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Ultraviolet radiation: effects on risks of prostate cancer and other internal cancers.

Governmental and research agencies worldwide have strongly advocated sun avoidance strategies in an attempt to counter marked increases in skin cancer incidence. Concurrently, there are reports describing widespread Vitamin D3 deficiency. Because 1,25-dihydroxyvitamin D3, through interaction with the Vitamin D receptor, exerts pleiotrophic effects, such deficiency might be expected to have clinical consequences. Indeed, various reports indicate that exposure to ultraviolet radiation (UVR) exerts a protective effect on development of some common diseases including internal cancers and multiple sclerosis. We describe studies indicating that modest exposure reduces risk of prostate cancer. The effect of UVR is mediated by skin type; at lower levels of exposure a relative inability to effect skin pigmentation is protective presumably because it allows more efficient Vitamin D3 synthesis. Polymorphic variants in genes associated with pigmentation including melanocyte stimulating hormone receptor and tyrosinase are also associated with prostate cancer risk. Overall, though preliminary and requiring cautious interpretation, these data indicate that moderate UVR exposure together with characteristics linked with less effective tanning confer reduced prostate cancer risk. Clearly, it is important to define safe levels of UVR that do not result in increased risk of skin cancers such as malignant melanoma.

Humans↗

Four paraoxonase gene polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-analysis of 43 studies.

BACKGROUND: Although there have been suggestions that serum paraoxonase is important in protecting against coronary heart disease (CHD), a large number of studies of genetic determinants of serum paraoxonase have reported apparently conflicting results about their association with CHD. METHODS: We conducted a meta-analysis of 43 studies of the Q192R, L55M, and T(-107)C polymorphisms in the paraoxonase PON1 gene and the S311C polymorphism in the PON2 gene (all of which are in moderately strong linkage disequilibrium with one another), involving a total of 11212 CHD cases and 12786 controls. We explored potential sources of heterogeneity. FINDINGS: In a combined analysis of all studies, the per-allele relative risk of R192 for CHD was 1.12 (95% CI 1.07-1.16), but in the five largest studies it was only 1.05 (0.98-1.13). Combined analyses of studies of the M55, (-107)T, and C311 variants showed no significant overall associations with CHD, yielding per-allele relative risks of 1.00 (0.95-1.06), 1.02 (0.92-1.14), and 1.04 (0.93-1.17), respectively. INTERPRETATION: In contrast to previous suggestions, this meta-analysis shows no significant association of CHD with the L55M or T(-107)C polymorphism in PON1 or with the S311C polymorphism in PON2. The weak overall association between the Q192R polymorphism and CHD is of uncertain relevance, particularly since there was no significant association among the larger studies which should be less prone to selective publication. These findings reinforce the need for much larger and more rigorous investigations of the genetic determinants of complex diseases than is now customary, as well as for regularly updated systematic appraisals of such studies to help improve interpretation and prioritise hypotheses.

Aryldialkylphosphatase↗

The nature and destiny of translocated B-chromosome-specific satellite DNA of rye.

Translocations of A chromosome-specific and B chromosome-specific satellite DNA were tracked by fluorescence in situ hybridisation from an irradiated M1 generation of an experimental population of rye (Secale cereale L.) to its M2 progeny. Although high frequencies of large structural rearrangements were detected in root-tip meristems of M1 plants, none was present at meiosis or in somatic cells of their progeny. These results are interpreted in terms of efficient "filtering" of translocations during vegetative development, and not in the more usual terms of meiosis presenting a physical barrier to structural variants. These observations highlight the fact that B-A translocations are not tolerated, and may explain why this form of chromosome mutation is largely absent from natural populations.

Chromosome Mapping↗

Functional mapping and annotation of genetic associations with FUMA.

