A Review and Framework for Categorizing Current Research and Development in Health Related Geographical Information Systems (GIS) Studies.

OBJECTIVES: The application of GIS in health science has increased over the last decade and new innovative application areas have emerged. This study reviews the literature and builds a framework to provide a conceptual overview of the domain, and to promote strategic planning for further research of GIS in health. METHOD: The framework is based on literature from the library databases Scopus and Web of Science. The articles were identified based on keywords and initially selected for further study based on titles and abstracts. A grounded theory-inspired method was applied to categorize the selected articles in main focus areas. Subsequent frequency analysis was performed on the identified articles in areas of infectious and non-infectious diseases and continent of origin. RESULTS: A total of 865 articles were included. Four conceptual domains within GIS in health sciences comprise the framework: spatial analysis of disease, spatial analysis of health service planning, public health, health technologies and tools. Frequency analysis by disease status and location show that malaria and schistosomiasis are the most commonly analyzed infectious diseases where cancer and asthma are the most frequently analyzed non-infectious diseases. Across categories, articles from North America predominate, and in the category of spatial analysis of diseases an equal number of studies concern Asia. CONCLUSION: Spatial analysis of diseases and health service planning are well-established research areas. The development of future technologies and new application areas for GIS and data-gathering technologies such as GPS, smartphones, remote sensing etc. will be nudging the research in GIS and health.

Validation of a morphometric analysis procedure using indomethacin-induced alterations in cultured hepatocytes.

Morphometric analysis was used to quantitate indomethacin-induced morphological changes in primary cultures of neonatal rat hepatocytes by comparison with standard assessments of functional integrity (i.e. enzyme release, urea levels, and dye exclusion). For this procedural validation, indomethacin concentrations were selected to correspond to the therapeutic plasma levels of rheumatoid arthritic or systemic lupus erythematosus patients having liver cell injury secondary to prolonged, high-dose administration of this nonsteroidal antiinflammatory agent. Primary cultures of neonatal rat hepatocytes were exposed for 12 h to 0, 100, 500 or 1000 microM indomethacin and subjected to a double-blind morphometric analysis procedure modified for use on cultured cells. This procedure systematically converted two-dimensional morphologic information into three-dimensional numerical data for statistical analysis. These optical measurements provided an accurate analysis following 4 h of measurements. When the concentration of indomethacin was increased from 0 to 1000 microM, the relative volume percent of Type I cells decreased. Therefore these cells, which were indistinguishable from healthy, untreated control cells, become less numerous as toxicant level increased. In contrast, the relative volume percent values of other progressively more damaged cell types (i.e. Types II, III, and IV cells) increased with elevation of indomethacin levels. Morphometric assessments paralleled functional assessments of indomethacin-induced cytotoxicity (r2: 0.88-0.99). Therefore, the present study validated this morphometric analysis procedure using a rigorous cellular exposure which caused substantial cell injury and subsequent lifting of 23% cells from the substrate. Combined with previous validation studies involving cadmium, erythromycin and benoxaprofen, the present study showed that morphometric analysis is a rapid, accurate method for the measurement of cell injury in cultured parenchymal hepatocytes.

Modulatory effect of calcium on the influx and binding of cadmium in primary cultures of neonatal rat hepatocytes.

Primary cultures of rat hepatocytes were exposed to 3 or 30 microM stable cadmium (Cd) in the presence or absence of 1.8 or 3.6 mM calcium (Ca). The presence of Ca significantly reduced the efflux of lactate dehydrogenase (LDH) from cells regardless of Cd concentration or exposure time. During a 3-h time interval, the influx of Cd into hepatocytes increased from about 5 to 14% of the total extracellular Cd present. The presence of Ca during 30 microM Cd exposures resulted in an 18% reduction (P less than 0.01 or 0.001) in Cd influx during a 3-h exposure. About 11% more Cd was bound to those cells exposed in the absence of Ca following 2-h, but not 0.5-h, exposures. Therefore, binding of Cd to hepatocytes was not related directly to Cd uptake since Cd uptake (but not binding) was elevated at the 0.5-h time interval. Although the presence of Cd did not affect the influx of Ca, the presence of Cd increased the binding of Ca by 557% (P less than 0.001). Interaction between these cations at the same binding and/or entry sites on (or adjacent to) phospholipid head groups could account for the modulatory effect of Ca on Cd-challenged hepatocytes.

