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PubMed1978

Role of autoregulation in spatial and temporal perfusion heterogeneity of canine myocardium.

Spatial heterogeneity, the region-to-region variation in flow at an instant, and temporal heterogeneity, the time variation of flow in a small region of myocardium, were investigated with radioactive labeled microspheres in 111 regions of left ventricular myocardium. The error of the method was measured by simultaneously injecting four differently labeled microspheres (15 +/- 5 (SD) micron). The coefficient of variation (CV) was 6.5 +/- 1.0%. Spatial variation with autoregulation intact was 21.7 +/- 1.4% (CV); with autoregulation abolished and low perfusion pressure, it was 34.3 +/- 3.7%; and with normal perfusion pressure, 30.8 +/- 6.4% (differences not significantly). This degree of variation was similar in the entire left ventricle and its layers. Forces which tended to cause vessel closure (low perfusion pressure, ventricular systolic pressure, and ventricular diastolic pressure) tended to increase CV. Temporal heterogeneity as measured by 20-s intervals between microsphere injections was 11.1 +/- 1.0% (CV) with autoregulation, 9.8 +/- 1.3% (P less than 0.05) with autoregulation abolished, and 8.4 +/- 0.8% (P less than 0.05) when perfusion pressure was restored. A periodicity of flow cycles of 30-90 s was suggested by the data. These results suggest that spatial heterogeneity is less influenced by autoregulation than by hydraulic considerations, whereas temporal heterogeneity is a component of autoregulation.

Animals↗
PubMed1993

Effect of inspired CO2 on ventilation and perfusion heterogeneity in hyperventilated dogs.

We studied the effect of inspired CO2 on ventilation-perfusion (VA/Q) heterogeneity in dogs hyperventilated under two different tidal volume (VT) and respiratory rate conditions with the use of the multiple inert gas elimination technique. Dogs anesthetized with pentobarbital sodium were hyperventilated with an inspired fraction of O2 of 0.21 by using an increased VT (VT = 30 ml/kg at 18 breaths/min) or an increased respiratory rate (VT = 18 ml/kg at 35 breaths/min). The arterial CO2 tension (PaCO2) was varied to three levels (20, 35, and 52 Torr) by altering the inspired PCO2. The orders of type of ventilation and PaCO2 level were randomized. Compared with normocapnia, VA/Q heterogeneity was increased during hypocapnia induced by increased respiratory rate ventilation, which was indicated by an increase in dispersion indexes and arterial-alveolar inert gas partial pressure difference areas (P < 0.01). In contrast, VA/Q heterogeneity was not affected by hypocapnia when a large VT ventilation was used. Under the conditions of our study, hypercapnia did not result in statistically significant changes in VA/Q heterogeneity with either type of ventilation. Increased VT ventilation reduced dead space at all PaCO2 levels (P < 0.01) and reduced the log standard deviation of the ventilation distribution during normocapnia (P < 0.05) and hypocapnia (P < 0.01). We conclude that hypocapnia increased VA/Q heterogeneity when hyperventilation was achieved with a rapid respiratory rate. Therefore, a lack of improvement in VA/Q matching with inhaled CO2 may be associated with the use of a large VT. These data suggest that hypocapnic bronchoconstriction may be important in mediating hypocapnia-induced VA/Q inequality in dogs.

Administration, Inhalation↗
PubMed1999

Airway remodeling in asthma amplifies heterogeneities in smooth muscle shortening causing hyperresponsiveness.

Although airway remodeling and inflammation in asthma can amplify the constriction response of a single airway, their influence on the structural changes in the whole airway network is unknown. We present a morphometric model of the human lung that incorporates cross-sectional wall areas corresponding to the adventitia, airway smooth muscle (ASM), and mucosa for healthy and mildly and severely asthmatic airways and the influence of parenchymal tethering. A heterogeneous ASM percent shortening stimulus is imposed, causing distinct constriction patterns for healthy and asthmatic airways. We calculate lung resistance and elastance from 0.1 to 5 Hz. We show that, for a given ASM stimulus, the distribution of wall area in asthmatic subjects will amplify not only the mean but the heterogeneity of constriction in the lung periphery. Moreover, heterogeneous ASM shortening that would produce only mild changes in the healthy lung can cause hyperresponsive changes in lung resistance and elastance at typical breathing rates in the asthmatic lung, even with relatively small increases in airway resistance. This condition arises when airway closures occur randomly in the lung periphery. We suggest that heterogeneity is a crucial determinant of hyperresponsiveness in asthma and that acute asthma is more a consequence of extensive airway wall inflammation and remodeling, predisposing the lung to produce an acute pattern of heterogeneous constriction.

