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X-linked extension of the revised Haseman-Elston algorithm for linkage analysis in sib pairs.

Haseman and Elston (H-E) proposed a regression-based robust test of linkage between a marker and an autosomal quantitative trait locus, using the squared sib pair trait difference as a dependent variable and the proportion of alleles shared identical by descent by the sib pair as an independent variable. Several authors have proposed improvement of the original H-E's seminal work by using an optimal linear combination of squared sum and squared difference as the dependent variable. In this paper, we extend Haseman and Elston's sib pair method to an X-linked locus. We give a general formulation of the complete regression model and details of the regression coefficients in terms of variance components. Simulation results are presented to describe the power of this technique for a theoretical best case scenario.

Algorithms↗

Complete amino acid sequence of the variable domains of two human IgM anti-gamma globulins (Lay/Pom) with shared idiotypic specificities.

On the basis of extensive shared idiotypic specificities, two human IgM anti-gamma-globulins (Lay/Pom) were selected for complete amino acid sequence analysis of their variable domains. Previous studies on the variable regions of the heavy chains of these proteins had shown but eight amino acid differences, only one of which was within a complementarity-determining hypervariable region. The complete amino acid sequence of the variable regions of the light chains of these two proteins is the subject of this report. Protein Lay is a typical VchiI protein with only five 'framework' differences when compared with protein Roy. Protein Pom is best classified as a VchiII, but in the 'framework' there are 16 differences between it and protein Ti. Although there are extensive differences in the first hypervariable region, the second and third light-chain hypervariable regions have an identical sequence. The finding of two identical light-chain and two identical heavy-chain hypervariable regions in these two proteins, which were selected on the basis of their combining specificities and their idiotypic cross-reactions, strongly implicates hypervariable regions in the constitution of the idiotypic determinants and the antibody combining site. Additionally, the finding of identical hypervariable regions in light chains of different V-region subgroups fulfills a prediction of the gene-interaction concept of antibody variability.

Amino Acid Sequence↗

Genetic and environmental vulnerabilities underlying adolescent substance use and problem use: general or specific?

Are genetic and environmental risks for adolescent substance use specific to individual substances or general across substance classes? We examined this question in 645 monozygotic twin pairs, 702 dizygotic twin pairs, 429 biological sibling pairs, and 96 adoptive (biologically unrelated) sibling pairs ascertained from community-based samples, and ranging in age from 12 to 18 years. Substance use patterns and symptoms were assessed using structured psychiatric interviews. Biometrical model fitting was carried out using age- and sex-specific thresholds for (a) repeated use and (b) problem use, defined as one or more DSM-IV symptoms of abuse or dependence. We hypothesized that problem use would be more heritable than use in adolescence, and that both genetic and environmental risks underlying tobacco, alcohol, and marijuana use and problem use would be significantly correlated. Results of univariate analyses suggested significant heritable factors for use and problem use for all substances with the exception of alcohol use. Shared environmental factors were important in all cases and special twin environmental factors were significant for tobacco use, tobacco problem use, and alcohol use. Multivariate analyses yielded significant genetic correlations between each of the substances (for both levels studied), and significant shared environmental correlations among use variables only. Our results suggest that tobacco, alcohol, and marijuana problem use are mediated by common genetic influences, but shared environmental influences may be more substance-specific for problem use.

Adolescent↗

Clinical features of illness in siblings with schizophrenia or schizoaffective disorder.

Evidence implicating genetic or prenatal-perinatal environmental causes in the familial aggregation of schizophrenia led us to study 53 sets of siblings, two or more of whom had chronic psychosis, either schizophrenia or schizoaffective disorder. We looked for similarities in clinical features and concordance of diagnosis within sibships to test for shared familial causes. Clinical variables, including diagnosis, specific symptoms, age at onset, and nongenetic perinatal factors, were studied. Auditory hallucinations, paranoid delusions, thought disorder, negative symptoms, and poor premorbid social adjustment did not significantly correlate in siblings. Concordance was found for schizoaffective disorder and history of major depressive episodes, suggesting that schizophrenia with a depressive component and Research Diagnostic Criteria schizoaffective illness may represent a specific etiologic subtype(s) of the illness, whereas the other noted symptoms may represent the variable expression of the disorder. Age at onset and at first hospitalization were significantly correlated, consistent with genetic or other familial factors on time of onset. Birth complications were significantly more frequent among the schizophrenic compared with non-psychotic siblings, had a familial component, and tended to be associated with an earlier age at onset. Thus, nongenetic perinatal factors may increase the risk for schizophrenia in a familial form of the illness and contribute to the correlation of ages at onset in siblings.

