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Results for “Spatial heterogeneity”

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PubMed2000

Heterogeneity of local myocardial flow and oxidative metabolism.

In mammalian hearts, local myocardial flow (LMF) varies between 20 and 200% of the mean. It is not clear whether oxidative metabolism has a similar degree of heterogeneity. Therefore, we investigated the relation between LMF and local oxidative metabolism in isolated rabbit hearts. Buffer oxygenation with (18)O(2) resulted in labeled myocardial oxidation water (H(2)(18)O). In four hearts, myocardial oxygen consumption (MVO(2)) was calculated from the H(2)(18)O production and compared with that calculated according to Fick. In eight additional hearts, LMF was measured using microspheres. Coronary venous H(2)(18)O kinetics and local H(2)(18)O residues were determined and analyzed by mathematical modeling. MVO(2) recovery from H(2)(18)O was >93% compared with that according to Fick. LMF ranged from 1.91 to 11.24 ml. min(-1). g(-1), and local H(2)(18)O residue ranged from 0.41 to 1.04 micromol/g. Both variables correlated (r = 0.62, n = 64, P < 0.001). Measurements in nine hearts were fitted by modeling using capillary permeability-surface area products (PS(c)) from 2 to 10 ml. min(-1). g(-1). With flow-proportional PS(c), a 3.33-fold difference in LMF was associated with a 6.45-fold difference in local MVO(2). Both LMF and local oxidative metabolism are spatially heterogeneous, and they correlate to one another.

Animals↗

PubMed1994

Heterogeneity in DNA content & proliferative status of human brain tumours.

Intra-tumour and inter-tumour heterogeneity in the cytokinetic organization was studied in 235 primary human brain tumours. DNA index (DI; relative tumour cell DNA content) and proliferating fraction (%PF; a measure of proliferative status) were analyzed in tumour biopsy by flow cytometry using a DNA specific fluorochrome (DAPI) and internal standards (chicken erythrocytes, CE). Incidence of micronuclei was studied in tumour biopsy tissue as well as in explants maintained in organ culture. Clonal diversity (implied by the presence of multiple peaks in the DNA histograms) was highest among medulloblastomas (44%) followed by gliomas (19%) and meningiomas (14%). Nearly 85 per cent of the malignant gliomas analyzed (histological grade III/IV) exhibited a great deal of regional variation in the proliferative status as well as micronuclei frequency as compared to meningiomas. Inter-tumoural variations in the DNA content was highest among gliomas (0.9 < DI < 3.6) and lowest among schwannomas (1.7 < DI < 2.2). Similarly, the distribution of %PF values was also broader (10-49%) in gliomas as compared to the other primary brain tumours (5-36%). Analysis of tumours taking both DI and %PF values improved the ability to discern histologically graded low and high tumours. Analysis of clonal diversity and spatial heterogeneity in the cytokinetic parameters could complement the clinicopathological findings in assessing the biological behaviour of human brain tumours, facilitating the prognostification and design of otpimal treatment regimen.

Brain Neoplasms↗

PubMed2004

Spatial dispersion of action potential duration restitution kinetics is associated with induction of ventricular tachycardia/fibrillation in humans.

