showed that sex initially caused an increase in the standardized variance of fitness and an initial drop in mean fitness, at least after a second or third sexual episode. These short-term effects were followed by a period of recovery during which the fitness of sexual lines eventually exceeded that of asexual lines. The increase in mean fitness was mirrored by a decrease in the standardized variance of fitness relative to asexuals, suggesting that directional selection used up the variation generated by meiotic recombination and thereby conferred a fitness advantage to the sexual lines. These results support the Weismann-Fisher-Muller hypothesis for the maintenance of sex in natural populations.

Adaptation, Physiological↗
PubMed2002

Evolution in the real world: stochastic variation and the determinants of fitness in Carlina vulgaris.

Empirical studies of life histories often ignore stochastic variation, despite theoretical demonstrations of its potential impact on life-history evolution. Here we use a novel approach to explore the effects of stochastic variation on life-history evolution and estimate the selection pressures operating on the monocarpic perennial Carlina vulgaris, in which flowering may be delayed by up to eight years. The approach is novel in that we use modern theoretical techniques to estimate selection pressures and the fitness landscape from a fully parameterised individual-based model. These approaches take into account temporal variation in demographic rates and density dependence. Analysis of 16 years' data revealed significant temporal variation in growth, mortality, and recruitment in our study population. Flowering was strongly size dependent and, unusually for such a species, also age dependent. Individual-based models of the flowering strategy, parameterized using field data, consistently underestimated the size at flowering, when temporal variation in demographic rates was ignored. In contrast, models that incorporated temporal variation in growth, mortality, and recruitment predicted sizes at flowering not significantly different from those observed in the field. Temporal variation in mortality, which had the largest effect on the flowering strategy, selected for increased size at flowering. An analytical approximation is presented to explain this result, extending the "1-year look-ahead criterion" presented in Rees et al. (2000). A fitness landscape generated by following the fate of rare mutant invaders with a broad range of alternative flowering strategies demonstrated that the observed parameters were adaptive. However, the fitness landscape reveals that approximately equal fitness is achieved by a broad range of strategies, providing a mechanism for the maintenance of genetic variation. To understand how the different parameters that defined our models determine the fitness of rare mutants, we numerically estimated the elasticities and sensitivities of mutant fitness. This demonstrated strong selection on a number of the parameters. Elasticities and sensitivities estimated in constant and random environments were significantly positively correlated, and both were negatively related to the standard error of the parameter. This last result is surprising and, we argue, reflects the genetic and phenotypic responses to selection.

Adaptation, Physiological↗
PubMed2003

Rapid fitness recovery in mutationally degraded lines of Caenorhabditis elegans.

Deleterious mutation accumulation has been implicated in many biological phenomena and as a potentially significant threat to human health and the persistence of small populations. The vast majority of mutations with effects on fitness are known to be deleterious in a given environment, and their accumulation results in mean population fitness decline. However, whether populations are capable of recovering from negative effects of prolonged genetic bottlenecks via beneficial or compensatory mutation accumulation has not previously been tested. To address this question, long-term mutation-accumulation lines of the nematode Caenorhabditis elegans, previously propagated as single individuals each generation, were maintained in large population sizes under competitive conditions. Fitness assays of these lines and comparison to parallel mutation-accumulation lines and the ancestral control show that, while the process of fitness restoration was incomplete for some lines, full recovery of mean fitness was achieved in fewer than 80 generations. Several lines of evidence indicate that this fitness restoration was at least partially driven by compensatory mutation accumulation rather than a result of a generic form of laboratory adaptation. This surprising result has broad implications for the influence of the mutational process on many issues in evolutionary and conservation biology.

Analysis of Variance↗
PubMed2006

A silver spoon for a golden future: long-term effects of natal origin on fitness prospects of oystercatchers (Haematopus ostralegus).

