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PubMed1990

Immunophenotype of thymoma-associated lymphoid cell component of T-cell type. A new analytic procedure in keeping with structural heterogeneities.

The phenotype of the lymphoid cell component of 35 thymomas was investigated by analyzing cryostat sections and lymphocyte suspensions. The morphology in each case was determined by examining multiple tissue samples from different parts of the tumor. Structural heterogeneity was shown in 14 thymomas, and a homogeneous morphology of cortical or medullary or mixed types in the others. To assess whether this heterogeneity was correlated with differences in the lymphoid phenotype, we analyzed both lymphocyte suspensions and frozen sections from the same samples. Phenotypical differences in the suspensions of each thymoma in the heterogeneous group were noted and similar differences were also observed in the cryostat sections. Phenotypical abnormalities were found in some thymomas. They consisted of the simultaneous expression of cortical and medullary markers, which was most marked in the heterogenous mixed-type thymomas invading the lung. Furthermore, the global phenotype was tested on a pool of lymphocyte suspensions in all thymomas. This procedure distinguished cortical, medullary and intermediate cortico-medullary immunophenotype models which closely correlated with the tumor histology. It was concluded that, due to the frequent structural and immunological heterogeneity of thymomas, correct assessment of their lymphoid component requires a two-step analysis. This comprises: 1) individual suspensions from samples taken from different areas of the same thymoma, and 2) a pool of these suspensions. The first step will reveal the different immunological characteristics. In the second, the lymphocyte phenotype, which may vary widely throughout the tumor, will be represented in its totality. These findings may be of great help in predicting clinical patterns, especially possible malignant evolution.

Cryopreservation↗
PubMed2001

Micro-heterogeneity study of trace elements in BCR CRM 680 by means of synchrotron micro-XRF.

BCR CRM 680 is a newly released reference material (RM) with a polyolefinic matrix, doped with various metallic compounds in trace concentrations, to be used for calibration of multi-element trace analytical methods. The micro-heterogeneity of this new CRM was investigated to evaluate the suitability as a RM for trace-level micro analytical techniques. Synchrotron micro-XRF, a trace-level micro analytical method, allows to quantitatively measure the degree of heterogeneity of inorganic trace constituents in solid materials with a homogeneous matrix. The procedure for calculating the minimal sampling mass for homogeneous measurements was employed for BCR CRM 680. By repeating the entire procedure on several samples of the same material, the repeatability of the micro-heterogeneity characterization based on micro-XRF was investigated. Afterwards, the micro-heterogeneity results from the BCR CRM 680 material were used to evaluate the suitability of the micro-heterogeneity procedure by means of a Monte Carlo simulation model. Also the existence of nuggets in the polymer material is looked into.

Journal Article↗
PubMed2002

Visual classification of emphysema heterogeneity compared with objective measurements: HRCT vs spiral CT in candidates for lung volume reduction surgery.

The aim of this study was to investigate whether spiral CT is superior to high-resolution computed tomography (HRCT) in evaluating the radiological morphology of emphysema, and whether the combination of both CT techniques improves the evaluation in patients undergoing lung volume reduction surgery (LVRS). The material consisted of HRCT (with 2-mm slice thickness) and spiral CT (with 10-mm slice thickness) of 94 candidates for LVRS. Selected image pairs from these examinations were evaluated. Each image pair consisted of one image from the cranial part of the lung and one image from the caudal part. The degree of emphysema in the two images was calculated by computer. The difference between the images determined the degree of heterogeneity. Five classes of heterogeneity were defined. The study was performed by visual classification of 95 image pairs (spiral CT) and 95 image pairs (HRCT) into one of five different classes of emphysema heterogeneity. This visual classification was compared with the computer-based classification. Spiral CT was superior to HRCT with 47% correct classifications of emphysema heterogeneity compared with 40% for HRCT-based classification ( p<0.05). The combination of the techniques did not improve the evaluation (42%). Spiral CT is superior to HRCT in determining heterogeneity of emphysema visually, and should be included in the pre-operative CT evaluation of LVRS candidates.

Adult↗
PubMed2003

Quantification of the heterogeneity of cerebral blood flow in vascular dementia.