Airway Resistance↗
PubMed2000

Ventilation heterogeneity in excised lobes: effect of tidal volume.

Although several factors are known to influence nonuniformity of ventilation, including lung mechanical properties (regional structure and compliance), external factors (chest wall, pleural pressure, heart), and ventilatory parameters (tidal and preinspiratory volume, flow rate), their relative contributions are poorly understood. We studied five excised, unperfused, canine right-middle lobes under varied levels of tidal volume (VT), thus eliminating many factors affecting heterogeneity. Multiple-breath washouts of N(2) were analyzed for anatomic dead space volume (VD(anat)), nonuniformity of N(2) washout, and nonuniformity between joined acinar regions vs. that occurring between larger joined regions. Approximately 80% of ventilation heterogeneity was found among joined acinar regions at resting levels of VT, but increasing VT reduced intra-acinar heterogeneity to about 25% of that found at resting levels. Increasing VT had essentially no effect on VD(anat) and heterogeneity among larger joined regions. The results indicate that the magnitude of VT is a major influence on the dominant intra-acinar component of ventilation heterogeneity and that VT effects on VD(anat) are likely due to perfusion and/or influences normally external to the lobar structure.

Animals↗
PubMed1999

Heterogeneity of DNA distribution in diploid cells: a new predictive discriminant factor for solid tumour behaviour.

Spatial nuclear DNA heterogeneity distribution of Feulgen-stained DNA diploid cells was studied by image cytometry in voided urine of 119 patients without bladder tumour (n = 20) and with initial (n = 23) or previous (n = 76) diagnosed bladder tumour. For each patient, repetitive DNA measurements were performed during 1-4 years of follow up. Only cells of diploid DNA histograms and diploid subpopulations of aneuploid DNA histograms were used for analysis. DNA heterogeneity distribution of these diploid cells was quantified by statistical parameters of each nuclear optical density distribution. Discriminant analysis was performed on three groups of DNA histograms. Group A (n = 44): aneuploid DNA histograms of patients with bladder tumour. Group D (n = 55): 38 diploid DNA histograms of the 20 patients without bladder tumour (subgroup D1) and 17 diploid DNA histograms of patients with a non-recurrent bladder tumour (subgroup D2). Group R (n = 27): diploid DNA histograms of patients with bladder tumour recurrence. No statistically significant discriminant function was found to separate D1 and D2. However, the first canonical discriminant function C1 differentiated diploid cells of diploid DNA histograms (group D and group R) from diploid cell subpopulations of aneuploid DNA histograms (group A). Mean C1 values were 1.06, 0.84 and -1.45 for groups R, D and A, respectively. The second canonical discriminant function C2 differentiated diploid DNA histograms of patients with bladder tumour recurrence (group R) from diploid DNA histograms of patients without bladder tumour or without bladder tumour recurrence (group D). Mean C2 values were 1.78 and -0.76 for groups R and D, respectively. In 95% confidence limit, the rate of rediscrimination using the two first canonical discriminant functions C1 and C2 were 86.4, 74.5 and 74.1% for groups A, D and R, respectively. Percent of "grouped" cases correctly classified was 78.6%. Thus spatial DNA heterogeneity distribution of diploid cells seems to quantitate probable genetic instability as a function of clinical evolution such as tumour recurrence, and suggests the possible presence of aneuploid stemlines in a heterogeneous tumour, even if a diploid DNA histogram is observed in a single sample. From standardized C1 and C2 canonical discriminant function coefficients, a DNA heterogeneity index (2c-HI) is proposed to characterize diploid cells providing a descriptive and predictive discriminant factor for solid tumour behaviour.

DNA, Neoplasm↗
PubMed2000

Evaluation of tumor heterogeneity of prostate carcinoma by flow- and image DNA cytometry and histopathological grading.

