Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Variant interpretation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,603 records · Page 89Linked to original sources
PubMedDate not supplied

[Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies. Part I].

In the first part of this work the main problems of prion diseases--also called transmissible cerebral amyloidoses (TCA) or subacute (transmissible) encephalopathies (SSE, TSE)--and clinical symptoms of Creutzfeldt-Jakob disease are presented. Some problems of neuropathology of Creutzfeldt-Jakob disease and basic informations about other human prion diseases will be presented in the second part. The growth of the interest in prion diseases during last years is caused by the problem of bovine spongiform encephalopathy (BSE or "mad cow disease") and its transmission into a human. The new variant of Creutzfeldt-Jakob disease (nvCJD) has appeared. Prion diseases: Gerstmann-Sträussler-Scheinker syndrome (GSS), kuru, fatal familial insomnia (FFI) and particularly the most frequent of them--Creutzfeldt-Jakob disease (CJD)--have nonspecific, sometimes variable clinical (psychopathological and neurological) symptoms. The imaging, EEG, cerebrospinal fluid tests and other laboratory tests are not specific either and their diagnostic value is limited. Neuropathological studies are needed but their interpretation is often difficult. The only certain diagnostic marker for TSE is the presence of PrP(Sc), the prion protein, which is presently believed to be a direct cause for all transmissible cerebral amyloidoses (TCA).

Animals↗
PubMed1991

Phase contrast cine magnetic resonance imaging.

Phase contrast cine magnetic resonance imaging (MRI) combines the flow-dependent contrast of phase contrast MRI with the ability of cardiac cine imaging to produce images throughout the cardiac cycle. Two pulse sequence types are used for sensitivity to flow in one direction, whereas four are needed for sensitivity in all directions. Several alternatives for synchronization of the data to the cardiac cycle exist. Retrospectively interpolated methods can image the entire cardiac cycle efficiently. Rapid interleaving of the various sequence types ensures immunity to motion misregistration. The technique produces images in which contrast is related to flow velocity as well as magnitude images such as those of conventional cine MRI. The data can be interpreted qualitatively to demonstrate the presence, magnitude, and direction of flow, and quantitatively to provide estimates of flow velocity, volume flow rate, and displaced volumes. Phase contrast cine MRI is helpful in the diagnosis of aortic dissections, in the study of flow distributions in large vessels such as pulmonary arteries, as well as in smaller vessels such as carotid and basilar arteries, and in the evaluation of complex anatomical variants. Future developments are expected to reduce imaging time and expand the quantitative applications.

Cardiovascular System↗
PubMed2006

Spinal muscle evaluation using the Sorensen test: a critical appraisal of the literature.

The first test for evaluating the isometric endurance of trunk extensor muscles was described by Hansen in 1964. In 1984, following a study by Biering-Sorensen, this test became known as the "Sorensen test" and gained considerable popularity as a tool reported to predict low back pain within the next year in males. The test consists in measuring the amount of time a person can hold the unsupported upper body in a horizontal prone position with the lower body fixed to the examining table. This test has been used in many studies, either in its original version or as variants. Although its discriminative validity, reproducibility, and safety seem good, debate continues to surround its ability to predict low back pain; in addition, the gender-related difference in position-holding time remains unexplained and the influence of body weight unclear. A contribution of the hip extensor muscles to position holding has been established, but its magnitude remains unknown. The influence of personal factors such as motivation complicates the interpretation of the results. Despite these drawbacks, the Sorensen test has become the tool of reference for evaluating muscle performance in patients with low back pain, most notably before and after rehabilitation programs.

Exercise Test↗
PubMed2006

AID mutates a non-immunoglobulin transgene independent of chromosomal position.

It is unknown how activation-induced cytidine deaminase (AID) targets immunoglobulin (Ig) genes during somatic hypermutation. Results to date are difficult to interpret: while some results argue that Ig genes have special sequences that mobilize AID, other work shows that non-Ig transgenes mutate. In this report, we have examined the effects of the intronic mu enhancer on the somatic hypermutation rates of a retroviral vector. For this analysis, we used centroblast-like Ramos cells to capture as much of the natural process as possible, used AIDhi and AIDlow Ramos variants to ensure that mutations are AID induced, and measured mutation of a GFP-provirus to achieve greater sensitivity. We found that mutation rates of the non-Ig provirus were AID-dependent, were similar at different genomic loci, but were approximately 10-fold lower than the V-region suggesting that AID can mutate non-Ig genes at low rates. However, the intronic mu enhancer did not increase the mutation rates of the provirus. Interestingly, exogenous over-expression of AID revealed that the V-region mutation rate can be saturated by lower levels of AID than the provirus, suggesting that selective mutation of Ig sequences is compromised in cells that over-express AID.