BACKGROUND: In vascular dementia (VaD), assessment of cerebral blood flow by single photon emission computed tomography (CBF SPECT) has been used to detect a patchy decrease of blood flow or a frontal reduction. In addition to reduced blood flow, the heterogeneous distribution of cerebral blood flow is often observed in VaD. However, no objective method to evaluate the heterogeneity has been established. In this study, we applied three-dimensional fractal analysis (3D-FA) to CBF SPECT images as a method for assessing the heterogeneity of the cerebral blood flow distribution in VaD. SUBJECTS AND METHODS: The subjects included 18 patients with a diagnosis of VaD (aged 69.7 +/- 8.3) based on neuropsychological testing and imaging findings and 18 age-matched controls (aged 66.9 +/- 10.3). CBF SPECT images were obtained with (99m)Tc-hexamethyl propyleneamine oxime. On the reconstructed images, we obtained a linear regression equation between the cut-off values (from 35 to 50 %) and the number of voxels with a radioactivity exceeding the cut-off value transformed into natural logarithms, and then calculated the fractal dimension from the slope of the regression line thus obtained. The Mini-Mental State Examination (MMSE) was used to evaluate cognitive function. RESULTS: The fractal dimensions were 1.084 +/- 0.153 and 0.853 +/- 0.062 (mean +/- SD) in the VaD and control groups, respectively. The fractal dimension was significantly greater in the VaD group than in the control group (p < 0.0001). A significant negative correlation was observed between the fractal dimension and the MMSE score in the VaD group (r = 0.871, p < 0.0001). CONCLUSIONS: Because the CBF SPECT images of VaD patients showed a higher fractal dimension, these images were quantitatively more heterogeneous than those of age-matched controls. In the VaD group, cognitive function was shown to decline as the fractal dimension increased and images became more heterogeneous.

Aged↗
PubMed2005

Heterogeneous airway versus tissue mechanics and their relation to gas exchange function during mechanical ventilation.

We have advanced a commercially available ventilator (NPB840, Puritan Bennett/Tyco Healthcare, Pleasanton, CA) to deliver an Enhanced Ventilation Waveform (EVW). This EVW delivers a broadband waveform that contains discrete frequencies blended to provide a tidal breath, followed by passive exhalation. The EVW allows breath-by-breath estimates of frequency dependence of lung and total respiratory resistance (R) and elastance (E) from 0.2 to 8 Hz. We hypothesized that the EVW approach could provide continuous ventilation simultaneously with an advanced evaluation of mechanical heterogeneities under heterogeneous airway and tissue disease conditions. We applied the EVW in five sheep before and after a bronchial challenge and an oleic acid (OA) acute lung injury model. In all sheep, the EVW maintained gas exchange during and after bronchoconstriction, as well as during OA injury. Data revealed a range of disease conditions from mild to severe with heterogeneities and airway closures. Correlations were found between the arterial partial pressure of oxygen (PaO2) and the levels and frequency-dependent features of R and E that are indicative of mechanical heterogeneity and tissue disease. Lumped parameter models provided additional insight on heterogeneous airway and tissue disease. In summary, information obtained from EVW analysis can provide enhanced guidance on the efficiency of ventilator settings and on patient status during mechanical ventilation.

Animals↗
PubMed2005

Global production increased by spatial heterogeneity in a population dynamics model.

Spatial and temporal heterogeneity are often described as important factors having a strong impact on biodiversity. The effect of heterogeneity is in most cases analyzed by the response of biotic interactions such as competition of predation. It may also modify intrinsic population properties such as growth rate. Most of the studies are theoretic since it is often difficult to manipulate spatial heterogeneity in practice. Despite the large number of studies dealing with this topics, it is still difficult to understand how the heterogeneity affects populations dynamics. On the basis of a very simple model, this paper aims to explicitly provide a simple mechanism which can explain why spatial heterogeneity may be a favorable factor for production. We consider a two patch model and a logistic growth is assumed on each patch. A general condition on the migration rates and the local subpopulation growth rates is provided under which the total carrying capacity is higher than the sum of the local carrying capacities, which is not intuitive. As we illustrate, this result is robust under stochastic perturbations.

Models, Theoretical↗
PubMed2006

Effects of unmeasured heterogeneity in the linear transformation model for censored data.