Adult↗

A meta-analysis of chromosome 18 linkage data for bipolar illness.

We find a meta-data set (715 families, up to 1,124 sib pairs) for bipolar illness to have a strong signal in a 10 cM region around D18S40, and excess paternal sharing on the q arm near marker D18S64. We describe a method for meta-analysis of microsatellite marker data using affected sib-pair (ASP) methodology. Inherent difficulties in such analysis include heterogeneity of allele frequencies and protocol design, measurement errors in genotyping, and map construction. Using identity-by-descent (IBD) allele sharing as the dependent variable, a logistic regression to test for heterogeneity finds only mild heterogeneity, and a limited parent-of-origin effect.

Alleles↗

Ankyloblepharon filiforme adnatum.

We treated 4 infants with ankyloblepharon filiforme adnatum (AFA), an uncommon anomaly in which the apposing eyelid margins are connected by abnormal tissue strands. One infant had AFA alone, one had Hay-Wells syndrome, characterized by ectodermal dysplasia, and the other 2 had chromosome abnormalities, trisomy 18, and complex chromosome rearrangement, with visceral malformations. Despite heterogeneity and phenotypic variability, these developmental abnormalities shared (1) involvement of tissues growing in apposition and (2) temporal overlap of their occurrence. This suggests a common defect in the mechanism(s) that regulate tissue fusion at multiple sites during development.

Abnormalities, Multiple↗

Late-onset mitochondrial myopathy.

In the majority of patients with mitochondrial encephalomyopathies, signs and symptoms appear in the first three decades of life. Here we report on a group of 9 older patients (> 69 years old) with late-onset skeletal myopathy characterized by focal accumulations of deleted mitochondrial DNAs (mtDNAs) and altered muscle energy status, suggestive of a primary mitochondrial disease. The clinical phenotype was somewhat variable. However, all patients shared a common feature of insidious moderate proximal muscle weakness; some also showed fatigability and axial muscle weakness. In situ hybridization analysis demonstrated accumulations of messenger RNAs transcribed from deleted mtDNAs in a relatively large number of muscle fibers in the patient group. These fiber segments appeared as ragged red with the modified Gomori trichrome stain and hyperreactive with a modified succinate dehydrogenase stain. Most were negative for cytochrome c oxidase activity. On transverse sections their mean frequency was 0.69% (trichrome) and 1.97% (succinate dehydrogenase) significantly above control levels. Multiple mtDNA deletions were demonstrated by the polymerase chain reaction in both the patients and an age-matched control group, but not in younger control subjects. Phosphorus 13 magnetic resonance spectroscopy of resting muscle showed a decreased phosphocreatine-inorganic phosphate ratio in the patient group. The myopathy in this group of patients appears to result from mitochondrial dysfunction related to the clonal expansion of different mtDNA deletions in individual fiber segments. While the origin of the mtDNA mutations is not clear, the phenotype seems to represent an exaggerated form of what is observed in the normal aging process.

Aged↗

Patterns of morphological, biochemical, and molecular evolution in the Oeneis chryxus complex (Lepidoptera: Satyridae): a test of historical biogeographical hypotheses.

Surveys of allozyme allele frequency and mitochondrial DNA (mtDNA) sequence variation were employed to test historical biogeographical hypotheses on the origin and unique distribution of the synchronized biennial, high-altitude butterflies of the Oeneis chryxus complex in western North America. Populations of O. c. stanislaus and O. ivallda from the central and northern Sierra Nevada are indistinguishable by use of allozyme allele frequency data, possessed nearly identical mtDNA cytochrome oxidase subunit 1 (COI) haplotypes, and were found to be relatively distantly related to O. c. chryxus from the Snake Range in eastern Nevada. However, individuals of O. ivallda from Piute Pass in the southern Sierra Nevada are more variable, with some individuals sharing mtDNA characteristics with O. c. chryxus. We find little support for the hypothesis proposed by W. Hovanitz in 1940 that O. c. stanislaus invaded the central Sierra Nevada from across the Great Basin and displaced O. ivallda, but cannot reject the hypothesis that ancestral Oeneis dispersed across the Great Basin to California. This result is congruent with hypotheses of dispersal across the Great Basin for the origin of some Sierran alpine organisms.

