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Spatial distribution of tumor-specific monoclonal antibodies in human melanoma xenografts.

The time-dependent (1-72-h) spatial distribution of three biotinylated anti-melanoma monoclonal antibodies (MAbs), a control MAb, and several macromolecular tracers was studied in two small (4-12-mg), well-characterized human melanoma xenografts (SK-MEL-2, M21) growing in the s.c. space of athymic nude mice. The specific MAbs (436, IND1, and 9.2.27) recognize two different melanoma cell surface antigens (Mr 125,000 glycoprotein melanoma-associated antigen and high molecular weight melanoma-associated antigen) and have equilibrium association constants differing by two orders of magnitude (10(8)-10(10) M-1). SK-MEL-2 tumors were poorly vascularized and were composed of one or several collections of tumor cells with few intratumor blood vessels. In contrast, M21 tumors induced a strong angiogenic response and were organized into multiple small tumor cell nests separated from each other by fine blood vessels. Neither tumor developed extensive connective tissue stroma. In both tumors, hyperpermeable blood vessels were concentrated at the tumor-host interface but some intratumor vessels in M21 tumors were also leaky. Macromolecular tracers extravasated extensively from leaky vessels into tumor stroma but penetrated poorly into tumor parenchyma. All three tumor-specific MAbs stained tumor cell surfaces in a time-dependent fashion such that one-half or more of all tumor cells were stained by 24-48 h. Tumor cell staining was favored by increased density of tumor cell antigens but, at the doses studied, was little affected by differences in affinity among tumor-specific antibodies. The distribution of MAb staining was nonuniform in two respects: (a) peripherally situated tumor cells were more likely to be stained than centrally placed cells, and only in the smallest tumors did MAb reach centrally placed tumor cells; and (b) staining was nonuniform in different parts of the same tumor. The inhomogeneity of tumor cell staining by tumor-specific MAb was attributable to several factors, including: tumor blood vessel number, distribution, perfusion and permeability; distribution of tumor connective tissue stroma; small volume of the parenchymal interstitial space and relatively impaired diffusion of macromolecules in that space (low effective diffusivity of MAb); and interactions between specific MAbs and tumor cells. Of these factors, those associated with the parenchymal compartment apparently were rate limiting, and strategies that enhance parenchymal penetration are likely to improve solid tumor therapy with MAbs.

Animals

[Spatial distribution of atrial late potentials on body surface mapping in patients with paroxysmal atrial fibrillation].

We investigated the spatial distribution of atrial late potentials (ALP) in patients with paroxysmal atrial fibrillation (Paf) by use of body surface signal-averaged ECG. The P wave-triggered signal-averaged ECG was recorded in 20 patients with Paf and 34 control patients from precordial 16 unipolar leads (standard V1-V6 and two intercostal spaces below and above V1, V2, V4-V6). The duration (Ad) and number of fragmented deflection (Nf) of filtered P wave were measured on each lead. % Area was also calculated by dividing the area for the last 20 msec by the total area of filtered P wave. The lead having any of a significantly longer Ad, larger Nf and smaller % Area in patients with Paf than the controls was designated as ALP positive lead. ALPs were observed in all other than two intercostal spaces above V5 and V6. This finding suggests that the electrophysiological disparity in the whole atrial muscle might be involved in patients with Paf.

Atrial Fibrillation

[Spatial distribution of light intensity with a phototherapy halogen lamp].

The spatial energy distribution under a phototherapy unit fitted with a special halide lamp (ex. Hereaus, "Photo-Therapie 800") is particularly uneven, with a pronounced decrease in energy towards the edges. With a correct positioning of the child in the centre of the luminous cone however, the energy of the effective light is still distinctly higher than that received from a phototherapy unit fitted with 6 blue fluorescent tubes (Philips 20W/52 BAM blue). With the addition of lateral aluminium reflectors, not only is the effective energy intensity increased, but also the spatial energy distribution becomes more even, so that a very exact positioning of the child is no longer required.