We investigate the effect of unobserved heterogeneity in the context of the linear transformation model for censored survival data in the clinical trials setting. The unobserved heterogeneity is represented by a frailty term, with unknown distribution, in the linear transformation model. The bias of the estimate under the assumption of no unobserved heterogeneity when it truly is present is obtained. We also derive the asymptotic relative efficiency of the estimate of treatment effect under the incorrect assumption of no unobserved heterogeneity. Additionally we investigate the loss of power for clinical trials that are designed assuming the model without frailty when, in fact, the model with frailty is true. Numerical studies under a proportional odds model show that the loss of efficiency and the loss of power can be substantial when the heterogeneity, as embodied by a frailty, is ignored.

Clinical Trials as Topic↗
PubMed1996

Heterogeneity in cytosolic calcium responses to hypoxia in carotid body cells.

Previous investigators have reported that intracellular pH responds to hypoxia with a heterogenous pattern in individual glomus cells of the carotid body. The aim of the present study was to examine whether hypoxia had similar effects on cytosolic calcium ([Ca2+]i) in glomus cells, and if so, whether a heterogenous response pattern is also seen in other cell types. Experiments were performed on glomus cells from adult rat carotid bodies, rat pheochromocytoma (PC12) and vascular smooth muscle (A7r5) cells. Changes in [Ca2+]i in individual cells were determined by fluorescence imaging using Fura-2. Glomus cells were identified by catecholamine fluorescence. [Ca2+]i in glomus cells increased in response to hypoxia (pO2 = 35 +/- 8 mmHg; 5 min), whereas hypoxia induced decreases in [Ca2+]i were not seen. Increases in [Ca2+]i were observed in 20% of the isolated cells and strings of cells, but clustered glomus cells never responded. The magnitude of the calcium change in responding cells was proportional to the hypoxic stimulus. Under a given hypoxic challenge, there were marked variations in the response pattern between glomus cells. The response pattern characteristic of any given cell was reproducible. At comparable levels of hypoxia, PC12 cells also responded with an increase in [Ca2+]i with a heterogenous response pattern similar to that seen in glomus cells. In contrast, increases in [Ca2+]i in A7r5 cells could be seen only with sustained hypoxia (approximately 20 min), and little heterogeneity in the response patterns was evident. These results demonstrate that: (a) hypoxia increases cytosolic calcium in glomus cells; (b) response patterns were heterogeneous in individual cells; and (c) the pattern of the hypoxia-induced changes in [Ca2+]i is cell specific. These results suggest that hypoxia-induced increases in [Ca2+]i are faster in secretory than in non-secretory cells.

Animals↗
PubMed1988

Evidence for increased perfusion heterogeneity in skeletal muscle during reduced flow.

Recently, it has been demonstrated (D. Cousineau, C. P. Rose, D. Lamoureux, and C. A. Goresky, 1983, Cir. Res., 53, 719-730; K. Tyml, 1986, Microvasc. Res., 32, 84-98) that heterogeneity of microvascular flow depends on tissue metabolism. The objective of this study was to examine the possibility that, independent of metabolism, heterogeneity is also a function of flow. Using an intravital video-microscopic approach, we evaluated heterogeneity in the frog sartorius muscle at different flow rates while maintaining the muscle in the same exercised state. The flow was altered via partial aortal clamping. Exercised state was achieved by direct electrical stimulation. Heterogeneity of flow was evaluated in terms of the coefficient of variation (CV = SD/mean) computed from simultaneous measurements of red cell velocities in a capillary network. In addition to velocity analysis, the number of perfused capillaries crossing a 1-mm test line on the video monitor was counted. Among 10 networks from eight muscles, the overall preocclusion hyperemic velocity and CV were 0.42 +/- 0.15 SD mm/sec and 40 +/- 12%, respectively. The overall capillary count was 16.4 +/- 3.0 cap/mm. In all networks, increasing clamping reduced the mean hyperemic velocity and increased CV. For reductions to less than 50% of the preocclusion velocity, CV increased significantly (P less than 0.05), up to 88%. In 6 networks only, increasing clamping reduced capillary count, down to 10.2 cap/mm. This reduction was due to flow stoppages in capillaries situated randomly throughout the network. The data demonstrate for the first time that, for the same exercised state, heterogeneity of velocity depends on the mean velocity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Assessment and impact of heterogeneities of convective oxygen transport parameters in capillaries of striated muscle: experimental and theoretical.

