Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Heterogeneity”

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 397 records · Page 22Linked to original sources
PubMed1998

Spatiotemporal effects of syncytial heterogeneities on cardiac far-field excitations during monophasic and biphasic shocks.

INTRODUCTION: It has recently been postulated that syncytial (anatomic) heterogeneities inherent within cardiac tissue might represent a significant mechanism underlying field-induced polarization of the bulk myocardium. This simulation study examines and characterizes the spatiotemporal excitatory dynamics associated with this newly hypothesized mechanism. METHODS AND RESULTS: Two-dimensional regions of syncytially heterogeneous cardiac tissue were simulated with active membrane kinetics. Heterogeneities were manifested via random spatial variations of intracellular volume fractions over multiple length scales. Excitation thresholds were determined for uniform rectangular monophasic (M) and symmetric biphasic (B) far-field stimuli, from which strength-duration and strength-interval relationships were constructed. For regions measuring 5.4 x 5.4 mm, baseline diastolic thresholds for longitudinal (L) and transverse (T) shocks of 5-msec total duration averaged (in V/cm, n = 10) M-L = 2.87+/-0.26, M-T = 6.71+/-0.83, B-L = 3.22+/-0.25, and B-T = 7.93+/-0.51. These thresholds decreased by 15% to 25% when the region sizes were increased to 10.8 x 10.8 mm. Strength-duration relationships correlated strongly with the Weiss-Lapicque hyperbolic relationship, with rheobases and chronaxies of 2.33 V/cm and 1.15 msec for M-L stimuli, and 2.28 V/cm and 2.04 msec for B-L stimuli. Strength-interval relationships for M-L and B-L stimuli decreased monotonically with increasing coupling intervals, with similar minimum coupling intervals at absolute refractoriness. However, the B-L thresholds were substantially less sensitive to changes in coupling intervals than their M-L counterparts. CONCLUSION: This study provides strong additional support for and understanding of the syncytial heterogeneity hypothesis and its manifested properties. Furthermore, these results predict that syncytial heterogeneities of even modest proportions could represent a significant mechanism contributing to the far-field excitation process.

Cell Membrane↗
PubMed1982

Heterogeneous nuclear RNA promotes synthesis of (2',5')oligoadenylate and is cleaved by the (2',5')oligoadenylate-activated endoribonuclease.

Heterogeneous nuclear RNA contains double-stranded regions that are not found in mRNA and that may serve as recognition elements for processing enzymes. The double-stranded regions of heterogeneous nuclear RNA prepared from HeLa cells promoted the synthesis of (2',5')oligoadenylate [(2',5')oligo(A) or (2'5')An] when incubated with (2',5')An polymerase. This enzyme is present in elevated levels in interferon-treated cells, and labeled heterogeneous nuclear RNA incubated with extracts of these cells is preferentially cleaved, since mRNA included in the same incubations is not appreciably degraded. The cleavage of heterogenous nuclear RNA is caused by the synthesis of (2'5')An and by a "localized" activation of the (2',5')An-dependent endonuclease, since it was enhanced by ATP, the substrate of the (2',5')An polymerase, and inhibited by 2'-dATP and ethidium bromide. Both of these compounds suppress the synthesis of (2',5')An, the first by competitive inhibition and the latter by intercalating into double-stranded RNA. The possible role of double-stranded regions and of the (2',5')An polymerase-endonuclease system in the processing of heterogeneous nuclear RNA is discussed.

2',5'-Oligoadenylate Synthetase↗
PubMed2003

Linkage analysis of quantitative trait loci in the presence of heterogeneity.