INTRODUCTION: Action potential duration restitution (APDR) plays a role in initiation and maintenance of ventricular tachycardia (VT)/ventricular fibrillation (VF). We hypothesized that the steeply sloped APDR and its spatial heterogeneity contribute to VT/VF inducibility in patients with ventricular arrhythmia. METHOD AND RESULTS: After programmed ventricular stimulation (PVS) for evaluation of clinically documented VT, patients (n = 20, 15 male, age 52.5 +/- 9.5 years) were divided into two groups: inducible sustained VT/VF (IVT, n = 10) and noninducible VT/VF (NVT, n = 10). Data were compared with the corresponding results obtained from normal controls (C, n = 10). Right ventricular (RV) monophasic action potential duration at 90% repolarization (APD90) and ventricular effective refractory period (VERP) in the right ventricular apex (RVA) and right ventricular outflow tract (RVOT) were determined. APDR was acquired by scanning diastole with premature ventricular beats during a pacing cycle length of 600 msec (S1-S2) in all patients and by rapid pacing at the cycle lengths that induced APD alternans in three patients. Maximal slopes (Smax) of the APDR curves and DeltaAPD90 (APD90 at S2 400 ms - APD90 at the shortest S2) were measured. VERP and APD90 at each RV site did not differ among the three groups. Smax obtained by S1-S2 (1.6 +/- 0.6) did not differ from Smax obtained by rapid pacing (1.2 +/- 0.7), with a significant correlation noted between these values (r = 0.92, P < 0.01). The IVT group had a higher spatial dispersion of Smax (Smax at RVOT - Smax at RVA) compared to the C group (P < 0.05), with no difference between the NVT group and the IVT or C groups. The IVT group had a higher spatial dispersion of DeltaAPD90 compared to the NVT and C groups (P < 0.01, respectively). Smax at the RVOT (2.7 +/- 1.9) was steeper than that at the RVA (1.9 +/- 1.2, P < 0.05). Inducibility of sustained VT/VF was greater at the RVOT (83.3%) than at the RVA (50.0%, P < 0.05). CONCLUSION: In patients with ventricular arrhythmia, VT/VF is highly inducible under conditions of greater spatial dispersion of ventricular refractoriness and APDR.

Action Potentials↗

PubMed2005

Multiple ryanodine receptor subtypes and heterogeneous ryanodine receptor-gated Ca2+ stores in pulmonary arterial smooth muscle cells.

Ryanodine receptors (RyRs) of pulmonary arterial smooth muscle cells (PASMCs) play important roles in major physiological processes such as hypoxic pulmonary vasoconstriction and perinatal pulmonary vasodilatation. Recent studies show that three subtypes of RyRs are coexpressed and RyR-gated Ca2+ stores are distributed heterogeneously in systemic vascular myocytes. However, the molecular identity and subcellular distribution of RyRs have not been examined in PASMCs. In this study we detected mRNA and proteins of all three subtypes in rat intralobar PASMCs using RT-PCR and Western blot. Quantitative real-time RT-PCR showed that RyR2 mRNA was most abundant, approximately 15-20 times more than the other two subtypes. Confocal fluorescence microscopy revealed that RyRs labeled with BODIPY TR-X ryanodine were localized in the peripheral and perinuclear regions and were colocalized with sarcoplasmic reticulum labeled with Fluo-5N. Immunostaining showed that the subsarcolemmal regions exhibited clear signals of RyR1 and RyR2, whereas the perinuclear compartments contained mainly RyR1 and RyR3. Ca2+ sparks were recorded in both regions, and their activities were enhanced by a subthreshold concentration of caffeine or by endothelin-1, indicating functional RyR-gated Ca2+ stores. Moreover, 18% of the perinuclear sparks were prolonged [full duration/half-maximum (FDHM) = 193.3 +/- 22.6 ms] with noninactivating kinetics, in sharp contrast to the typical fast inactivating Ca2+ sparks (FDHM = 44.6 +/- 3.2 ms) recorded in the same PASMCs. In conclusion, multiple RyR subtypes are expressed differentially in peripheral and perinuclear RyR-gated Ca2+ stores; the molecular complexity and spatial heterogeneity of RyRs may facilitate specific Ca2+ regulation of cellular functions in PASMCs.

Animals↗

PubMed2005

Larval sensory abilities and mechanisms of habitat selection of a coral reef fish during settlement.

Sensory abilities and preferences exhibited by mobile larvae during their transition to juvenile habitats can establish spatial heterogeneity that drives subsequent species interactions and dynamics of populations. We conducted a series of laboratory and field experiments using coral reef fish larvae (Chromis viridis) to determine: ecological determinants of settlement choice (conspecifics vs. heterospecifics vs. coral substrates); sensory mechanisms (visual, acoustic/vibratory, olfactory) underlying settlement choice; and sensory abilities (effective detection distances of habitat) under field conditions. C. viridis larvae responded positively to visual, acoustic/vibratory, and olfactory cues expressed by conspecifics. Overall, larvae chose compartments of experimental arenas containing conspecifics in 75% of trials, and failed to show any significant directional responses to heterospecifics or coral substrates. In field trials, C. viridis larvae detected reefs containing conspecifics using visual and/or acoustic/vibratory cues at distances <75 cm; detection distances increased to <375 cm when olfactory capacity was present (particularly for reefs located up-current). We conducted high performance liquid chromatography (HPLC) analyses of seawater containing C. viridis juveniles and isolated high concentrations of several organic compounds. Subsequent laboratory trials demonstrated that C. viridis larvae responded positively to only one of these organic compounds. This compound was characterized by a weak polarity and was detected at 230 nm with a 31-min retention time in HPLC. Overall, our results suggest that fishes may use a range of sensory mechanisms effective over different spatial scales to detect and choose settlement sites, and species-specific cues may play a vital role in establishment of spatial patterns at settlement.

