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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↗

Examination of the spatially heterogeneous electroactivity of boron-doped diamond microarray electrodes.

Spatial variations in the electrical and electrochemical activity of microarray electrodes, fabricated entirely from diamond, have been investigated. The arrays contain approximately 50-mum-diameter boron-doped diamond (BDD) disks spaced 250 mum apart (center to center) in insulating intrinsic diamond supports, such that the BDD regions are coplanar with the intrinsic diamond. Atomic force microscopy (AFM) imaging of the surface reveals a roughness of no more than +/-10 nm over the array. Each BDD microdisk within the array contains polycrystalline BDD with a variety of different grains exposed. Using conducting-AFM, the conductivity of the different grains was found to vary within a BDD microdisk. Electrochemical imaging of the electroactivity of the microdisk electrodes using scanning electrochemical microscopy operating in substrate generation-tip collection mode revealed that, under apparently diffusion-limited steady-state conditions, there was a small variation in the response between electrodes. However, the majority of electrodes in the array appeared to show predominantly metallic behavior. For the electrodes that showed a lower activity, all grains within the microdisk supported electron transfer, albeit at different rates, as evidenced by studies on the electrodeposition of metallic silver, at potentials far negative of the flat band potential of oxygen-terminated polycrystalline diamond. The possibility of using these array electrodes for steady-state diffusion-limited measurements in electroanalytical applications is far-reaching. However, caution should be exercised in the kinetic analysis of voltammetric measurements, since wide variations in the electroactivity of individual grains are apparent when the potential is below the diffusion-limited value.

Journal Article↗

Spatial heterogeneity in striated muscle arteriolar tone, cell flow, and capillarity.

Spatial variations in microvascular function are described at two tissue sites in hamster cremaster muscle (pentobarbital sodium, 70 mg/kg ip). Arterioles observed include terminal arterioles and their feeding vessels, termed capillary network controllers (CNC). Although terminal arterioles at both sites had similar maximum diameters and cell flows, those at site I were significantly more constricted at rest (2.7 +/- 0.3 vs. 5.1 +/- 0.3 microns at site II) and showed lower resting flows (19.0 +/- 5.5 vs. 174 +/- 34 cells/s at site II). There were no spatial differences in CNC maximal parameters or CNC resting tone, yet CNC resting flow at site II (798 +/- 118 cells/s) significantly exceeded the value at site I (460 +/- 85 cells/s). At rest, median capillary cell flow at site I (3.3 cells/s) was half that at site II (6.3 cells/s). During hyperemia, perfused capillary segment length per unit volume was 84% greater at site I and estimated tissue erythrocyte content nearly double that at site II. Thus significant spatial differences in microvascular function exist in cell flow and vessel tone among terminal arterioles, in cell flow among CNC, and in capillarity and indices of capillary exchange.

Animals↗

Spatial heterogeneity of blood flow in the dog heart. II. Temporal stability in response to adrenergic stimulation.

The effects of adrenergic stimulation on local myocardial blood flow in the left ventricle were studied in 13 anaesthetized Beagle dogs using the tracer microsphere technique. Adrenergic stimulation was induced by intravenous infusion of orciprenaline (1-2 microg kg-1 min-1) over 15 min or by electrical stimulation of the left ansa subclavia (10 Hz, 1 ms, 4-8 V) over 5 min. Local myocardial blood flow was analysed in 256 samples with an average (+/-SD) mass of 318+/-49 mg from the left ventricular myocardium using a standardized dissection procedure. Orciprenaline increased the average myocardial blood flow from 0.85+/-0.18 to 1.73+/-0.27 ml min-1 g-1, while oxygen consumption and the pressure-rate product increased by 129 and 119% respectively. The coefficients of variation of local myocardial blood flow, a measure of spatial blood flow heterogeneity, were 0.21 and 0.18 under control and orciprenaline respectively. Except for a slight transmural gradient (endomyocardium/epimyocardium flow ratio 1.19) myocardial blood flow did not exhibit significant spatial gradients. Stimulation with orciprenaline increased the average blood flow in all regions of the left ventricle by comparable extents. However, local blood flow during orciprenaline was significantly lower in samples from regions which had a lower blood flow under resting control conditions. A significant positive relationship was obtained between local myocardial blood flow under resting conditions and orciprenaline (r=0.45+/-0.18). Moreover, after recovery from orciprenaline stimulation (i.e. 40-112 min after the end of orciprenaline infusion) local myocardial blood flow exhibited a high degree of correlation with local flow before orciprenaline (r=0.71+/-0.08). Comparable results were obtained with electrical stimulation of the left ansa subclavia. For the comparison stimulation vs. control, the correlation coefficient of local blood flow was 0.52+/-0.04 and for recovery vs. control 0.77+/-0.06. From these results it is concluded firstly that local myocardial blood flow under resting conditions is an important determinant of local flow during adrenergic stimulation. Secondly, the anatomical region does not have any predictive value for the blood flow change during adrenergic stimulation and finally, the close relationship between local blood flow before and after cardiac stimulation indicates that the spatial blood flow heterogeneity is temporally stable over hours.