Variance component modeling for linkage analysis of quantitative traits is a powerful tool for detecting and locating genes affecting a trait of interest, but the presence of genetic heterogeneity will decrease the power of a linkage study and may even give biased estimates of the location of the quantitative trait loci. Many complex diseases are believed to be influenced by multiple genes and therefore genetic heterogeneity is likely to be present for many real applications of linkage analysis. We consider a mixture of multivariate normals to model locus heterogeneity by allowing only a proportion of the sampled pedigrees to segregate trait-influencing allele(s) at a specific locus. However, for mixtures of normals the classical asymptotic distribution theory of the maximum likelihood estimates does not hold, so tests of linkage and/or heterogeneity are evaluated using resampling methods. It is shown that allowing for genetic heterogeneity leads to an increase in power to detect linkage. This increase is more prominent when the genetic effect of the locus is small or when the percentage of pedigrees not segregating trait-influencing allele(s) at the locus is high.

Chromosome Mapping↗
PubMed2006

Dissecting trait heterogeneity: a comparison of three clustering methods applied to genotypic data.

BACKGROUND: Trait heterogeneity, which exists when a trait has been defined with insufficient specificity such that it is actually two or more distinct traits, has been implicated as a confounding factor in traditional statistical genetics of complex human disease. In the absence of detailed phenotypic data collected consistently in combination with genetic data, unsupervised computational methodologies offer the potential for discovering underlying trait heterogeneity. The performance of three such methods--Bayesian Classification, Hypergraph-Based Clustering, and Fuzzy k-Modes Clustering--appropriate for categorical data were compared. Also tested was the ability of these methods to detect trait heterogeneity in the presence of locus heterogeneity and/or gene-gene interaction, which are two other complicating factors in discovering genetic models of complex human disease. To determine the efficacy of applying the Bayesian Classification method to real data, the reliability of its internal clustering metrics at finding good clusterings was evaluated using permutation testing. RESULTS: Bayesian Classification outperformed the other two methods, with the exception that the Fuzzy k-Modes Clustering performed best on the most complex genetic model. Bayesian Classification achieved excellent recovery for 75% of the datasets simulated under the simplest genetic model, while it achieved moderate recovery for 56% of datasets with a sample size of 500 or more (across all simulated models) and for 86% of datasets with 10 or fewer nonfunctional loci (across all simulated models). Neither Hypergraph Clustering nor Fuzzy k-Modes Clustering achieved good or excellent cluster recovery for a majority of datasets even under a restricted set of conditions. When using the average log of class strength as the internal clustering metric, the false positive rate was controlled very well, at three percent or less for all three significance levels (0.01, 0.05, 0.10), and the false negative rate was acceptably low (18 percent) for the least stringent significance level of 0.10. CONCLUSION: Bayesian Classification shows promise as an unsupervised computational method for dissecting trait heterogeneity in genotypic data. Its control of false positive and false negative rates lends confidence to the validity of its results. Further investigation of how different parameter settings may improve the performance of Bayesian Classification, especially under more complex genetic models, is ongoing.

Algorithms↗
PubMed2002

Structuring the genetic heterogeneity of the Basque population: a view from classical polymorphisms.

In this study we analyze 18 classical polymorphisms (ABO, Rh, MNSs, Lewis, P, Duffy, Kell, ADA, ESD, PGM1, PGD, AK1, ACP1, GLO1, HP, GC, TF, and PI) in over 2000 autochthonous individuals from 14 natural districts in three provinces of the Basque Country (Alava, Guipuzcoa, and Biscay). Heterogeneity analysis via the chi2 test and a calculation of F(ST) indicate that there is significant genetic heterogeneity between the Basque districts. The R matrix informs us that this heterogeneity is not significantly concentrated in a single district or in the districts of a single province, but is rather distributed among several districts belonging to the three provinces analyzed. We undertake to assess the influence of various historical, geographical, and cultural factors on the genetic structure of the Basque population. Analysis suggests that allele distribution is geographically patterned in the Basque Country. The gradient distributions observed in the case of some alleles (ABO*O, RH*cDE, RH*cde, MNS*MS, and ACP1*C) on the basis of Moran's autocorrelation coefficient I, along with the influence of the two main travel routes through the Basque Country (western route through Bilbao and eastern route through Vitoria), suggest that the gene flow tends toward the coast. As regards other factors considered (administrative division, repopulation processes, linguistic heterogeneity, and north vs. south cultural heterogeneity), we detected only a certain influence exerted by an old tribal differentiation (2000 B.P.), which would diminish with the passage of time.