Animals↗

PubMed2003

AIDS in the HAART era: New York's heterogeneous geography.

During the 1990s, the number of new AIDS cases in New York City, USA, declined precipitously. The declines, beginning before highly active antiretroviral therapy (HAART) was introduced, were geographically heterogeneous across two New York City boroughs analyzed. From 1993 to 1998, zip codes in Lower Manhattan, with large white and affluent populations, had declines as much as 55% more than the rest of Manhattan. Bronx zip codes underwent still lesser declines. Declines also differed within zip codes among subpopulations. White zip code populations tended to have greater declines than Latino populations, which in turn tended to have greater declines than black populations. According to bivariate and stepwise regressions, an array of socioeconomic and community stress variables acted in combination on the decline in New York AIDS. Manhattan's declines in total AIDS incidence were primarily defined by changes in AIDS incidence for whites and for men who have sex with men, racial segregation, and the proportions of households in upper income classes and under rent stress. Bronx declines in total AIDS are principally explained by a broader range of income classes, and social instability as marked by housing overcrowding and cirrhosis and drug mortalities. Whatever the combination of proximate causes for the decline in AIDS incidence in 1990s New York (educational campaigns, HAART, demographic stochasticity), the decline was shaped by the city's socioeconomic structure and political and ecological history. That structure and history generates the geographically defined aggregates of behaviors that promote or impede AIDS decline. Such spatial heterogeneity may provide for HIV refugia, areas where the virus can weather the epidemic's contraction, a troubling possibility with the accelerating microbicidal failures of combination therapies.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Intracellular stress transmission through actin stress fiber network in adherent vascular cells.

Intracellular stress transmission through subcellular structural components has been proposed to affect activation of localized mechano-sensing sites such as focal adhesions in adherent cells. Previous studies reported that physiological extracellular forces produced heterogeneous spatial distributions of cytoplasmic strain. However, mechanical signaling pathway involved in intracellular force transmission through basal actin stress fibers (SFs), a mechano-responsive cytoskeletal structure, remains elusive. In the present study, we investigated force balance within the basal SFs of cultured smooth muscle cells and endothelial cells by (i) removing the cell membrane and cytoplasmic constituents except for materials physically attaching to the substrate (i.e., SF-focal adhesion complexities) or (ii) dislodging either mechanically or chemically the cell processes of the cells expressing fluorescent proteins-labeled actin and focal adhesions in order, to examine stress-release-induced deformation of the basal SFs. The result showed that a removal of mechanical restrictions for SFs resulted in a decrease in the length of the remaining SFs, which means SFs bear tension. In addition, a release of the preexisting tension in a single SF was transmitted to another SF physically linked to the former, but not transmitted to the other ones physically independent of the former, suggesting that the prestress is balanced in tensed SF networks. These results support a hypothesis regarding cell structural architecture that physiological extracellular forces can produce in the basal SF network a directional intracellular stress or strain distribution. Therefore, consideration of the coexistence of the directional stretching strain along the axial direction of SFs and the heterogeneous strain in the other cytoplasmic region will be essential for understanding intracellular stress transmission in the adherent cells.

Actins↗

PubMed1996

Extracellular matrix organization in various regions of rat brain grey matter.

