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PubMed1991

Heterogeneous size of the parathyroid glands in familial multiple endocrine neoplasia type 1.

OBJECTIVE: We wished to determine whether there was size heterogeneity of the parathyroid glands in patients with familial multiple endocrine neoplasia type 1 (FMEN1) and primary hyperparathyroidism. DESIGN: At the National Institutes of Health we performed a retrospective analysis of parathyroid gland volume either from initial or repeat parathyroid exploration. PATIENTS: We studied subjects with FMEN1 and primary hyperparathyroidism. MEASUREMENTS: The parathyroid gland volume was estimated from recorded orthogonal diameters. Volume could also be estimated conservatively in many glands for which one or more diameters were not recorded. Reproducibility of volume measurements was tested with a series of clay gland models. Indices of variability (among glands at an operation or among replicate measurements of a clay model) were the ratio of maximum volume/minimum volume and the average standard deviation of the log volume. RESULTS: The most complete data were from eight initial operations with three dimensions recorded for all four glands. Volume heterogeneity was indicated by the average ratio of 9.6 for the maximum/minimum gland volume within an operation. The size heterogeneity was even greater among other subgroups. For example, the average ratio of maximum/minimum gland volume within an operation was 17 among five initial operations with four glands removed, but lacking measurements of three dimensions for some glands. Little of this size heterogeneity could be attributed to measurement error since eight replicate measurements on a model gland yielded a maximum/minimum volume ratio of 1.45. CONCLUSIONS: There is a wide heterogeneity in size of the parathyroid glands in the patients with FMEN1 and primary hyperparathyroidism.

Humans↗
PubMed2006

Variations on a theme: sources of heterogeneity in the form of the interspecific relationship between abundance and distribution.

1. A positive interspecific relationship between abundance and distribution is widely considered to be one of the most general patterns in ecology. However, the relationship appears to vary considerably across assemblages, from significant positive to significant negative correlations and all shades in between. 2. This variation has led to the suggestion that the abundance-distribution relationship has multiple forms, with the corollary that different patterns may inform about, or have different, causes. However, this variation has never been formally quantified, nor has it been determined whether the observed variation is indicative of sampling error in estimating a single effect or of real heterogeneity in such relationships. Here, we use the meta-analytical approach to assess variation in abundance-distribution relationships, and to test different hypotheses for it. 3. Analysis of 279 relationships found a mean effect size of 0.655, which was both highly significantly different from zero and indicative of a strong positive association between abundance and distribution. However, effect sizes were highly heterogeneous, supporting the contention that this relationship does indeed have multiple forms. 4. Most notably, relationships vary significantly in strength across realms, with the strongest in the marine and intertidal, intermediate relationships for terrestrial and parasitic assemblages, and the weakest relationships in freshwater systems. Effect sizes in all of the aquatic realms are homogeneous, suggesting that realm is an important source of the heterogeneity observed across all studies. We posit that this may be because the different spatial structure of the environment in each realm affects the opportunity for the dispersal of individuals between sites. 5. Some of the remaining heterogeneity in effect sizes for terrestrial assemblages could be explained by partitioning assemblages by habitat, scale, biogeographical region and taxon, but considerable heterogeneity in effect sizes for terrestrial and parasitic assemblages remained unexplained.

Amphibians↗
PubMed1976

The structure of kinetoplast DNA. 1. The mini-circles of Crithidia lucilae are heterogeneous in base sequence.

