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PubMed1997

Higher-order statistics: a robust vehicle for diagnostic assessment and characterisation of lung sounds.

The use of higher-order statistics for diagnostic assessment and characterisation of lung sounds is presented in this article. The parametric approach of bispectrum estimation, which is a third-order spectrum, based on a non-Gaussian white noise driven autoregressive (AR) model, reveals information about lung sounds that is not contained in the ordinary power spectrum, such as the degree of nonlinearity and deviations from normality. Characterisation of source and transmission of lung sounds is achieved using an AR model based on third-order statistics. Furthermore, harmonic analysis of lung sounds is combined with the bicoherence index in order to obtain information regarding possible quadratic phase coupling among harmonic components of musical lung sounds. Experiments have shown that higher-order statistics can offer reliable evaluation of lung sounds characteristics, since their general properties and robustness in noiseless or noisy environments (lung sounds contaminated with additive symmetrical noise, e.g., Gaussian) proved to have superior advantages in objective analysis of pulmonary dysfunction.

Humans↗
PubMed1997

[Limits of perceptual robustness in perspective distortion].

Pictures often do not appear distorted even when viewed at oblique angles. Three hypotheses have been put forth to explain this robustness of virtual space toward affine transformations. First, array specificity holds that the perception of depicted space is fully specified by the information available at the point of observation. Second, the notion of a compensatory mechanism involves an unconscious recreation of the scene according to the original viewpoint. Third, the indiscrimination hypothesis denies the ability of the visual system to resolve or detect affine transformations up to a certain degree. Three experiments were conducted to investigate these claims. Using a double projection technique devised by Cutting (1987), Experiment I showed that observers are able to discriminate and compensate, to some degree, for affine transformations if information about the projection surface is available. However, observers relied on relative image velocities rather than reconstructing the object. In Experiment 2 additional observer motion was simulated. In single and double projection trials that required more difficult judgments of object rotation, compensation was poor and observers seemed to rely on local cues. Finally, real and simulated rotation of the projection surface revealed that observers are able to compensate for only one primary projection surface slant. The results reject the indiscrimination hypothesis and support the notion of array specificity.

Adult↗
PubMed1998

Efficient, robust, and unified method for mapping complex traits (I): two-point linkage analysis.

The completion of a preliminary human genome map and development of molecular methods have enabled researchers to assay a large number of polymorphic markers that are evenly spaced along the entire human genome. Among many applications, marker data are valuable for mapping complex traits through linkage or linkage-disequilibrium analysis, the former of which is the focus of this paper, the first in a series on this subject. Formalizing the concept and computation for linkage analysis, Elston and Stewart [1971; Human Heredity 21:523-542] introduced a likelihood function to capture relevant genetic information and a recursive algorithm for computing the likelihood function. However, the computing burden is prohibitive in processing complex pedigrees. Since that fundamental development, improving the computational algorithm and extending the method has been a dynamic area of research. The primary objective of this communication is to introduce a semiparametric method for linkage analysis. It is a particularly suitable approach with desirable properties for mapping complex traits that may be binary, continuous, and partially observed (i.e., censored). It incorporates candidate genes, environmental factors, and their interactions with the putative gene and is expected to be robust and efficient in comparison with likelihood-based methods. The properties of the estimates have been studied in finite samples with a limited simulation study. This method is illustrated with an application to family data contributed to the Breast Cancer Consortium.

Algorithms↗
PubMed1998

A robust method for isotopic riboprobe in situ hybridisation to localise mRNAs in routine pathology specimens.

In situ Hybridisation (ISH) to detect mRNA is widely applicable to studies of human pathology and experimental models including transgenic mice, where it can provide crucial information as to where a gene is expressed, that is not available in other ways. ISH was used to establish that relatively high levels of expression of E-cadherin mRNA were associated with long-term survival in colorectal cancer, before suitable antisera became available. There is increasing awareness that ISH can be used to help select between candidate disease genes found at a linked locus, and that ISH can help validate therapeutic targets. For instance, when several closely related receptor genes are expressed in a tissue, it may be possible to determine which combinations are expressed together in a single cell type. These diverse applications demand a robust method that works on a variety of clinical and experimental materials, and is easily interpreted. To date, the ICRF in situ Hybridisation Service has hybridised over 30,000 sections of principally formalin-fixed, paraffin-embedded tissues, with a high success rate. The practicalities of our preferred method are discussed and key steps for quality control highlighted.

