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PubMed1997

Heterogeneity of DNA content in multiple synchronous hepatocellular carcinomas.

Heterogeneity of DNA content in multiple hepatocellular carcinomas (HCCs) was investigated by flow cytometry in 62 tumours from 26 patients who had undergone surgical treatment for multiple synchronous HCCs. Heterogeneity of DNA content was defined (a) when tumours had a different DNA ploidy pattern or (b) when the difference in the DNA index of the aneuploid clone was more than 0.1. A tumour with DNA aneuploidy was observed in 17 (66%) of the 26 patients. Heterogeneity of the DNA content was demonstrated in 12 (46%) out of 26 patients: in ten cases by definition (a) and in two cases by definition (b). Histological examination revealed that, of the 12 patients with a heterogeneous tumour DNA content, seven (58%) had a heterogeneous and the remaining five (42%) had a homogeneous type and grade of differentiation among the tumours, showing the absence of a relationship between histological heterogeneity and DNA content. The present results suggest the clinical relevance of DNA content analysis for identifying the clonal origin of multiple HCCs.

Aged↗
PubMed1985

Evaluation of the extent of heterogeneity in the Glycera dibranchiata monomer haemoglobin fraction by the use of n.m.r. and ion-exchange chromatography.

The coelomic haemoglobin of Glycera dibranchiata is known to be separable into monomeric and higher-Mr fractions. Although exhibiting homogeneity with respect to Mr, the extent of haemoglobin heterogeneity for the monomer fraction has never been adequately assayed. In the present paper we demonstrate that there exists in the monomer haemoglobin fraction reproducibly detectable heterogeneity regardless of the presence or absence of proteinase inhibitors during the isolations. These results show that, considered on the same time scale as previous preparations used for amino acid sequencing, crystallography and kinetics, the monomer haemoglobin fraction is highly heterogeneous. Application of ion-exchange chromatography and ion-filtration methods resulted in the isolation of four resolvable haem protein components from the Glycera monomer haemoglobin fraction. Three of these components were isolated in sufficient quantity to employ proton n.m.r. as a successful analytical tool for discriminating the individual haemoglobins. These results are not surprising. Several previous studies indicated less extensive heterogeneity in the monomer fraction. Moreover, the ability of the Glycera monomer haemoglobin to bind oxygen at even quite low partial pressures has been attributed to functional diversity originating in multiple haemoglobin components. The present work reveals the extent of the haemoglobin heterogeneity. The results show that it is more extensive than previously believed. Examination of this monomer fraction is particularly important, since crystallography indicates that one of the components of the monomer fraction lacks the E-7 (distal) histidine residue. As a consequence, the identification of such extensive heterogeneity is important to many previously published ligand-binding studies.

Animals↗
PubMed1996

Morphological, molecular, and functional heterogeneity of cholangiocytes from normal rat liver.

BACKGROUND & AIMS: While the lobular heterogeneity of hepatocytes is established, limited data suggest that bile duct epithelial cells, of cholangiocytes, are heterogeneous along the normal intrahepatic biliary tree. Thus, we tested the hypothesis that cholangiocytes are structurally and functionally heterogeneous in the biliary tract of normal rats. METHODS: A series of in situ and in vitro experiments was performed in normal rats using complementary morphometric, molecular, and functional approaches. RESULTS: In situ morphometry showed that (1) intrahepatic bile ducts are heterogeneous in external diameter (5-200 mum); (2) individual cholangiocytes lining bile ducts are heterogeneous in area (3-80 mum2); and (3) a significant relationship exists between bile duct diameter and cholangiocyte area. Using a novel approach developed by us, we isolated three subpopulations of small, medium, and large cholangiocytes and compared them at the molecular and functional level. The expression of two cholangiocyte-specific genes (gamma-glutamyl transpeptidase and cytokeratin 19) was similar among the three subpopulations. In contrast, secretion receptor, Cl-/HCO3- exchanger, and cystic fibrosis transmembrane conductance regulator messenger RNAs were differentially expressed, being present on medium and large but not small cholangiocytes. At the functional level, adenosine 3', 5'-cyclic monophosphate and intracellular pH responses and Cl-/HCO3- exchanger activity was enhanced by secretion in medium and large but not small cholangiocytes. CONCLUSIONS: These data indicate that cholangiocytes are morphologically and functionally heterogeneous along the normal intrahepatic biliary tree and suggest that secretion-regulated transport of water and electrolytes occurs principally in medium and large ducts.