Intravenous administration mode for lead inclusion development in mouse tissues.

B6CF1 mice were injected with a 80 mg lead (Pb)/kg. One week later, the liver retained about 0.13 mg Pb/g or 9.8 +/- 1.5% of the injected dose (ID)/g fresh weight (mean +/- SE, n = 4). This level decreased to 3.9 +/- 0.6% ID/g (n = 5) after 2 weeks. Intranuclear Pb inclusions averaging 1.6 +/- 0.1 micron in diameter (n = 10) were present within parenchymal hepatocytes. Intravenous (i.v.) injections of 2.6 microCi were adequate for autoradiographic localization of Pb deposits within the liver. One week after Pb injection, most tracts were present over endothelial lining cells of the hepatic sinusoids; however, Pb, deposited within intranuclear inclusions of parenchymal hepatocytes was inadequate for tract development. Therefore, i.v. administration of 80 mg/kg Pb resulted in the formation of inclusions within nuclei of parenchymal hepatocytes of B6CF1 mice.

Selenium accumulation, reproductive status, and histopathological changes in environmentally exposed redear sunfish.

Comparisons were made of the accumulation of selenium, histopathological damage, and reproductive status of redear sunfish (Lepomis microlophus) collected in July 1986 from Martin Lake (a contaminated site) and Lake Tyler (a reference site). Hepatic concentrations of selenium were four times higher in Martin Lake sunfish (7.6 +/- 0.5 ppm) than in fish from the reference lake (2.1 +/- 0.2 ppm). Redears collected from the contaminated lake had lower condition factors than individuals collected from the reference site. Sunfish with elevated levels of hepatic selenium had substantial alterations in the liver including necrosis, cytoplasmic vacuolation, and Kupffer cell proliferation. The ovaries of mature fish collected from Martin Lake frequently had atretic follicles, abnormally shaped follicles, connective tissue hypertrophy, asynchronous oocyte development, and an overall reduction in the number of developing oocytes. These histopathological changes in the ovaries of Martin Lake sunfish were not accompanied by alterations in gonadal steroid titers in the blood. No histopathological lesions could be detected in the testes of Martin Lake fish. Most of the males collected from the contaminated site were immature and had lower circulating levels of sex steroid hormones than reference males. The results show that tissue burdens of selenium have declined by 25% since this sunfish population was sampled last in 1981. Further, the results of this study indicate that the overall health and reproductive status of selenium-contaminated fish collected from Martin Lake is still seriously impaired.

Autopsy of teleosts from contaminated areas.

A systematic procedure provides one method of assessing xenobiotic-induced abnormalities in fish following environmental exposures. Behavioral, external (or gross), histopathological, and internal organ changes allow determination of the severity of toxicant impact on an endemic population provided a sufficient number of specimens is analyzed. Over the past 15 years, these methods have led to the establishment of causal factors in metal- and metalloid-induced toxicity.

Morphological and surface temperature changes in femoral arteries following laser irradiation.

A low-power carbon dioxide laser was to irradiate rat femoral arteries under the same conditions required to anastomose several human arteries by thermal coagulation. Mean surface temperature changes were measured at the site of laser impact with the artery to evaluate the resultant histopathological changes as a function of laser power. More severe thermal coagulative changes, necrosis, and swelling resulted with increased laser power. Comparison of the temperature-time relationships showed that the peak surface temperature rise at the surface of these arteries was about 25 degrees C for one pulse at 200 mW laser power, compared to an approximate 7 degrees C rise for one pulse at 120 or 150 mW laser power. Increase in the surface temperature resulted in an increased severity of histopathological injury. These results showed that necrosis of medial layer smooth muscle cells occurred beyond the laser exposure site, suggesting that heat conduction could result in significant damage to reconnected vessel and could be a factor in the formation of a weak bond or an aneurysm.