A main challenge in genome-wide association studies (GWAS) is to pinpoint possible causal variants. Results from GWAS typically do not directly translate into causal variants because the majority of hits are in non-coding or intergenic regions, and the presence of linkage disequilibrium leads to effects being statistically spread out across multiple variants. Post-GWAS annotation facilitates the selection of most likely causal variant(s). Multiple resources are available for post-GWAS annotation, yet these can be time consuming and do not provide integrated visual aids for data interpretation. We, therefore, develop FUMA: an integrative web-based platform using information from multiple biological resources to facilitate functional annotation of GWAS results, gene prioritization and interactive visualization. FUMA accommodates positional, expression quantitative trait loci (eQTL) and chromatin interaction mappings, and provides gene-based, pathway and tissue enrichment results. FUMA results directly aid in generating hypotheses that are testable in functional experiments aimed at proving causal relations.

Chromatin↗

Fine needle aspiration of the thyroid: a cytohistologic correlation and study of discrepant cases.

OBJECTIVE: Fine needle aspiration (FNA) is a reliable method in the initial assessment of thyroid nodules. The purpose of this study was to evaluate the causes for discordance between the interpretation on FNA and the pathologic findings in the resected thyroid. METHODS: A computer search of all thyroidectomy specimens with previous FNA from January 1998 to December 2001 was obtained from the files of the Lauren V. Ackerman laboratory of surgical pathology, Barnes-Jewish Hospital. Excluded from the study were those FNAs performed for suspected and confirmed metastatic disease to the thyroid as well as those cases unavailable for review. A total of 45 FNA cases were identified with cytologic and histologic discrepancies. RESULTS: Of the 1253 individual thyroid FNA performed during the study period, 255 patients (20%) subsequently had an open surgical procedure on the thyroid. Of those who underwent surgery, 196 cases (77%) were concordant, whereas 45 patients (18%) were discordant, and 14 cases were excluded due to unavailability of slides for review (for example, returned consult slides). The causes of the 45 discordant cases were: 20 cases (44%) were unsatisfactory for diagnosis, 14 cases (31%) were due to interpretation error (false positive), and 11 cases (24%) were due to sampling error (false negative). CONCLUSIONS: The most common causes of our discrepant cases are those whose FNA diagnosis was interpreted as "unsatisfactory for diagnosis," in 20 (7.8%) of 255 surgical cases. The false negative rate due to sampling error in 11 (4%) of 255 cases was mainly due to the presence of microscopic papillary thyroid carcinoma (PTC); the false positive rate was due to interpretation error in 14 (6%) of 255 cases, and those were explained by the occurrence of overlapping cytologic features among adenomatous nodules, follicular neoplasms, the follicular variant of PTC, and Hashimoto's thyroiditis.

Biopsy, Fine-Needle↗

Phenotype-genotype association grid: a convenient method for summarizing multiple association analyses.

BACKGROUND: High-throughput genotyping generates vast amounts of data for analysis; results can be difficult to summarize succinctly. A single project may involve genotyping many genes with multiple variants per gene and analyzing each variant in relation to numerous phenotypes, using several genetic models and population subgroups. Hundreds of statistical tests may be performed for a single SNP, thereby complicating interpretation of results and inhibiting identification of patterns of association. RESULTS: To facilitate visual display and summary of large numbers of association tests of genetic loci with multiple phenotypes, we developed a Phenotype-Genotype Association (PGA) grid display. A database-backed web server was used to create PGA grids from phenotypic and genotypic data (sample sizes, means and standard errors, P-value for association). HTML pages were generated using Tcl scripts on an AOLserver platform, using an Oracle database, and the ArsDigita Community System web toolkit. The grids are interactive and permit display of summary data for individual cells by a mouse click (i.e. least squares means for a given SNP and phenotype, specified genetic model and study sample). PGA grids can be used to visually summarize results of individual SNP associations, gene-environment associations, or haplotype associations. CONCLUSION: The PGA grid, which permits interactive exploration of large numbers of association test results, can serve as an easily adapted common and useful display format for large-scale genetic studies. Doing so would reduce the problem of publication bias, and would simplify the task of summarizing large-scale association studies.

Computer Graphics↗

Muscarinic stimulation of alpha1E Ca channels is selectively blocked by the effector antagonist function of RGS2 and phospholipase C-beta1.