Alleles↗
PubMed2003

A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity.

Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of beta-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.

Adolescent↗
PubMed2001

Nasopharyngeal carcinoma heterogeneity of DNA content identified on cytologic preparations.

OBJECTIVE: To evaluate tumor heterogeneity of DNA content in nasopharyngeal carcinoma (NPC) performed on cytologic specimens. STUDY DESIGN: Image cytometric analysis of DNA ploidy status of 40 NPCs was performed on nasopharyngeal brushing smears stained with the Feulgen method after hematoxylin eosin staining. If the DNA distribution pattern from the same tumor exhibited diploid, aneuploid or/and tetraploid peaks or some combination of these patterns, the presence of tumor heterogeneity of DNA content was identified. RESULTS: Thirty-four cases (85%) had a nondiploid DNA pattern among the 40 NPCs. Twenty-eight cases exhibited tumor heterogeneity of DNA content (70%). Of the 28 tumors, 13 (46%) had a combination of diploid and tetraploid patterns, 10 (37%) had a combination of diploid and aneuploid patterns, 3 cases (11%) had a combination of tetraploid and aneuploid patterns, and 2 cases had two aneuploid stem lines. The relationship between DNA ploidy pattern and tumor histologic and cytologic morphology was also examined. CONCLUSION: There is a high incidence of DNA content heterogeneity in NPC. The relevance of tumor heterogeneity to the biologic behavior of NPC awaits further study. DNA quantification with image cytometry on destained cytologic preparations is feasible and reliable.

Aneuploidy↗
PubMed1996

Histological grade heterogeneity in multifocal prostate cancer. Biological and clinical implications.

In order to understand the clinical and biological implications of prostate cancer multifocality and heterogeneity, we investigated their occurrence in relation to variables such as tumour volume, local invasion, and biopsy findings. In a series of 61 completely sectioned whole-mount radical prostatectomy specimens with clinical stage T2 prostate cancer, we mapped histological grade heterogeneity and tumour multifocality. We also evaluated 55 prostate biopsy cases to assess the accuracy of pre-operative grading. Among all of the prostates, only 28 per cent had a single tumour and in 16 per cent one histological grade of cancer was evident. Extracapsular invasion was not restricted to the largest tumour in each case, but also occurred in tumours of relatively small volume and low histological grade. Variability of histological grade was directly proportional to tumour volume. Both grade heterogeneity and tumour multifocality of the prostatectomy specimen showed no significant relationship to the grade accuracy of biopsies. Biopsy grading error proved greatest among small, well-differentiated, tumours. Whole-mount sectioning of prostatectomy specimens in patients with clinically localized adenocarcinoma demonstrates that grade heterogeneity is most closely related to tumour volume; that the largest (index) tumour lesion may not be representative of the pathological stage; and that grading error in prostate needle biopsies can be only partly explained by grade heterogeneity or tumour multifocality.

Adenocarcinoma↗
PubMed1998

Detecting and describing heterogeneity in meta-analysis.

The investigation of heterogeneity is a crucial part of any meta-analysis. While it has been stated that the test for heterogeneity has low power, this has not been well quantified. Moreover the assumptions of normality implicit in the standard methods of meta-analysis are often not scrutinized in practice. Here we simulate how the power of the test for heterogeneity depends on the number of studies included, the total information (that is total weight or inverse variance) available and the distribution of weights among the different studies. We show that the power increases with the total information available rather than simply the number of studies, and that it is substantially lowered if, as is quite common in practice, one study comprises a large proportion of the total information. We also describe normal plots that are useful in assessing whether the data conform to a fixed effect or random effects model, together with appropriate tests, and give an application to the analysis of a multi-centre trial of blood pressure reduction. We conclude that the test of heterogeneity should not be the sole determinant of model choice in meta-analysis, and inspection of relevant normal plots, as well as clinical insight, may be more relevant to both the investigation and modelling of heterogeneity.