We have analysed limit digests of mini-circles from kinetoplast DNA of Crithidia luciliae by gel electrophoresis. Endonucleases HapII and AluI cut the circles into at least 37 and 21 fragments, respectively, and leave no circles intact. In both cases the added molecular weights of the fragments, estimated from mobility in gels, exceeds 18 X 10(6), i.e. more than 12 times the molecular weight of the mini-circle DNA. Endonucleases HindII + III, EcoRI and HpaI cut only part of the circles. These results show that the mini-circles are heterogeneous in base sequence. Different sequence classes are present in different amounts. DNA-DNA renaturation analysis of mini-circle DNA yields a complexity of about 3 X 10(6), i.e. twice the molecular weight on one mini-circle. The delta tm of native and renatured duplexes is about 1 degree C, showing that the sequence heterogeneity is a micro-heterogeneity. Electron microscopy, gel electrophoresis and sedimentation analysis show that the circles that are not cut by endonucleases HindII + III remain catenated in very large associations. These associations lack the 'rosette' structures and the long edge loops characteristic of intact kinetoplast DNA. This suggests that the mini-circle classes cut by endonucleases HindII + III are present throughout the network and that the maxi-circle component of the network (see accompanying paper) is not essential to hold the network together. Prolonged electrophoresis on 1.5% or 2% agarose gels resolves the open mini-circles into three and linearized mini-circles into four bands, present in different amounts. We conclude that the mini-circles are also heterogeneous in size, the difference in size between the two extreme size classes being 4% of the contour length. Digestion with endonuclease HapII shows that at least three out of these four bands differ in sequence. Possible mechanisms that could account for the micro-heterogeneity in sequence of mini-circles are discussed.

Animals↗
PubMed1981

Compositional heterogeneity of the chloroplast DNAs from Euglena gracilis and Spinacia oleracea.

The chloroplast genomes of Euglena gracilis and Spinacia oleracea were investigated in their compositional heterogeneity, by using different experimental approaches. Euglena chloroplast DNA has a dG + dC content of 28%. Preparations averaging 20 x 10(6) in molecular weight exhibit a gross heterogeneity in their elution profiles from hydroxyapatite and in their buoyant densities because the rRNA genes have a high rG + rC content. Finer analysis by melting, buoyant density of restriction fragments and micrococcal nuclease degradation have revealed an extended compositional heterogeneity. From micrococcal nuclease digestion data, approximately 30% of the chloroplast genome is as low as 12% in its dG + dC content, whereas 10% is higher than 60% dG + dC. Since the average dG + dC content of large restriction endonuclease fragments varied to a lesser extent, most of dA + dT-rich sequences must occur in short stretches interspersed with dG + dC-rich stretches. Spinach chloroplast DNA (dG + dC = 36.5%) did not exhibit any gross compositional heterogeneity in its hydroxyapatite elution or in its buoyant density profile. But the higher resolution methods of melting, bouyant densities of restriction fragments and micrococcal nuclease degradation revealed a high degree of heterogeneity which appears to be due to interspersion of short DNA stretches of different base composition. About 30% of genome is as low as 22% in dG + dC, while 10% is higher than 60% in dG + dC.

Base Composition↗
PubMed2004

Assessing heterogeneity in meta-analyses of Helicobacter pylori infection-related clinical studies: a critical appraisal.

OBJECTIVE: To critically assess the meta-analyses of Helicobacter pylori infection-related clinical studies, particularly the handling of between-study heterogeneity. METHODS: A qualitative, all-language, systematic literature search was performed in Medline, PubMed, BioMed Central and Embase up to February 2003, supplemented by a manual search of major relevant journals. Assessment was according to modified criteria for literature searching, eligibility criteria, validity assessment, data extraction and presentation. Five parameters were used to assess the quality of the meta-analyses in handling between-study heterogeneity. RESULTS: Of 84 potentially relevant citations, 47 were systematic reviews and of them 38 were meta-analyses. Of these 38 studies, 15 (39.5%) had conducted a literature search of multiple databases and 34 (89.5%) had conducted a supplementary manual search. The eligibility criteria were clearly presented in 81.6% of studies, but the quality of the primary studies was assessed in only 26.3%. The process and strategy for data extraction was reported in 57.9% of all studies; 19 (50%) studies planned statistical tests of between-study homogeneity and the results were reported in 18, but the level of statistical significance was reported in only 11 (57.9%). The selection of and justification for a statistical model was presented in 39.5% and 26.3% of studies, respectively. Among the 11 meta-analyses in which statistical between-study heterogeneity was reported, 54.5% ignored the statistical findings and proceeded to pool the study results. The implications of between-study heterogeneity were discussed in only 8 studies. CONCLUSIONS: Many methodological flaws were identified in the meta-analyses of H. pylori-related clinical studies, particularly for assessing, reporting and interpreting between-study heterogeneity. This warrants consistent and urgent adherence by reviewers and journal editors to the methodological guidelines for meta-analyses.