Neuronal alpha1E Ca channel subunits are widely expressed in mammalian brain, where they are thought to form R-type Ca channels. Recent studies have demonstrated that R-type channels contribute to neurosecretion and dendritic Ca influx, but little is known concerning their modulation. Here we show that alpha1E channels are strongly stimulated, and only weakly inhibited, through M1 muscarinic acetylcholine receptors. Both forms of channel modulation are mediated by pertussis toxin-insensitive G-proteins. Channel stimulation is blocked by regulator of G-protein signaling 2 (RGS2) or the C-terminal region of phospholipase C-beta1 (PLCbeta1ct), which have been previously shown to function as GTPase-activating proteins for Galphaq. In contrast, RGS2 and PLCbeta1ct do not block inhibition of alpha1E through M1 receptors. Inhibition is prevented, however, by the C-terminal region of beta-adrenergic receptor kinase 1, which sequesters Gbetagamma dimers. Thus, stimulation of alpha1E is mediated by a pertussis toxin-insensitive Galpha subunit (e.g., Galphaq), whereas inhibition is mediated by Gbetagamma. The ability of RGS2 and PLCbeta1ct to selectively block stimulation indicates these proteins functioned primarily as effector antagonists. In support of this interpretation, RGS2 prevented stimulation of alpha1E with non-hydrolyzable guanosine 5'-0-(3-thiotriphosphate). We also report strong muscarinic stimulation of rbE-II, a variant alpha1E Ca channel that is insensitive to voltage-dependent inhibition. Our results predict that Galphaq-coupled receptors predominantly stimulate native R-type Ca channels. Receptor-mediated enhancement of R-type Ca currents may have important consequences for neurosecretion, dendritic excitability, gene expression, or other neuronal functions.

Animals↗

[The storiform M-8333/1,3 neurofibroma].

Attention concentrated on features of storiform neurofibroma failed to find an unambiguous universal interpretation. 15 consecutively published cases were collectively revised with partial conclusions from a comparison of findings and references: Nosological identity of dermatofibrosarcoma protuberans and its "pigmented variant" is substantiated but fails to solve histogenetic embarrassment of both items. Characteristic storiform structure is connected with layered very flat cells. No doubt they remind of spindle-shaped fibroblasts in cross section but flat dendritic cells remain an essential component no matter whether pigmented or not. Open to discuss is whether fibroblasts belong to adaptable cells which generally can get a flat shape among dendritic cells. Their pigmentation may have local origin according to paraneuronal theory.

Fibrosarcoma↗

Congruity and predictability between two measures of nonstandard dialect usage on four grammatical forms.

This study investigated whether Nonstandard English (NSE) dialect responses to an examiner-constructed sentence completion test were congruent with and predictive of use of NSE during spontaneous conversation. The sentence completion test was designed to evoke either NSE or Standard English (SE) dialect variants of four grammatical forms for which the NSE dialect variants are highly stigmatized. The 76 Black male subjects were between the ages of 15:8 and 23:5 years. The grammatical forms assessed were verb-subject agreement third person singular, negative concord, possessive suffix, and continuative be. A low but statistically significant correlation was found between the percentage of NSE usage on the test and during conversation when all four grammatical forms were combined (r = .2344, p less than .05). Only the possessive suffix form showed a statistically significant correlation between the two measures when correlations were computed for individual grammatical forms (r = .4341, p less than .05). Thus, congruency was interpreted to be highly variable and dependent on the particular grammatical form. To measure predictability, data were inspected for each grammatical form to determine the percentage of subjects who used at least one NSE dialect variant for sentence completion test items when at least one NSE variant of that form occurred during spontaneous conversation. Responses to the sentence completion test were predictive of NSE during conversation for more than 90% of the subjects only for the negative concord grammatical form. It was concluded that the sentence completion test is satisfactorily congruent with and predictive of patterns of dialect used in spontaneous conversation only for certain specific grammatical forms. Some possible reasons for these variable results and their implications for second dialect assessment are offered.