Animals↗
PubMed2001

Pharmacokinetics and pharmacodynamics of methadone enantiomers after a single oral dose of racemate.

BACKGROUND: The pharmacokinetics and dynamics of methadone are characterized by high interindividual variability. This study aimed to examine a number of factors that may contribute to this variability. METHODS: Eight healthy drug-free women were administered 0.2 mg/kg of R,S-methadone orally. The concentrations of methadone's enantiomers in plasma and urine were monitored for 96 hours. Vital signs, blood biochemical parameters, and pupillary diameter were monitored frequently during this period. Cytochrome P450 3A (CYP3A) activity and alpha1-acid glycoprotein (alpha1-AGP) concentrations and phenotypes were determined. Pharmacokinetic and pharmacodynamic modeling was used to assess the influence of the above-mentioned covariables on methadone enantiomer disposition and actions. RESULTS: The pharmacokinetic profile of the active enantiomer of methadone, R -methadone, showed a relatively normal distribution with 38% to 90% of the interindividual variability in modeled pharmacokinetic parameters being explained by their individual variability in CYP3A activity, the cumulative amount of the main CYP3A4 metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrolidine, excreted in the urine, the fraction unbound in plasma, and the alpha1-AGP orosomucoid 2 (ORM2) variant plasma concentration. S-Methadone showed an idiosyncratic distribution with largely unpredictable pharmacokinetics. Pupillary constriction response was highly variable between individuals. CONCLUSIONS: The disposition of the active enantiomer, R -methadone, can be predicted in part by CYP3A activity and protein binding to alpha1-AGP (ORM2), whereas S-methadone disposition is not well explained by the factors examined in this study. Central nervous system effects were difficult to interpret on the basis of plasma R-methadone pharmacokinetics.

Administration, Oral↗
PubMed2003

X-ray absorption spectroscopy reveals a substantial increase of sulfur oxidation in transthyretin (TTR) upon fibrillization.

Transthyretin (TTR) amyloid fibrils are the main component of the amyloid deposits occurring in Familial Amyloidotic Polyneuropathy patients. This is 1 of 20 human proteins leading to protein aggregation disorders such as Alzheimer's and Creutzfeldt-Jakob diseases. The structural details concerning the association of the protein molecules are essential for a better understanding of the disease and consequently the design of new strategies for diagnosis and therapeutics. Disulfide bonds are frequently considered essential for the stability of protein aggregates and since in the TTR monomers there is one cysteine residue, it is important to determine unambiguously the redox state of sulfur present in the fibrils. In this work we used x-ray spectroscopy to further characterize TTR amyloid fibrils. The sulfur K-edge absorption spectra for the wild type and some amyloidogenic TTR variants in the soluble and fibrillar forms were analyzed. Whereas in the soluble proteins the thiol group from cysteine (R-SH) and the thioether group from methionine (R-S-CH(3)) are the most abundant forms, in the TTR fibrils there is a significant oxidation of sulfur to the sulfonate form in the cysteine residue and a partial oxidation of sulfur to sulfoxide in the methionine residues. Further interpretation of the data reveals that there are no disulfide bridges in the fibrillar samples and suggest conformational changes in the TTR molecule, namely in strand A and/or in its vicinity, upon fibril formation.

Benzothiazoles↗
PubMed1995

Hepatic arterial anatomy: demonstration of normal supply and vascular variants with three-dimensional CT angiography.

Three-dimensional (3D) helical computed tomographic (CT) angiography is a promising method of determining vascular anatomy. This technique is useful in delineating the arterial anatomy of the liver, demonstrating the normal anatomy and vascular variants in a highly visual fashion. The "typical" hepatic arterial anatomy occurs in only 55% of the population, and numerous variants exist; the standard classification system for hepatic arterial anatomy includes 10 variations. After helical scanning, postprocessing with reconstruction algorithms such as shaded surface display and maximum-intensity projection provides highly graphic, easily understandable views of vascular anatomy. The 3D CT angiograms, with their global view of the anatomy and inherent advantage of volumetric rotation of the vascular system, are useful to surgeons and others with limited experience in interpreting axial anatomy. Determination of hepatic arterial anatomy with 3D CT angiography has already been shown to be clinically useful in patients being evaluated for liver transplantation.