Convective oxygen transport parameters were determined in arteriolar (n = 5) and venular (n = 5) capillary networks in the hamster cheek pouch retractor muscle. Simultaneously determined values of red blood cell velocity, lineal density, red blood cell frequency, hemoglobin oxygen saturation (SO2), oxygen flow (QO2), longitudinal SO2 gradient, and diameter were obtained in a total of 73 capillaries, 39 at the arteriolar ends of the network (arteriolar capillaries) and 34 at the venular ends (venular capillaries). We found that the hemodynamic variables were not different at the two ends. However, not unexpectedly, SO2 and QO2 were significantly higher at the upstream end of arteriolar capillaries (60.8 +/- 9.8 (SD)% and 0.150 +/- 0.081 pl/sec, respectively) compared with the downstream end of venular capillaries (39.9 +/- 13.6% and 0.108 +/- 0.095 pl/sec, respectively). Heterogeneities in red blood cell velocity, lineal density, SO2, and QO2, assessed by their coefficients of variation, were significantly greater in venular capillaries. To evaluate the impact of these heterogeneities on oxygen exchange, we incorporated these unique experimental data into a mathematical model of oxygen transport which accounts for variability in red blood cell frequency, lineal density, inlet SO2, capillary diameter, and, to some degree, capillary flow path lengths. An unexpected result of the simulation is that only the incorporation of variability in capillary flow path lengths had any marked effect on the heterogeneity in end-capillary SO2 in resting muscle due to extensive diffusional shunting of oxygen among adjacent capillaries. We subsequently evaluated, through model simulations, the effect of these heterogeneities under conditions of increased flow and high oxygen consumption. Under these conditions, the model predicts that heterogeneities in the hemodynamic parameters will have a marked effect on oxygen transport in this muscle.

Animals↗
PubMed1984

Molecular weight and charge heterogeneity of Thy-1 glycoprotein in different populations of T-cells.

Molecular weight and charge microheterogeneity of Thy-1 glycoprotein expressed on different T-cell populations were compared by two-dimensional gel electrophoresis and endoglycosidase treatment. Thy-1 was immunoprecipitated from detergent lysates of radioiodinated T-cells of spleens, lymph nodes, Peyer's patches, peripheral blood, IL-2-cultured thymocytes and peanut agglutinin (PNA) separated thymocytes. In general, thymocytes and IL-2-cultured thymocytes expressed the highest levels of Thy-1 with a large Mr and charge variation. The Thy-1 of these cells was basic and contained low levels of sialic acid. On the other hand, peripheral T-lymphocytes exhibited a restricted Mr and more limited charge heterogeneity with higher amounts of sialic acid. The Thy-1 glycoprotein of mature, low Thy-1 PNA- thymocytes had Mr and charge heterogeneity identical to peripheral T-lymphocytes. The Mr and charge variation of immature PNA+ thymocytes was essentially identical to that of whole thymocytes. The molecular source of Mr heterogeneity in thymocyte Thy-1 and restricted Mr in lymph node Thy-1 was studied by analysis with endoglycosidase-H (Endo-H) and Endo-D. The results of Endo-H digestion showed that most of the Thy-1 polypeptides from both thymocyte and lymph node contained one high-mannose type oligosaccharide which was relatively small and not heterogeneous with respect to Mr. The complex-type oligosaccharides (Endo-D-sensitive) were larger and were responsible for the broad Mr-heterogeneity found in thymocyte Thy-1. Both thymocyte and lymph node Thy-1 generally appear to contain three N-linked oligosaccharides (one high-mannose and two complex) and sequential hydrolysis with Endo-H and Endo-D resulted in an unglycosylated polypeptide with an Mr of approx. 12,500.

Animals↗
PubMed1986

Human melanoma-associated antigens: analysis of antigenic heterogeneity by molecular, serologic and flow-cytometric approaches.