Automation↗
PubMed1998

Alternative ways for knowledge collection, indexing and robust language retrieval.

Definitions are provided of the key entities in knowledge representation for Natural Language Processing (NLP). Starting from the words, which are the natural components of any sentence, both the role of expressions and the decomposition of words into their parts are emphasized. This leads to the notion of concepts, which are either primitive or composite depending on the model where they are created. The problem of finding the most adequate degree of granularity for a concept is studied. From this reflection on basic Natural Language Processing components, four categories of linguistic knowledge are recognized, that are considered to be the building blocks of a Medical Linguistic Knowledge Base (MLKB). Following on the tracks of a recent experience in building a natural language-based patient encoding browser, a robust method for conceptual indexing and query of medical texts is presented with particular attention to the scheme of knowledge representation.

Abstracting and Indexing↗
PubMed2026

A stable and potent buffalo EF1α1 promoter for robust gene expression in mammalian systems.

This study reports the first isolation and characterization of the buffalo EF1α1 promoter, demonstrating its strong gene expression activity both in vitro across diverse cultured cell types and in vivo across multiple mouse organs. Although viral promoters, such as cytomegalovirus (CMV) and simian virus (SV40), are widely used for their strong expression in various cell lines in mammalian expression systems and in animal tissues, they are prone to methylation-induced transcriptional silencing and subsequent loss of exogenous gene expression. The most effective alternative to viral promoters is the synthetic hybrid CAG promoter (cytomegalovirus major immediate-early enhancer combined with the chicken beta-actin promoter) or mammalian cellular promoter such as human elongation factor 1 alpha (hEF1α), which drives strong gene expression but lacks consistency and is limited in their in vivo expression potential due to their vulnerability to epigenetic silencing. To overcome these challenges, the bbEF1α1 promoter was cloned and evaluated both in vitro and in vivo. It consistently drives higher levels of exogenous gene expression than CMV in diverse cell lines. Importantly, transgene expression was achieved in various organs of transgenic mice and in muscle tissue following in vivo electroporation. These findings establish the bbEF1α1 promoter as a powerful ubiquitous driver of gene expression, offering high stability with broad applications in gene therapy, biopharmaceutical production, and functional genomics.

Animals↗
PubMed1996

How and why humans grow thin skulls: experimental evidence for systemic cortical robusticity.

To what extent is cranial vault thickness (CVT) a character that is strongly linked to the genome, or to what extent does it reflect the activity of an individual prior to skeletal maturity? Experimental data from pigs and armadillos indicate that CVT increases more rapidly in exercised juveniles than in genetically similar controls, despite the low levels of strain generated by chewing or locomotion in the neurocranium. CVT increases in these individuals appear to be a consequence of systemic cortical bone growth induced by exercise. In addition, an analysis of the variability in vault thickness in the genus Homo demonstrates that, until the Holocene, there has been only a slight, general decrease in vault thickness over time with no consistent significant differences between archaic and early anatomically modern humans from the Late Pleistocene. Although there may be some genetic component to variation in CVT, exercise-related, non-genetically heritable stimuli appear to account for most of the variance between individuals. The thick cranial vaults of most hunter-gatherers and early agriculturalists suggests that they may have experienced higher levels of sustained exercise relative to body mass than the majority of recent, post-industrial humans.

Animals↗
PubMed1998

Determination of low isotopic enrichment of L-[1-13C]valine by gas chromatography/combustion/isotope ratio mass spectrometry: a robust method for measuring protein fractional synthetic rates in vivo.