BACKGROUND: Heterogeneity of prostate carcinoma is one of the reasons for pretreatment underestimation of tumor aggressiveness. We studied tumor heterogeneity and the probability of finding the highest tumor grade and DNA aneuploidy with relation to the number of biopsies. MATERIAL AND METHODS: Specimens simulating core biopsies from five randomly selected tumor areas from each of 16 Böcking's grade II and 23 grade III prostate carcinomas were analyzed for tumor grade and DNA ploidy by flow- and fluorescence image cytometry (FCM, FICM). Cell cycle composition was measured by FCM. RESULTS: By determination of ploidy and cell cycle composition, morphologically defined tumors can further be subdivided. Heterogeneity of tumor grade and DNA ploidy (FCM) was 54% and 50%. Coexistence of diploid tumor cells in aneuploid specimens represents another form of tumor heterogeneity. The proportion of diploid tumor cells decreased significantly with tumor grade and with increase in the fraction of proliferating cell of the aneuploid tumor part. The probability of estimating the highest tumor grade or aneuploidy increased from 40% for one biopsy to 95% for 5 biopsies studied. By combining the tumor grade with DNA ploidy, the probability of detecting a highly aggressive tumor increased from 40% to 70% and 90% for one and two biopsies, respectively. CONCLUSION: Specimens of the size of core biopsies can be used for evaluation of DNA ploidy and cell cycle composition. Underestimation of aggressiveness of prostate carcinoma due to tumor heterogeneity is minimized by simultaneous study of the tumor grade and DNA ploidy more than by increasing the number of biopsies. The biological significance of coexistent diploid tumor cell in aneuploid lesions remains to be evaluated.

Biopsy↗
PubMed2000

Heterogeneous chromosomal aberrations in intraductal breast lesions adjacent to invasive carcinoma.

There is evidence that breast cancer is a heterogeneous disease phenotypically as well as molecular biologically. So far, heterogeneity on the molecular biological level has not been investigated in potential precursor lesions, such as ductal hyperplasia (DH) and ductal carcinoma in situ (DCIS). In this study we applied comparative genomic hybridization (CGH) to formalin-fixed, paraffin-embedded breast tissue with DH and DCIS, adjacent to invasive ductal carcinoma (IDC), to screen these potential precursor lesions for whole genomic chromosomal imbalances. Laser-microdissection was used to select pure cell populations from the sections. Isolated DNA was amplified by degenerate oligonucleotide primed PCR (DOP-PCR) and further processed for CGH analysis. Investigating multiple samples (n = 25) from four patients we found an average of 5.6 +/- 0.9 (mean +/- SEM) chromosomal imbalances already present in DH. In the twelve DCIS lesions an average of 10.8 (+/- 0.9) aberrations was identified with 14.8 (+/- 0.8) aberrations in the four adjacent IDC lesions. The increasing number of chromosomal changes in parallel with the histopathological sequence corroborate the hypothesis, that the carcinomas may have developed through a sequential progression from normal to proliferative epithelium and eventually into carcinoma. However, heterogeneous results were identified in the multiple samples per entity from the same patient, demonstrated mainly in the DCIS samples in the chromosomal regions 6p, 9p, 11q, 16p and 17q, in the DH samples by 3p, 16p and 17q. This heterogeneous findings were most pronounced within the DH and was less in the DCIS and IDC samples. The only aberration consistently found in all samples-even in all DH sample-was amplification of the 20q13 region. Our results demonstrate, that the applied combination of laser-microdissection, DOP-PCR and CGH, may serve to analyse breast carcinogenesis pathways in suitable histological material. However, so far, it is unclear how to handle heterogeneous results and these make identification of relevant changes more difficult. Setting a threshold and evaluating only those chromosomal changes which are present in a majority of samples may be one possibility. This involves however, the risk that infrequent but possibly significant aberrations may be missed. Figures on http://www.esacp.org/acp/2000/20-1/aubele. htm.

Breast Neoplasms↗
PubMed1989

Actinomycin D affects thyrotropin-releasing hormone-induced heterogeneous forms of glycosylated thyroid-stimulating hormone in rat anterior pituitary.