Alleles↗

Enterococcal resistance to vancomycin and related cyclic glycopeptide antibiotics.

Enterococci belonging to various species resistant to vancomycin and related cyclic glycopeptide antibiotics have been isolated from hospitalized patients in France, the UK and the USA. All such strains examined display inducible synthesis of a membrane protein associated with resistance. The mechanism by which the membrane protein acts has not been definitively established, but it may block the access of the antibiotic to its peptidoglycan target. That the protein could be a bypass enzyme has not been ruled out. Transfer of glycopeptide resistance by conjugation to either Enterococcus faecium or Enterococcus faecalis and by transformation of Streptococcus sanguis Challis has been reported. The structural and regulatory genes encoding this resistance can be localized on plasmid and, apparently, chromosomal DNA. The plasmids encoding this resistance appear to differ from each other and have variable host ranges, but share at least some DNA sequence homology.

Aminoglycosides↗

Factors related to dissociation among patients with gastrointestinal complaints.

OBJECTIVES: Several recent reports have suggested that the process of dissociation is independently associated with several distressing conditions such as psychiatric diagnoses, somatization, current psychological distress, and past sexual and physical victimization. These studies, however, have not taken into account possible shared variance between these variables. Is dissociation uniquely related to each of these outcomes or do they, as a group, have common underlying factors that account for the relationship with dissociation? METHOD: As part of a larger study of gastroenterology clinic patients with irritable bowel syndrome and patients with inflammatory bowel disease (n = 103), we used stepwise multiple regression to select the factors most associated with dissociation, while controlling for the effects of other variables. Variable domains included demographics, psychiatric diagnoses, personality factors, functional disability, and trauma history. These domains as well as individual variables within these domains were systematically evaluated for their unique contribution to the prediction of dissociation as measured by the Dissociative Experiences Scale (DES). RESULTS: The best multivariable model for estimating dissociation magnitude included severe child sexual abuse, perceived physical disability, and lifetime dysthymia, alcoholism, and generalized anxiety disorder. These factors accounted for 37% of the variance in DES score and increased the correct classification of patients as either low-, middle-, or high-level dissociators. CONCLUSIONS: Dissociation among this convenience sample of IBS and IBD patients is a long-term coping pattern that is associated primarily with past sexual trauma, chronic emotional distress, alcoholism, and physical disability. Prospective studies are needed to test whether these findings also occur in other more generalizable samples.

Adolescent↗

A method of quantify confounding in regression analyses applied to data on diet and CHD incidence.

We present a method to display the results of linear regression when the independent variables are highly correlated. In this method the sum of squares of regression (SSR) for pairs of variables are partitioned into orthogonal and shared components. A shared component is the reduction in the SSR of one of the variables when the other variable is added to the regression equation. This method shows how the SSR for one variable depends on the other variables present in the regression equation and explains apparent inconsistencies between forward and backward stepwise regression. To demonstrate the potential usefulness of this method we reanalyzed previously reported data on the relationship between coronary heart disease (CHD) and diet. The analysis suggested that carbohydrate and alcohol intake are negatively associated with CHD because they are associated with greater caloric intake. Protein and fat intake are also associated with greater caloric intake, but in addition they are associated with factors that increase the risk of CHD.

Alcohol Drinking↗

Adversity among drug users: relationship to impulsivity.

Illicit substance users experience adverse life events, but few studies have examined the role of impulsivity in these events. The present investigation sought to establish a link between negative life experiences and a trait measure of impulsivity and demonstrate that this association remains even accounting for potential confounds. Participants were 330 heroin and cocaine users recruited from the community for a health service research study. Participants completed a structured interview that assessed topics including drug and alcohol use, impulsivity, and negative life events. This group of drug users reported high rates of adverse life events in the 6 months prior to the assessment. No specific substance abuse/dependence diagnosis or combination of diagnoses was associated with adversity. Number of substance-related diagnoses was associated with adverse life events, but not when adjusting for impulsivity. Experience of these events was significantly associated with impulsivity (p<.001), above and beyond the shared relation with demographic variables, substance abuse and dependence, and number of substance-related diagnoses. These findings document the high frequencies of recent adverse life events among illicit drug users and indicate that trait impulsivity is associated with increased risk of these life events.