Helicobacter Infections↗
PubMed1998

Syncytial heterogeneity as a mechanism underlying cardiac far-field stimulation during defibrillation-level shocks.

INTRODUCTION: The mechanisms by which a defibrillation shock directly stimulates regions of cardiac tissue distal to the stimulus electrodes ("far-field" stimulation) are still not well understood. Existing hypotheses have proposed that intercellular discontinuities and/or fiber curvatures induce the requisite membrane polarizations. This article hypothesizes a third potential mechanism: one based on the existence and influences of syncytial (anatomic) heterogeneities inherent throughout the bulk myocardium itself. METHODS AND RESULTS: We simulated the effects of such heterogeneities in a model of a two-dimensional region of passive cardiac tissue subjected to uniform 1 V/cm longitudinal or transverse field stimuli. Heterogeneities were manifested via random spatial variations of intracellular volume fractions (fi) over multiple length scales, with mean fi of 80% and standard deviation of fi (sigma[fi]) ranging from 0% to 10%. During field stimulation, many interspersed and variously shaped and sized islands of hyperpolarization and depolarization developed across the tissue, with their locations and extents correlated to the spatial gradients of the underlying heterogeneities. Increases in sigma(fi) correspondingly increased the shock-induced magnitudes of resulting membrane polarizations. The ratio of maximal polarizations for equivalent longitudinal and transverse shocks approximated 2:1 across all sigma(fi) tested. At sigma(fi) = 5%, these maximal induced polarizations were 17.4 +/- 2.4 mV and 8.18 +/- 1.5 mV, respectively. Assuming an excitation threshold of 25 mV, these data suggest corresponding diastolic thresholds of 1.47 +/- 0.20 V/cm and 3.14 +/- 0.50 V/cm, respectively. CONCLUSION: This study predicts that syncytial heterogeneities inherent within cardiac tissue could represent a significant-and heretofore unappreciated-mechanism underlying field-induced polarizations throughout the bulk myocardium.

Arrhythmias, Cardiac↗
PubMed1995

Tumor heterogeneity and immunotherapy of cancer.

Tumor heterogeneity is the presence of intercellular differences, either from clonal origin or present within subpopulations of tumor cells. Recent advances in immuno-histology, flow cytometric analysis, molecular biological techniques, and tissue culture methods makes it possible to investigate tumor heterogeneity in detail. In this review data are presented to document that this hallmark of neoplastic disease results from DNA-instability and the interactions of tumor cells with their environment. The present inability to treat most patients effectively with immunotherapy may partly be due to the occurrence of tumor heterogeneity. Therefore, the heterogeneity of the tumor phenotype is discussed in conjunction with the various immunotherapeutic treatment modalities. In addition to local cytokine production by immune cells and tumor cells, and limited access of either antibodies or immune cells into the tumor, tumor heterogeneity is an important factor that determines the progress of immunotherapy of cancer. Therefore, accurate quantitative methods using antibodies and molecular probes to identify HLA-associated target peptides, tumor-associated antigens and accessory molecules, to predict which patients will have a high probability of responding to treatment, are needed.

Animals↗
PubMed2006

Assessment of sex differences and heterogeneity in motor milestone attainment among populations in the WHO Multicentre Growth Reference Study.