Animals↗
PubMed1996

The clinical significance of changes in genetic heterogeneity of the hypervariable region 1 in chronic hepatitis C with interferon therapy.

We examined changes in the hypervariable region 1 of the hepatitis C virus (HCV) RNA that occurred with interferon therapy in 33 patients with chronic hepatitis C to assess the clinical significance of this region. The 33 patients had HCV genotype 1b and were classified into three groups based on serum aminotransferase levels during and after therapy with alpha interferon; long-term responders (n = 9), short-term responders (n = 11), and nonresponders (n = 13). Changes in the genetic heterogeneity of the hypervariable region 1 were determined by using nonisotopic polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). HCV RNA levels were evaluated by reverse transcriptase PCR and branched DNA probe assays. Changes in sequences were determined by cloning and sequencing analysis. Before therapy, the long-term responders had significantly lower degrees of heterogeneity and lower viral levels than nonresponders. There were no significant differences between short-term and nonresponders. With interferon therapy, viral levels and degree of heterogeneity decreased to a greater extent among long-term and short-term responders than among nonresponders. Sequencing analysis showed that the three groups had similar clone numbers initially, but long-term responders had rather homogeneous viral populations, whereas short-term and nonresponders had heterogeneous populations, but that there were no nucleotide sequences or amino acid alignments that were specific for any group before, during, and 6 months after therapy. Approximately half of short-term and nonresponders received a second course of interferon 7 to 10 months after the initial therapy; all showed an identical response to the second course of therapy regardless of interim changes in the heterogeneity of hypervariable region 1. These findings suggest that (1) patients who were nonresponders or short-term responders had mixed viral populations that had differing sensitivities to interferon, (2) the changes in the hypervariable region 1 (HVR 1) did not affect responsiveness to interferon, and (3) the lower heterogeneity in the HVR 1 was associated with a long-term response to interferon only when the viral levels were low.

Chronic Disease↗
PubMed2003

Frontal sinus obliteration with heterogeneous corticocancellous bone versus spontaneous osteoneogenesis in monkeys (Cebus apella): histologic analysis.

PURPOSE: In this study, we evaluated the results of spontaneous osteoneogenesis of the frontal sinus with autogenous bone plug versus obliteration with heterogeneous (human) bone in monkeys (Cebus apella). MATERIALS AND METHODS: Eight young adult male C apella monkeys underwent an ostectomy of the anterior wall of the frontal sinus, removal of the sinus mucosa, and inner decortication of the bony walls and then were divided into 2 groups of 4 each, as follows. Group I monkeys underwent obliteration of the nasofrontal ducts with a free segment of frontallis muscle and corticocancellous heterogeneous bone, followed by full obliteration of the sinus with corticocancellous heterogeneous bone (Dayton Regional Tissue Bank, Dayton, OH). Group II monkeys underwent obliteration of the nasofrontal ducts with a frontal muscle segment and tibial autogenous bone plug, without full obliteration of the frontal sinus. In all animals, the sinus anterior wall was repositioned and fixed with 1.0 plate and screws. The monkeys were killed after 180 days, and routine laboratory procedures were followed for hematoxylin-eosin staining and histologic evaluation of the specimens. RESULTS: The 2 studied techniques were both effective in obliterating the frontal sinus with newly formed bone. The nasofrontal ducts were obliterated by new bone formation or fibrous tissue (1 animal only). CONCLUSIONS: Both methods used for frontal sinus obliteration were effective; the heterogeneous bone (human bone) was well tolerated and presented low antigenicity. The nasofrontal duct obliteration with autogenous muscle associated with autogenous tibial bone (group II) or with heterogeneous bone (group I) was effective, isolating the frontal sinus from the nasal cavity. The spontaneous obliteration resulted, in the period analyzed, in earlier bone maturation compared with the obliteration by heterogeneous bone.

Adipose Tissue↗
PubMed1987

Tumor cell heterogeneity: divided-colony assay for measuring drug response.