The relationship of antigenic heterogeneity to the epitope recognized by an antibody was examined with monoclonal antibodies to human melanoma-associated antigens. Expression of the human melanoma-associated antigens, 250-Kd glycoprotein/proteoglycan and p97, was examined quantitatively by flow cytometry on fresh cell suspensions of human melanoma. Percent positive cells and mean fluorescence intensity were consistently higher with antibody 9.2.27 to the 250-Kd glycoprotein/proteoglycan than with antibody to p97. In addition, assessment of percent positive cells in multiple skin lesions biopsied from individual patients indicated that in 26 of 30 lesions, greater than 90% of the cells stained positively with 9.2.27. This relative lack of antigenic heterogeneity with antibody 9.2.27 contrasted with previous reports which showed considerable antigenic heterogeneity with other antibodies to the 250-Kd glycoprotein/proteoglycan. The explanation for this distinction was sought by quantitative flow cytometric and sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) techniques. Comparison by flow cytometry and immunoperoxidase of three antibodies, which recognized distinct epitopes of the 250-Kd glycoprotein/proteoglycan, indicated that 9.2.27 reacted more intensely with cultured cells and tissue sections than other antibodies to the same antigen. Examination by SDS-PAGE indicated that 9.2.27 could immunoprecipitate a larger proportion of 250-Kd glycoprotein molecules than other antibodies. In addition, immunodepletion experiments in gels indicated that the 9.2.27 determinant was present on a higher proportion of 250-Kd glycoprotein molecules than PG-2 antibody to a separate determinant. It is likely that 9.2.27 antibody displays less antigenic heterogeneity because its epitope is represented on a higher proportion of the antigen molecules. Thus, not only the nature of the antigen but also the epitope recognized by an antibody influences the degree of antigenic heterogeneity.

Antibodies, Monoclonal↗
PubMed1992

Clinical implications of heterogeneity of tumor response to radiation therapy.

Heterogeneity of response of tumor tissue to radiation clearly exists. Major parameters include histopathologic type, size (number of tumor rescue units (TRUs)), hemoglobin concentration, cell proliferation kinetics and immune rejection reaction by host. Further, normal and presumably tumor tissue response is altered in certain genetic diseases, e.g. ataxia telangiectasia. Any assessment of response of tumor tissue to a new treatment method or the testing of a new clinical response predictor is optimally based upon a narrow strata, viz., uniform with respect to known parameters of response, e.g. size, histological type. Even among tumors of such a clinically defined narrow strata, there will be residual heterogeneity with respect to inherent cellular radiation sensitivity, distributions of pO2, (SH), cell proliferation etc. The value of a response predictor of an individual tumor will be determined by the heterogeneity of values for these and or other characteristics and by the coefficient of variation (CV) of the measured values of the individual parameters. Heterogeneity of one or more parameters of response is reflected in the slope of the dose response curve for local control, viz. the greater the heterogeneity the less steep the slope. To examine for this effect, the slope of dose response curves for control of model tumors of 10(8) tumor rescue units (TRU) and the SF2 = 0.5 (survival fraction after a single dose of 2 Gy) has been used to assess the impact of inter- and intra-tumoral variation of SF2 on slope, defined as gamma 50 values. The gamma 50 is the increase in local control expressed in percent points for a one percentage increment in dose, at the mid-point on the dose-response curve. The gamma 50 was 6.5 for CV = 0.0. For inter-tumoral CVs of 10%, 20% and 40%, the gamma 50 rapidly decreased to 2.4, 1.3 and 0.7. Intra-tumoral variation was less important, viz., for CVs of 10%, 20%, and 40% the gamma 50 values were reduced to 5.3, 3.8 and 2.2. Combining inter- and intra-tumoral variation reduced the gamma 50 only slightly below that for inter-tumoral variation alone. For example, were the CV 10% for inter- and intra-tumoral variation, the gamma 50 would be 2.1 as compared to 2.4 for inter-tumoral variation alone. The number of TRUs also affects slope, viz. gamma 50 increased from 1 to 9.7 as the TRU number increased from 10(1) to 10(12).(ABSTRACT TRUNCATED AT 400 WORDS)

Dose-Response Relationship, Radiation↗
PubMed1993

Intratumoral heterogeneity of malignant gliomas measured in vitro.