Ultrastructural cytochemical analysis of intranuclear arsenic inclusions.

To establish the chemical composition of the arsenic inclusion, freshly isolated preparations of inclusions and epon-embedded thin sections of inclusions were subjected to ultrastructural cytochemical analysis. Intranuclear inclusions are composed of amorphous, arsenic-containing subunits aligned linearly to form a coiled complex. Lipase, ribonuclease, deoxyribonuclease, trypsin, pepsin, protease, amylase, or ethylenediaminetetraacetic acid (EDTA) was used to digest or chelate these inclusions. Following enzymatic digestion or chelation, the electron opacity of inclusions was compared with that of control sections exposed for equal times to equivalent solutions lacking the enzymes. Exposure to amylase caused a consistent reduction in the electron opacity of thin sections of inclusions and almost complete digestion of the freshly isolated preparations of inclusions. This was indicative of the presence of a carbohydrate moiety within arsenic inclusions. Incubation of inclusions with EDTA resulted in solubilization of freshly isolated and thin-sectioned embedded material. These data indicated that the intranuclear arsenic inclusion is composed of both metallic and carbohydrate moieties, confirming earlier studies which identified arsenic within inclusions using instrumental neutron activation analysis and X-ray microprobe analysis.

Morphometric analysis of cultured hepatocytes exposed to benoxaprofen.

This study was undertaken to quantitate morphological changes in primary cultures of liver cells exposed to benoxaprofen and to compare morphological assessments with standard assessments of functional integrity. Rat hepatocytes were exposed for 12 h to 0, 100, 500, or 1000 microM concentrations of benoxaprofen and subjected to double-blind morphometric analysis. As benoxaprofen concentration was increased from 0 to 1000 microM, the relative percentage of morphologically normal cells was reduced, whereas the percentages of damaged cell types increased. These results paralleled those obtained from functional assessments. Therefore, the use of morphometric techniques provided a good assessment of benoxaprofen-induced cytotoxicity and demonstrated the value of quantitative estimates in the evaluation of cellular injury.

Stereological analyses of hepatocyte changes parallel arsenic accumulation in the livers of green sunfish.

Cellular changes in hepatocytes of green sunfish (Lepomis cyanellus) exposed to arsenic-contaminated or control lake water were compared with the level of arsenic in the liver. Standard stereological procedures involved conversion of two-dimensional data (i.e. fractional measurements of morphological changes) to three-dimensional data for interpretation. Both the volume and numbers of nuclei increased slightly with increasing concentration of arsenic in the liver. Significant increases (p less than 0.01) were observed in the volumes occupied by necrotic and fibrous bodies as arsenic levels in the liver increased; linear regression analysis of these data resulted in 0.9066 and 0.9359 correlation coefficients for necrotic and fibrous bodies, respectively, when volume changes were considered on a unit body weight basis. The volume occupied by necrotic areas, abnormal lysosomes, and autophagic vacuoles increased with increased arsenic concentration. The surface density of rough endoplasmic reticulum increased with increasing arsenic concentration; linear regression resulted in a correlation coefficient of 0.8367 when data were based on unit body weight.

Erythromycin estolate-induced toxicity in cultured rat hepatocytes.

Primary cultures of rat hepatocytes were exposed to several concentrations of erythromycin estolate (EE). Hepatotoxicity was evaluated using lactate dehydrogenase (LDH) leakage and morphometric analysis of representative populations of cells examined optically. Results of the two techniques provided parallel information: cells exposed to the higher concentrations of EE had significantly greater LDH release and higher percentages of morphologically damaged cells. Planimetric analysis of a second set of hepatocytes showed increasing swelling of cells with increasing concentration of EE. Severe cellular swelling preceded disintegration, as hepatocytes became progressively more damaged by EE.

An in vitro approach to the study of target organ toxicity of drugs and chemicals.

A major goal of our laboratory has been the development of primary culture systems that retain differentiated functions and responses characteristic of intact tissues in vivo. Specifically, we have developed cellular models of primary cultures of rat heart, liver, and kidney cells to explore the mechanisms by which drugs or chemicals may be toxic to key organs of the body and to develop new techniques by which xenobiotics may be evaluated or identified as potential toxicants to living systems. The purpose of this paper is to describe our rationale and approach to the study of target organ toxicology with in vitro cellular systems.