Previous studies revealed the concentration of extracellular matrix proteoglycans in the so-called perineuronal nets on the one hand and in certain zones of the neuropil on the other. This nonhomogeneous distribution suggested a non-random chemical and spatial heterogeneity of the extracellular space. In the present investigation, regions dominated by one of both distribution patterns, i.e. piriform and parietal cortex, reticular thalamic nucleus, medial septum/diagonal band complex and cerebellar nuclei, were selected for correlative light and electron microscopic analysis. The labelling was performed by the use of the N-acetylgalactosamine-binding plant lectin Wisteria floribunda agglutinin visualized by peroxidase staining and additionally by photoconversion of red carbocyanine fluorescence labelling for electron microscopy. The intense labelling of the neuropil of a superficial piriform region, presumably identical with sublayer Ia, was confined to a fine meshwork spreading over the extracellular space between non-myelinated axons, dendrites and glial profiles. In the reticular thalamic nucleus the neuronal cell bodies were embedded in zones of labelled neuropil. In contrast to these patterns, the labelled extracellular matrix in different cortical layers and in the other subcortical regions was concentrated in perineuronal nets as large accumulations at surface areas of the neuronal perikarya and dendrites and the attached presynaptic boutons. Astrocytic processes usually were separated from the neuronal surface by the interposed extracellular material. Despite a great variability, the width of the extracellular space containing the labelled matrix components in all perineuronal nets appeared to be considerably larger than that in the labelled zones of neuropil and the non-labelled microenvironment of other neurons. Our results support the view that differences expressed in topographical and spatial peculiarities of the extracellular matrix constituents are related to neuron-type and system-specific functional properties.

Acetylgalactosamine↗

PubMed2006

Modeling the environmental fate of cadmium in a large wastewater irrigation area.

The fate of cadmium in soils is governed by spatially heterogeneous processes that proceed from decades to centuries. This study aimed at modeling the fate of Cd within the wastewater irrigation area (WIA) of Braunschweig (Germany). The sandy soils (mainly Dystric Cambisol or Typic Haplumbrept) at this site (28 km2) have received considerable loads of heavy metals by irrigation of municipal wastewater for up to 40 yr. The soils of the WIA are in agricultural use. The main crops are sugar beet (Beta vulgaris L.), potato (Solanum tuberosum L.), and wheat (Triticum aestivum L.). As a result of asparagus (Asparagus officinalis L.) cropping, about 15% of the soils have been converted to Rigosols. In 1996, we measured the vertical distribution (0 to 1.2 m) of soil pH, organic carbon content, and the EDTA-extractable content and the solution phase concentration of Cd at 153 sites. At sites not used for asparagus cultivation, Cd has migrated on average to a depth of about 0.5 m. Due to deep plowing, which accelerates migration, Cd has been displaced on average to about 0.7 m at the Rigosol sites. To model the fate of Cd at the scale of the WIA, we used different parallel soil column approaches. In each column the local model SEFAH was used to simulate both displacement and plant uptake of Cd. The model was fed with measured or randomly generated soil data. The results of retrospective simulations from 1957 to 1996 agreed well with observed Cd profiles. The better the spatial variability of sorption was described, the better the performance. Our simulation results show that Cd pollution of soil at first affects the soil-plant pathway. The breakthrough of Cd to the groundwater is dampened and is delayed for many decades.

Cadmium↗

PubMed1998

Preserved relative dispersion but blunted stimulation of mean flow, absolute dispersion, and blood volume by insulin in skeletal muscle of patients with essential hypertension.