A method was developed for measuring protein fractional synthetic rates using the N-methoxycarbonylmethyl ester (MCM) derivative of L-[1-13C]valine and on-line gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS). The derivatization procedure can be performed rapidly and GC separation of valine from the other branched-chain amino acids, leucine and isoleucine, is easily obtained. A good linear relationship was observed between the increment of the 13C/12C isotope ratio in CO2 gas derived from the combustion of derivatized valine and the tracer mole ratio of L-[1-13C]valine to unlabelled valine. The limit of quantitation was at an L-[1-13C]valine tracer mole ratio of 0.0002. The method was used to measure the isotopic enrichment of L-[1-13C]valine in standard mixtures and in skeletal muscle of six growing piglets infused with L-[1-13C]valine (2 mg kg-1 h-1 for 6 h). After infusion of L-[1-13C]valine the mean tracer mole ratio in plasma of L-[1-13C]valine at the isotopic steady state was 0.0740 +/- 0.0056 (GC/MS, mean +/- SEM) and the mean tracer mole ratio of valine in muscle protein fraction at 6 h was 0.000236 +/- 0.000038 (GC/C/IRMS). The resulting mean protein fractional synthetic rate in piglet skeletal muscle was 0.052 +/- 0.007% h-1, which is in good agreement with literature data obtained with alternative, more elaborate techniques. By this method protein fractional synthetic rates can be measured at low isotopic enrichment levels using L-[1-13C]valine, the MCM derivative and on-line GC/C/IRMS.

Animals↗
PubMed1996

Exploring the energy landscapes of molecular recognition by a genetic algorithm: analysis of the requirements for robust docking of HIV-1 protease and FKBP-12 complexes.

Energy landscapes of molecular recognition are explored by performing "semi-rigid" docking of FK-506 and rapamycin with the Fukisawa binding protein (FKBP-12), and flexible docking simulations of the Ro-31-8959 and AG-1284 inhibitors with HIV-1 protease by a genetic algorithm. The requirements of a molecular recognition model to meet thermodynamic and kinetic criteria of ligand-protein docking simultaneously are investigated using a family of simple molecular recognition energy functions. The critical factor that determines the success rate in predicting the structure of ligand-protein complexes is found to be the roughness of the binding energy landscape, in accordance with a minimal frustration principle. The results suggest that further progress in structure prediction of ligand-protein complexes can be achieved by designing molecular recognition energy functions that generate binding landscapes with reduced frustration.

Algorithms↗
PubMed2000

Robust estimation of the probabilities of 3-D clusters in functional brain images: application to PET data.

Recently, we presented a method (the CS method) for estimating the probability distributions of the sizes of supra threshold clusters in functional brain images [Ledberg A, Akerman S, Roland PE. 1998. Estimating the significance of 3D clusters in functional brain images. NeuroImage 8:113-128]. In that method, the significance of the observed test statistic (cluster size) is assessed by comparing it with a sample of the test statistic obtained from simulated statistical images (SSIs). These images are generated to have the same spatial autocorrelation as the observed statistical image (t-image) would have under the null hypothesis. The CS method relies on the assumptions that the t-images are stationary and that they can be transformed to have a normal distribution. These assumptions are not always valid, and thus limit the applicability of the method. The purpose of this paper is to present a modification of the previous method, that does not depend on these assumptions. This modified CS method (MCS) uses the residuals in the linear model as a model of a dataset obtained under the null hypothesis. Subsequently, datasets with the same distribution as the residuals are generated, and from these datasets the SSIs are derived. These SSIs are t-distributed. Thus, a conversion to normal distribution is no longer needed. Furthermore, no assumptions concerning the stationarity of the statistical images are needed. The MCS method is validated on both synthetical images and PET images and is shown to give accurate estimates of the probability distribution of the cluster size statistic.

Brain↗
PubMed1998

Robust and realistic approaches to carry-over.

The relationship between choice of model for carry-over and choice of efficient cross-over design is studied in particular with reference to two treatment designs in four periods and two sequences. The effect of model miss-specification is also examined. It is concluded that previous claims regarding efficient designs are not necessarily reasonable.

Bias↗
PubMed1997

Adenoviral vector-directed expression of neurotrophin-3 in rat dorsal root ganglion explants results in a robust neurite outgrowth response.