1. Long-term effects of conditions during early development on fitness are important for life history evolution and population ecology. Using multistrata mark-recapture models on 20 years of data, we quantified the relation between rearing conditions and lifetime fitness in a long-lived shorebird, the oystercatcher (Haematopus ostralegus). We addressed specifically the relative contribution of short- and long-term effects of rearing conditions to overall fitness consequences. 2. Rearing conditions were defined by differences in natal habitat quality, in which there is a clear dichotomy in our study population. In the first year of life, fledglings from high-quality natal origin had a 1.3 times higher juvenile survival. Later in life (age 3-11), individuals of high-quality natal origin had a 1.6 times higher adult prebreeder survival. The most striking effect of natal habitat quality was that birds that were reared on high-quality territories had a higher probability of settling in high-quality habitat (44% vs. 6%). Lifetime reproductive success of individuals born in high-quality habitat was 2.2 times higher than that of individuals born in low-quality habitat. This difference increased further when fitness was calculated over several generations, due to a correlation between the quality of rearing conditions of parents and their offspring. 3. Long-term effects of early conditions contributed more to overall fitness differences as short-term consequences, contrary to common conceptions on this issue. 4. This study illustrates that investigating only short-term effects of early conditions can lead to the large underestimation of fitness consequences. We discuss how long-term consequences of early conditions may affect settlement decisions and source-sink population interactions.

Animals↗
PubMed2006

To eject or to abandon? Life history traits of hosts and parasites interact to influence the fitness payoffs of alternative anti-parasite strategies.

Hosts either tolerate avian brood parasitism or reject it by ejecting parasitic eggs, as seen in most rejecter hosts of common cuckoos, Cuculus canorus, or by abandoning parasitized clutches, as seen in most rejecter hosts of brown-headed cowbirds, Molothrus ater. What explains consistent variation between alternative rejection behaviours of hosts within the same species and across species when exposed to different types of parasites? Life history theory predicts that when parasites decrease the fitness of host offspring, but not the future reproductive success of host adults, optimal clutch size should decrease. Consistent with this prediction, evolutionarily old cowbird hosts, but not cuckoo hosts, have lower clutch sizes than related rarely- or newly parasitized species. We constructed a mathematical model to calculate the fitness payoffs of egg ejector vs. nest abandoner hosts to determine if various aspects of host life history traits and brood parasites' virulence on adult and young host fitness differentially influence the payoffs of alternative host defences. These calculations showed that in general egg ejection was a superior anti-parasite strategy to nest abandonment. Yet, increasing parasitism rates and increasing fitness values of hosts' eggs in both currently parasitized and future replacement nests led to switch points in fitness payoffs in favour of nest abandonment. Nonetheless, nest abandonment became selectively more favourable only at lower clutch sizes and only when hosts faced parasitism by a cowbird- rather than a cuckoo-type brood parasite. We suggest that, in addition to evolutionary lag and gape-size limitation, our estimated fitness differences based on life history trait variation provide new insights for the consistent differences observed in the anti-parasite rejection strategies between many cuckoo- and cowbird-hosts.

Animals↗
PubMed1996

Effect of model fitting artifacts on the stepwise approach to identifying patterns of attachment loss.

The stepwise approach to the determination of periodontal attachment loss involves fitting linear, logarithmic, and exponential models to individual site data and concluding that the form of loss is consistent with the model that has the greatest r-value, provided that the model predicts loss in excess of a site-specific threshold. Logarithmic and exponential fits are considered to define early and late bursts, respectively, while linear fit describes loss at a constant rate. In a recently published study, the stepwise approach was applied to 6,935 sites in patients with established periodontitis and, of 581 loss detections, 195 (33.6%) were linear, 224 (38.6%) logarithmic, and 162 (27.9%) exponential. However, curvilinear patterns may occur by chance and regression algorithms that can fit such curvature may have an advantage unrelated to the true mechanism(s) [correction of mchanism(s)] of periodontal destruction. To investigate the implications of this possibility, proportions of linear, logarithmic, and exponential fit were estimated by simulation under four different conditions. These conditions incorporated random or random plus linear change, but no nonlinear effects. The relative proportions of model fits described in the published study were approximated in all of these conditions. It would appear that the observed proportions are ubiquitous to the modelling approach itself, and do not constitute evidence of a causal non-linear biological mechanism. The stepwise approach may be useful for detecting change but relevance to causal processes seems problematic.

Algorithms↗
PubMed2006

Effects of random mutations in the human immunodeficiency virus type 1 transcriptional promoter on viral fitness in different host cell environments.