BACKGROUND: We examined the integrity of the effects of insulin on mean muscle blood flow, flow heterogeneity, and blood volume in essential hypertension. METHODS AND RESULTS: Positron emission tomography, combined with [15O]H2O and [15O]CO as tracers for direct measurement of blood flow and volume in skeletal muscle, and a new bayesian iterative reconstruction algorithm allowing pixel-by-pixel quantitation of blood flow and flow dispersion, were used. Measurements were performed basally after an overnight fast and under normoglycemic hyperinsulinemic conditions in 11 newly diagnosed, untreated mildly hypertensive men (age, 35 +/- 1 years; body mass index, 25.2 +/- 0.4 kg/m2, blood pressure 141 +/- 4/96 +/- 2 mm Hg, mean +/- SE) and 11 matched normotensive men. Insulin-stimulated whole body glucose uptake was significantly decreased in the hypertensive men (41 +/- 4 mumol/kg per minute) compared with the normotensive (59 +/- 4 mumol/kg per minute, P < 0.005) men. Mean blood flow in skeletal muscle was significantly lower in the hypertensive than the normal subjects basally (1.7 +/- 0.2 versus 2.7 +/- 0.4 mL/0.1 kg per minute, P < 0.05) and during hyperinsulinemia (2.3 +/- 0.2 versus 4.2 +/- 0.8, P < 0.05). The flow response to insulin (0.6 +/- 0.2 versus 1.9 +/- 0.5 mL/0.1 kg per minute, hypertensive versus normal subjects, P < 0.05) was also significantly blunted. Muscle blood volume was significantly lower in the hypertensive than in the normal subjects, both basally (3.0 +/- 0.2 versus 3.5 +/- 0.2 mL/0.1 kg, P < 0.05) and during hyperinsulinemia (3.1 +/- 0.2 versus 4.0 +/- 0.2 mL/0.1 kg muscle, P < 0.02). The increase in muscle blood volume by insulin was significant in the normal (P < 0.05) but not the hypertensive subjects. Regional pixel-by-pixel analysis within femoral muscles revealed significant spatial heterogeneity of blood flow. Insulin increased absolute dispersion of blood flow significantly more in the normal subjects than in the hypertensive subjects (P < 0.05). CONCLUSIONS: True flow heterogeneity, as judged from the coefficients of variation (relative dispersion), was comparable between the groups basally and during hyperinsulinemia. We conclude that mean flow, its absolute dispersion, and blood volume exhibit insulin resistance in patients with essential hypertension.

Adult↗

PubMed2002

Longitudinal processes in Salto Grande Reservoir (Americana, SP, Brazil) and its influence in the formation of compartment system.

Studies on the longitudinal processes in reservoirs, involving physical, chemical and biological processes have been thoroughly appraised, suggesting the existence of a longitudinal organization controlled by the entrance and circulation of water which inserts modifications in the structuring of the system. To evaluate this effect, the Salto Grande reservoir (Americana, SP) was analyzed in 11 sampling stations in its longitudinal axis, in the rainy and dry seasons of 1997 considering the physical chemical and biological variables. Analyzing the results in agreement with the declining concentration degree of the river-barrage direction, a more significant correlation was verified in the dry period for total phosphorus (r2 = 0.86), dissolved total phosphate (r2 = 0.83), nitrite (r2 = 0.93), inorganic phosphate (r2 = 0.89), ammonium (r2 = 0.84) and suspended material (r2 = 0.85). In the rainy period, only nitrite (r2 = 0.90) and conductivity (r2 = 0.89) presented correlation with the distance of the dam, which demonstrates the effects of precipitation and the operational mechanism of the dam, as well as the distinction among the physical (sedimentation), chemical (oxidation) and biological (decomposition) processes in spatial heterogeneity of the system. These factors were decisive in the organization of these communities, with higher occurrence of rotifers and copepods in relation to cladocerans, the first ones being more abundant in the entrance of the Atibaia river, decreasing towards the dam direction, while copepods presented an inverse pattern. A distribution pattern similar to Copepoda was also verified for the Cladocera, evidencing a tendency to increase the density of organisms in the stations distant to the entrance of the Atibaia river, not being registered, however, a distribution gradient in the longitudinal axis, as observed for rotifers and copepods. In relation to the trophic degree a longitudinal gradient was also verified from eutrophic to oligotrophic depending on the location of the sampling station in relation to the longitudinal axis and period of analysis. The differences obtained, relating to the distribution of the environmental variables, demonstrate a characteristic pattern for reservoirs, with a longitudinal gradient in the sense river-barrage that inserts changes in the physical and chemical composition of the water, contributing to the differentiated establishing of biological communities.

Animals↗

PubMed2006

A cross-sectional study of the prevalence of intensity of infection with Schistosoma japonicum in 50 irrigated and rain-fed villages in Samar Province, the Philippines.