AIM: To assess the heterogeneity of gross motor milestone achievement ages between the sexes and among study sites participating in the WHO Multicentre Growth Reference Study (MGRS). METHODS: Six gross motor milestones (sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone, and walking alone) were assessed longitudinally in five of the six MGRS sites, namely Ghana, India, Norway, Oman and the USA. Testing was started at 4 mo of age and performed monthly until 12 mo, and bimonthly thereafter until all milestones were achieved or the child reached 24 mo of age. Four approaches were used to assess heterogeneity of the ages of milestone achievement on the basis of sex or study site. RESULTS: No significant, consistent differences in milestone achievement ages were detected between boys and girls, nor were any site sex interactions noted. However, some differences among sites were observed. The contribution of inter-site heterogeneity to the total variance was < 5% for those milestones with the least heterogeneous ages of achievement (hands-and-knees crawling, standing alone, and walking alone) and nearly 15% for those with the most heterogeneous ages of achievement (sitting without support, standing with assistance, and walking with assistance). CONCLUSION: Inter-site differences, most likely due to culture-specific care behaviours, reflect normal development among healthy populations across the wide range of cultures and environments included in the MGRS. These analyses support the appropriateness of pooling data from all sites and for both sexes for the purpose of developing an international standard for gross motor development.

Child Development↗
PubMed1989

Heterogeneous blood flow distribution within single skeletal muscles in the rabbit: role of vasomotion, sympathetic nerve activity and effect of vasodilation.

A major heterogeneous distribution of blood flow has been described on a non-microvascular level within single skeletal muscles at rest and during exercise hyperaemia both in the dog and in the rabbit. The heterogeneity in blood flow distribution could be composed of both a steady-state region-to-region variability (spatial) and a time-dependent variability (temporal) in blood flow to each region. In the present study we estimated their relative contributions to the variations in blood flow within the muscles. Furthermore, we determined whether sympathetic nerve activity contributed to and whether pharmacologically induced vasodilation affected the heterogeneous blood flow pattern. Regional blood flow measurements were based on microsphere infusions into anaesthetized rabbits. Blood flow was determined under both resting conditions and during exercise hyperaemia in regions weighing 0.25 g each within hind leg muscles. The coefficient of variation for the spatial variability was twice that of the temporal one: 0.32 and 0.16 (mean) respectively. Neither stimulation of the sympathetic nerves, sympathectomy nor vasodilation affected the heterogeneity in blood flow. When exercise hyperaemia was induced, blood flow increased in all regions so that a positive (P less than 0.05) correlation was present between resting and exercising blood flow values in the individual regions. Although regional variation in vascularization could explain the observations during exercise hyperaemia, we have at present no fully satisfying explanation for the observed regional heterogeneity in blood flow.

Animals↗
PubMed1988

Variation of population release kinetics in polydisperse multiparticulate systems (microcapsules, microspheres, droplets, cells) with heterogeneity of one, two or three parameters in the population of individuals.

Release kinetics of active substances from ensembles of microparticles such as microcapsules, cells, droplets and liposomes constituted of individual entities releasing their contents at constant rates may follow zero order, first order, sigmoid or biphasic equations. The release equation observed depends upon the statistical distribution of release-determining parameters among the population. Typical cases are presented in terms of the distribution of two parameters, payload (m infinity) and time for complete payload release (t infinity) which also define the release rate constant (k). Heterogeneity of the two parameters generally leads to first order ensemble behaviour, whereas heterogeneity of one parameter only may lead to different ensemble release equations, viz. zero order (m infinity heterogeneous) or first order (t infinity heterogeneous). Biphasic distribution can lead to an apparent 'burst' effect, with apparent change of kinetics. The presence of a third heterogeneous parameter, lag time, yields a sigmoid ensemble release curve. These conclusions are demonstrated by simulations or experimentally, and are also valid for linearized curves of microparticles following matrix kinetics.

Capsules↗
PubMedDate not supplied

Temporospatial heterogeneity of myocardial perfusion and blood volume in the porcine heart wall.