Adrenergic Agonists↗

Spatial heterogeneity of intracellular Ca2+ concentration in nonbeating guinea pig ventricular myocytes.

The spatial distribution of intracellular Ca2+ concentration was determined by fluorescent digital imaging microscopy in fura-2-loaded quiescent cardiac myocytes isolated from guinea pig ventricle. Fluorescent ratio images revealed discrete as well as clustered bright fluorescent spots ("hot spots"), which occupied approximately 20-50% of an individual cell's area. The fluorescent intensity and the area of the hot spots were increased by agents that deplete Ca2+ in the sarcoplasmic reticulum, namely, ryanodine (20-40 nM) and caffeine (5-15 mM). However, when cells were exposed to agents that deplete mitochondrial Ca2+, such as the protonophore, carbonyl cyanide m-chlorophenyl-hydrazone (CCCP, 100-300 nM), or the inhibitor of electron transport, antimycin A (4-40 nM), the fluorescent intensity and the area of the hot spots were reduced. These results indicate that the spatial distribution of intracellular Ca2+ concentration in the ventricular myocytes of guinea pig is quite heterogeneous. The ability of CCCP and antimycin A, but not of caffeine and ryanodine, to reduce the fluorescent intensity in the hot spots implies that Ca2+ compartmentation in the mitochondria is largely responsible for the intracellular Ca2+ heterogeneity seen in the present study.

Animals↗

Spatial heterogeneity in normal skin perfusion recorded with laser Doppler imaging and flowmetry.

Spatial and temporal variations in forearm skin perfusion captured by laser Doppler perfusion imaging (LDI) have been compared with topographic maps recorded by laser Doppler flowmetry. In order to determine the shortest LDI sampling time required at each measurement site, with an adequate signal-to-noise ratio and with the ability to display the heterogeneity in skin perfusion, the noise-limited resolution of the LDI system as well as various sampling times were tested. The noise-limited resolution for medium and high light intensities were less than 0.5% (temporal) and 0.3% (spatial) of full scale. A sampling time of 1 sec was selected and image presentation was made by performing bilinear interpolation between perfusion values. The same area (10 x 10 mm) was mapped with LDI and topographic mapping at seven different sites. In addition, a larger area covering the surrounding skin was recorded with LDI. The small area recordings with LDI and topographic mapping could be identified in the larger LDI image. High-and low-perfusion spots coincided between the two systems. Temporal variations were studied by repeated LDI recordings of the same areas as above. Small spots were selected in the areas and plotted versus time. Without provocation, the total perfusion changes at each spot showed large variations, but the relative perfusion levels between neighboring spots persisted. Provocation with heat increased the perfusion in all spots.

Adult↗

Effects of temporal and spatial heterogeneities created by consumer-driven nutrient recycling on algal diversity.

A spatially explicit plant-herbivore model composed of planktonic herbivores, algal preys and nutrients was constructed to examine the effects of consumer-driven nutrient recycling (CNR) on the algal species richness with and without spatial structure. The model assumed that either of two essential nutrients (N and P) limited growth of algal populations and that consumer individuals moved randomly in the lattice and grazed all the algal species with the same efficiency. The results showed that when there was no CNR, the number of persistent algal species was affected by neither supply rates of external nutrients nor spatial structure and was consistently low. When consumers recycled nutrients according to their stoichiometry, the algal species richness changed with supply rates of external nutrients depending on spatial structure: the algal species richness decreased with increasing nutrient loadings when there were no spatial structure because CNR increased the probability of stochastic extinction of algal species by amplifying the oscillation of algae-consumer dynamics. However, when spatial structures were created by the migration of consumers, CNR increased the algal species richness in a range of nutrient loadings because spatial variation of grazing pressure functioned to stabilize the algal-consumer dynamics. The present study suggests that through grazing and nutrient recycling, consumer individuals can create ephemeral heterogeneity in growth environments for algal species and that this ephemerality is one of the keys to understanding algal species in nature.

Animals↗

Spatially heterogeneous dynamics in a model for granular compaction.