The neurotrophins are a family of proteins that promote neuronal survival and neurite outgrowth during development and can also enhance the regeneration of injured adult neurons. The local and continuous delivery of these proteins at the site of injury is problematic, since this requires repeated intraparenchymal injections or the use of invasive canula-micropump devices. In the present study we report the generation and characterization of an adenoviral vector for a member of the neurotrophins, neurotrophin-3 (Ad-NT-3). Using Ad-NT-3, we examined the expression and biological activity of NT-3 in dorsal root ganglia (DRG) explant cultures. Gene transfer with Ad-NT-3 results in the synthesis of genuine NT-3 and in a dosage-dependent neurite outgrowth response in DRG explants. Transduction of DRG explants with a viral vector dosage of 5 x 10(5) to 5 x 10(6) plaque-forming units induced the formation of a dense halo of neurites comparable to outgrowth observed following the addition of 100 ng/mL exogenous NT-3. In addition, a single infection with Ad-NT-3 produced biologically active NT-3 for at least 20 days in culture, as evidenced by continued neurite extension. This indicates that adenoviral vector-mediated expression of NT-3 results in high-level production of biologically active NT-3 and could therefore be used as a strategy to promote the regeneration of injured peripheral and central nerve projections.

Adenoviridae↗
PubMed1999

Neurite outgrowth from progeny of epidermal growth factor-responsive hippocampal stem cells is significantly less robust than from fetal hippocampal cells following grafting onto organotypic hippocampal slice cultures: effect of brain-derived neurotrophic factor.

Epidermal growth factor (EGF)-responsive stem cells from both developing and adult central nervous system (CNS) can be expanded and induced to differentiate into neurons and glia in vitro. Because of their self-renewal and multipotent properties, these cells can potentially provide an unlimited tissue source for neural grafting in neurodegenerative disorders. However, the capability of neurons derived from these stem cells to project axons to distant targets following grafting, thereby enabling the restoration of damaged CNS circuitry, remains unknown. We hypothesize that grafted EGF-responsive stem cells and their progeny are not competent to project axons into distant target sites unless exposed to specific neurotrophic factors. We compared neurite outgrowth between gestation day 14 primary mouse hippocampal cells and EGF-generated secondary neurospheres of postnatal mouse hippocampal stem cells, following grafting onto the CA3 region of organotypic hippocampal slice cultures prepared from postnatal rats. Neurite outgrowth from grafted cells was visualized using immunohistochemical staining for the mouse specific antigen M6. Fetal hippocampal cells showed extensive and specific neurite outgrowth into many regions of the slice, including the CA1 region and distant subiculum, by 7 days after grafting. In contrast, neurite outgrowth from neurosphere cells was nonspecific and restricted to the immediate surrounding region after either 7 or even 15 days following grafting. Application of brain-derived neurotrophic factor (BDNF) (5 ng in 0.5 microL) to slices on day 1 after grafting significantly enhanced neurite outgrowth from neurosphere cells, but overall neurite outgrowth from neurosphere cells remained decreased compared to that from fetal hippocampal cells. These results underscore that EGF-responsive stem cell-derived neurons possess limited intrinsic capability for long-distance neurite outgrowth compared to fetal neurons. However, neurite outgrowth from EGF-responsive stem cell-derived neurons can be enhanced by treating with specific neurotrophic factors such as BDNF.

Animals↗
PubMed1996

Improving the robustness of the weighted pairwise correlation test for linkage analysis.

The weighted pairwise correlation (WPC) approach provides simple and flexible tests for genetic linkage which may be adapted to qualitative, quantitative, or age-dependent traits. These tests also seem to have good power. However, when working with large pedigrees, a disease susceptibility gene not linked to the marker studied induces correlations of the trait values, leading to inflated type-I errors for these tests. Thus, in its first version, the WPC approach is reliable when using sibships but not when using larger pedigrees. We propose a way for correcting the variances of the WPC statistics to take these correlations into account. A simulation study shows that the type I errors of the corrected statistics are good. The approach is based on a transformation which yields uncorrelated residuals. We study three statistics, based on the permutation distributions of residuals: one based on ordinary residuals adapted to quantitative traits, another based on martingale residuals adapted to survival data, and one based on rank residuals which can be used in both situations. We apply the corrected WPC tests to pedigrees of Alzheimer's disease previously analyzed with the first version of the method (WRPC).

Adolescent↗
PubMed1997

Robust sensitization to amphetamine following intra-VTA cholera toxin administration.