Adult↗

Multivariate receptive field mapping in marmoset auditory cortex.

We describe a novel method for estimation of multivariate neuronal receptive fields that is based on least-squares (LS) regression. The method is shown to account for the relationship between the spike train of a given neuron, the activity of other neurons that are recorded simultaneously, and a variety of time-varying features of acoustic stimuli, e.g. spectral content, amplitude, and sound source direction. Vocalization-evoked neuronal responses from the marmoset auditory cortex are used to illustrate the method. Optimal predictions of single-unit activity were obtained by using the recent-time history of the target neuron and the concurrent activity of other simultaneously recorded neurons (R: 0.82 +/- 0.01, approximately 67% of variance). Predictions based on ensemble activity alone (R: 0.63 +/- 0.18) were equivalent to those based on the combination of ensemble activity and spectral features of the vocal calls (R: 0.61 +/- 0.24). This result suggests that all information derived from the spectrogram is embodied in ensemble activity and that there is a high level of redundancy in the marmoset auditory cortex. We also illustrate that the method allows for quantification of relative and shared contributions of each variable (spike train, spectral feature) to predictions of neuronal activity and describe a novel "neurolet" transform that arises from the method and that may serve as a tool for computationally efficient processing of natural sounds.

Acoustic Stimulation↗

An etiologic model proposing that sporadic adult-onset carcinoma is extramedullary hematopoiesis.

This model proposes that primary carcinomatous tumors and almost all metastases are extramedullary hematopoietic tissue formed to compensate for reduced hematopoietic activity in the bone marrow. These marrow lesions are currently considered to be metastatic in origin, but as fibrosis and sclerosis are identifying features they are here equated to myelofibrosis. Myelofibrotic marrow is characterized by an increase in the number and size of vascular sinusoids. The increased blood flow suggested by this morphology, and observed in myelofibrosis patients, causes a rise in marrow pressure which may trigger the fibrosis. Specific carcinoma morphologies are equated to stages in endochondral bone and marrow formation and, as such, cancer cell identity varies with morphology. For example, infiltrating carcinomas of the breast consist of collagen and mucoid secreting cells in single file formation. This morphology is equated to the cartilagenous stage of marrow formation, when mesenchymal stem cells proliferate and differentiate into chondroblasts. In this model "infiltrating" cells arise in situ from stem cells located in the connective tissue. Tubular breast carcinoma, with its single layer of osteoblast-like carcinoma cells encircling small lumens and long branching tubules, is equated to the trabecular stage of marrow formation during which osteoblasts surround small pieces of calcified cartilage and begin secreting osteoid that will form the trabeculae. Lobular carcinoma in situ consists of cancer cell clusters separated by narrow clear spaces that, under high magnification, appear vascular. This morphology is equated to hematopoietic tissue in which primitive hematopoietic cells lie between anastomosing sinusoids. Similar cartilagenous, trabecular and hematopoietic morphologies can be found in carcinomatous tumors of most organs, but the nomenclature is variable. The hematopoietic carcinomas share numerous features with hematopoietic tissue including a structure composed of intermingled normoxic and hypoxic regions and a metabolism characterized by elevated levels of glycolysis. They also contain similar proportions of clonal cells. If this model is correct it necessitates a change in the treatment of carcinoma. If cancer cells are not the enemy, but desperately needed immature blood cells, and the medical problem is not the presence of tumors, but the inefficiency of this extramedullary hematopoietic tissue, then treatment should focus on increasing marrow hematopoiesis. As evidence suggests that the marrow lesion is the result of increased hydrostatic pressure this could be done by reducing blood volume. One way to accomplish this may be through the ingestion of ephedrine, as it is hypothesized to increase vascular tone.

Adult↗

Identification and characterization of a new pair of immunoglobulin-like receptors LMIR1 and 2 derived from murine bone marrow-derived mast cells.