Actinomycin D and cycloheximide were used to clarify the tight relationship between protein synthesis and heterogeneous carbohydrate synthesis of rat pituitary thyroid-stimulating hormone (TSH) under thyrotropin-releasing hormone (TRH) stimulation in vitro. Rat anterior pituitaries were incubated with [3H]glucosamine in the presence of TRH, cycloheximide and actinomycin D at 37 degrees C for 3 and 6 h. The TSH fraction of pituitary homogenates was obtained using affinity chromatography coupled with anti-TSH globulin, and was analyzed by isoelectric focusing. Anterior pituitary in the presence of TRH showed heterogeneous components of [3H]glucosamine-labeled TSH with 6 different isoelectric points (components I-VI). Radioactivities of the components increased with the incubation period. Cycloheximide changed these heterogeneous components. Actinomycin D also caused a striking change in the heterogeneity of pituitary [3H]glucosamine-labeled TSH: components I and II decreased and components III and IV increased as compared to the control group after a 6-hour incubation. The present study implies that actinomycin D affects the TRH-induced heterogeneous components of pituitary TSH glycosylation. The data indicate that messenger RNA is essential for the normal processing of carbohydrate synthesis of pituitary TSH.

Animals↗
PubMed1992

Hepatocyte heterogeneity in bile formation and hepatobiliary transport of drugs.

In the past two decades many studies have been devoted to the involvement of the periportal (zone-1) and perivenous (zone-3) hepatocytes in bile formation and hepatobiliary transport of endogenous and exogenous compounds. It became clear that such a heterogeneity in transport function can, in principle, be due to the different localization of the cells in the acinus with respect to the incoming blood, to intrinsic differences between the cells or to both. In this review we first discuss the techniques used to study hepatocyte heterogeneity in hepatobiliary transport function. Combinations of such techniques can be used to discriminate between cellular heterogeneity due to acinar localization as opposed to intrinsic differences. These techniques include: normal and retrograde perfusions of isolated perfused livers; autoradiographic, fluorimetric and histochemical localization of injected substrates; separation of isolated hepatocytes into fractions enriched in periportal and perivenous cells; measurements of fluorescent surface signals with microlight guides; selective zonal toxicity, and pharmacokinetic modelling and analysis. Subsequently, for each of the rate-limiting steps in the hepatobiliary transport of organic compounds, the basic mechanisms are summarized and the available knowledge on the involvement of the cells from the various zones in these transport steps is discussed. The available literature data indicate that heterogeneity in transport function is often due to the localization of the cells in the acinus: the periportal cells are the first to come into contact with the portal blood and are thus exposed to the highest substrate concentration. Consequently they obtain the most prominent task in further disposition of the particular compound. It follows that the extent of involvement of the perivenous cells in drug disposition is implicitly determined by the activity of the periportal cells. Because of the potential saturation of elimination processes in the periportal cells, the involvement of perivenous cells may vary with the input concentration. In addition, real intrinsic differences have been established in the hepatobiliary transport of some substrates. These are probably based on differences in the cellular content of carrier- and receptor-binding and/or metabolizing proteins. In some cases these intrinsic differences may be secondary to existing sinusoidal gradients of endogenous compounds, such as O2, amino acids, bile acids or monosaccharides. Yet, data on the heterogeneity of hepatocytes in the various transport steps are far from complete or are even totally lacking, especially for human liver. A multi-experimental approach and advanced technology will be needed in the future to gain more insight into the acinar organization of bile formation and hepatobiliary transport of drugs in the human.

Animals↗
PubMed1991

Intratumoral heterogeneity of DNA indexes in transitional cell bladder cancer: relation to tumor histology.

DNA flow cytometry (FCM) was performed from multiple samples in 60 transitional cell bladder carcinomas (TCC) to detect intratumoral heterogeneity of DNA index (DI). The samples for analysis were selected randomly and they were paraffin-embedded peroperative biopsy specimens from the primary TCCs. Intratumoral heterogeneity of DI was found in 12 of 60 (20%) samples. All WHO grade I tumors were diploid whereas 12 of 41 (29%) WHO grade II-III tumors showed a heterogeneous DI. DI heterogeneity was related to WHO grade (p = 0.004), mitotic frequency (p = 0.002), inflammatory cell infiltration (ICI; p = 0.003) and nonpapillar growth pattern (p = 0.06). In multivariate analysis, the WHO grade (p = 0.027) and the degree of ICI (p = 0.041) were independently related to heterogeneous DI. The results show that (a) many of the WHO grade II-III TCCs are composed of diploid and aneuploid cell populations; (b) the presence of dense ICI and TCCs may lead to false diploid DI. Consequently, the analysis of multiple samples is recommended in WHO grade II-III tumors to detect aneuploidy particularly when dense ICIs are present.