Bilirubin

Fertilization alters the spatial distribution and the density of voltage-dependent sodium current in the egg of the ascidian Boltenia villosa.

The spatial distribution of voltage-dependent ionic currents was characterized in Boltenia villosa eggs before and after fertilization using two-microelectrode voltage clamp of paired animal-vegetal halves of eggs (merogones) made surgically. Major voltage-dependent conductances in the Boltenia egg are a transient inward Na current, a transient inward Ca current, and an inwardly rectifying K current. These currents were randomly distributed along the animal-vegetal axis in the unfertilized egg. When paired merogones (surgically prepared egg fragments) were made at the vegetal cap stage, 15-30 min after fertilization, Ca and K currents remained randomly distributed along the animal-vegetal axis. In contrast, the relative Na current density was found to be twofold lower in the vegetal vs the animal merogones made at the vegetal cap stage. By making pairs of merogones from unfertilized eggs and subsequently fertilizing one merogone of a pair, we showed that this change in current density ratio was due to a loss of absolute Na current density in the vegetal hemisphere shortly after fertilization. These results also show that this loss was intrinsic to the vegetal hemisphere, rather than being determined solely by the point of sperm entry. A second decrease in Na current was observed during the hour before first cleavage, 60-120 min after fertilization (M.L. Block and W.J. Moody, 1987, J. Physiol. 393, 619-634), both in fertilized eggs and in animal merogones fertilized after isolation. This second loss of Na current was not observed in vegetal merogones fertilized after isolation or in either animal or vegetal merogones made from fertilized eggs at the vegetal cap stage. Possible mechanisms for te rapid (complete by 40 min after fertilization) and the late (occurring from ca. 60 to 120 minutes after fertilization) Na current losses are discussed.

Action Potentials

Origin and spatial distribution of maternal messenger RNA during oogenesis of an insect, Oncopeltus fasciatus.

In order to investigate the origin and spatial distribution of maternal mRNA during oogenesis, in situ hybridization with [3H]-poly(U) was utilized for the detection of poly(A)-containing RNA [poly(A)+RNA] in histological sections of Oncopeltus fasciatus ovaries. In the germarium poly(A)+RNA was found to accumulate in the trophocyte cytoplasm concomitant with the maturation of these cells. Poly(A)+RNA was also detected in the trophic cores and nutritive tubes suggesting that these channels participate in the transport of trophocyte-derived mRNA to the oocytes. Although large amounts of poly(A)+RNA were also detected in the cytoplasm of the follicle cells, particularly during late vitellogenesis when pseudopod-like processes projected into the ooplasm, no evidence was obtained for the transport of poly(A)+RNA from these processes to the oocytes. The content of poly(A)+RNA in the oocyte cytoplasm continually increased during oogenesis. In stage 2--4 oocytes poly(A)+RNA accumulation occurred in the apparent absence of transcriptional activity in the germinal vesicle nuclei suggesting that most maternal mRNA molecules synthesized during early oogenesis are of trophocyte origin. Poly(A)+RNA also continued to accumulate after chorion formation, when the nutritive tubes are longer active in RNA transport. This implies that other sources of maternal mRNA may exist during late oogenesis. The distribution of poly(A)+RNA molecules in the oocyte cytoplasm appeared to be uniform throughout oogenesis with one exception. During late vitellogenesis poly(A)+RNA activity was significantly enhanced in the anterior and posterior periplasmic cytoplasms relative to the lateral periplasm and the endoplasm. After chorion formation these variations disappeared. The results suggest that maternal mRNA molecules arise from at least 2 sources during oogenesis. During late vitellogenesis these molecules appear to be subject to differential localization in the polar perimeters of the oocyte cytoplasm.

Animals

Spatial distribution of the capacity to initiate a secondary embryo in the 32-cell embryo of Xenopus laevis.