Adult↗
PubMed1999

Assessing heterogeneity and correlation of paired failure times with the bivariate frailty model.

We consider bivariate survival times for heterogeneous populations, where heterogeneity induces deviations in an individual's risk of an event as well as associations between survival times. The heterogeneity is characterized by a bivariate frailty model. We measure the heterogeneity effects through deviations associated with hazard functions and an association function defined through the conditional hazard functions: the cross-ratio function proposed by Oakes. We show how the deviation and association measures are determined by the frailty distribution. A Gibbs sampling method is developed for Bayesian inferences on regression coefficients, frailty parameters and the heterogeneity measures. The method is applied to a mental health care data set.

Algorithms↗
PubMed1998

Fibronectin and avidin-biotin as a heterogeneous ligand system for enhanced endothelial cell adhesion.

A preadsorbed layer of "heterogeneous" integrin-dependent and -independent protein was used to enhance initial integrin-mediated endothelial cell attachment and spreading. Glass substrates were treated with fibronectin (Fn) and avidin coupled through adsorbed biotinylated bovine serum albumin (b-BSA). The slides then were seeded with biotinylated BAEC. Control "homogeneous" surfaces were slides adsorbed with either Fn or avidin coupled to b-BSA. The cells were incubated for 0.5 h in serum-containing media and exposed to a range of shear stresses in a laminar flow variable-height flow chamber. The critical shear stress to detach 50% of the seeded cells on the heterogeneous ligand surface was significantly greater than for either of the control homogeneous ligand systems (p < 0.001). Cellular spreading during the initial period of 0-2 h also was higher (p < 0.05) on the heterogeneous ligand-treated surface than on the surface of either of the homogeneous controls. The close contact area of the cell membrane with the substrate 1 h after seeding in serum-containing media was measured using TIRFM. Cells attached onto the heterogeneous ligand-treated surfaces had a significantly (p < 0.01) higher area of close contact with the substrate, which is consistent with a greater degree of attachment and spreading. The results indicate that the combination of integrin-dependent and -independent adhesion systems using heterogeneous ligands further enhances initial endothelial cell attachment and spreading.

Animals↗
PubMed1986

DNA stemline heterogeneity in colorectal cancer.

The current study was carried out on 88 colorectal carcinomas to assess the degree of intratumor heterogeneity as reflected by multiple aneuploid DNA stemlines and their relation to tumor stage and morphologic differentiation. Each tumor was segregated into an average of nine specimens (3-15), which were analyzed separately. DNA aneuploidies were identified in 72 cases (82%), 29 revealing multiple aneuploid DNA stemlines with up to four aneuploid subpopulations. In 10 of the 29 carcinomas with DNA stemline heterogeneity, a ratio of 2:1 was calculated from the different DNA indices, possibly indicating that the additional DNA stemline emerged from the first one by doubling its DNA content. No correlation was found between the overall frequency of DNA aneuploidies or heterogeneous DNA stemlines and the tumor stage according to Dukes' staging. Well-differentiated carcinomas tended to express aneuploid DNA stemlines more frequently than moderately or poorly differentiated tumors, although the morphologic intratumor heterogeneity did not correspond to the appearance of multiple aneuploid DNA stemlines. These data indicate a high degree of intraneoplastic diversity in colorectal cancer and emphasize the usefulness of DNA analyses for the quantitative assessment of tumor heterogeneity.

Aneuploidy↗
PubMed1987

Lung cancer heterogeneity. Prognostic implications.