Aneuploidy↗
PubMed1999

Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo: A new method of detection by application of a special thermography catheter.

BACKGROUND: Activated macrophages play an important role in the pathogenesis of acute ischemic syndromes. It has been postulated that detection of heat released by activated inflammatory cells of atherosclerotic plaques may predict plaque rupture and thrombosis. Previous ex vivo studies have shown that there is thermal heterogeneity in human carotid atherosclerotic plaques. METHODS AND RESULTS: To measure the temperature of human arteries in vivo, we developed a catheter-based technique. Ninety patients (45 with normal coronary arteries, 15 with stable angina [SA], 15 with unstable angina [UA], and 15 with acute myocardial infarction [AMI]) were studied. The thermistor of the thermography catheter has a temperature accuracy of 0.05 degrees C, a time constant of 300 ms, and a spatial resolution of 0.5 mm. Temperature was constant within the arteries of the control subjects, whereas most atherosclerotic plaques showed higher temperature compared with healthy vessel wall. Temperature differences between atherosclerotic plaque and healthy vessel wall increased progressively from SA to AMI patients (difference of plaque temperature from background temperature, 0. 106+/-0.110 degrees C in SA, 0.683+/-0.347 degrees C in UA, and 1. 472+/-0.691 degrees C in AMI). Heterogeneity within the plaque was shown in 20%, 40%, and 67% of the patients with SA, UA, and AMI, respectively, whereas no heterogeneity was shown in the control subjects. CONCLUSIONS: Thermal heterogeneity within human atherosclerotic coronary arteries was shown in vivo by use of a special thermography catheter. This heterogeneity is larger in UA and AMI, suggesting that it may be related to the pathogenesis.

Aged↗
PubMed1997

Transit time heterogeneity in canine small intestine: significance for oxygen transport.

We previously found that local O2 extraction efficacy in isolated pump-perfused intestine was enhanced when systemic reflex vasoconstriction was stimulated by hypovolemia (Samsel, R.W., and P.T. Schumacker. 1994. J. Appl. Physiol. 77: 2291-2298). The microvascular mechanism underlying this beneficial effect could involve a redistribution of flow between mucosa and serosa, or an adjustment in the heterogeneity of perfusion within those regions. We measured regional blood flows and distributions of flow and capillary erythrocyte transit times in two segments of small intestine in anesthetized dogs (n = 10). Each vascularly isolated segment of intestine was pump-perfused under high flow (O2 supply-independent VO2) and low flow (O2 supply-dependent) conditions. During the first gut segment, the animal was kept normovolemic using i.v. fluids to minimize reflex vasoconstriction. During the second, the animal was hemorrhaged to augment vasoconstriction (n = 7), or kept normovolemic to control for the effects of time (n = 3). Blood flow distributions were measured using 15 microm radiolabeled microspheres. Tissue blood volume was measured using 99mTc-labeled red blood cells. Capillary volume was determined as the product of tissue blood volume and the histologically derived fraction of vascular volume in the capillaries. Transit times were calculated as the ratio of capillary volume to flow. Each gut segment was fixed and sectioned into 350 approximately 100 mg tissue pieces for analysis. Data revealed significant spatial heterogeneity of blood flow and capillary transit times in both mucosa and muscularis, with relative dispersions (SD/Mean) ranging from 23 to 97%. Hypovolemia caused an increase in flow heterogeneity in muscularis at both high and low flow states, and in mucosa under high flow conditions. However, hypovolemia also elicited changes in capillary volume, such that transit time heterogeneity remained unchanged. Augmentation of vasoconstrictor tone caused a redistribution of flow toward mucosa (P < 0.003) under high and low flow conditions. This redistribution correlated with the improvements in O2 extraction ratio (P = 0.022). Thus, the improvement in gut O2 extraction efficacy seen with increased vasoconstriction may be explained mostly by an intramural redistribution of flow between mucosa and muscularis. Capillary transit time heterogeneity remained unchanged, suggesting that this variable is tightly regulated.

Animals↗
PubMed2001

Methods for exploring heterogeneity in meta-analysis.