Spatial heterogeneity of myocardial perfusion has been recognized for many years. Whether this is primarily the result of heterogeneity of parameters such as myocardial metabolism, of intramyocardial mechanical forces, or of vasomotor function within the myocardial microcirculation, is not clear. A practical problem is that it has been almost impossible to measure any two of these parameters simultaneously in the same piece of myocardium so that an unambiguous correlation, much less a cause-and-effect relationship, has been difficult to establish. In this study of six anesthetized pigs, we propose that whole-body computed tomography is a method for providing the simultaneous measurement of heterogeneity of myocardial perfusion (F) and myocardial blood volume (rho). The first finding was that the empirical relationship rho=AF+BF(0.5) between myocardial blood flow (F) and intramyocardial blood volume (rho) is maintained over a range of sizes of regions of interest (approximately 1 to 0.125 cm3) within the myocardium of each individual animal despite the spatial heterogeneity of the F and the rho values. The value of A ranges from 0.014 to 0.021 min and of B ranges from 0.061 to 0.076 ml(0.5) g(-0.5) min(0.5). A second finding was that the pattern of spatial heterogeneity of F and of rho remained reasonably stable over at least a 1 h period.

Animals↗
PubMed2003

Vancomycin treatment failure associated with heterogeneous vancomycin-intermediate Staphylococcus aureus in a patient with endocarditis and in the rabbit model of endocarditis.

Heterogeneous resistance to vancomycin is thought to precede emergence of intermediate susceptibility to vancomycin in Staphylococcus aureus, but the clinical significance of heterogeneous resistance is unknown. Paired S. aureus isolates from a patient with endocarditis who relapsed after vancomycin treatment were tested for heterogeneous resistance to vancomycin. The pretreatment and the relapse clinical isolates (strains SF1 and SF2, respectively) were genotyped by pulsed-field gel electrophoresis. Susceptibility to vancomycin was assessed by the broth dilution method, population analysis, and time-kill studies and in the rabbit model of endocarditis. Strains SF1 and SF2 had similar genotypes, and the vancomycin MICs for the strains were </=2 micro g/ml. SF2 exhibited heterogeneous resistance to vancomycin. Vancomycin eradicated SF1 in the rabbit model of endocarditis, while SF2 persisted at pretreatment levels. Vancomycin treatment failure in this patient with endocarditis was attributable to heterogeneous resistance to vancomycin.

Animals↗
PubMed2002

Grassland management regimens reduce small-scale heterogeneity and species diversity of beta-proteobacterial ammonia pxidizer populations.

The impact of soil management practices on ammonia oxidizer diversity and spatial heterogeneity was determined in improved (addition of N fertilizer), unimproved (no additions), and semi-improved (intermediate management) grassland pastures at the Sourhope Research Station in Scotland. Ammonia oxidizer diversity within each grassland soil was assessed by PCR amplification of microbial community DNA with both ammonia oxidizer-specific, 16S rRNA gene (rDNA) and functional, amoA, gene primers. PCR products were analysed by denaturing gradient gel electrophoresis, phylogenetic analysis of partial 16S rDNA and amoA sequences, and hybridization with ammonia oxidizer-specific oligonucleotide probes. Ammonia oxidizer populations in unimproved soils were more diverse than those in improved soils and were dominated by organisms representing Nitrosospira clusters 1 and 3 and Nitrosomonas cluster 7 (closely related phylogenetically to Nitrosomonas europaea). Improved soils were only dominated by Nitrosospira cluster 3 and Nitrosomonas cluster 7. These differences were also reflected in functional gene (amoA) diversity, with amoA gene sequences of both Nitrosomonas and Nitrosospira species detected. Replicate 0.5-g samples of unimproved soil demonstrated significant spatial heterogeneity in 16S rDNA-defined ammonia oxidizer clusters, which was reflected in heterogeneity in ammonium concentration and pH. Heterogeneity in soil characteristics and ammonia oxidizer diversity were lower in improved soils. The results therefore demonstrate significant effects of soil management on diversity and heterogeneity of ammonia oxidizer populations that are related to similar changes in relevant soil characteristics.

Ammonia↗
PubMed1982

Heterogeneity in the rate of benzo[a]pyrene metabolism in single cells: quantitation using flow cytometry.