PURPOSE: To evaluate the extent of intratumoral heterogeneity of radiation sensitivity in malignant gliomas, by comparing the intrinsic radiation sensitivity of different glioma sublines derived from the same tumor. METHODS AND MATERIALS: The study was performed on five early established malignant gliomas (passage 3-10). Each specimen was quickly cut into three equal pieces (except for one specimen, where only two pieces were obtained). Each piece was processed independently, disintegrated into single cell suspension using a cocktail of enzymes. Survival curve assays, using colony formation as an end-point, were performed for each subline. Comparison between the intrinsic radiation sensitivity of sublines was calculated using the surviving fraction at 2 Gy and the mean inactivation dose as the measured parameters. The DNA content of the cell lines as well as their cell cycle analysis was determined using flow cytometry. RESULTS: The mean calculated surviving fraction at 2 Gy of all the sublines was 0.37 +/- 0.14, the mean mean inactivation dose was 1.98 +/- 0.63. The intertumoral coefficient of variation for the calculated surviving fraction at 2 Gy of all cell lines was 38%, while that for intratumoral heterogeneity was 25%. Three of the 5 tumors showed a statistically significant difference in the surviving fraction at 2 Gy and mean inactivation dose values of their sublines (p < 0.05). This difference in radiation sensitivity between sublines of the same tumor was not attributed to a difference either in the ploidy status or in the distribution of cells in the cell cycle. CONCLUSION: There is a significant intratumoral heterogeneity of radiation sensitivity in some malignant gliomas. This heterogeneity may limit the predictive power of surviving fraction at 2 Gy or mean inactivation dose, especially when their values are based upon a single measurement/single biopsy. In the meantime, this heterogeneity may be a factor in the discrepancy between unexpectedly sensitive tumor cell lines in vitro and their high clinical radiation resistance.

Brain Neoplasms↗
PubMed1994

Transmural heterogeneity of norepinephrine uptake in failing human hearts.

OBJECTIVES: The aim of this study was to determine whether regional heterogeneity in myocardial sympathetic neural function measured by the uptake of norepinephrine could account for the spatial heterogeneity of beta-adrenergic receptor down-regulation that occurs in the failing human heart. BACKGROUND: Myocardial beta-adrenergic receptor density and function are diminished in patients with chronic heart failure. Down-regulation occurs predominantly in the subendocardium, suggesting that local rather than systemic alterations in sympathetic neural function may be responsible. Although some studies have implicated hypofunction of cardiac sympathetic nerves with defective norepinephrine uptake, others suggest increased cardiac sympathetic nerve activity with unimpaired uptake. METHODS: We measured norepinephrine uptake by incubating transmural slices of the left ventricle from 19 patients who had chronic heart failure and three nonfailing control hearts with [3H]norepinephrine with or without desipramine, a neuronal uptake blocker. The density of uptake sites was measured in subepicardial and subendocardial myocyte regions with light microscopic autoradiography. RESULTS: Although the amount of [3H]norepinephrine uptake varied considerably in failing ventricles, uptake was directly proportional (r = 0.46, p < 0.05) to beta 1-adrenergic receptor density measured in additional slices with radioligand binding assays. In addition, marked transmural heterogeneity in [3H] norepinephrine uptake was consistently observed in failing ventricles. Uptake in subendocardial myocyte regions was significantly less than in subepicardial regions (mean [ +/- SD] subepicardial/subendocardial uptake ratio 4.7 +/- 4.8, p < 0.01). The extent of transmural heterogeneity in norepinephrine uptake was similar in patients with idiopathic and ischemic cardiomyopathy. In contrast, nonfailing hearts exhibited more uniform transmural [3H]norepinephrine uptake (subepicardial/subendocardial uptake ratio 1.8 +/- 1.2, p = NS). CONCLUSIONS: Specific [3H]norepinephrine accumulation is approximately fivefold lower in subendocardial regions of failing left ventricles than in subepicardial regions. These findings support the hypothesis that a subendocardial defect in norepinephrine uptake may chronically elevate local interstitial catecholamine levels and thereby down-regulate beta-adrenergic receptors in a spatially heterogeneous distribution.

Adult↗
PubMed1995

Heterogeneity of ventricular function and myocardial oxidative metabolism in nonischemic dilated cardiomyopathy.