In meta-analysis, when the difference in results between studies is greater than would be expected by chance, one needs to investigate whether the observed variation in results across studies is associated with clinical and/or methodological differences between studies. This article reviews methods used in meta-analysis for exploring heterogeneity, including statistical tests for homogeneity, methods for visually displaying results of primary studies, methods for reducing heterogeneity, methods for investigating sources of heterogeneity, and identification of moderator variables or effect modifiers. The investigation of sources of heterogeneity in meta-analysis is by nature exploratory, and therefore its results should always be interpreted with caution. However, careful investigation of heterogeneity may provide an important second level of evidence that can be useful in suggesting direction of future research. Sometimes, it may provide clinically important results by indicating who might benefit more or less from a treatment or how an intervention should be applied.

Data Interpretation, Statistical↗
PubMed1996

Properties of heterogeneous apatites containing magnesium, fluoride, and carbonate.

Biological apatites present in the mineral phases of normal and pathological calcifications contain magnesium, Mg, and carbonate, CO3. As a consequence of fluctuations in the composition of the micro-environment, these apatites may sometimes form by heterogeneous precipitation. The purpose of this study was to investigate the properties of (Mg, CO3)-apatites formed heterogeneously in the presence of fluoride, F. Two types of fluoridated (Mg, CO3)-apatites formed from solutions with low and high levels of Mg were prepared at 80 degrees C, pH 7.4. We prepared FMgCO3-MgCO3AP (Type 1) by adding the F-containing solution to those containing calcium, Mg, and phosphate ions during the first half of the precipitation period. We prepared MgCO3-FMgCO3Ap (Type 2) by adding the F-containing solution during the final half of the period. The apatites were analyzed by x-ray diffraction (XRD), infrared absorption spectroscopy, and scanning electron microscopy (SEM). SEM and XRD analyses showed evidence of mixed crystals in the heterogeneous apatites. The presence of Mg inhibits, while F promotes, apatite crystal growth. In addition, Mg incorporation increased with increasing fluoride concentration. The extent of dissolution in acid buffer of both types of heterogeneous apatites increased with Mg: Type 1 > Type 2. These results suggest that the crystal and dissolution properties of heterogeneous fluoridated (Mg, CO3)-apatites are greatly affected by the mode of F incorporation and Mg concentrations in the environment.

Apatites↗
PubMed2006

Phenotypic heterogeneity is an evolutionarily conserved feature of the endothelium.

Mammalian endothelial cells (ECs) display marked phenotypic heterogeneity. Little is known about the evolutionary mechanisms underlying EC heterogeneity. The last common ancestor of hagfish and gnathostomes was also the last common ancestor of all extant vertebrates, which lived some time more than 500 million years ago. Features of ECs that are shared between hagfish and gnathostomes can be inferred to have already been present in this ancestral vertebrate. The goal of this study was to determine whether the hagfish endothelium displays phenotypic heterogeneity. Electron microscopy of the aorta, dermis, heart, and liver revealed ultrastructural heterogeneity of the endothelium. Immunofluorescent studies demonstrated marked differences in lectin binding between vascular beds. Intravital microscopy of the dermis revealed histamine-induced adhesion of leukocytes in capillaries and postcapillary venules, but no such adhesion in arterioles. Together, these data suggest that structural, molecular, and functional heterogeneity of the endothelium evolved as an early feature of this cell lineage.

Animals↗
PubMed2001

Evidence for spatial heterogeneity in insulin- and exercise-induced increases in glucose uptake: studies in normal subjects and patients with type 1 diabetes.

It is unknown whether resistance to insulin- or exercise-stimulated glucose uptake reflects a spatially uniform or nonuniform decrease in glucose uptake within skeletal muscle. We compared the distributions of muscle glucose uptake and blood flow in eight patients with type 1 diabetes (age 24 +/- 1 yr, body mass index 22.0 +/- 0.8 kg/m2) and seven age- and weight-matched normal subjects using positron emission tomography, [18F]-fluoro-deoxy-glucose, and [15O]-water. Both groups were studied during euglycemic hyperinsulinemia and one-legged exercise. Heterogeneity was evaluated by calculating relative dispersion (SD divided by mean * 100%) of glucose uptake (RD(g)) and flow (RD(f)) in all pixels within a region of interest in femoral muscle. At rest insulin-stimulated glucose uptake was significantly lower in the type 1 diabetic patients (42 +/- 7 micromol/kg per min) than in the normal subjects (78 +/- 9 micromol/kg per min, P < 0.001), while muscle blood flows were similar (26 +/- 1 vs. 31 +/- 3 ml/kg muscle per min, respectively). The exercise-induced increment in glucose uptake but not in blood flow was also significantly lower in the type 1 diabetic patients than in the normal subjects. Heterogeneity of glucose uptake but not of blood flow was greater in the insulin-resistant type 1 diabetic patients both at rest (RD(g) 31 +/- 1 vs. 25 +/- 2%, patients with type 1 diabetes vs. normal subjects, P < 0.05) and during exercise, compared with normal subjects (27 +/- 1 vs. 21 +/- 2%, respectively, P < 0.05). Exercise increased both glucose uptake and blood flow several-fold and significantly decreased both RD(g) and RD(f). Heterogeneity of RD(g), was inversely associated with total glucose uptake (r = -0.54, P < 0.001, pooled data) and was highest in the most insulin-resistant patients. We concluded that both glucose uptake and blood flow are characterized by heterogeneity in human skeletal muscle, whose magnitude is inversely proportional to respective mean values. This implies that an increase in glucose uptake in human skeletal muscle is not a phenomenon, by which each unit increases its glucose uptake by a fixed amount but rather a spatially heterogeneous process.