BACKGROUND: Few studies have described heterogeneity in Schistosoma japonicum infection intensity, and none were done in Philippines. The purpose of this report is to describe the village-to-village variation in the prevalence of two levels of infection intensity across 50 villages of Samar Province, the Philippines. METHODS: This cross-sectional study was conducted in 25 rain-fed and 25 irrigated villages endemic for S. japonicum between August 2003 and November 2004. Villages were selected based on irrigation and farming criteria. A maximum of 35 eligible households were selected per village. Each participant was asked to provide stool samples on three consecutive days. All those who provided at least one stool sample were included in the analysis. A Bayesian three category outcome hierarchical cumulative logit regression model with adjustment for age, sex, occupation and measurement error of the Kato-Katz technique was used for analysis. RESULTS: A total of 1427 households and 6917 individuals agreed to participate in the study. A total of 5624 (81.3%) participants provided at least one stool sample. The prevalences of those lightly and at least moderately infected varied from 0% (95% Bayesian credible interval (BCI): 0%-3.1%) to 45.2% (95% BCI: 36.5%-53.9%) and 0% to 23.0% (95% BCI: 16.4%-31.2%) from village-to-village, respectively. Using the 0-7 year old group as a reference category, the highest odds ratio (OR) among males and females were that of being aged 17-40-year old (OR = 8.76; 95% BCI: 6.03-12.47) and 11-16-year old (OR = 8.59; 95% BCI: 4.74-14.28), respectively. People who did not work on a rice farm had a lower prevalence of infection than those working full time on a rice farm. The OR for irrigated villages compared to rain-fed villages was 1.41 (95% BCI: 0.50-3.21). DISCUSSION: We found very important village-to-village variation in prevalence of infection intensity. This variation is probably due to village-level variables other than that explained by a crude classification of villages into the irrigated and non-irrigated categories. We are planning to capture this spatial heterogeneity by updating our initial transmission dynamics model with the data reported here combined with 1-year post-treatment follow-up of study participants.

Adolescent↗

PubMed2004

Ozone and short-term mortality in 95 US urban communities, 1987-2000.

CONTEXT: Ozone has been associated with various adverse health effects, including increased rates of hospital admissions and exacerbation of respiratory illnesses. Although numerous time-series studies have estimated associations between day-to-day variation in ozone levels and mortality counts, results have been inconclusive. OBJECTIVE: To investigate whether short-term (daily and weekly) exposure to ambient ozone is associated with mortality in the United States. DESIGN AND SETTING: Using analytical methods and databases developed for the National Morbidity, Mortality, and Air Pollution Study, we estimated a national average relative rate of mortality associated with short-term exposure to ambient ozone for 95 large US urban communities from 1987-2000. We used distributed-lag models for estimating community-specific relative rates of mortality adjusted for time-varying confounders (particulate matter, weather, seasonality, and long-term trends) and hierarchical models for combining relative rates across communities to estimate a national average relative rate, taking into account spatial heterogeneity. MAIN OUTCOME MEASURE: Daily counts of total non-injury-related mortality and cardiovascular and respiratory mortality in 95 large US communities during a 14-year period. RESULTS: A 10-ppb increase in the previous week's ozone was associated with a 0.52% increase in daily mortality (95% posterior interval [PI], 0.27%-0.77%) and a 0.64% increase in cardiovascular and respiratory mortality (95% PI, 0.31%-0.98%). Effect estimates for aggregate ozone during the previous week were larger than for models considering only a single day's exposure. Results were robust to adjustment for particulate matter, weather, seasonality, and long-term trends. CONCLUSIONS: These results indicate a statistically significant association between short-term changes in ozone and mortality on average for 95 large US urban communities, which include about 40% of the total US population. The findings indicate that this widespread pollutant adversely affects public health.

Air Pollution↗

PubMedDate not supplied

Covariate adjusted mixture models and disease mapping with the program DismapWin.

The analysis and recognition of disease clustering in space and its representation on a map is an important problem in epidemiology. An approach using mixture models to identify spatial heterogeneity in disease risk and map construction within an empirical Bayes framework is described. Once heterogeneity is detected, the question arises as how explanatory variables could be included in the model. A mixed Poisson regression approach to include covariates is presented. The methods are illustrated using data for tuberculosis from Berlin in 1991.

Algorithms↗

PubMed1998

CT-simulator based brachytherapy planner: seed localization and incorporation of biological considerations.