To examine the spatial distribution of dorsal determinants in the early embryos of Xenopus laevis, individual cells from the 32-cell embryo were transplanted into the same tier of the ventral side of a synchronous recipient. Their abilities to initiate a secondary embryo were measured by the incidence of secondary embryos and by the length of the secondary axis relative to the primary embryo. The ability was found to be localized in all cells (A1, B1, C1, and D1) of the dorsal most column and in the vegetal cells (C2 and D2) of the dorsolateral column. Transplanted C1 (subequatorial) cells caused the highest incidence of a secondary embryo and the average relative length of the secondary embryo was also greatest. Effectiveness decreased in the order: D1, B1, D2, C2, and A1. When these results were compared with Dale and Slack's fate map of the 32-cell embryo, it was concluded that the distribution of dorsal determinants is unique and does not coincide with the prospective regions for any tissues, though it is somewhat similar to the prospective region of dorsal endoderm or notochord. From these results it seems that dorsal determinants do not determine a particular tissue in an embryo but rather the "dorsal" region of an embryo.

Animals

The molluscicidal properties of Ambrosia maritima L. (Compositae). 4. Temporal and spatial distribution of Biomphalaria alexandrina in Egyptian village irrigation systems with reference to schistosomiasis transmission control.

Data on the temporal and spatial distribution of Biomphalaria alexandrina were collected throughout one year in two village irrigation systems near Alexandria, Egypt. Snails bearing Schistosoma mansoni cercariae were found from May to December but about 80% of annual transmission potential was confined from June to August. Although snail infection rates were generally 0-2%, higher rates were recorded and tended to be associated with smaller number snail collections. Infected snails were found in most canal and drain types and were judged to be present across most of the irrigated area of each village. In view of the dispersed nature of both infected snails and human-water contact in the area, it is suggested that schistosomiasis transmission is more widespread than focal. Effective transmission control using molluscicides should therefore require application to all village irrigation water-courses. The difficulties these various findings might impose on the use of commercial molluscicides are discussed and some possible advantages of the alternative plant molluscicide, Ambrosia maritima are noted.

Animals

The spatial distribution of calcium signals in squid presynaptic terminals.

1. The fluorescent Ca2+ indicator dye, fura-2, was used to examine the spatial distribution of intracellular Ca2+ signals in giant presynaptic terminals of squid. Brief trains of presynaptic action potentials were evoked to open Ca2+ channels within the giant presynaptic terminals and elevate presynaptic Ca2+ concentration. 2. Electrical stimulation produced pronounced rises in presynaptic Ca2+ concentration. These rises were much larger in the terminal region than in the adjacent axonal region of the presynaptic neuron, suggesting that Ca2+ channels are most abundant in the terminal. 3. Stimulation also produced gradients in Ca2+ concentration across the width of the presynaptic terminal. During stimulation, Ca2+ concentration was highest in the compartment of the presynaptic terminal closest to the postsynaptic neuron. This suggests that the Ca2+ channels are localized to this region of the presynaptic terminal. 4. Following the end of action potential trains, the rises in Ca2+ concentration became uniform across the width of the terminal. The redistribution of Ca2+ presumably is due to diffusion of Ca2+ throughout the presynaptic cytoplasm. Stimulus-evoked rises in Ca2+ declined slowly over several tens of seconds. 5. Histological examination of a giant presynaptic terminal used for imaging experiments revealed that the spatial compartments where stimulus-induced rises in Ca2+ concentration were highest were also enriched in active zones, the presynaptic sites of transmitter secretion. The co-localization of Ca2+ transients and active zones strongly suggests that neurons cluster Ca2+ channels selectively at active zones and that they do so to enhance the magnitude of Ca2+ signals in the vicinity of the active zone. 6. Longitudinal gradients in Ca2+ concentration also occur within presynaptic terminals and can be quantitatively accounted for by gradients in surface/volume ratio and density of active zones along the length of the presynaptic terminal.