We have identified and characterized two mouse cDNAs in a mouse antigen-stimulated bone marrow-derived mast cell cDNA library, both of which encode type I transmembrane proteins. The genes were closely mapped in the distal region of mouse chromosome 11 and expressed not only in mast cells but also widely in leukocytes. The extracellular domains of their encoded proteins contain a single variable immunoglobulin (Ig) motif sharing about 90% identity with amino acids, showing that they comprise a pair of molecules and belong to the Ig superfamily. We named these molecules leukocyte mono-Ig-like receptor1 and 2 (LMIR1 and 2). The intracellular domain of LMIR1 contains several immunoreceptor tyrosine-based inhibition motifs (ITIMs). When cross-linked, the intracellular domain was tyrosine phosphorylated and capable of recruiting tyrosine phosphatases, SHP-1 and SHP-2 and inositol polyphosphate 5-phosphatase, SHIP. LMIR2, on the other hand, contains a short cytoplasmic tail and a characteristic transmembrane domain carrying two positively charged amino acids associated with three kinds of immunoreceptor tyrosine-based activation motif (ITAM)-bearing molecules, DAP10, DAP12, and FcRgamma. These findings suggest that a new pair of ITIM/ITAM-bearing receptors, LMIR1 and 2, regulate mast cell-mediated inflammatory responses through yet to be defined ligand(s).

Amino Acid Sequence↗

A prospective twin study of birth weight discordance and child problem behavior.

BACKGROUND: We investigated whether low birth weight constitutes a causal risk factor for child problem behavior, using a variation of the co-twin control method. METHODS: In a representative sample of 745 twin pairs (monozygotic: 324 pairs), birth weight was recorded at birth and child problem behavior at mean age 10 years was measured with the Child Behaviour Checklist (CBCL). RESULTS: Lower birth weight was a continuous risk factor for later child problem behavior (adjusted regression coefficient over units of 500 g: beta = -.15, p =.046), and greater levels of within-pair CBCL discordance did not result in a reduced effect size. Greater within-pair birth weight discordance was associated with greater within-pair CBCL score discordance (beta =.35, p <.001). This latter effect was similar in monozygotic (beta =.34, p =.005) and dizygotic twins (beta =.37, p =.003). CONCLUSIONS: The fact that (1) the effect size of the association between low birth weight and child problem behavior was not reduced in pairs with greater levels of CBCL discordance, and (2) similar effect sizes were found in monozygotic and dizygotic twins for the within-pair association between birth weight discordance and CBCL score discordance, suggests that the observed relationship between low birth weight and child problem behavior is not due to a shared environmental or genetic variable that influences both characteristics. Lower birth weight is a causal risk factor for child problem behavior, the effects of which may well extend into adulthood.

Adolescent↗

Combined adrenorenal fusion and adrenohepatic adhesion: a case report with review of the literature and discussion of pathogenesis.

The second case of combined adrenorenal fusion and adrenohepatic adhesion on the right side is reported. It is hypothesized that the basic lesion underlying this innocuous anomaly rests in the periadrenal mesenchyme. In the case of fusion of adrenal with kidney or liver the mesenchymal defect causes 1) retardation of capsule formation with parenchymal mixing and 2) failure of local differentiation into fetal and later adult fat cells. In the case of adhesion of adrenal to kidney or liver there is no retardation of capsule formation with parenchymal mixing but only failure to differentiate locally into fat cells. Consequently, there is no physical separation of these organs by interposition of fat cells and there is variable party-wall sharing of the capsule.

Adrenal Glands↗

How shared are age-related influences on cognitive and noncognitive variables?

Several theories have suggested that age-related declines in cognitive processing are due to a pervasive unitary mechanism, such as a decline in processing speed. Structural equation model tests have shown some support for such common factor explanations. These results, however, may not be as conclusive as previously claimed. A further analysis of 4 cross-sectional data sets described in Salthouse, Hambrick, and McGuthry (1998) and Salthouse and Czaja (2000) found that although the best fitting model included a common factor in 3 of the data sets, additional direct age paths were significant, indicating the presence of specific age effects. For the remaining data set, a factor-specific model fit at least as well as the best fitting common factor model. Three simulated data sets with known structure were then tested with a sequence of structural equation models. Common factor models could not always be falsified--even when they were false. In contrast, factor-specific models were more easily falsified when the true model included a unitary common factor. These results suggest that it is premature to conclude that all age-related cognitive declines are due to a single mechanism. Common factor models may be particularly difficult to falsify with current analytic procedures.

Adolescent↗