Adult↗
PubMed2005

Fibrosis heterogeneity in nonalcoholic steatohepatitis and hepatitis C virus needle core biopsy specimens.

We examined 46 nonalcoholic steatohepatitis (NASH) and 52 hepatitis C virus (HCV) biopsy specimens to determine the magnitude of fibrosis heterogeneity and minimum length for accurate fibrosis staging. Three fibrosis scores were recorded: lowest regional, highest regional, and most common overall. Mean specimen lengths were 1.6 and 1.8 cm in NASH and HCV, respectively (P = .283). Mean (highest minus lowest) fibrosis heterogeneity scores (highest regional fibrosis - lowest regional fibrosis) were 3.7 and 2.0 in NASH and HCV, respectively (P < .001). Of 36 NASH specimens longer than 1.0 cm, 31 (86%) had the highest regional fibrosis in the deepest sampled parenchyma. Shorter specimens were associated significantly with greater fibrosis heterogeneity in NASH (coefficient, -1.3; P < .001) but not in HCV (P = .901). NASH specimens longer than 1.6 cm had significantly lower mean heterogeneity scores than specimens 1.6 cm or shorter (1.2 vs 3.4; P = .012). In NASH, fibrosis heterogeneity can be substantial and is greater than in HCV, and parenchymal injury, fibrosis, and healing might vary in different regions of the liver. The fibrosis stage in patients with NASH might not be assessed accurately in short specimens. Individual needle cores should be longer than 1.6 cm in NASH for accurate fibrosis staging.

Biopsy, Needle↗
PubMed2005

Dermatoglyphic fingerprint heterogeneity among individuals with nonsyndromic cleft lip with or without cleft palate and their unaffected relatives in China and the Philippines.

Cleft lip with or without cleft palate (CL/P) is a common birth defect (birth prevalence ranging from 1/500 to 1/2,000) with a complex etiology. Traits potentially related to CL/P, such as dermatoglyphics, may reflect the genetic and epidemiologic heterogeneity observed in CL/P. Such phenotypic heterogeneity in dermatoglyphic patterns may account for some of the variability in previously reported associations of dermatoglyphics and CL/P. To test this hypothesis, we took dermatoglyphic prints from individuals with nonsyndromic CL/P (n = 460) and their unaffected relatives (n = 254) from the Philippines and China. For both samples three raters designated the patterns as arch, ulnar loop, radial loop, whorl, or "other." Chi-square analysis and standard ANOVA were used to investigate heterogeneity between Filipino and Chinese study subjects. The significant associations between particular pattern types and CL/P were not the same in both populations, demonstrating population-specific association of CL/P and dermatoglyphic pattern types. The ANOVA of pattern type included both CL/P cases and their relatives, with affection status, sex, and population group as variables. For each pattern type except arches, population was significant (p < 0.0001); for radial loops, affection status was additionally significant (p < 0.0001). When only CL/P cases were considered, population was again significant for the ulnar loop (p < 0.0001), whorl (p < 0.0001), and "other" (p = 0.0002) patterns. The ANOVAs demonstrate between-population heterogeneity in dermatoglyphic pattern types. These results support our hypothesis that population-specific associations and population heterogeneity in dermatoglyphic patterns exist for CL/P cases and their relatives.

Analysis of Variance↗