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PubMed2002

Spatial heterogeneity of transmembrane potential responses of single guinea-pig cardiac cells during electric field stimulation.

Changes in transmembrane voltage (V(m)) of cardiac cells during electric field stimulation have a complex spatial- and time-dependent behaviour that differs significantly from electrical stimulation of space-clamped membranes by current pulses. A multisite optical mapping system was used to obtain 17 or 25 microm resolution maps of V(m) along the long axis of guinea-pig ventricular cells (n = 57) stained with voltage-sensitive dye (di-8-ANEPPS) and stimulated longitudinally with uniform electric field (2, 5 or 10 ms, 3-62 V cm(-1)) pulses (n = 201). The initial polarizations of V(m) responses (V(mr)) varied linearly along the cell length and reversed symmetrically upon field reversal. The remainder of the V(m) responses had parallel time courses among the recording sites, revealing a common time-varying signal component (V(ms)). V(ms) was depolarizing for pulses during rest and hyperpolarizing for pulses during the early plateau phase. V(ms) varied in amplitude and time course with increasing pulse amplitude. Four types of plateau response were observed, with transition points between the different responses occurring when the maximum polarization at the ends of the cell reached values estimated as 60, 110 and 220 mV. Among the cells that had a polarization change of > 200 mV at their ends (for fields > 45 V cm(-1)), some (n = 17/25) had non-parallel time courses among V(m) recordings of the various sites. This implied development of an intracellular field (E(i)) that was found to increase exponentially with time (tau = 7.2 +/- 3.2 ms). Theoretical considerations suggest that V(ms) represents the intracellular potential (phi(i)) as well as the average polarization of the cell, and that V(mr) is the manifestation of the extracellular potential gradient resulting from the field stimulus. For cells undergoing field stimulation, phi(i) acts as the cellular physiological state variable and substitutes for V(m), which is the customary variable for space-clamped membranes.

Animals↗
PubMed2006

Spatial heterogeneity in the parasite communities of creek chub (Semotilus atromaculatus) in southeastern Nebraska.

The intestinal helminth communities of creek chub (Semotilus atromaculatus) were studied in the streams of southeastern Nebraska to characterize spatial variation, to determine whether drainages act as regional species pools, and to examine the spatial patterning of individual parasite species within and among drainages. Creek chub were sampled in the summer of 2003 and the spring of 2004 at each of 12 sites distributed evenly among 3 drainages in the Big Nemaha River watershed. Four intestinal helminths were recovered: Allocreadium lobatum, Proteocephalus sp., Rhabdochona canadensis, and Paulisentis missouriensis. Host size had little or no effect on the composition of the parasite communities of creek chub, either among individual fish or among samples. In contrast, drainage and sample date explained 82% of the variation in mean infracommunity species richness among samples, and 62% of the variation in mean infracommunity abundance among samples. Drainage differences were determined by the distributions of P. missouriensis and R. canadensis; whereas, A. lobatum and Proteocephalus sp. were more uniformly distributed among drainages. Each drainage was characterized by a unique pattern of species diversity at infracommunity, component community, and drainage levels of organization.

Analysis of Variance↗
PubMed2006

Reversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable variable to improve drug delivery.

Maturation of tumor vasculature involves the recruitment of pericytes that protect the endothelial tubes from a variety of stresses, including antiangiogenic drugs. Mural cells also provide mature tumor blood vessels with the ability to either relax or contract in response to substances present in the tumor microenvironment. The observed cyclic alterations in tumor blood flow and the associated deficit in chemotherapeutic drug delivery could in part arise from this vasomodulatory influence. To test this hypothesis, we focused on endothelin-1 (ET-1), which, besides its autocrine effects on tumor cell growth, is a powerful vasoconstrictor. We first document that an ET(A) receptor antagonist induced relaxation of microdissected tumor arterioles and selectively and quantitatively increased tumor blood flow in experimental tumor models. We then combined dye staining of functional vessels, fluorescent microsphere-based mapping, and magnetic resonance imaging to identify heterogeneities in tumor blood flow and to examine the reversibility of such phenomena. Data from all these techniques concurred to show that administration of an ET(A) receptor antagonist could reduce the extent of underperfused tumor areas, proving the key role of vessel tone variations in tumor blood flow heterogeneity. We also provide evidence that ET(A) antagonist administration could, despite an increase in tumor interstitial fluid pressure, improve access of cyclophosphamide to the tumor compartment and significantly influence tumor growth. In conclusion, tumor endogenous ET-1 production participates largely in the temporal and spatial variations in tumor blood flow. ET(A) antagonist administration may wipe out such heterogeneities, thus representing an adjuvant strategy that could improve the delivery of conventional chemotherapy to tumors.