Adult↗
PubMed2006

Topographic product models applied to natural scene statistics.

We present an energy-based model that uses a product of generalized Student-t distributions to capture the statistical structure in data sets. This model is inspired by and particularly applicable to "natural" data sets such as images. We begin by providing the mathematical framework, where we discuss complete and overcomplete models and provide algorithms for training these models from data. Using patches of natural scenes, we demonstrate that our approach represents a viable alternative to independent component analysis as an interpretive model of biological visual systems. Although the two approaches are similar in flavor, there are also important differences, particularly when the representations are overcomplete. By constraining the interactions within our model, we are also able to study the topographic organization of Gabor-like receptive fields that our model learns. Finally, we discuss the relation of our new approach to previous work--in particular, gaussian scale mixture models and variants of independent components analysis.

Algorithms↗
PubMed1976

[Some aspects of evaluating the thyroid gland scanning image normally and in pathology].

The authors studied 1252 scannograms of 1170 patients. Plane image variants of the shape of normal, dystopic and maldeveloped thyroid gland were studied. Scannographic image of the structure of pathology of the organ and peculiarities of absorption and distribution of radioactive indicators (I131, Tc99m), depending on the histological picture of the pathological process and other factors stimulating or blocking its function are discussed. Practical significance of the method in clinical endocrinology is emphasized and sources of diagnostic errors possible in interpretation of the form and structure of the scannographic picture of the gland under normal and pathological conditions are elucidated.

Adult↗
PubMed1991

Influenza surveillance.

The main objectives of influenza surveillance are: collection of influenza virus isolates and analysis of their antigenic characteristics so that the most appropriate virus variants can be recommended as constituents of influenza vaccines for use during the next epidemiological season; collection and analysis of information on influenza morbidity and mortality; and earliest possible detection of influenza epidemics. Exact estimates of the specific morbidity and mortality due to influenza are now being carried out in only certain countries. Simple notification of clinical cases and deaths without laboratory confirmation is unsatisfactory and leads to errors in interpretation. The methods used to predict baseline mortality may be inaccurate, resulting in underestimation of mortality associated with influenza virus infection. Comparison of the impact of influenza in different countries is also difficult owing to a variety of methods used for the estimation of mortality and morbidity. Although the laboratory aspects of influenza epidemiology are more uniformly covered worldwide than the statistical aspects, it is still necessary to increase laboratory coverage of some parts of the world and to improve the techniques for the isolation and characterization of not only influenza viruses but also other acute respiratory viruses. The systems and methods for influenza surveillance should be improved and standardized.

Epidemiologic Methods↗
PubMed1998

Screening for variability in the ciliary neurotrophic factor (CNTF) gene: no evidence for association with human obesity.

Systemic administration of the neurocytokine ciliary neurotrophic factor (CNTF) normalizes the obese phenotype of ob/ob and db/db mice. CNTF exerts its multiple effects through a receptor complex whose sequence, localization in hypothalamic nuclei and mode of signal transduction share remarkable similarities with the leptin receptor. In the human CNTF gene, a mutation in the first intron creates a new splice acceptor site, with the resulting mRNA coding for an aberrant protein (Takahashi et al., 1994). Given the potential of CNTF to influence energy homeostasis, this study was undertaken to determine whether variability in the CNTF gene is associated with human obesity. The previously described mutation was found in 30.3% of obese children and adolescents, 7 of which were homozygous (allele frequency 0.163). 29.5% of lean subjects carried the mutation, none of which were homozygous (allele frequency 0.148; corrected p = 1 compared to obese). No further mutations were detected by single strand conformational polymorphism (SSCP) analysis. In conclusion, variants in the CNTF gene are unlikely to be associated with the development of early-onset obesity.

Adolescent↗
PubMed2002

Variance stabilization applied to microarray data calibration and to the quantification of differential expression.

We introduce a statistical model for microarray gene expression data that comprises data calibration, the quantification of differential expression, and the quantification of measurement error. In particular, we derive a transformation h for intensity measurements, and a difference statistic Deltah whose variance is approximately constant along the whole intensity range. This forms a basis for statistical inference from microarray data, and provides a rational data pre-processing strategy for multivariate analyses. For the transformation h, the parametric form h(x)=arsinh(a+bx) is derived from a model of the variance-versus-mean dependence for microarray intensity data, using the method of variance stabilizing transformations. For large intensities, h coincides with the logarithmic transformation, and Deltah with the log-ratio. The parameters of h together with those of the calibration between experiments are estimated with a robust variant of maximum-likelihood estimation. We demonstrate our approach on data sets from different experimental platforms, including two-colour cDNA arrays and a series of Affymetrix oligonucleotide arrays.