Adolescent↗

Kinetic and thermodynamic properties of two electrophoretically similar genetic variants of human erythrocyte glucose-6-phosphate dehydrogenase.

Glucose-6-phosphate dehydrogenase (G6PD) A(+) and G6PD A(-) were purified to electrophoretic homogeneity from human male erythrocytes. The steady state kinetics of the binding reaction of NADP+ to the two variants were studied as a function of pH and temperature at a constant ionic strength of 0.01. The interaction coefficient, obtained according to the Hill equation, rises with an increase in pH and temperature. The observed variation of cooperative interaction is interpreted in terms of an increase in the percentage of the dimeric form of the enzyme as pH or temperature increases. The more rapid increase in the interaction coefficient with increase in pH or temperature for G6PD A(-) as compared with G6PD A(+) shows that G6PD A(-) forms dimers at a lower pH or temperature than G6PD A(+). Analysis of the log Vmax versus pH curves and their temperature dependence for the two enzyme variants indicates the participation in the reaction mechanism of sulphydryl groups or imidazolium group of histidine. The two variants show very similar but minor specific and significant differences in kinetic and thermodynamic properties with respect to NADP+ binding. Thus the additional mutation in G6PD A(-) must be responsible for its increased affinity for NADP(+) when compared to G6PD A(+) from which it has been derived. These results are consistent with an earlier report (Babalola O et al (1972) Proc Natl Acad Sci USA 69, 946-950) that enzyme 'deficiency' in vivo is due mainly to a loss of active enzyme molecules, rather than to a decreased activity of each molecule.

Dimerization↗

[Bettelheim's witch: the questionable relation between fantasy and psychoanalysis].

Literary and folk narrative scholars understand fairy tales in ways which differ radically from the readings of Bruno Bettelheim and of many other psychoanalytically-oriented interpreters. Their exegeses ignore--or are ignorant of--information which has been basic to folk and fairy tale scholarship for nearly two hundred years. This includes careful distinctions between that material which is common to many different cultures and that which differs profoundly from one culture to another. Such categories include the identity of evil incarnate, the significance of particular colours, social values with reference to gender, variant analysis, and the impact of nineteenth century values on nineteenth century tale collections, especially the Grimms' Kinder- und Hausmärchen.

Adolescent↗

Study of ten anatomical variants of the foot and ankle.

This study examined the occurrence rate of ten lower extremity anatomical variants occurring over a 6-year period from 1988 to 1994 in a sample range of 166 to 279 cadavers at the University of Osteopathic Medicine and Health Sciences. Literature review of these anomalies shows similar findings for all presented structures with the exception of two. The peroneus quartus muscle was found to be significantly less prevalent than previous studies have indicated. This difference may be attributed to the larger sample size used in this study or differences of interpretation of the definition of the peroneus quartus muscle. Additionally, the flexor digitorum brevis tendon to the fifth digit was found to be absent much more than Sarrafian reports in a total sample size of 926. The importance of these anatomical variants, both in surgery and while using advanced diagnostic imaging such as computed tomography and magnetic resonance imaging, should be realized by the podiatric physician. Awareness of these variants will decrease confusion when considering treatment options.

Ankle↗

The clinical use of monoclonal anti-T-cell antibodies.

Monoclonal anti-T-cell antibodies are progressively replacing other T-cell markers in clinical immunology. A number of problems persist however, that urge for caution in interpreting the data issued from their in vitro use. Several antibodies directed against the same molecule may give different results according to the subject (due to genetic variants) or according to stage T-cell differentiation. The expression of antigenic determinants (epitopes may vary under the effect of drugs, positively (cimetidine, thymic hormones) or negatively (indomethacin). Lastly the correlation between phenotype and function of T-cell subsets may be very poor in the same pathological settings. In spite of these pitfalls, monoclonal anti-T-cell antibodies have proven to be very useful in several circumstances. Thus, in renal allograft recipients immunological monitoring with monoclonals helps the diagnosis of rejection in patients treated with conventional immunosuppression and permits early detection of antigenic modulation and xenosensitization in patients treated with the anti-T-cell OKT3 antibody.