We describe a method for quantitating heterogeneity in the rate of benzo[a]pyrene metabolism in single cells by using flow cytometry. We have used the technique to study the response of Hepa-1c1c7 mouse hepatoma cells to the microsomal enzyme inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin. Cells responded in a relatively homogeneous fashion at different times of induction with a maximally inducing concentration of the inducer. However, the induction response could be heterogeneous at a submaximal inducer concentration. We found even higher heterogeneity of enzyme activity among low-activity variants derived from the Hepa-1c1c7 cell line. When cells of either high or low activity were isolated from such a clonal population, propagated, and reanalyzed, they displayed average enzyme activity and heterogeneity identical to the parental cells; therefore, the heterogeneity represents transient, nonheritable differences between cells within the population.

Animals↗
PubMed1996

Tumour heterogeneity of DNA cell cycle variables in breast cancer measured by flow cytometry.

AIM/BACKGROUND: Conflicting results have been reported concerning the prognostic value of DNA flow cytometric variables (DNA ploidy, DNA index, %S phase fraction) in breast cancer. Selection bias and differences in treatment may have contributed to these conflicting prognostic results. Differences in tissue processing, the number of nuclei measured, DNA histogram/cell cycle analysis, and intra-tumour heterogeneity may also have played a role. The aim of the present study was to assess intra-tumour heterogeneity of DNA flow cytometric variables in breast cancer. METHODS: Fresh frozen specimens (n = 274) (0.3 x 0.3 x 0.3 cm) of 17 breast cancers and 167 slices, 50 microns thick, of 58 paraffin wax embedded blocks of 21 breast cancers were studied. All samples were prepared individually for DNA flow cytometry. DNA histograms were interpreted by semi-automated cell cycle analysis (MultiCycle) by two observers to avoid biased interpretation. An artificial averaged DNA histogram of each case was composed to simulate a sample prepared from whole tumour tissue. RESULTS: With regard to DNA ploidy, classified as diploid or aneuploid, the fresh frozen and paraffin wax embedded breast cancers showed intra-tumour heterogeneity in 53% and 38% of cases, respectively. For fresh frozen and paraffin wax embedded material, respectively, six samples had to be measured to detect the highest DNA ploidy class in 71% and 86% of cases. Averaged DNA histograms showed a loss of DNA aneuploidy in 36% and 6% of fresh frozen and paraffin wax embedded samples, respectively. High intra-tumour heterogeneity (wide ranges) was found for the %S phase fraction. Average %S phase fraction and average aneuploid %S phase fraction had the widest ranges at 9.5-31.6% and 0.0-62.7%, respectively. There was no correlation between the number of stemlines and intra-tumour %S phase variability on the one hand and tumour size and grade on the other. CONCLUSIONS: High intra-tumour heterogeneity for breast cancer was found for DNA ploidy, the DNA index and %S phase fraction as measured by flow cytometry, which may explain the conflicting prognostic results reported in the literature. To detect aneuploid cells, six samples may have to be prepared and measured separately. Measurement of these variables may be more reliable in paraffin wax sections because the thick slices provide a more representative sample. Prospective studies are required to determine whether the highest %S phase fraction value or the average value is more useful in the clinical context.

Breast Neoplasms↗
PubMed1993

pH heterogeneity during exercise in localized spectra from single human muscles.

We investigated whether pH heterogeneity in skeletal muscle during exercise, observed with 31P nuclear magnetic resonance, represents muscle fiber type heterogeneity. Localized spectra were simultaneously acquired from the soleus, medial, and lateral gastrocnemius using a multivolume localization technique, the Hadamard spectroscopic imaging (HSI) technique. Contamination of nonselected regions to the localized volumes was < 5%. HSI-localized spectra were obtained from the calf muscles of untrained subjects and a small group of athletes. Two plantar flexion exercise protocols were implemented: a "maximal" high frequency protocol and a "steady-state" protocol at low contraction frequency (0.25 Hz). pH heterogeneity was observed in localized spectra of single muscles during both exercise protocols, as indicated by the large Pi line width. During maximal exercise the Pi line width was up to three times wider than the phosphocreatine line width, covering an entire pH unit. During the steady-state exercise, in three subjects the Pi peak clearly resolved into two distinct peaks, one at low pH and one at high pH. As pH heterogeneity was observed in localized spectra of single muscles during both exercise protocols, it most likely reflects the metabolic heterogeneity between fiber types.