Animals↗
PubMed2006

Small-scale spatial heterogeneity of arbuscular mycorrhizal fungal abundance and community composition in a wetland plant community.

Although it has become increasingly clear that arbuscular mycorrhizal fungi (AMF) play important roles in population, community, and ecosystem ecology, there is limited information on the spatial structure of the community composition of AMF in the field. We assessed small-scale spatial variation in the abundance and molecular diversity of AMF in a calcareous fen, where strong underlying environmental gradients such as depth to water table may influence AMF. Throughout an intensively sampled 2 x 2 m plot, we assessed AMF inoculum potential at a depth of 0-6 and 6-12 cm and molecular diversity of the AMF community using terminal restriction fragment length polymorphism of 18S rDNA. Inoculum potential was only significantly spatially autocorrelated at a depth of 6-12 cm and was significantly positively correlated with depth to water table at both depths. Molecular diversity of the AMF community was highly variable within the plot, ranging from 2-14 terminal restriction fragments (T-RFs) per core, but the number of T-RFs did not relate to water table or plant species richness. Plant community composition was spatially autocorrelated at small scales, but AMF community composition showed no significant spatial autocorrelation. Saturated soils of calcareous fens contain many infective AMF propagules and the abundance and diversity of AMF inoculum is patchy over small spatial scales.

DNA, Fungal↗
PubMed2003

Spatial heterogeneity and temporal kinetics of photosensitizer (AlPcS2) concentration in murine tumors RIF-1 and MTG-B.

In this study we compared the photosensitizer concentration in two experimental murine tumors using an in situ fluorescence detection instrument to examine temporal and spatial variations, after intravenous versus intratumor injection. Also, the variations in the estimate as detected by large area sampling and micro-region sampling are compared, in order to determine what the inter-tissue and inter-animal variations are, and how the method of sampling affects this estimate. The latter study was carried out ex vivo in the same tumors, which had been harvested and frozen after in vivo measurements were made. The photosensitizer, disulphonated aluminum phthalocyanine (AlPcS2) was injected either intravenously (IV) or directly into the tumor (ITu), using two murine models, MTG-B (mammary adenocarcinoma) and RIF-1 (radiation-induced fibrosarcoma) grown subcutaneously on the flank. An in situ microsampling fluorescence probe was used to assess photosensitizer concentration, through real-time measurement of the remitted intensity. The photosensitizer concentration was evaluated at 8 time endpoints between 15 min and 48 h post-injection. Inter-tumor and intra-tumor variations were assessed by repeated samples from the tumor tissues. The average photosensitizer level reaches a peak between 3 to 6 h in both tumor and normal tissues using IV administration, but peaks within 1 h following ITu administration. MTG-B tumors demonstrated a factor of 2 higher uptake than RIF-1 tumors. The pharmacokinetic uptake rates of the RIF-1 tumor were 3 times faster than for MTG-B, while there was no statistical difference in their clearance rates. Preferential uptake of AlPcS2 by both tumors compared to contra-lateral flank subcutaneous normal tissue was documented, with ITu injection exceeding IV injection by a factor of 10 in the tumor to normal tissue ratio. Inter-animal standard deviation in the mean fluorescence was near 76% for both routes of administration, but estimates of the variation within tumor were near 16% standard deviation when a large sampling volume was used. In contrast, microscopic intra-tumor standard deviation in the mean estimate was near 76%, with IV injection, indicating that high heterogeneity exists in the photosensitizer concentration on a smaller distance scale. The inter-tumor variation was reduced by ITu injection, but at the expense of increasing intra-tumor variation.

Adenocarcinoma↗
PubMedDate not supplied

Dynamic susceptibility-weighted perfusion imaging of high-grade gliomas: characterization of spatial heterogeneity.