Effects of cadmium and calcium on the fluidity of plasma membranes.

The fluidity of plasma membranes was assessed by steady-state fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH), a fluorescent probe. The presence of increasing concentrations of calcium (Ca) (0.5-4 mM), cadmium (Cd) (50-500 microM), or both decreased the motional freedom of the fluorescent probe molecules in plasma membranes derived from both human erythrocytes and rat hepatocytes. The effects of Cd were 3-10 times greater than those of Ca. Increasing concentrations of Cd in the presence of Ca increased the anisotropy parameter, which plateaued at lower Cd concentrations. The presence of Ca diminished the overall effects of Cd on these membranes.

Relative toxicities of several nonsteroidal antiinflammatory compounds in primary cultures of rat hepatocytes.

Primary cultures of intact, functional heptocytes were used to compare the relative toxicity of four nonsteroid antiinflammatory agents (NSAID)--benoxaprofen, orpanoxin, aspirin, and ibuprofen--with that of indomethacin. The relative toxicity of these compounds was evaluated on the basis of the release of lactate dehydrogenase, levels of urea (an indicator of a liver specific function), viability (based on dye exclusion), and morphology after a 12-h exposure to concentrations ranging from 0 to 1000 microM. Evaluation of the data obtained from these three parameters enabled us to rank these compounds from toxic to nontoxic, in decreasing order to toxicity: indomethacin greater than benoxaprofen greater than ibuprofen greater than or equal to aspirin greater than or equal to orpanoxin. Morphological evaluations of hepatocytes exposed to these agents under the same conditions supported the order of ranking for these compounds. Ultrastructurally, cells exposed to the two highest concentrations of indomethacin were severely damaged, as evidenced by marked cellular necrosis, nuclear pleomorphism, margination, swollen mitochondria, reductions in the number of microvilli, smooth endoplasmic reticulum proliferation, and cytoplasmic vacuolation. In comparison, exposure of hepatocytes to the highest dose of orpanoxin resulted only in increased vacuolation, a slight increase in cellular debris, and increased electron density of the cytoplasm of hepatocytes.

Comparison of dantrolene sodium with erythromycin estolate using primary cultures of rat hepatocytes.

Using primary cultures of parenchymal hepatocytes as a model system, the cytotoxic potential of dantrolene sodium (DS) was compared with that of erythromycin estolate (EE)--a known hepatotoxin. Parallel morphological and functional comparisons were made, following 4-, 8-, or 24-h exposures of hepatocyte cultures, using phase contrast microscopy and lactate dehydrogenase (LDH) leakage, respectively. Four-hour exposures of cultures to rather low concentrations of EE (i.e. 50 microM) resulted in cellular necrosis and significantly elevated LDH release. As the concentration of this hepatotoxin was increased, the changes were more pronounced. However, even 4- or 8-h exposures of cultures to a maximum of 100 microM DS did not affect LDH leakage or morphological integrity, although marginally detectable morphological changes did not occur at the highest concentration after 24-h. The value of using primary parenchymal hepatocyte cultures as a model system for the assessment of xenobiotic-induced hepatotoxicity was confirmed.

Cadmium-induced hepatotoxicity in cultured rat hepatocytes as evaluated by morphometric analysis.