Radiation dose prescription, interpretation, and planning can be problematic for brachytherapy due to high spatial heterogeneity, varying and various dose rates, absence of superimposed calculated isodose distributions onto affected tissues, and lack of dose volume histograms. A new treatment planner has been developed to reduce these limitations in brachytherapy planning. The PC-based planning system uses a CT-simulator to sequentially scan the patient to generate orthogonal images (to localize seed positions) and subsequently axially scan the patient. This sequential scanning procedure avoids using multiple independent patient scans, templates, external frames, or fiducial markers to register the reconstructed seed positions with patient contours. Dose is computed after assigning activity to (low dose rate) Ir192, linear Cs137, or I125 seeds or dwell times (high dose rate) to the Ir192 source. The planar isodose distribution is superimposed onto axial, coronal, or sagittal views of the tissues following image reconstruction. The treatment plan computes (1) direct and cumulative volume dose histograms for individual tissues, (2) the average, standard deviation, and coefficient of skewness of the dose distribution within individual tissues, (3) an average (over all tissue pixels) survival probability (S) and average survival dose DASD for a given radiation treatment, (4) normal tissue complication probability (NTCP) delivered to a given tissue. All four computed quantities account for dose heterogeneity. These estimates of the biological response to radiation from laboratory-based studies may help guide the evaluation of the prescribed low- or high-dose rate therapy in retrospective and prospective clinical studies at a number of treatment sites.

Brachytherapy↗

PubMed1999

Dynamic imaging of perfusion in human skeletal muscle during exercise with arterial spin labeling.

MR images acquired by using an arterial spin-labeling technique showed spatial and temporal variations of perfusion in the skeletal muscle of exercising humans. Perfusion measurements made during plantar flexion exercise in normal volunteers were consistent with those obtained by traditional techniques reported in the literature. Spatial heterogeneity of perfusion values clearly delineated the various muscle groups within the lower leg. These results are interpreted in terms of a quantitative model for the perfusion signal in muscle. This method can provide a useful tool in the study of muscle physiology. Magn Reson Med 42:258-267, 1999. Published 1999 Wiley-Liss, Inc.

Arteries↗

PubMed2025

Advances and challenges in human 3D solid tumor models.

The field of cancer biology and therapeutics has soared in the past several decades with new therapeutic modalities and options for patients, such as chemoradiotherapy, immunotherapy, and combination therapy. This dramatic success in expanding patient options is primarily attributed to the development of various model systems to elucidate drivers of oncogenesis, tumor maturation and evolution, and response to therapeutics. While mouse models have been a workhorse of cancer research, technological progress in ex vivo patient-derived tumor models has afforded more tunable and scrutable systems for patient-predictive platforms and mechanistic study. This review explores the technological innovations in 3D solid tumor models and their applicability to various aspects of cancer biology and identification of therapeutics. Features of the tumor and tumor microenvironment like spatial heterogeneity, multicellular populations and genomic variations are addressed and elaborated through the establishment of new in vitro models. We further address the integration of perfusable vasculature with 3D tumor models and the potentially wide-ranging applications of these more complex platforms in precision medicine and cancer immunotherapy. Finally, we provide an outlook on the future of experimental cancer models for both biological investigation and bench-to-bedside pipeline development.

Journal Article↗

PubMed2003

Further studies related to the scale-up of high cell density Escherichia coli fed-batch fermentations: the additional effect of a changing microenvironment when using aqueous ammonia to control pH.

In this work, we report on the further development of the scale-down, two-compartment (STR + PFR) experimental simulation model. For the first time, the effect on high cell density Escherichia coli fed-batch fermentations of a changing microenvironment with respect to all three of the major spatial heterogeneities that may be associated with large-scale processing (pH, glucose, and dissolved oxygen concentration) were studied simultaneously. To achieve this, we used traditional microbiological analyses as well as multiparameter flow cytometry to monitor cell physiological response at the individual cell level. It was demonstrated that for E. coli W3110 under such conditions in a 20 m(3) industrial fed-batch fermentation, the biomass yield is lower and final cell viability is higher than those found in the equivalent well-mixed, 5L laboratory scale case. However, by using a combination of the well-mixed 5L stirred tank reactor (STR) with a suitable plug flow reactor (PFR) to mimic the changing microenvironment at the large scale, very similar results to those in the 20 m(3) reactor may be obtained. The similarity is greatest when the PFR is operated with a mean residence time of 50 sec with a low level of dO(2) and a high glucose concentration with either a pH of 7 throughout the two reactors or with pH controlled at 7 in the STR by addition into the PFR where the pH is > 7.

Ammonia↗