In vitro tests for predicting the response of tumors to chemotherapeutic agents might be improved if they were modified to take into account tumor-cell heterogeneity. We have studied the heterogeneity of cellular growth rate and drug response in mouse fibroblast NIH 3T3 cells and in NIH 3T3 cells transformed with the human HRAS gene (homologue of the Harvey sarcoma virus oncogene v-Ha-ras) from the EJ human bladder carcinoma cell line. Growth-rate heterogeneity was detected as a broad distribution of numbers of cells per colony. In spite of this heterogeneity, secondary colonies have numbers of cells per colony that resemble that of the primary colony from which they were derived. The variance between unrelated secondary colonies is increased by HRASEJ. Colony-size measurements are reliable because primary colonies divided in half formed two groups of secondary colonies (on two separate plates) that had indistinguishable mean colony sizes. Based on these observations, a divided-colony procedure was devised to detect the drug response of heterogeneous cell populations. Primary colonies are divided into two groups of cells, one of which is treated with a drug and the other is left untreated as a control. The size distribution of treated secondary colonies is then compared to that of the untreated control and to that of the primary colony from which it was derived. The divided-colony procedure is proposed as a modification of the human-tumor-cloning system to increase the sensitivity and reliability of in vitro procedures used to determine the drug response of heterogeneous tumor-cell populations.

Animals↗
PubMed2000

Methylation patterns of the E-cadherin 5' CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression.

Metastatic progression of most common epithelial tumors involves a heterogeneous, transient loss of expression of the homotypic cell adhesion protein, E-cadherin, rather than the uniform loss of a functional protein resulting from coding region mutation. Indeed, whereas E-cadherin loss may promote invasion, reexpression may facilitate cell survival within metastatic deposits. The mechanisms underlying such plasticity are unclear. We now show that the heterogeneous loss of E-cadherin expression in primary human breast cancers reflects a heterogeneous pattern of promoter region methylation, which begins early prior to invasion. In cultured human tumor cells, such heterogeneous methylation is dynamic, varying from allele to allele and shifting in relation to the tumor microenvironment. Following invasion in vitro, which favors diminished E-cadherin expression, the density of promoter methylation markedly increased. When these cells were cultured as spheroids, which requires homotypic cell adhesion, promoter methylation decreased dramatically, and E-cadherin was reexpressed. These data show that the methylation associated with E-cadherin loss in human breast cancer is heterogeneous and unstable and suggest that such epigenetic plasticity may contribute to the dynamic, phenotypic heterogeneity that drives metastatic progression.

Alleles↗
PubMed2000

Heterogeneity in Individual Mortality Risk and Its Importance for Evolutionary Studies of Senescence.

Mortality was simulated under the assumption of heterogeneity in individual age-specific mortality risk. Heterogeneity was modeled by assigning each individual its own Gompertz mortality function. Means and variances of the Gompertz intercept and slope parameters were based on published data for Drosophila melanogaster. Simulations of large cohorts reproduced mortality plateaus similar to those observed for actual cohorts of flies. Catastrophic late-age mortality was not observed except when heterogeneity was very low and rates of senescence were very high. A second set of simulations was designed to mimic experiments that have investigated age-specific patterns of genetic variance in mortality rates. Within-genotype heterogeneity in mortality risk resulted in a decline in genetic variance of mortality rates at old ages. That result suggests that the decline in genetic variance at old ages that has been observed in some experiments is an artifact of heterogeneity. Mortality rate plateaus, decrease in genetic variance of mortality rates at old ages, and absence of catastrophic late-age mortality all appear to contradict predictions of the evolutionary theory of senescence. Heterogeneity in mortality risk may explain those contradictions.

Gompertz function↗
PubMed2005

Are variance components of exposure heterogeneous between time periods and factories in the European carbon black industry?

Occupational exposure to chemical agents can vary enormously within- and between-workers, even when carrying out the same jobs. When repeated measurements are available, the variance components can be estimated using random- or mixed-effects models. Pooling the variance components across the fixed effects, in mixed-effects models, reduces the complexity of the models; especially, when there are a large number of fixed effects. The analyses presented in this paper tested the assumptions of homogeneity in the variance components between factories and surveys for inhalable dust exposure in the European carbon black manufacturing industry. In total, 5296 measurements from 1771 workers were available collected during two surveys carried out between 1991 and 1995. Workers were grouped into eight job categories, and for each of these separate mixed-effects models were developed, including factory, survey and in some cases the interaction term as the fixed effects. The likelihood ratio test was used to test the assumptions of homogeneity of the variance components. Statistically significant heterogeneity of the variance components was observed for two of the eight job categories, 'Fitter/Welder' and 'Warehouseman'. The heterogeneity was due mainly to differences in variance between the factories. When estimating the probability of overexposure for all the factories combined, there was little difference between the models with and without heterogeneous variance components for 'Fitters/Welders'. For the 'Warehousemen' the probability of overexposure in the last survey changed marginally from 4% in the pooled model to 6% in the heterogeneous model. Larger differences between the models were observed when estimating the probability of overexposure for individual factories, which was due to over- or under-estimation of the variance components in the pooled models. In conclusion, for most job categories pooling of the variance components appears to be justified in this database. In addition, no large differences were found when determining the industry-wide probability of 'overexposure' when comparing the pooled with the heterogeneous models. However, when evaluating the factory-specific probability of 'overexposure' or when using the models to provide exposure estimates for epidemiological studies heterogeneity in the variance components should be investigated.