Exercise↗
PubMed1987

Proteins are secreted from heterogeneous prestored sources in the exocrine pancreas.

Recent studies demonstrating nonparallel regulated secretion of prestored digestive enzymes in tightly linked groups consistent with the exocytosis mechanism led us to predict that digestive enzymes would be found to be secreted from heterogeneous sources within the exocrine pancreas (J. W. Adelson, and P.E. Miller, Science Wash. DC 228: 993-996, 1985). We explored whether the gland was heterogeneous with respect to its sources of prestored secretory proteins with a double isotopic label method not dependent on activity of secreted digestive enzymes. Rabbit pancreatic proteins were double labeled in vivo by injection of each animal with chemically identical but isotopically distinct mixtures of 3H- and 14C-labeled amino acids, which were administered separately or together on consecutive days after partial depletion of prestored proteins by administration of cholecystokinin (CCK), methacholine chloride, or saline in a protocol in which order of both isotope and secretagogue administration was varied. Three days after labeling, proteins were recovered by collection from cannulated pancreatic ducts of anesthetized animals after stimulation with alternating increasing doses of CCK and methacholine chloride. Pooled secretory data were analyzed to determine whether secretagogue pretreatment resulted in specific and heterogeneous sequestration of proteins after synthesis; data after final secretory stimulation with methacholine chloride and CCK were individually analyzed to determine whether presequestered proteins were mobilized from heterogeneous compartments during secretion. Correlation and regression analysis of isotopic outputs and variance analysis of specific radioactivities of secreted proteins showed sequestration into and secretion from heterogeneous pools of secretory proteins, directly confirming out hypothesis. These results provide a cell biological mechanism explaining regulated nonparallel secretion of digestive enzymes.

Animals↗
PubMed2004

Transmembrane action potential heterogeneity in the canine isolated arterially perfused right atrium: effect of IKr and IKur/Ito block.

The role of electrical heterogeneity in development of cardiac arrhythmias is well recognized. The extent to which transmembrane action potential (TAP) heterogeneity contributes to the normal electrophysiology of well-oxygenated atria is not well defined. The principal objective of the present study was to define regional and transmural differences in characteristics of the TAP in isolated superfused and arterially perfused canine right atrial (RA) preparations under baseline, rapidly activating delayed rectifier K(+) current (I(Kr)) block, and combined block of ultrarapid delayed rectifier and transient outward K(+) current (I(Kur)/I(to) block). Superfused preparations that survived generally displayed a triangle-shaped TAP. Exceptions included cells from the crista terminalis, where TAPs with a normal plateau could be recorded. In contrast, most TAPs recorded from throughout the perfused RA displayed a spike-and-dome and/or plateau morphology. The perfused RA displayed a heterogeneous distribution of repolarization, V(max), and spike-and-dome morphology along the epicardial and endocardial surfaces as well as transmurally, in the region of the upper crista terminalis. I(Kr) block with E-4031 prolonged repolarization homogeneously in the perfused RA, whereas I(Kur)/I(to) block using low concentrations of 4-aminopyridine abbreviated action potential duration at 90% repolarization heterogeneously, leading to a reduction in dispersion of repolarization. Our data indicate that the electrical heterogeneities, previously described for the canine ventricle, also exist within the atria and that I(Kr) block does not accentuate and I(Kur)/I(to) block reduces RA dispersion of repolarization. Our study also points to major differences in the transmembrane activity recorded using superfused vs. arterially perfused atrial preparations.

Action Potentials↗