Algorithms↗
PubMed2026

PRISM-G: an interpretable privacy scoring framework for assessing risk in synthetic human genome data.

MOTIVATION: Synthetic genomic data promises broader data access, but unresolved privacy risks remain a major concern. Existing evaluations often rely on similarity-based metrics that measure proximity between real and synthetic genomes, overlooking additional mechanisms through which genomic information may leak. RESULTS: We introduce PRISM-G, a model-agnostic framework that quantifies privacy exposure in synthetic genomic data across three complementary components: proximity to real genomes in genetic-coordinate space, replay of familial or population-structure patterns, and trait-linked exposure through rare variants and membership-inference signals. These components are normalized and combined through a risk-averse aggregation into a single 0-100 PRISM-G score. By pairing PRISM-G with downstream utility metrics, the framework also enables analysis of privacy-utility trade-offs across generative models. We evaluated PRISM-G on synthetic cohorts generated by a generative adversarial network (GAN), a restricted Boltzmann machine (RBM), and a logic-based SAT solver (Genomator). Our results show that privacy vulnerabilities arise along different axes across models and marker densities, demonstrating that a single similarity-based metric is insufficient to characterize genomic privacy risk. AVAILABILITY AND IMPLEMENTATION: The source code of PRISM-G is available at https://github.com/alejocrojo09/prismg.

Humans↗
PubMed1996

Interphase fluorescence in situ hybridization in a Turner syndrome variant with IsoXq. A case report.

BACKGROUND: Performing fluorescence in situ hybridization (FISH) on uncultured amniotic fluid cells has been known to produce rapid diagnoses of major chromosomal aberrations. However, if the aberration involves a structural chromosomal anomaly, the FISH result may be not only uninformative but misleading. CASE: FISH with alpha-satellite probes of chromosomes X and Y was performed on the uncultured amniocytes of a prenatal amniotic fluid specimen. Eighty-five percent of the hybridized interphase nuclei displayed two signals when probing with X; no significant hybridization was found when probing with Y. This FISH result was interpreted as normal, disomic for chromosome X. Cytogenetic analysis later, however, disclosed the fetal karyotype to be 46,X,i(Xq). CONCLUSION: Interphase FISH with an alpha-satellite probe (or probe made of repeat centromeric sequences) may be useful in the detection of a numerical anomaly of a chromosome but not of a structural anomaly within the chromosome itself.

Amniotic Fluid↗
PubMed1985

Neuropathologic study in the heterozygotes of X-linked brindled mutant mouse.

The clinical and morphological features were studied in female heterozygotes of the sex-linked brindled mutant mice, which are an appropriate animal model for human Menkes' kinky hair disease (MKHD). Clinically, female heterozygotes presented phenotypical variety. In these heterozygotes, we distinguished the unique group of mice, which showed mottled white and dark brown fur and curly whiskers. We designated this unique group "heterozygote, variant type", in contrast to the remaining group--"heterozygote, usual type"--, of which the fur was mottled dark and light brown, and the whiskers were straight. Ultrastructurally, various degrees of mitochondrial changes, from an almost normal appearance of the mitochondria to similar to those of the hemizygotes, were observed. Furthermore we noticed that, in the heterozygotes, there were positive correlations between this morphological spectrum and those phenotypical varieties. These findings were interpreted as a possible subclinical copper deficiency in the heterozygotes, and the morphological alterations in heterozygotes were probably due to X-chromosome inactivation according to Lyon's hypothesis. The presence, however, of clinical and morphological varieties in the heterozygotes leads us to the hypothesis that the inactivation rate is not necessarily the same for all carriers. Moreover, it can be speculated that pathologic changes similar to those in heterozygotes may be present in the female carriers of human MKHD.

Animals↗
PubMed1987

Active avoidance performance in genetically defined mice.