Although histologic heterogeneity of lung cancer is well recognized, little information is available related to possible effects of this heterogeneity on prognosis. We collected 100 consecutive lung cancer cases, including 35 autopsies and 65 surgical resections, which were extensively sampled (average, ten blocks per case) and analyzed for histologic heterogeneity. Slides were randomized and classified by five pathologists using the 1981 World Health Organization (WHO) classification scheme. Five-year follow-up data were obtained for the surgical cases, and detailed information on staging and survival from time of diagnosis was available in 91 cases. Survival time was analyzed with respect to the patient's age, sex, stage, predominant histologic pattern, and presence or absence of major heterogeneity. The latter is defined as the presence on at least one slide of a major histologic pattern different from that of the remaining slides for that case. The only statistically significant predictor of survival was tumor stage (P less than 0.0001). Heterogeneous tumors appeared to have a worse survival, but this did not reach statistical significance. There was no relationship between survival and predominant histologic pattern (cell type), sex, or age.

Adult↗
PubMed1993

DNA heterogeneity in prostatic adenocarcinoma. A DNA flow cytometric mapping study with whole organ sections of prostate.

BACKGROUND: The degree of DNA heterogeneity varies between tumors arising at different sites. The presence of a significant degree of variability within a given tumor may result in problems in the interpretation of DNA flow cytometric findings. This study evaluated the degree of DNA heterogeneity in prostatic adenocarcinoma. METHODS: A total of 122 3-mm punch biopsy specimens were evaluated from single representative whole organ sections from nine cases of prostate cancer (range, 4-18 samples per case; mean, 12 samples; median, 14 samples). Individual punch biopsy specimens were graded and reviewed to confirm the presence of carcinoma and processed for DNA ploidy analysis. RESULTS: Assessable histograms, defined as having a coefficient of variation of the diploid G0/G1 peak of 7.5% or less, were available for 111 (91%) of the samples. Of the nine cases studied, five (56%) showed heterogeneity in the DNA pattern (diploid plus aneuploid, n = 1; diploid plus tetraploid, n = 2; and diploid plus tetraploid plus aneuploid, n = 2). All four cases having a homogeneous DNA content were DNA diploid in all samples. In those cases with a heterogeneous pattern, the areas having abnormal DNA patterns could not be predicted by histologic pattern or grade. CONCLUSIONS: From this study, the authors conclude that a significant degree of DNA heterogeneity exists within individual cases of prostatic adenocarcinoma, and this may be an important confounding factor in DNA ploidy studies.

Adenocarcinoma↗
PubMed1985

Substrain heterogeneity in prostaglandin E2 synthesis of human dermal fibroblasts. Differences in prostaglandin E2 synthetic capacity of substrains are not stimulus-restricted.

We examined prostaglandin E2 (PGE2) biosynthetic heterogeneity in fibroblast substrains and possible mechanisms that might mediate this heterogeneity. PGE2 synthesis of fibroblast substrains, in response to phytohemagglutinin-stimulated mononuclear cell supernates, ranged from 9.0 +/- 1.0 ng/ml to 79.3 +/- 7.4 ng/ml (mean +/- SD). The phenotypic behavior of individual substrains was stable. Substrains were also heterogeneous in PGE2 response to phorbol myristate acetate, and displayed stability in this phenotype as well. Substrains which were high responders to mononuclear cell supernate also ranked high in response to phorbol myristate acetate. Similar heterogeneity was observed in response to purified interleukin-1. Arachidonic acid added exogenously did not raise interleukin-1 responsiveness of low-producer substrains to that of high producers, suggesting that differences in PGE2 synthesis among substrains did not reflect differences in substrate availability or phospholipase activity. Supernates of high- and low-responder phenotype substrains, when added to cells of the reciprocal strain or to unrelated fibroblasts, did not affect the pattern of PGE2 synthesis. The concordance of substrain responsiveness to mononuclear cell supernate and phorbol myristate acetate suggests that heterogeneity among substrains in PGE2 synthesis is related to the ability to produce PGE2, rather than to the ability to respond to a given mediator. In addition, differences in PGE2 synthesis among substrains do not appear to result from release of regulatory autokines.