Analysis of Variance↗
PubMed2004

The effects of environmental heterogeneity on root growth and root/shoot partitioning.

AIMS: The purpose of this Botanical Briefing is to stimulate reappraisal of root growth, root/shoot partitioning, and analysis of other aspects of plant growth under heterogeneous conditions. SCOPE: Until recently, most knowledge of plant growth was based upon experimental studies carried out under homogeneous conditions. Natural environments are heterogeneous at scales relevant to plants and in forms to which they can respond. Responses to environmental heterogeneity are often localized rather than plant-wide, and not always predictable from traditional optimization arguments or from knowledge of the ontogenetic trends of plants growing under homogeneous conditions. These responses can have substantial impacts, both locally and plant-wide, on patterns of resource allocation, and significant effects on whole-plant growth. Results from recent studies are presented to illustrate responses of plants, plant populations and plant communities to nutritionally heterogeneous conditions. CONCLUSIONS: Environmental heterogeneity is a constant presence in the natural world that significantly influences plant behaviour at a variety of levels of complexity. Failure to understand its effects on plants prevents us from fully exploiting aspects of plant behaviour that are only revealed under patchy conditions. More effort should be invested into analysis of the behaviour of plants under heterogeneous conditions.

Biomass↗
PubMed2003

A statistical measure of tissue heterogeneity with application to 3D PET sarcoma data.

In vivo measurement of local tissue characteristics by modern bioimaging techniques such as positron emission tomography (PET) provides the opportunity to analyze quantitatively the role that tissue heterogeneity may play in understanding biological function. This paper develops a statistical measure of the heterogeneity of a tissue characteristic that is based on the deviation of the distribution of the tissue characteristic from a unimodal elliptically contoured spatial pattern. An efficient algorithm is developed for computation of the measure based on volumetric region of interest data. The technique is illustrated by application to data from PET imaging studies of fluorodeoxyglucose utilization in human sarcomas. A set of 74 sarcoma patients (with five-year follow-up survival information) were evaluated for heterogeneity as well as a number of other potential prognostic indicators of survival. A Cox proportional hazards analysis of these data shows that the degree of heterogeneity of the sarcoma is the major risk factor associated with patient death. Some theory is developed to analyze the asymptotic statistical behavior of the heterogeneity estimator. In the context of data arising from Poisson deconvolution (PET being the prime example), the heterogeneity estimator, which is a non-linear functional of the PET image data, is consistent and converges at a rate that is parametric in the injected dose.

Algorithms↗
PubMed1991

Maldistribution of heterogeneous coronary blood flow during canine endotoxin shock.

STUDY OBJECTIVE - The aim was to investigate whether heterogeneous coronary blood flow is maldistributed during endotoxin shock. DESIGN - Variables were studied before (t = 0) and at t = 90 and t = 120 min after bolus injection of saline (n = 6) or endotoxin (n = 6). SUBJECTS - 12 anaesthetised mongrel dogs, weight 20-27 kg, were used. MEASUREMENTS AND MAIN RESULTS - We studied myocardial blood flows in small tissue sections (of about 1 g in left and 2 g in right ventricle) with radioactive microspheres, together with haemodynamic variables and global myocardial metabolism. At t = 0 min in controls, regional flows per 100 g were heterogeneous and ranged from a factor 0.2 to 2.7 and 0.6 to 1.6 of mean flow per 100 g to the left and right ventricle respectively; heterogeneity was unchanged at t = 90 and t = 120 min. Between t = 0, t = 90, and t = 120 min regional flows correlated: r = 0.78(SD 0.14), n = 18, for left ventricle, and r = 0.70(0.17) for right ventricle. In the endotoxin group, cardiac output and mean arterial pressure decreased by 44(7) and 48(11)% respectively, and lactate increased by 3.2(0.6) mmol.litre-1 at t = 120 min. Global left ventricle blood flow and delivery and metabolism of O2 were unchanged; lactate extraction and external work fell. The ratio between global right ventricular O2 delivery and external work also rose. Regional blood flows ranged from a factor 0.2 to 2.7 and 0.1 to 1.8 of mean flow to left and right ventricles respectively; heterogeneity did not differ from controls and did not change with time. Flow correlations with time were reduced: 0.45(0.24) for left ventricle and 0.45(0.26) for right ventricle (both n = 18, p less than 0.005 v controls). The left ventricular endocardial to epicardial flow ratio fell; flow was redistributed to both layers. CONCLUSIONS - Heterogeneous blood flow is redistributed throughout the heart during canine endotoxin shock so that, at unchanged global blood flow and flow heterogeneity, flow decreases in some but increases in other areas. Flow maldistribution may be associated with focal ischaemia, which may be masked by a rise in O2 uptake for a given workload (contractile inefficiency) in overperfused areas, and may thereby contribute to a fall in global myocardial external work for a given O2 delivery.