It has been concluded by several investigators that active avoidance performance in mice is primarily influenced or even determined by a single gene. The genetically defined strains C57BL/6 and BALB/c have provided evidence that an aberrant development of pyramidal cells and mossy fiber configuration in the hippocampus of BALB/c mice also is determined by a single gene. As a test of the generality of the single gene influence on avoidance learning, and to examine the relationship of the hippocampal defect to avoidance learning, adult male mice of the inbred progenitor strains C57BL/6ByJ and BALB/cByJ and their seven recombinant inbred strains were tested in a variant of the shuttle-box paradigm used in previous studies. BALB/c were found to acquire the avoidance response at a faster rate than C57BL/6, consistent with most earlier reports, but performances of the recombinant inbred strains failed to dichotomize about the progenitor strains. The rank order of performance scores for the recombinant inbred strains was different from that reported in previous studies. Thus the present data failed to support the interpretation of a single major gene influencing active avoidance learning. It is concluded that avoidance learning and performance cannot be considered as unitary variables and that the interaction of genetic with environmental factors, including the conditions of the specific testing situation, are important considerations in any interpretation of genetic effects. No relationship between the hippocampal lamination defect and avoidance performance was demonstrated.

Animals↗
PubMed1995

Analysis of the pH dependence of the neonatal Fc receptor/immunoglobulin G interaction using antibody and receptor variants.

The neonatal Fc receptor (FcRn) binds maternal immunoglobulin G (IgG) from ingested milk in the gut (pH 6.0-6.5) and delivers it to the bloodstream of the newborn (pH 7.0-7.5). A soluble version of FcRn reproduces the physiological pH-dependent interaction with IgG, showing high-affinity binding at pH 6.0-6.5 but weak or no binding at pH 7.0-7.5. We have studied the pH dependence of the FcRn/IgG interaction using a surface plasmon resonance assay to measure kinetic and equilibrium constants. We show that the affinity of FcRn for IgG is reduced about 2 orders of magnitude as the pH is raised from 6.0 to 7.0. A hill put analysis suggests that several titrating residues participate in the pH-dependent affinity transition. Histidine side chains are likely candidate for residues that titrate between pH 6.0 and 7.0, and previous biochemical and structural work identified several histidines on the Fc portion of IgG that are located at the FcRn binding site. Using mutant IgG molecules and IgG subtype variants that differ in the number of histidines at the IgG/FcRn interface, we demonstrate that IgG histidines located at the junction between the CH2 and CH3 domains (residues 310 and 433) contribute to the pH-dependent affinity transition. Experiments with a mutant FcRn molecule show that two histidines on the FcRn heavy chain (residues 250 and 251) also contribute to the pH dependence of the FcRn/IgG interaction. There results are interpreted using the crystal structures of FcRn and an FcRn/Fc complex.

Antibodies, Monoclonal↗
PubMed1999

The structural and functional role of lysine residues in the binding domain of cytochrome c in the electron transfer to cytochrome c oxidase.

The interactions of yeast iso-1 cytochrome c with bovine cytochrome c oxidase were studied using cytochrome c variants in which lysines of the binding domain were substituted by alanines. Resonance Raman spectra of the fully oxidized complexes of both proteins reveal structural changes of both the heme c and the hemes a and a3. The structural changes in cytochrome c are the same as those observed upon binding to phospholipid vesicles where the bound protein exists in two conformers, B1 and B2. Whereas the structure of B1 is the same as that of the unbound cytochrome c, the formation of B2 is associated with substantial alterations of the heme pocket. In cytochrome c oxidase, the structural changes in both hemes refer to more subtle perturbations of the immediate protein environment and may be a result of a conformational equilibrium involving two states. These changes are qualitatively different to those observed for cytochrome c oxidase upon poly-l-lysine binding. The resonance Raman spectra of the various cytochrome c/cytochrome c oxidase complexes were analyzed quantitatively. The spectroscopic studies were paralleled by steady-state kinetic measurements of the same protein combinations. The results of the spectra analysis and the kinetic studies were used to determine the stability of the complexes and the conformational equilibria B2/B1 for all cytochrome c variants. The complex stability decreases in the order: wild-type WT > J72K > K79A > K73A > K87A > J72A > K86A > K73A/K79A (where J is the natural trimethyl lysine). This order is not exhibited by the conformational equilibria. The electrostatic control of state B2 formation does not depend on individual intermolecular salt bridges, but on the charge distribution in a specific region of the front surface of cytochrome c that is defined by the lysyl residues at positions 72, 73 and 79. On the other hand, the conformational changes in cytochrome c oxidase were found to be independent of the identity of the bound cytochrome c variant. The maximum rate constants determined from steady-state kinetic measurements could be related to the conformational equilibria of the bound cytochrome c using a simple model that assumes that the conformational transitions are faster than product formation. Within this model, the data analysis leads to the conclusion that the interprotein electron transfer rate constant is around two times higher in state B2 than in B1. These results can be interpreted in terms of an increase of the driving force in state B2 as a result of the large negative shift of the reduction potential.

Alanine↗