Action Potentials

Spatial distribution of nerve injury after occlusion of individual major vessels in rat sciatic nerves.

In an attempt to better understand the spatial distribution of ischemic injury secondary to occlusion of major arteries, we measured nerve blood flow (NBF) and studied morphologic changes at various levels distal to the ligature site. Arterial ligation of the femoral, internal iliac, or superior gluteal artery was preceded and followed by measurement of NBF using laser Doppler flowmetry which helped identify "watershed areas" and guided the sampling process as nerves were examined pathologically and areas of injury were identified. Femoral artery ligation produced the most severe ischemia, focally reducing NBF by 80% in the tibial nerve at a level just below the knee. Within these ischemic nerve segments there were degenerative changes of nerve fibers seen mainly in the subperineurial region. Ligation of the internal iliac artery caused an approximately 60% reduction in NBF at the upper and mid-thigh levels of the sciatic nerve which resulted only in endoneurial edema in tissue taken at this level. Following superior gluteal artery ligation. NBF was reduced by only 20% at the pelvic level of the sciatic nerve and there was neither endoneurial edema nor fiber abnormalities. This study demonstrates the watershed pattern of ischemic injury associated with single vessel ligation by correlating neuropathologic change with quantitative measures of local nerve blood flow. The data further support the concept that mild levels of ischemia cause endoneurial edema, while moderate levels of ischemia produce demyelination and severe ischemia produces Wallerian degeneration.

Animals

PML-containing nuclear bodies: their spatial distribution in relation to other nuclear components.

The PML protein is a human growth suppressor concentrated in 10 to 20 nuclear bodies per nucleus (PML bodies). Disruption of the PML gene has been shown to be related to acute promyelocytic leukaemia (APL). To obtain information about the function of PML bodies we have investigated the 3D-distribution of PML bodies in the nucleus of T24 cells and compared it with the spatial distribution of a variety of other nuclear components, using fluorescence dual-labeling immunocytochemistry and confocal microscopy. Results show that PML bodies are not enriched in nascent RNA, the splicing component U2-snRNP, or transcription factors (glucocorticoid receptor, TFIIH, and E2F). These results show that PML bodies are not prominent sites of RNA synthesis or RNA splicing. We found that a large fraction of PML bodies (50 to 80%) is closely associated with DNA replication domains during exclusively middle-late S-phase. Furthermore, in most cells that we analysed we found at least one PML body was tightly associated with a coiled body. In the APL cell line NB4, the PML gene is fused with the RAR alpha gene due to a chromosomal rearrangement. PML bodies have disappeared and the PML antigen, i.e., PML and the PML-RAR fusion protein, is dispersed in a punctated pattern throughout the nucleoplasm. We showed that in NB4 cells the sites that are rich in PML antigen significantly colocalize with sites at which nascent RNA accumulates. This suggests that, in contrast to non-APL cells, in NB4 cells the PML antigen is associated with sites of transcription. The implications of these findings for the function of PML bodies are consistent with the idea that PML bodies are associated with specific genomic loci.

Cell Nucleus

The spatial distribution of attention during covert visual orienting.

Many studies of covert orienting of visual attention in response to informative pre-cues have focused on the spatial distribution of improved or impaired performance. One can find at least four different models in the literature, each describing a different distribution: the fixed gradient spotlight; the zoom lens spotlight; the hemifield activation hypothesis; and the flexible allocation of resources model. In previous work examining procedural details that might have led to the formulation of the hemifield activation hypothesis, it was postulated (Klein and McCormick 1989) that under conditions of uncertainty about which of two locations to attend, an observer may focus attention on a visual channel (i.e., midlocation placement of a fixed gradient spotlight) that is spatially intermediate. The present experiment was designed to distinguish among the four models of attentional distribution, and to test the midlocation placement strategy. Our findings show support for midlocation placement, demonstrate evidence against flexible allocation and hemifield activation, but could not differentiate between fixed gradient and zoom lens variants of the spotlight model.