A mutation's effect on fitness or phenotype may in part depend on the interaction of the mutation with the environment. The resulting phenotype or fitness is important, since it determines the adaptive potential of a species. To date, most studies have focused on alterations to protein-coding regions of the genome and their consequential fitness effects. Non-protein-coding regulatory regions have been largely neglected, although they make up a large and important part of an organism's genome. Here, we use human immunodeficiency virus type 1 as a model system to investigate fitness effects of random mutations in noncoding DNA-binding sites of the transcriptional promoter. We determined 242 fitness values for 35 viral promoter mutants with one, two, or three mutations across seven distinct cellular environments and identified that (i) all mutants have an effect in at least one cellular environment; (ii) fitness effects are highly dependent on the cellular environment; (iii) disadvantageous and advantageous mutations occur at high and similar frequencies; and (iv) epistatic effects of multiple mutations are rare. Our results underline the evolutionary potential of regulatory regions and indicate that DNA-binding sites evolve under strong selection, while at the same time, they are very plastic to environmental change.

Cell Line↗
PubMed2006

The fitness cost of mutations associated with human immunodeficiency virus type 1 drug resistance is modulated by mutational interactions.

It is generally accepted that the fitness cost of resistance mutations plays a role in the persistence of transmitted drug-resistant human immunodeficiency virus type 1 and that mutations that confer a high fitness cost are less able to persist in the absence of drug pressure. Here, we show that the fitness cost of reverse transcriptase (RT) mutations can vary within a 72-fold range. We also demonstrate that the fitness cost of M184V and K70R can be decreased or enhanced by other resistance mutations such as D67N and K219Q. We conclude that the persistence of transmitted RT mutants might range widely on the basis of fitness and that the modulation of fitness cost by mutational interactions will be a critical determinant of persistence.

Anti-HIV Agents↗
PubMed1999

Exponential fitness gains of RNA virus populations are limited by bottleneck effects.

Fitness is a parameter that quantitatively measures adaptation of a virus to a given environment. We have previously reported exponential fitness gains of large populations of vesicular stomatitis virus replicating in a constant environment (I. S. Novella et al., Proc. Natl. Acad. Sci. USA 92:5841-5844, 1995). In this paper, we report that during long-term passage of such large viral populations, fitness values reached a high-fitness plateau during which stochastic fitness variations were observed. This effect appears likely to be due to bottleneck effects on very high fitness populations.

Adaptation, Biological↗
PubMed2004

Transmitted human immunodeficiency virus type 1 carrying the D67N or K219Q/E mutation evolves rapidly to zidovudine resistance in vitro and shows a high replicative fitness in the presence of zidovudine.

Drug-naive patients infected with drug-resistant human immunodeficiency virus type 1 (HIV-1) who initiate antiretroviral therapy show a shorter time to virologic failure than patients infected with wild-type (WT) viruses. Resistance-related HIV genotypes not commonly seen in treated patients, which likely result from reversion or loss of primary resistance mutations, have also been recognized in drug-naive persons. Little work has been done to characterize the patterns of mutations in these viruses and the frequency of occurrence, their association with phenotypic resistance, and their effect on fitness and evolution of resistance. Through the analysis of resistance mutations in 1082 newly diagnosed antiretroviral-naive persons from the United States, we found that 35 of 48 (72.9%) persons infected with HIV-1 containing thymidine analog mutations (TAMs) had viruses that lacked a primary mutation (T215Y/F, K70R, or Q151M). Of these viruses, 9 (25.7%) had only secondary TAMs (D67N, K219Q, M41L, or F77L), and all were found to be sensitive to zidovudine (AZT) and other drugs. To assess the impact of secondary TAMs on the evolution of AZT resistance, we generated recombinant viruses from cloned plasma-derived reverse transcriptase sequences. Two viruses had D67N, three had D67N and K219Q/E, and three were WT. Four site-directed mutants with D67N, K219Q, K219E, and D67N/K219Q were also made in HIV-1(HXB2). In vitro selection of AZT resistance showed that viruses with D67N and/or K219Q/E acquired AZT resistance mutations more rapidly than WT viruses (36 days compared to 54 days; P = 0.003). To investigate the factors associated with the rapid selection of AZT mutations in these viruses, we evaluated fitness differences among HXB2(WT) and HXB2(D67N) or HXB2(D67N/K219Q) in the presence of AZT. Both HXB2(D67N/K219Q) and HXB2(D67N) were more fit than HXB2(WT) in the presence of either low or high AZT concentrations, likely reflecting low-level resistance to AZT that is not detectable by phenotypic testing. In the absence of AZT, the fitness cost conferred by D67N or K219Q was modest. Our results demonstrate that viruses with unique patterns of TAMs, including D67N and/or K219Q/E, are commonly found among newly diagnosed persons and illustrate the expanding diversity of revertant viruses in this population. The modest fitness cost conferred by D67N and K219Q supports persistence of these mutants in the untreated population and highlights the potential for secondary transmission. The faster evolution of these mutants toward AZT resistance is consistent with the higher viral fitness in the presence of AZT and shows that these viruses are phenotypically different from WT HIV-1. Our study emphasizes the need for clinical studies to better define the impact of these mutants on treatment responses and evolution of resistance.