We suggest the emergence of spatially correlated dynamics in slowly compacting dense granular media by analyzing analytically and numerically multipoint correlation functions in a simple particle model characterized by slow nonequilibrium dynamics. We show that the logarithmically slow dynamics at large times is accompanied by spatially extended dynamic structures that resemble the ones observed in glass-forming liquids and dense colloidal suspensions. This suggests that dynamic heterogeneity is another key common feature present in very different jamming materials.

Journal Article↗

Spatial heterogeneity of aggregate stability and soil carbon in semi-arid rangeland.

To measure and manage for C sequestration in heterogeneous rangeland systems, we need to more fully understand spatial patterns of soil resources. Spatial distributions of aggregate stability and soil carbon were investigated in a semiarid rangeland in New Mexico, USA. Soil was analyzed from plant interspaces, black grama (Bouteloua eriopoda (Torr.) Torr.), and mesquite (Prosopis glandulosa Torr.) in a landscape-replicated study. Aggregate stability at the 250 microm scale, carbonate C, organic C and N, C:N ratio, and glomalin, were all highest under mesquite. Soil C:N ratio was the best predictor of aggregate stability. Estimates of metric tons of C per hectare in the top 10 cm were highly variable at patch and landscape scales, varying from 4.2 to 10.5 under mesquite and from 3.0 to 7.0 in interspaces. High variability of aggregate stability and soil C has important implications for C sequestration. We argue that this multi-scale soil heterogeneity must be considered when measuring and managing for C sequestration.

Carbon↗

SIMS evidence that carbimazole enhances spatial heterogeneity of thyroid iodine storage and targeting in a woman with Graves' disease.

Antithyroid drugs (ATD) are known to reduce 131I efficacy in thyrotoxicosis, though the underlying mechanism remains misunderstood. To study the impact of long term administration of carbimazole on both iodine stores (127I, secondary ion mass spectrometry microscopy) and targeting (125I, radioautography) at the intraglandular level in a woman who underwent surgery for Graves' disease. 125I distribution was dramatically heterogenous and large areas of the sample appeared poorly or no stained at all. This may correspond to flat follicles, hypofunctioning or ATD blocked ones and to the various histological changes related to the thyroiditis. SIMS counting showed huge variations of the interfollicular iodine stores (0 to 1.18 microg/mg) and lower mean values than those observed in nodular goiters. SIMS imaging depicted iodine free areas and others with preserved thyroglobulin synthesis, as assessed via 32S- mapping, but low to undetectable 127I, suggesting focal organification defects. Since ATD reduce iodine storage and uptake capabilities and enhance the iodine heterogeneity of interfollicular targeting, a related enhancement of the spatial 131I dose distribution is unavoidable. ATD may reduce 131I efficacy by variably reducing the number of follicles which can be actually or significantly targeted, e.g. irradiated (antirecruitement effect).

Antithyroid Agents↗

Radon concentration in soil gas: a comparison of the variability resulting from different methods, spatial heterogeneity and seasonal fluctuations.

From the end of 1996 through March 1999, the spatial and temporal variability of the soil 222Rn concentration was investigated at a 20 m x 20 m test field with porous soil in 0.5 m and 1.0 m depth at nine positions each and at 1 m x 1 m plots at four positions each. For this, soil gas was collected weekly into evacuated scintillation cells and was analysed subsequently for radon activity. In the 20 m x 20 m field the spatial variability was characterized by coefficients of variation (C.V.) of 26% at 0.5 m, and 13% at 1.0 m depth. Within the 1 m x 1 m plots the C.V. values were 4% and 2%, i.e. within the uncertainty of the method. Time series analysis (TSA) of the soil radon data shows seasonal variations with maximum concentrations in the winter months. Radon concentrations ranged from 6 to 50 kBq m(-3) in 0.5 m depth, and from 8 to 34 kBq m(-3) in 1.0 m depth. Mostly, the concentrations were higher in 0.5 depth than in 1.0 m depth. However, seasonal variation of the 0.5 m to the 1.0 m concentration ratio has been verified by TSA. To test the variability resulting from different methods, additional procedures and instruments were investigated at the 20 m x 20 m field and at a second test field with a different soil type. Soil gas sampling into evacuated scintillation cells was selected as the reference procedure. Soil radon concentrations obtained with the different sampling procedures and detection methods at the 20 m x 20 m field essentially agreed within the limits of uncertainty of the methods tested. At the second test field, i.e. in a largely impermeable soil, deviations up to a factor of two related to the reference procedure were observed.