Attention

The spatial distribution of cavitation induced acoustic emission, sonoluminescence and cell lysis in the field of a shock wave lithotripter.

This study examines the spatial distribution of various properties attributed to the cavitation field generated by a shock wave lithotripter. These properties include acoustic emission and sonoluminescence, which result from violent bubble collapse, and the degree of cell lysis in vitro, which appears to be related to cavitation. The acoustic emission detected with a 1 MHz, 12 cm diameter focused hydrophone occurs in two distinct bursts. The immediate signal is emitted from a small region contained within the 4 MPa peak negative pressure contour. A second, delayed, burst is emitted from a region extending further along the beam axis. The delay between these two bursts has also been mapped, and the longest delay occurs at positions close to the regions of maximum peak negative pressure. Sonoluminescence from both single and multiple shocks occurs in a broader region than the acoustic emission but the measurement technique does not allow time resolution of the signal. Cell lysis occurs in a relatively small region that correlates closely with the immediate acoustic emission for a shock propagating in a gelatine solution.

Acoustics

Spatial distribution of disease: three case studies.

Maps transformed so as to have constant density of residential population were used to analyze the spatial distribution of disease in three specific areas. Each area had received recent attention because of suspected environmental pollution. The area adjacent to the Rocky Flats Facility (CO) was examined to identify any association between possible plutonium releases and increases in lung cancer or leukemia incidence. The industrial area of northern Contra Costa County (CA) was studied to explore a relationship between petrochemical industrial emissions and histologic-specific lung cancers. Finally, a suspected increase in the risk of congenital cardiac defects possibly related to pollution of the Santa Clara County (CA) water supply was investigated. No evidence of elevated risk of disease was found to be associated with either the Rocky Flats Facility or the polluted water of Santa Clara County. An increase in lung cancer, found by other investigators in earlier years, was shown to persist in association with industrial emissions in Contra Costa County.

Adult

Spatial distribution of potential in a flat cell. Application to the catfish horizontal cell layers.

An analytical solution is obtained for the three-dimensional spatial distribution of potential inside a flat cell, such as the layer of horizontal cells, as a function of its geometry and resistivity characteristics. It was found that, within a very large range of parameter values, the potential is given by [Formula: see text] where r = rho/rho(0), z = z/rho(0), rho = (R(i)/R(m)).rho(0), delta = h/rho(0); K is a constant; J is the assumed synaptic current; rho, z are cylindrical coordinates; rho(0) is the radius of the synaptic area of excitation; h is the cell thickness; and R(i), R(m) are the intracellular and membrane resistivities, respectively. Formula A closely fits data for the spatial decay of potential which were obtained from the catfish internal and external horizontal cells. It predicts a decay which is exponential down to about 40% of the maximum potential but is much slower than exponential below that level, a characteristic also exhibited by the data. Such a feature in the decay mode allows signal integration over the large retinal areas which have been observed experimentally both at the horizontal and ganglion cell stages. The behavior of the potential distribution as a function of the flat cell parameters is investigated, and it is found that for the range of the horizontal cell thicknesses (10-50 mu) the decay rate depends solely on the ratio R(m)/R(i). Data obtained from both types of horizontal cells by varying the diameter of the stimulating spot and for three widely different intensity levels were closely fitted by equation A. In the case of the external horizontal cell, the fit for different intensities was obtained by varying the ratio R(m)/R(i); in the case of the internal horizontal cell it was found necessary, in order to fit the data for different intensities, to vary the assumed synaptic current J.

Animals

Spatial distribution of sperm-derived chromatin in zygotes determined by fluorescence in situ hybridization.