Antibodies, Monoclonal↗

Cross-sectional imaging of the pancreas.

CT is the primary modality for the evaluation of patients with pancreatic disease. A number of pitfalls can occur in interpretation of the scans, but most can be avoided by using state-of-the-art scanners and dynamic contrast enhancement techniques and by recognizing normal anatomic variants. However, in other cases, CT may show only nonspecific findings and a correct diagnosis can be reached only by utilization of additional imaging techniques or guided FNAB.

Humans↗

Effect of B vitamins and genetics on success of in-vitro fertilisation: prospective cohort study.

BACKGROUND: There is a need to understand what affects the success of in-vitro fertilisation (IVF) and the rate of resulting twin births so that pregnancy rates can be improved and multiple gestations avoided. Our aim was to assess the role of B vitamins and genetics. METHODS: We did a prospective cohort study of 602 women undergoing fertility treatment. We assessed intake of folate and vitamin B12 with a questionnaire and measured their plasma and red-blood-cell concentrations by radioimmunoassay. We measured five B-vitamin-related gene variants in women who received treatment and in 932 women who conceived naturally. FINDINGS: The likelihood of a twin birth after IVF rose with increased concentrations of plasma folate (1.52, 1.01-2.28; p=0.032) and red-cell folate (1.28, 1.00-1.65; p=0.039). There was no association between folate and vitamin B12 levels and likelihood of a successful pregnancy. Women homozygous for the 1298 CC variant of methylenetetrahydro-folate reductase (MTHFR), rather than the AA variant, were less likely to produce a livebirth after IVF (0.24, 0.08-0.71; p=0.003) or to have had a previous pregnancy (0.42, 0.21-0.81; p=0.008). INTERPRETATION: Our findings suggest that MTHFR genotype is linked to a woman's potential to produce healthy embryos (possibly through interaction with genes related to DNA methylation). In women likely to have a successful IVF pregnancy, high folate status increases the likelihood of twin birth after multiple embryo transfer. Proposals to fortify the UK diet with folic acid could lead to an increase in the number of twins born after IVF.

Chorionic Gonadotropin↗

[MRI of hippocampal malformations in patients with intractable temporal lobe epilepsy].

OBJECTIVE: In some patients with temporal lobe epilepsy, recent MRI studies have revealed several morphological features indicative of discrete hippocampal malformation (HM). Its prevalence is unknown and the relationship between the HM and the origin of seizures has never been investigated. Our purpose is to define the MRI findings of this new entity and to determine its incidence in a group of patients and in a control group in order to evaluate its clinical significance. MATERIALS AND METHODS: MR imaging findings in 97 patients suffering from medically intraceable temporal epilepsy were prospectively evaluated during the preoperative evaluation of surgical candidates. The MR-imaging protocol included oblique coronal slices perpendicular to the temporal lobes using high resolution T2 weighted (HR TSE T2), Fluid attenuated inversion recovery (FLAIR) and inversion-images. This protocol has been completed by axial FLAIR images and axial and sagittal IR images of the whole brain. Coronal HR TSE T2 images were performed in 50 healthy control subjects. Cerebral lesion and hippocampal morphology were evaluated in both groups. RESULTS: Fourteen patients (14%) showed hippocampal morphological modification. The most frequent and specific findings were lack of visualization of the internal hippocampal (lack of linear T2 hypointensity within the hippocampus) and the abnormal shape (pyramidal, vertically oriented or globular-shaped). Other signs were: abnormal position of the hippocampus (medically located hippocampus) and vertical collateral sulcus. Cases without visualization of the internal structure of the hippocampus were considered as a complete form of HM and were correlated with temporal epilepsy. A vertical collateral sulcus was observed in some control group subjects. CONCLUSION: Complete forms of HM could be considered as epileptogenic lesions. Nevertheless, interpretation of the incomplete form is delicate: the abnormal angle of the collateral sulcus can be encountered in healthy subjects and could therefore be considered a normal variant.

Adolescent↗