Air Pollutants, Radioactive↗

Heterogeneity, spatial population dynamics, and the migration rate.

"In this paper, I examine some of the ways in which widely used migration indices are affected by the impacts of heterogeneity and selection, which act within a multistate perspective of spatial population dynamics that permits increments as well as decrements in the selectivity (and return) process. As a result, several commonly used indices of migration introduce a specification bias into the analysis--a bias that reflects the relative weighting accorded to component migration rates by the initial population compositions and spatial distributions." This paper was originally presented at the 1991 Annual Meeting of the Population Association of America.

Bias↗

Spatial heterogeneity and function of voltage- and ligand-gated ion channels in retinal amacrine neurons.

The spatial distribution of ion channels within amacrine cells of the tiger salamander retina was studied using patch recording in the retinal slice preparation. By focally puffing kainate, GABA and glycine at amacrine cell processes in the inner plexiform layer, it was determined that the cell's glutamate receptors were located in a confined region of the processes near the soma, while glycine and GABA receptors were located throughout the processes. Likewise, similar techniques in conjunction with voltage steps demonstrated that voltage-gated sodium channels were located throughout the cell and were shown to generate sodium-dependent spikes, while only the processes contained voltage-gated calcium channels. These results suggest that this form of transient amacrine cell collects its excitatory synaptic inputs in a region confined to a central annular region near the soma, that the signal is actively propagated throughout its processes by voltage-gated sodium channels and that calcium-dependent neurotransmitter release of glycine from this neuron can occur throughout its processes. Thus, excitatory signals are collected in the processes near the soma, inhibitory signals throughout the processes and excitation is probably propagated throughout the processes of the amacrine cell.

Ambystoma↗

Spatial distribution patterns of malaria vectors and sample size determination in spatially heterogeneous environments: a case study in the west Kenyan highland.

The current study examined temporal and spatial distribution patterns of anopheline malaria vectors in a highland site and determined the number of houses to be sampled to achieve the targeted precision level. Adult mosquito sampling was conducted seasonally in May and August 2002 in a 3 by 3-km2 area, and in November 2002 and February 2003 in an expanded 4 by 4-km2 area in Kakamega District, western Kenya. Anopheles gambiae Giles was the predominant malaria vector species, constituting 84.6% of the specimens, whereas Anopheles funestus Giles constituted 15.4% of the vector populations. An. gambiae abundance increased by six- to eight-fold in the long rainy season over the dry seasons, but An. funestus abundance peaked 3 mo after the long rainy season. For both species, the coefficient of variation was larger than 1, suggesting that the distribution of mosquito adults was aggregated. Mosquito clustering occurred in houses <400 m from a valley bottom. The negative binomial distribution was accepted in one sample period (August 2002) for An. gambiae and in two sampling periods (May and August 2002) for An. funestus. Taylor's power law analyses indicated that An. gambiae distribution was more aggregated in the wet seasons than in the dry seasons, whereas the degree of aggregation of An. funestus was similar in all four seasons. The minimum number of houses required to estimate anopheline female abundance within the commonly acceptable precision level (0.2) should be 17 houses per km2 for An. gambiae and 42 houses per km2 for An. funestus. The potential factors causing aggregated anopheline mosquito distribution are discussed.

Animals↗

Spatial heterogeneity of mucosal blood flow during ischemia-reperfusion injury of rat stomach investigated by laser Doppler perfusion imaging.

Spatial alterations in blood flow during the development of mucosal injury induced by ischemia-reperfusion in rats were determined with a two-dimensional laser Doppler tissue perfusion imager. The rats were anesthetized with pentobarbital, and the stomach was exteriorized on a stage; the mucosa was then sequentially scanned. The mucosa was constantly superfused with 0.1 N HCl in physiological saline. Systemic arterial pressure was continuously monitored and blood was stepwisely withdrawn from the femoral artery by 20-mmHg stage and then maintained at 20 mmHg for 20 min. The shed blood was reinfused and the stomach was removed 30 min later. Under control conditions, the average perfusion of the forestomach was usually greater than that in the glandular stomach. When systemic blood pressure was stepwisely decreased, the extent of decrease in the mucosal blood perfusion unit was always greater than that in systemic blood pressure, but mucosal perfusion appeared to be uniformly decreased throughout the stomach. Ten min after reperfusion, a hypoperfused area began to appear in the corpus near the greater curvature, and this area subsequently increased. The area of ulcer formation corresponded with the hypoperfused area in the gastric mucosa 30 min after reperfusion. Pretreatment with CV-6209, a platelet-activating factor antagonist, significantly attenuated the hypoperfusion induced by reperfusion and also prevented gastric mucosal damage. Our results suggest that hypoperfusion in the mucosal microcirculation is indeed an important factor contributing to the localized occurrence of gastric mucosal lesions and that the laser Doppler perfusion imager is useful for the detection of local hypoperfused areas in the gastric mucosa.