Fluorescence in situ hybridization was used to determine the spatial distribution of chromatin in zygote pronuclei. A hybrid system involving golden hamster eggs and individual human sperm permitted use of DNA probes specific for the entire human chromosome 4, for the heterochromatic region on the long arm of the human Y chromosome and for unique DNA sequences on human chromosome 19. Chromosome 4 occupied a circumscribed domain in the pronuclei, similar to findings in somatic interphases. Unlike the situation in somatic interphases, the Y heterochromatin was extended throughout the first cell cycle. Pronuclear chromatin was extended 3- to 4-fold compared to somatic interphase chromatin. The extended pronuclear chromatin conformation is likely to affect a zygote's susceptibility to environmental hazards.

Animals

Temporal and spatial distribution of Ixodes pacificus and Dermacentor occidentalis (Acari: Ixodidae) and prevalence of Borrelia burgdorferi in Contra Costa County, California.

The seasonal activity and spatial distribution of adult and immature Ixodes pacificus Cooley & Kohls and Dermacentor occidentalis Marx were determined along trails and on hillsides in two parks in Contra Costa County, CA. I. pacificus and D. occidentalis adults were most numerous in January and May, respectively. Adult ticks were significantly more abundant along heavily vegetated trails than on open grassy hillsides, and on the uphill versus the downhill side of trails. Five species of rodents were captured, and numbers of I. pacificus and D. occidentalis larvae per rodent were highest in May-June and July, respectively. Few nymphs were recovered either by flagging or from captured rodents. An average of 2.2 and 2.8% of the I. pacificus adults collected from the two parks were infected with the Lyme disease spirochete, Borrelia burgdorferi Johnson, Schmid, Hyde, Steigerwalt & Brenner. The greatest risk of contracting Lyme disease from adult I. pacificus in these two Contra Costa County parks is during the winter months, especially while hiking near the uphill side of trails.

Acari

Spin-echo fluorine magnetic resonance imaging at 2 T: in vivo spatial distribution of halothane in the rabbit head.

Spin-echo 19F magnetic resonance imaging was performed at 2.0 T to explore the in vivo spatial distribution of halothane in the rabbit head. Because the halothane concentration is low in vivo, and because the measured relaxation times of the 19F resonance peak for halothane were T1 approximately equal to 1.0 sec and T2 approximately equal to 3.5-65 msec, 1-3-h imaging times were required (TR = 1 sec, TE = 9 msec) in order to obtain adequate images with a 64 X 256 raw data matrix and a 20-mm slice thickness. With this technique, halothane was primarily detected in lipophilic regions of the rabbit head, but little or no halothane was observed in brain tissue. Because T2 was shorter in brain tissue than in surrounding fat, a shorter TE than we could obtain is needed for optimal spin-echo imaging of brain halothane.

Animals

Temporal-spatial distribution of SP-B and SP-C proteins and mRNAs in developing respiratory epithelium of human lung.

We determined the temporal and spatial distribution of surfactant protein B (pro-SP-B) and C (pro-SP-C) mRNAs and proteins by immunohistochemistry and in situ hybridization in fetal, neonatal, and adult human lung. Pro-SP-B and SP-B mRNA were detected in bronchi and bronchioles by 15 weeks' gestation. After 25 weeks, pro-SP-B, active SP-B peptide, and SP-B mRNA were co-localized in bronchiolo-alveolar portal cells and in Type II epithelial cells. In adult lung, pro-SP-B and SP-B mRNA were detected primarily in non-ciliated bronchiolar epithelial cells and in Type II cells in the alveolus. Pro-SP-C and SP-C mRNA were detected in cells lining terminal airways from 15 weeks' gestation and thereafter. After 25 weeks, SP-C mRNA and precursor protein were detected in epithelial cells of the bronchiolo-alveolar portals and in Type II cells, where expression increased with advancing gestational age. Distinct cellular patterns of staining for pro-SP-B compared with SP-B active peptide support the concept that its proteolytic processing or cellular routing may be influenced by cell type and/or cell differentiation. SP-B and SP-C are expressed primarily in distal conducting and terminal airway epithelium of human fetal lung well in advance of surfactant lipid synthesis or physiologic requirements to produce pulmonary surfactant at the time of birth.

Adult