Freshly isolated hepatocytes from neonatal rats were cultured for approximately 24 h; incubated for 5, 30, or 60 min in solutions containing 0, 50, 100, or 200 microM cadmium; embedded in plastic; and sectioned for optical microscopy. The extent of cadmium-induced hepatotoxicity was evaluated by double-blind morphometric analysis (a geometricostatistical processing of two-dimensional data for the collection of three-dimensional information) whereby hepatocytes were classified on the basis of the severity of morphologic damage at the optical level. Both time and concentration effects were studied. Cultures exposed to 200 microM cadmium, for various intervals of time from 5 to 60 min, showed statistically significant reductions in the relative volume percent of normal hepatocytes, elevations (then reductions) in the relative volume percent of slightly damaged hepatocytes, increases in the relative volume percent of moderately damaged cells, and increases in the relative volume percent of severely damaged liver cells. As the concentration of cadmium was increased from 50 to 200 microM cadmium (during both 30 and 60-min exposures), significant trends were observed in cellular distribution patterns based on relative volume percent. Morphologically normal cells decreased, both slightly damaged and moderately damaged cells increased, and severely damaged cells remained unchanged. These results indicated that morphometric analysis at the optical level provided quantitative estimates for the evaluation of time- and concentration-effects of cadmium on cultured hepatocytes.

Calcium amelioration of cadmium-induced cytotoxicity in cultured rat hepatocytes.

Parenchymal hepatocytes from neonatal rats were isolated, cultured about 24 h, exposed to cadmium with or without calcium, and processed for scanning electron microscopy. To assess the severity of cadmium-induced changes, exposed hepatocytes were categorized based upon the extent of morphological damage. Differences in surface blebbing, alterations in microvilli, variations in the degree of swelling, and changes in cell shape were used to categorize the severity of cell damage. A double-blind morphometric analysis (a geometricostatistical processing of two-dimensional data for the collection of three-dimensional information) of cellular changes was conducted for each exposure time and for each concentration of cadmium in the presence or absence of calcium. Significant decreases occurred in the percent relative volume of normal, flattened cells present in cultures exposed for 30 min to 50 or 100 microM cadmium in the absence of calcium. In contrast, the percent relative volume of severely damaged spherical cells was significantly increased after exposure to solutions containing 50 or 100 microM cadmium and lacking calcium. Percent relative volume of intermediate cells (which were slightly swollen and showed changes in microvillar number) was significantly increased following a 30 min exposure to all cadmium concentrations in the absence of calcium. The examination of hepatocytes exposed for 60 min showed that the degree of cadmium-induced cytotoxicity was more severe in the absence of calcium than was the case for the hepatocyte cultures exposed for 30 min: approximately 30% more spherical cells and 30% fewer flattened cells were present if cultures were exposed in the absence of calcium for 60 min compared to those exposed for 30 min. The degree of blebbing was significantly greater at all cadmium concentrations in the absence of calcium. The presence of calcium, therefore, reduced cadmium-induced cytotoxicity in primary cultures of rat hepatocytes subjected to morphometric analysis after scanning electron microscopy.

Enhanced acute lung damage following corticosteroid treatment.

The administration of butylated hydroxytoluene (BHT) to mice has been shown to produce diffuse alveolar epithelial cell damage, which is largely resolved within 2 wk. Treatment with the corticosteroid prednisolone, 30 mg/kg twice daily during the first 5 days after BHT, greatly exacerbated the initial damage. A severe interstitial pneumonitis was evident histologically 15 days after BHT-treatment. The infiltrate became even more extensive 22 days after BHT with a massive consolidation of the lungs. The pneumonitis was characterized by cellular infiltrates, alveolar thickening, and the deposition of fibrillar collagenous material. This massive steroid-induced pneumonitis was virtually gone at 60 days after BHT-treatment. The extent of the fibrotic changes, as quantitated by measuring total lung hydroxyproline levels, was dependent both on the corticosteroid dose and the time when they were administered. Increases in total lung hydroxyproline were seen following the administration of 30 mg/kg prednisolone or methylprednisolone acetate twice daily on Days 1 to 5 after BHT. These biochemical changes were evident 15 days after BHT and, in contrast to the histologic findings, persisted to Day 60. The administration of prednisolone on Days 3 to 7, 6 to 10, or 1 to 10 after BHT, or at a lower doses had no effect on the development of fibrosis. Single 30 mg/kg doses of prednisolone and methylprednisolone acetate inhibited the increased lung DNA synthesis normally seen after BHT. This inhibition was maintained by twice daily doses of prednisolone on Days 1 to 5 after BHT, and was followed by a rebound in DNA synthesis on Day 7.(ABSTRACT TRUNCATED AT 250 WORDS)