OBJECTIVES: This study was performed to test the hypothesis that regional variation in ventricular function in patients with nonischemic dilated cardiomyopathy is related to regional variation in oxidative metabolism. BACKGROUND: Heterogeneity in regional left ventricular function has long been noted in patients with nonischemic dilated cardiomyopathy. Regional variation in wall stress has been proposed as the pathophysiologic mechanism. By correlating regional function with oxidative metabolism, one can test the hypothesis that heterogeneity in wall stress is responsible for heterogeneity in function. We hypothesized that preserved function as a result of more favorable loading conditions would be associated with regional oxidative metabolism that is equal to or lower than that in other regions. METHODS: Fifteen patients with nonischemic dilated cardiomyopathy (mean [+/- SD] ejection fraction 20.7 +/- 4.0%) were studied. Regional ventricular function was determined using short-axis chordal shortening on two-dimensional echocardiography. Regional oxidative metabolism was assessed by carbon-11 acetate clearance kinetics on dynamic positron emission tomography. An eight-segment model of the left ventricle was used. Segmental function and oxidative metabolism were defined as increased if they varied at least 1 SD from the respective mean value for that patient. RESULTS: Thirteen (87%) of 15 patients exhibited segments with increased function. In 7 (54%) of 13 patients, regional function was increased in the proximal lateral wall. Multivariate linear regression analysis showed a direct relation between regional function and oxidative metabolism (p = 0.02). The average concordance between increased function and increased oxidative metabolism among patients was 0.87 +/- 0.11 (95% confidence interval 0.70 to 1.00). CONCLUSIONS: Patients with nonischemic dilated cardiomyopathy display heterogeneity in regional ventricular function. Relative preservation is observed most frequently in the proximal lateral wall. Relative preservation of function is associated with higher regional oxidative metabolism, suggesting that mechanisms other than or in addition to local loading conditions may be responsible for heterogeneity in function.

Acetates↗
PubMed1995

Heterogeneity of Brucella abortus lipopolysaccharides.

This work demonstrates that Brucella lipopolysaccharide (LPS) preparations are a family of related molecules which display heterogeneity not only at the level of the O polysaccharide, but also at the core oligosaccharide and the lipid A. Sodium dodecyl sulphate/polyacrylamide gel electrophoresis and Western blotting showed that LPS from Brucella strains displayed molecular weight and antigenic heterogeneity. Smooth-type LPS (S-LPS) from B. abortus demonstrated three broad high-molecular-weight bands corresponding to S-LPS, and a low-molecular-weight band corresponding to O antigen lacking rough-type LPS (R-LPS). B. abortus R-LPS displayed four bands in increasing proportions as the molecular weight diminished. Immunodetection on high-performance thin-layer chromatography (HPTLC) with monoclonal antibodies (mAb) showed that R-LPS displayed three diffuse bands. HPTLC of O polysaccharide revealed two fast migrating bands recognized by antibodies. Gel chromatography and HPTLC analysis of core oligosaccharides from R-LPS demonstrated molecular weight heterogeneity as well as heterogeneous banding pattern, with no obvious correspondence between the two profiles. Immunodetection of lipid A on HPTLC plates revealed two major and three minor bands. Reactivity with mAbs suggested that regardless of the lipid A heterogeneity the basic structure of lipid A backbone is maintained.

Brucella abortus↗
PubMed1992

The effect of oxidation/reduction on the charge heterogeneity of the human glucocorticoid receptor.

In order to investigate the molecular basis for the charge heterogeneity which has been reported for the glucocorticoid receptor, we have analyzed the [3H]dexamethasone mesylate ([3H]DM)1 affinity labeled receptor from HeLa S3 cells by high resolution two-dimensional gel analysis. The [3H]DM labeled glucocorticoid receptor from HeLa cells exists as a population of 5-6 isoforms which range over approx. 0.6 pI units but have similar molecular weights. This heterogeneity is apparently the result of modification(s) of a single gene product since the affinity labeled receptor from Chinese hamster ovary (CHO) cells transfected with the human glucocorticoid receptor cDNA displays the same pattern of heterogeneity on two-dimensional gels. Since previous one-dimensional gel studies from our laboratory showed that the structure of the [3H]DM labeled glucocorticoid receptor from HeLa cells is highly susceptible to sulfhydryl group modification, we investigated the potential role of the same modifications in the apparent charge heterogeneity of the glucocorticoid receptor. Treatment of the affinity labeled receptor with iodoacetamide which alkylates free sulfhydryl groups and irreversibly prevents the formation of intra- or intermolecular disulfide bonds, reproducibly resulted in the appearance of 5-6 discrete isoforms of the receptor protein. Treatment with dithiothreitol, a reversible reducing reagent, resulted in detection of 3 to 4 isoforms of the glucocorticoid receptor. In marked contrast, treatment with sodium tetrathionate, which induces intramolecular disulfide bond formation, resulted in only one detectable isoform of the [3H]DM labeled glucocorticoid receptor. These data demonstrate that the oxidation/reduction state of sulfhydryl groups within the receptor protein can account for much of the charge heterogeneity of this ligand dependent transcription factor.

Affinity Labels↗