Studies were conducted regarding the hypothesis that enhanced cAMP formation in the ventral tegmental area (VTA) affects the magnitude of the behavioral responses elicited by psychostimulant drugs. In the first paradigm, spontaneous and amphetamine-elicited locomotor activity was measured at various times following injection of cholera toxin (CTX), a known activator of adenylate cyclase, into the VTA. Adult male rats showed enhanced amphetamine-stimulated locomotor activity when tested 1 or 3 days after treatment with 0.5 microgram CTX into the VTA. Spontaneous activity was markedly increased 1 and 3 days following treatment with the higher dose of 1.0 microgram CTX into the VTA, and amphetamine was still capable of eliciting an increased level of locomotor activity above this high baseline. Using a paradigm in which repeated amphetamine injections were given on an intermittent schedule following injection of CTX into the VTA, it was observed that a single low dose of amphetamine (0.5 mg/kg) given 1 day after CTX (0.5 microgram) injection into the VTA led to a markedly potentiated locomotor activity response to subsequent treatment with amphetamine. Evaluation of this protocol (initial amphetamine dose 24 h after CTX injection, and challenge treatment of amphetamine at various times thereafter) showed that the sensitization was long-lasting and could be observed after an initial dose of amphetamine as low as 0.1 mg/kg. A sensitized response was also expressed when the challenge dose was given directly into the nucleus accumbens. These data suggest that injection of CTX into the VTA enhances the induction of locomotor sensitization to amphetamine.

Adenylyl Cyclases↗
PubMed1999

HMO selection and Medicare costs: Bayesian MCMC estimation of a robust panel data tobit model with survival.

The fraction of US Medicare recipients enrolled in health maintenance organizations (HMOs) has increased substantially over the past 10 years. However, the impact of HMOs on health care costs is still hotly debated. In particular, it is argued that HMOs achieve cost reduction through 'cream-skimming' and enrolling relatively healthy patients. This paper develops a Bayesian panel data tobit model of HMO selection and Medicare expenditures for recent US retirees that accounts for mortality over the course of the panel. The model is estimated using Markov Chain Monte Carlo (MCMC) simulation methods, and is novel in that a multivariate t-link is used in place of normality to allow for the heavy-tailed distributions often found in health care expenditure data. The findings indicate that HMOs select individuals who are less likely to have positive health care expenditures prior to enrollment. However, there is no evidence that HMOs disenrol high cost patients. The results also indicate the importance of accounting for survival over the panel, since high mortality probabilities are associated with higher health care expenditures in the last year of life.

Aged↗
PubMed2000

Laminin-coated poly(L-lactide) filaments induce robust neurite growth while providing directional orientation.

Cellular channels during development and after peripheral nerve injury are thought to provide guidance cues to growing axons. In tissue culture where these cues are absent, neurites from dorsal root ganglion neurons grow with a radial distribution. To induce directional axonal growth and to enhance the rate of axonal growth after injury, we have designed microfilaments of poly(L-lactide). We demonstrate that dorsal root ganglia grown on these filaments in vitro extend longitudinally oriented neurites in a manner similar to native peripheral nerves. The extent of neurite growth was significantly higher on laminin-coated filaments compared with uncoated and poly-L-lysine-coated filaments. As high as 5.8 +/- 0.2 mm growth was observed on laminin-coated filaments compared with 2.0 +/- 0.2 mm on uncoated and 2.2 +/- 0.3 mm on poly-L-lysine-coated filaments within 8 days. Schwann cells were found to grow on all types of filaments. They were, however, absent in the leading edges of growth on laminin-coated filaments. Photolysis of Schwann cells caused a significant reduction in the neurite length on all types of filaments. Laminin-coated filaments, however, induced significantly longer neurites compared with uncoated and/or poly-L-lysine-coated filaments even in the absence of Schwann cells. Our results suggest that laminin-coated poly(L-lactide) filaments are suitable for inducing directional and enhanced axonal growth. Implants designed by arranging these microfilaments into bundles should aid regenerating axons by providing guidance cues and channels to organize matrix deposition, cell migration, axon growth, and improve functional recovery.

Animals↗