Anti-HIV Agents↗
PubMed2005

Simian immunodeficiency virus variants that differ in pathogenicity differ in fitness under rapid cell turnover conditions.

Simian immunodeficiency virus (SIV) has been shown to progress through a number of changes that lead to the emergence of pathogenic viral variants in macaques initially infected with a mildly cytopathic variant, SIVMneCL8. One of these late-stage isolates, SIVMne170, replicates to high levels in vivo and causes a rapid disease course when reintroduced into naïve macaques, resulting in a viral set point up to 3,000-fold higher than the set point of the parental virus, SIVMneCL8. However, in cell culture both viruses replicate with similar kinetics. One major difference between in vivo and in vitro cultures is the life span of the infected cells. Here, we manipulated the life span of infected cells in vitro, and we show that the fitness of SIVMne170 in cultures with a limited cell life span dramatically increased compared to its fitness in cultures with a nonlimited life span of cells. The increase in fitness was at least partially due to the fact that the rapid turnover system eliminates the negative influence of the cytopathic effects associated with replication of SIVMne170. Because the relative fitness of SIVMneCL8 and SIVMne170 observed in the rapid turnover system more accurately reflects their fitness in vivo, the system represents an improved approach to comparing relative fitness of viruses.

Cell Line↗
PubMed2002

Older people and ill fitting shoes.

BACKGROUND: Foot health is an important issue in older people. Inappropriate shoes increase the risk of callous and ulcer formation, as well as increasing the risk of falls. There are no data defining the size of this problem. OBJECTIVE: The aim of the study was to investigate the proportion of elderly people on a general rehabilitation ward wearing incorrectly sized shoes and to look for the presence of complications. METHODS: Sixty five consecutive patients (mental state questionnaire score >6) admitted to a rehabilitation ward had their foot length and width measured, and the size of their current footwear recorded. Sensation was tested with a standard 10 g monofilament. The presence of ulceration was noted. Foot pain was recorded by the patient on a visual analogue scale. Any history of diabetes mellitus, peripheral vascular disease, or peripheral neuropathy was noted. RESULTS: The median age of the subjects was 82 (range 64-93). Six (9%) had a history of diabetes, seven (11%) had symptomatic peripheral vascular disease, and 17 (26%) had sensory impairment. Ten patients (15%) had foot ulceration present, and 47 patients (72%) had ill fitting shoes (a discrepancy in length of more than half a British shoe size fitting or more than one British width fitting, 7 mm). Incorrect shoe length was significantly associated with the presence of ulceration (odds ratio (OR) = 10.04, p = 0.016). Presence of ulceration was significantly associated with a history of peripheral vascular disease (OR = 11.56, p = 0.008). Pain was significantly associated with incorrect shoe length (p = 0.0238) and with sensory impairment (p = 0.0314). CONCLUSION: Most older people on a rehabilitation ward wore ill fitting shoes. An association was found between ill fitting shoes and self reported pain, and between ill fitting shoes and ulcer formation. A straightforward assessment of footwear in older people could improve comfort and avoid preventable foot disorders.

Accidental Falls↗