BACKGROUND AND PURPOSE: The advent of new anti-angiogenic therapies has created the need for better defining regions of abnormal vascularity in order to add specificity to the classification of high-grade gliomas. This study investigated MR imaging parameters corresponding to the peak height and percent recovery of the T2* relaxivity curve to characterize angiogenesis and microvascular leakage within the T2 and contrast-enhancing abnormalities in high-grade gliomas. METHODS: Dynamic susceptibility-weighted MR imaging was performed in 41 patients with untreated high-grade glioma during the first pass and recirculation phase of a gadolinium bolus injection. Normalized peak height and percent recovery of the post-bolus signal were calculated on a voxel by voxel basis within the T2 and contrast-enhancing lesions (T2L, CEL) and compared between grade III and grade IV gliomas. RESULTS: Grade IV gliomas showed significantly larger volumes of abnormal peak height and recovery compared to grade III patients (P < .01). Within the CEL, grade IV gliomas exhibited significantly higher peak height values than grade III patients (P < .05). Enhancing grade III patients (n = 7) demonstrated higher minimum values of percent recovery within both regions compared to grade IV patients. Non-enhancing grade III gliomas (n = 11) had significantly elevated minimum percent recovery values when compared to the T2L-CEL region in grade IV patients (n = 23; P < .05). CONCLUSION: Direct measurement of the spatial distribution of tumor microvasculature characteristics has shown considerable heterogeneity within different regions of grade III and grade IV gliomas. Peak height and percent recovery parameters help to improve the specificity for characterization of the degree of angiogenesis and microvascular leakage in these tumors and may be useful in evaluating response to treatment.

Brain Neoplasms↗
PubMedDate not supplied

Spatial heterogeneity of mitochondrial DNA and allozymes among populations of white-tailed deer and mule deer.

A white-tailed deer (Odocoileus virginianus) population in northeastern Minnesota and a mule deer (O. hemionus) population in the Bridger Mountains Montana, have previously been shown to be spatially subdivided into contiguous subpopulations. We assessed the degree of genetic differentiation among subpopulations and tested the hypothesis that differentiation will be greater for mitochondrial DNA (mtDNA) than for nuclear-encoded allozymes. Differentiation of the white-tailed deer subpopulations was significant for two allozyme loci but not for mtDNA, and the overall degree of differentiation was low. Gene flow, recent founding of the subpopulations, and polygamous breeding structure may all have contributed to this pattern. Greater differentiation was evident among disjunct populations than between the contiguous subpopulations of white-tailed deer. The contiguous mule deer subpopulations were significantly differentiated for mtDNA and one allozyme locus. Differentiation was greater for mtDNA than for allozymes. These results are consistent with demographic data that indicate mule deer males disperse more than do females. Disjunct mule deer populations may be similar or dramatically different in mtDNA haplotype frequencies that do not necessarily vary with geographic distance. Current and historical gene flow and breeding structure will influence population genetic patterns.

Animals↗
PubMed2004

Spatial heterogeneity of crenarchaeal assemblages within mesophilic soil ecosystems as revealed by PCR-single-stranded conformation polymorphism profiling.

Microbial ecologists have discovered novel rRNA genes (rDNA) in mesophilic soil habitats worldwide, including sequences that affiliate phylogenetically within the division Crenarchaeota (domain Archaea). To characterize the spatial distribution of crenarchaeal assemblages in mesophilic soil habitats, we profiled amplified crenarchaeal 16S rDNA sequences from diverse soil ecosystems by using PCR-single-stranded-conformation polymorphism (PCR-SSCP) analysis. PCR-SSCP profiles provide a measure of relative microbial diversity in terms of richness (number of different phylotypes as estimated from the number of unique PCR-SSCP peaks) and evenness (abundance of each phylotype as estimated from the relative area under a peak). Crenarchaeal assemblages inhabiting prairie, forest, turf, and agricultural soils were characterized at six sampling locations in southern and central Wisconsin. Phylotype richness was found to be more stable than evenness among triplicate samples collected within 30 cm at each sampling location. Transformation of the PCR-SSCP data by principal-component analysis, followed by statistical testing (analysis of variance [P < 0.0001] and least-significant-difference analysis [alpha = 0.5]), supported the conclusion that each location exhibited a unique profile. To further characterize the spatial distribution of crenarchaeal assemblages at one location, additional soil samples (a total of 30) were collected from agricultural field plots at the Hancock Agricultural Research Station. PCR-SSCP revealed a patchy spatial distribution of crenarchaeal assemblages within and between these plots. This mosaic of crenarchaeal assemblages was characterized by differences in phylotype evenness that could not be correlated with horizontal distance (15 to 30 m) or with depth (0 to 20 cm below the surface). Crenarchaeal 16S rDNA clone libraries were produced and screened for unique SSCP peaks. Clones representing the dominant phylotypes at each location were identified, sequenced, and found to group phylogenetically with sequences in crenarchaeal clade C1b.