Animals↗
PubMed1996

Restriction of hepatitis C virus heterogeneity during prolonged interferon-alpha therapy in relation to changes in virus load.

To determine how interferon-alpha (IFN-alpha) treatment changes the heterogeneity of the hepatitis C virus (HCV) population, the hypervariable region 1 (HVR1) was directly sequenced, and the virus load was quantified in 15 patients who had received IFN-alpha for 15 months. Before treatment, 13 patients exhibited heterogeneous HVR1 sequences. In 7 subjects who did not respond or did not sustain a response to treatment, significantly decreased heterogeneity of the HVR1 was found at the end of treatment (P=.01). In 6 of these patients, the virus load decreased in parallel with the changes in HVR1 heterogeneity. At follow-up, both the virus load and the heterogeneity increased in 4 patients, and the virus load, but not the heterogeneity, increased in 2. In the seventh patient, the virus load steadily increased during treatment and follow-up. These results suggest that a selection of HVC strains may occur during prolonged IFN-alpha treatment, concomitant with general suppression of the viral replication.

Amino Acid Sequence↗
PubMed2025

Robustness of Ancestral Sequence Reconstruction to Among-site and Among-lineage Evolutionary Heterogeneity.

Ancestral sequence reconstruction is typically performed using homogeneous evolutionary models, which assume that the same substitution propensities affect all sites and lineages. These assumptions are routinely violated: heterogeneous structural and functional constraints favor different amino acids at different sites, and these constraints often change among lineages as epistatic substitutions accrue at other sites. To evaluate how violations of the homogeneity assumption affect ancestral sequence reconstruction under realistic conditions, we developed site-specific substitution models and parameterized them using data from deep mutational scanning experiments on three protein families; we then used these models to perform ancestral sequence reconstruction on the empirical alignments and on alignments simulated under heterogeneous conditions derived from the experiments. Extensive among-site and -lineage heterogeneity is present in these datasets, but the sequences reconstructed from empirical alignments are almost identical when heterogeneous or homogeneous models are used for ancestral sequence reconstruction. Using models fit to deep mutational scanning data from distantly related proteins in which mutational effects are very different also has a minimal impact on ancestral sequence reconstruction. The rare differences occur primarily where phylogenetic signal is weak-at fast-evolving sites and nodes connected by long branches. When ancestral sequence reconstruction is performed on simulated data, errors in the reconstructed sequences become more likely as branch lengths increase, but incorporating heterogeneity into the model does not improve accuracy. These data establish that ancestral sequence reconstruction is robust to unincorporated realistic forms of evolutionary heterogeneity, because the primary determinant of ancestral sequence reconstruction is phylogenetic signal, not the substitution model. The best way to improve accuracy is therefore not to develop more elaborate models but to apply ancestral sequence reconstruction to densely sampled alignments that maximize phylogenetic signal at the nodes of interest.

Phylogeny↗
PubMed1998

Improved tests for heterogeneity across a region of DNA sequence in the ratio of polymorphism to divergence.