Analysis of Variance↗

Temporal and spatial heterogeneities of Ca2+ signaling: mechanisms and physiological roles.

In the cells of the gastrointestinal tract, as in most other types of cells, many of the fundamental cellular functions are mediated by increases of intracellular Ca2+. These increases are mediated primarily by elevations of inositol 1,4,5-trisphosphate (IP3), which, in turn, are a consequence of the activation of specific plasma membrane receptors. Extensive investigations of these intracellular processes in the last few years have revealed the complexities of Ca2+ signaling. The extreme heterogeneity of Ca2+ signaling, which is manifest by variations in both the time course and the spatial distribution of these signals, forms the central theme of this review. On the basis of the available information, the various intracellular mechanisms that allow the manifestation of this heterogeneity are discussed. It is argued that these variations in Ca2+ response are the result not only of the existence of multiple, complex mechanisms participating in the generation and maintenance of the agonist-evoked Ca2+ signal but also of the existence of various isoforms for almost every one of the main molecules involved in signaling and the concomitant participation of many intracellular modulators.

Animals↗

Temporal and spatial heterogeneity of mtDNA polymorphisms in natural populations of Drosophila mercatorum.

Restriction endonuclease analysis of mtDNA was used to examine the genetic relatedness of several geographically separated isolines of the Drosophila mercatorum subgroup. In addition, we examined the temporal and spatial distribution of two mtDNA restriction site polymorphisms produced by the enzymes BstEII and BstNI at a single locality--Kamuela, Hawaii. Due to small sample sizes of some collections and the undesirable dependance of the estimation of polymorphism frequency on its variance, an arcsin square root transformation of the frequency data was used. We also use an Fst estimator of our transformed frequencies to demonstrate considerable spatial and temporal differentiation within the Kamuela population. In contrast, isozyme data from the same population reveals no pattern of differentiation. The temporal and geographic heterogeneity and population subdivision detected with mtDNA analysis also is consistent with the known dispersal behavior and ecological constraints of this species. The mtDNA data in conjunction with the isozyme data show that the population structure of the Kamuela D. mercatorum is close to the boundary line separating panmixia from subdivision, a conclusion that could not be made from isozyme data alone.

Alleles↗

The role of nitric oxide in the spatial heterogeneity of basal microvascular blood flow in the rat diaphragm.

The effects of N omega-nitro-L: -arginine (L: -NOARG) and N(G)-monomethyl-L: -arginine (L: -NMMA) on the spatial distribution of diaphragmatic microvascular blood flow were assessed in anesthetized, mechanically ventilated rats. Microvascular blood flow was measured after different periods at either a fixed site (Q stat) or 25 different sites (Q scan) using computer-aided laser-Doppler flowmetry (LDF) scanning. The value of Q stat was unaffected after 15-20 min superfusion with any one of the following agents: L: -NOARG (0.1 mM), L: -NMMA (0.1 mM), L: -arg (10 mM). The cumulative frequency histogram of the Q scan value in the control group displayed a non-Gaussian distribution that was not significantly affected after 15 min superfusion with the vehicle of L: -NOARG. Superfusion with either L: -NMMA or L: -NOARG at 0.1 mM for 15 min displaced the histogram of cumulative frequency to the left, with the median value of blood flow decreasing by 10 to 20%. However, skewness and kurtosis of the distribution of basal Q(scan) were unaffected after superfusion of either of the L: -arg analogues. Pretreatment with L: -arg (10 mM), followed by co-administration of L: -arg (10 mM) with L: -NOARG (0.1 mM) only partially prevented L: -NOARG from exerting this inhibitory effect on the distribution of basal Q scan, while pretreatment with L: -arg in the same manner could prevent L: -NMMA from exerting its inhibitory effect. There was a weak but significant linear relationship between the magnitude of basal Q(scan) and normalized changes in basal Q scan after superfusion of either of the L: -arg analogues. In conclusion, a basal NO activity is present in the diaphragmatic microvascular bed of rats. LDF scanning rather may yield more vivid information about the extent of overall tissue perfusion than conventional LDF whenever basal NO activity is involved. Moreover, the parallel flow profiles after NO synthase blockade suggest that the spatial inhomogeneity of basal diaphragmatic microvascular blood flow is not dependent on basal NO formation.

Animals↗