Base Sequence↗
PubMed2002

Spatially heterogeneous expression of aromatase P450 through promoter II is closely correlated with the level of steroidogenic factor-1 transcript in endometrioma tissues.

Endometriosis is an estrogen-dependent disease of women of reproductive age. Recent studies demonstrate that endometriosis per se express high levels of estrogen synthetase (aromatase P450). The resulting estrogen synthesized in situ may play a role in the development and exacerbation of the disease. For ovarian endometrioma, previous studies have been conducted ex vivo using cells obtained from endometrioma and have demonstrated that steroidogenic factor-1 is involved in the expression of aromatase. The aim of the present study was to provide in vivo evidence that steroidogenic factor-1 plays an important role in the regulation and overexpression of aromatase P450 in situ. First, promoter use of aromatase P450 in endometrioma tissue was determined using quantitative methods. Ovarian endometrioma tissue was chopped into small pieces, and two exon 1-specific transcripts of aromatase P450 (PII-specific and I.4-specific transcripts) were quantified using competitive RT-PCR. PII-specific transcript was more abundant than the I.4-specific transcript in 13 of the 15 endometriomas and less abundant in the remaining two. Spatial distribution of aromatase P450 transcripts in these endometrioma tissues revealed heterogeneous expression in the cyst wall, demonstrating wide variability even in the same endometrioma. Two possible regulators of aromatase expression (steroidogenic factor-1 and IL-1 beta) were then measured in all endometrioma samples and the correlation between aromatase P450 transcripts and these possible regulators in the endometrioma samples were tested using Spearman's rank order correlation test. Levels of steroidogenic factor-1 transcript were found to correlate closely with levels of PII-specific transcript in eight of nine endometriomas examined. On the other hand, the level of IL-1 beta weakly correlated with I.4-specific transcripts in three of the nine endometriomas. We next histologically examined samples of four endometriomas in which complete sets of tissue samples corresponded to the RNA samples. We could not identify any specific pathology to explain the heterogeneous expression of PII-specific transcripts of aromatase P450, although the number of CD-68 positive macrophages in the tissue sections weakly correlated with the level of I.4-specific transcript in two of four endometriomas. These results provide strong evidence that promoter II is the predominant promoter of aromatase P450 in endometrioma tissues in vivo and that steroidogenic factor-1 in situ is a major determinant of aromatase P450 overexpression in endometrioma tissues in vivo.

Adult↗
PubMed1995

Piriform cortex late activity revealed functional spatial heterogeneity.

Optical signals were recorded in the in vivo rat piriform cortex (PC) in response to olfactory bulb electrical stimulation. Sometimes the early response was followed by a longer latency component with an occurrence probability of 0.25. In order to compare the early and late activity, the ratio between early (disynaptic) and late wave amplitudes was measured at each recording site on the whole PC. Its spatial distribution revealed that the relative importance of the late activity was larger in the most posterior part of the PC whereas the late wave was rarely observed in the anterior PC. Such a result gave new information on the functional heterogeneity of the PC.

Animals↗
PubMedDate not supplied

[Spatially heterogeneous distribution of phytoplankton in a model of a regulated population].

With the help of the mathematical model is shown that the existence of the phitoplankton's mechanism of growth-speed regulation by means of excretion to the environment of biologically active substances, may lead to a considerable inhomogenity of it's spatial distribution, that is, patchness. There appears an intensive crowding of phitoplankton with homogenious distribution of nutrients, while some limitations of excretion rate and of dispersion coefficients are taken into account.

Mathematics↗
PubMed2001

Models of infectious diseases in spatially heterogeneous environments.

Most models of dynamics of infectious diseases have assumed homogeneous mixing in the host population. However, it is increasingly recognized that heterogeneity can arise through many processes. It is then important to consider the existence of subpopulations of hosts, and that the contact rate within subpopulations is different than that between subpopulations. We study models with hosts distributed in subpopulations as a consequence of spatial partitioning. Two types of models are considered. In the first one there is direct transmission. The second one is a model of dynamics of a mosquito-borne disease, with indirect transmission, and applicable to malaria. The contact between subpopulations is achieved through the visits of hosts. Two types of visit are considered: a first one in which the visit time is independent of the distance travelled, and a second one in which visit time decreases with distance. There are two types of spatial arrangement: one dimensional, and two dimensional. Conditions for the establishment of the disease are obtained. Results indicate that the disease becomes established with greater difficulty when the degree of spatial partition increases, and when visit time decreases. In addition, when visit time decreases with distance, the establishment of the disease is more difficult when the spatial arrangement is one dimensional than when it is two dimensional. The results indicate the importance of knowing the spatial distribution and mobility patterns to understand the dynamics of infectious diseases. The consequences of these results for the design of public health policies are discussed.