Arachidonic Acid↗
PubMed1992

Dynamic lipid-bilayer heterogeneity: a mesoscopic vehicle for membrane function?

The lipid-bilayer component of cell membranes is an aqueous bimolecular aggregate characterized by a heterogeneous lateral organization of its molecular constituents. The heterogeneity may be sustained statically as well as dynamically. On the basis of recent experimental and theoretical progress in the study of the physical properties of lipid-bilayer membranes, it is proposed that the dynamically heterogeneous membrane states are important for membrane functions such as transport of matter across the membrane and enzymatic activity. The heterogeneous membrane states undergo significant structural changes in response to changes in compositional, thermodynamic, and environmental conditions. The diverse effects of a variety of molecular compounds interacting with membranes, such as cholesterol and drugs like anaesthetics, may be understood in terms of the ability of these compounds to affect and modulate the dynamic membrane heterogeneity.

Anesthetics↗
PubMed1995

Heterogeneity of chromosome 17 and erbB-2 gene copy number in primary and metastatic bladder cancer.

To study the relationship of tumor genomic heterogeneity with bladder cancer phenotype and p53 gene alterations, 138 primary bladder tumors were examined by dual labeling fluorescence in situ hybridization (FISH) using probes for chromosome 17 centromere (p17H8) and p53 (17p13.1). The number of different aneusomic populations > 5% (and monosomic populations > 20%) of cells served as a marker for heterogeneity. Nuclear p53 overexpression and Ki67 labeling index (Ki67 LI) were determined by immunohistochemistry. The number of aneusomic populations was 0 in 53 tumors, 1 in 18, 2 in 47, 3 in 9, and > 3 in 11 tumors. Presence of aneusomy was associated with tumor grade and stage (P < 0.0001 each). Ki67 LI was low in disomic tumors (11.0 +/- 7.7), higher in tumors with 1-3 aneusomic populations (17.4 +/- 11.3), and highest in tumors with > 3 aneusomic populations (25.8 +/- 10.9; P = 0.02 for > 3 vs. 1-3 populations). Aneusomy and heterogeneity were associated with p53 alterations. Aneusomy was seen in 35% of tumors with neither p53 expression nor p53 deletion but in 97% of tumors with both p53 deletion and expression. Nine of 11 tumors with > 3 aneusomic populations exhibited both p53 deletion and overexpression. To study genomic heterogeneity in tumor progression, two recurrences and three metastases of a tumor with known erbB-2 amplification were examined for centromere 17 and erbB-2 copy number. A considerable heterogeneity in centromere 17 and erbB-2 gene copy number was found in both recurrences and metastases, indicating a marked genomic instability in these metastatic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Transitional Cell↗
PubMed1993

Heterogeneity of carbonic anhydrase and 68 kDa neurofilament in nerve roots analyzed by two-dimensional electrophoresis.

The heterogeneity of carbonic anhydrase (CA) and 68 kDa neurofilament (NF) in nerve roots of Japanese monkeys (Macaca Macacus) was analyzed by two-dimensional electrophoresis combined with immunoblotting. CA was detected as heterogeneous spots of type I and II having the same molecular weight (M(r)) but different isoelectric point (pI), in the range of pH 4.5-5.5. CA had much higher concentrations in soluble fractions of dorsal roots than ventral roots but not in membrane-bound fractions of either root. NF was detected as a single spot at the position of 68 kDa and pI 5.2 in soluble fractions of both roots, however, it was detected in the membrane-bound fractions as heterogeneous spots having different molecular masses and pI in the range of 60-68 kDa and 5.0-5.5, respectively. The presence of heterogeneous CA type I and II at high concentrations in dorsal roots enables us to distinguish the sensory nerves from the motor nerves. Furthermore, the heterogeneity of NF in membrane-bound fractions gives us information for understanding the dynamic assembly and the degradation of NF in nerve roots.

Animals↗