The neutral theory of molecular evolution predicts that the ratio of polymorphisms to fixed differences should be fairly uniform across a region of DNA sequence. Significant heterogeneity in this ratio can indicate the effects of balancing selection, selective sweeps, mildly deleterious mutations, or background selection. Comparing an observed heterogeneity statistic with simulations of the heterogeneity resulting from random phylogenetic and sampling variation provides a test of the statistical significance of the observed pattern. When simulated data sets containing heterogeneity in the polymorphism-to-divergence ratio are examined, different statistics are most powerful for detecting different patterns of heterogeneity. The number of runs is most powerful for detecting patterns containing several peaks of polymorphism; the Kolmogorov-Smirnov statistic is most powerful for detecting patterns in which one end of the gene has high polymorphism and the other end has low polymorphism; and a newly developed statistic, the mean sliding G statistic, is most powerful for detecting patterns containing one or two peaks of polymorphism with reduced polymorphism on either side. Nine out of 27 genes from the Drosophila melanogaster subgroup exhibit heterogeneity that is significant under at least one of these three tests, with five of the nine remaining significant after a correction for multiple comparisons, suggesting that detectable evidence for the effects of some kind of selection is fairly common.

Animals↗
PubMed2003

Heterogeneity of chemosensitivity of esophageal and gastric carcinoma.

Esophageal and gastric cancer have a poor prognosis, and chemotherapy is rarely of long-term benefit. This may be related in part to heterogeneity of chemosensitivity and to constitutive resistance to individual cytotoxic drugs. This study aimed to demonstrate the degree of heterogeneity of chemosensitivity between tumors. We have examined the heterogeneity of chemosensitivity in esophageal and gastric cancer specimens (n=85) using an ex vivo ATP-based chemosensitivity assay (ATP-TCA). A variety of chemotherapeutic agents were tested. Sixty-four specimens were endoscopic biopsy samples; the remainder were from resection specimens. Cells were obtained from 62 specimens (73%). Eight assays were infected due to contamination/infection of the biopsy material, giving an evaluability rate of 87%. Analysis of the data showed considerable heterogeneity of chemosensitivity. The most active single agents identified by the assay were mitomycin C (56% sensitivity) and 5-fluorouracil (5-FU; 42% sensitivity). Exposure of tumor cells to combinations of drugs showed ECF (epirubicin, cisplatin, 5-FU) and mitomycin C+5-FU to be moderately active regimens. Other experimental drug combinations showed greater activity. There is a marked heterogeneity of chemosensitivity in esophageal and gastric cancers. The degree of heterogeneity observed suggests that the ATP-TCA could be used to individualize chemotherapy by selecting agents for particular patients. This approach provides the rationale for a trial of ATP-TCA-directed therapy to determine whether individualization of chemotherapy might improve patient response and survival.

Adenocarcinoma↗
PubMed1995

Dynamic interactions in malaria: host heterogeneity meets parasite polymorphism.

The spectrum of disease severity in Plasmodium falciparum malaria can be attributed to heterogeneity in parasite virulence or to heterogeneity in host factors. However, the two are not necessarily separate explanations for the same phenomena: they may actually complement each other. The conjoint effects of host and parasite heterogeneity can serve to explain certain intriguing epidemiological observations, such as, why there is a reduction in incidence of severe malaria in certain host genotypes without a concomitant reduction in mild disease. By assuming that severe disease is caused by a rare independently transmitted parasite strain, and that the probability of disease is nonlinearly related to the number of effective infections by a certain strain, the disproportionate reduction in the rate of the rarer disease within resistant host genotypes may be explained. Conversely, heterogeneity in host resistance may, under certain circumstances, facilitate the maintenance of diversity in parasite virulence. In this paper we discuss the coevolutionary consequences of heterogeneity in host resistance and diversity in parasite virulence by using a simple mathematical model that attempts to integrate the population genetics of the system with its ecological dynamics. This allows a unified perspective on malaria transmission that synthesises current evidence regarding the effects of host and parasite heterogeneities on malarial disease.

Animals↗
PubMed2006

The role of heterogeneities and intercellular coupling in wave propagation in cardiac tissue.

Electrical heterogeneities play a role in the initiation of cardiac arrhythmias. In certain pathological conditions such as ischaemia, current sinks can develop in the diseased cardiac tissue. In this study, we investigate the effects of changing the amount of heterogeneity and intercellular coupling on wavefront stability in a cardiac cell culture system and a mathematical model of excitable media. In both systems, we observe three types of behaviour: plane wave propagation without breakup, plane wave breakup into spiral waves and plane wave block. In the theoretical model, we observe a linear decrease in propagation velocity as the number of heterogeneities is increased, followed by a rapid, nonlinear decrease to zero. The linear decrease results from the heterogeneities acting independently on the wavefront. A general scaling argument that considers the degree of system heterogeneity and the properties of the excitable medium is used to derive a dimensionless parameter that describes the interaction of the wavefront with the heterogeneities.

Action Potentials↗