Animals↗
PubMed1988

Spatial heterogeneity of metabolism in skeletal muscle in vivo studied by 31P-NMR spectroscopy.

Phase-modulated rotating-frame imaging, a localization technique for phosphorus nuclear magnetic resonance spectroscopy, has been applied to obtain information on heterogeneity of phosphorus-containing metabolites in skeletal muscle of the rat in vivo. The distal muscles of the rat hindlimb have been studied at rest and during steady-state isometric twitch contraction; the use of a transmitter surface coil and an electrically isolated, orthogonal receiver Helmholtz coil ensure accurate spatial assignment (1 mm resolution). At rest, intracellular pH was higher and PCr/(PCr + Pi) was lower in deeper muscles compared with superficial muscle of the distal hindlimb. Upon steady-state stimulation, the relatively more alkaline pH of deep muscle was maintained, whereas greater changes in PCr/(PCr + Pi) and Pi/ATP occurred in the superficial muscle layer. This method allows rapid (75 min for each spectral image) acquisition of quantitative information on metabolic heterogeneity in vivo.

Adenosine Triphosphate↗
PubMed2003

Spatial heterogeneity of action potential alternans during global ischemia in the rabbit heart.

Cardiac ischemia causes beat-to-beat fluctuation in action potential duration (APD) alternans, which leads to T wave alternans and arrhythmias. Occurrence of APD alternans that is out of phase at two sites is especially important, but most APD alternans studies have involved rapid pacing of normal myocardium rather than ischemia. To determine the spatial features of APD alternans during ischemia, blood-perfused rabbit hearts were stained with 4-[beta-[2(di-n-butylamino)-6-napthyl]vinyl]pyridinium (di-4-ANEPPS) and imaged with a high-resolution camera. Hearts were perfused with oxygenated Tyrode solution at 37 degrees C for staining and then switched to a 50:50% blood/Tyrode mixture. Hearts were paced from the right ventricle at 3/s, and made ischemic by stopping flow for 6 min. Images of 10,000 pixels were obtained at 300 frames/s. Motion artifact was controlled by immobilization and by manual selection of undistorted single-pixel records. Upstroke propagation and conduction isochrones were displayed by computerized image processing. APD alternans was demonstrated in six of seven hearts, and was out of phase in different regions of the image in three hearts. The largest spatial variation in the onset of depolarization to 50% repolarization (APD50) was 155%. This caused beat-to-beat reversal of repolarization. An alternans map could be constructed for well-immobilized portions of the image. There were discrete regions of APD alternans separated by a boundary, as occurs with intracellular Ca2+ concentration alternans. Pixels as close together as 1.1 mm showed an APD alternans that was out of phase. The out-of-phase APD alternans was not due to conduction alternans, as shown by upstroke intervals and conduction isochrones. This contrasts with rapid pacing, where a causal relationship appears to exist. These new observations suggest distinct mechanisms for the genesis of arrhythmias during ischemia.

Action Potentials↗
PubMedDate not supplied

Temporally and spatially heterogeneous distribution of mTHPC in a murine tumor observed by two-color confocal fluorescence imaging and spectroscopy in a whole-mount model.

Efficient intratumor delivery of anticancer drugs and photosensitizers is an important factor in the success of chemotherapy and photodynamic therapy, respectively. Unfortunately, their adequate and uniform intratumor distribution is impeded by several physiological barriers and by binding to tissue components. Measurement of gross tumor drug accumulation is a routine method of investigating the uptake and clearance of chemotherapy agents and photosensitizers but tells little about their extravascular spatial distribution. We use whole-mount two-color confocal fluorescence imaging and imaging spectroscopy of unprocessed excised murine tumor fragments to investigate the intratumor distribution of the photosensitizer meso-tetrahydroxyphenyl chlorin (mTHPC) as a function of distance from blood vessels perfused with 0.2 mum diameter fluorescent microspheres. Significant mismatches between drug and perfused vasculature are caused by heterogeneities in tumor blood supply. We describe complex microscopic mTHPC gradients that reverse dramatically relative to the perfused vasculature with time after injection. This imaging technique can be applied to screen the dynamic intratumor distribution of other fluorescent photosensitizers and anticancer drugs.

Animals↗