DETERMINANTS OF THE SELECTIVE PHAGOCYTOSIS OF CARCINOGENIC PARTICULATE NICKEL COMPOUNDS

Certain inorganic nickel compounds such as crystalline NiS and Ni(,3)S(,2) are potent inducers of carcinogenesis and in vitro cell transformation, while several closely-related compounds such as amorphous NiS are essentially devoid of genotoxic activity. The phenomenon of selectivity of phagocytosis among such particulate nickel compounds has been hypothesized to account for their widely varying toxicological potency, yet the determinants of this selectivity have not been well characterized. Extracellular medium composition, particle dissolution, and particle surface charge were examined as potential determinants of selective phagocytosis for the carcinogenic crystalline and noncarcinogenic amorphous modifications of NiS. Selectivity and avidity of uptake of crystalline NiS by CHO cells was not dependent upon serum: phagocytosis of crystalline, but not amorphous NiS proceeded readily in a minimal salts/glucose medium at 37(DEGREES)C. The evolution of phagocytosis-inhibiting Ni(II) from the surface of amorphous NiS particles did not demonstrably contribute to the lower uptake of these noncarcinogenic particles despite their somewhat greater dissolution rate than the readily phagocytosed crystalline NiS particles. Significant differences in surface charge were noted between crystalline and amorphous NiS, the former being more negative in charge in distilled water suspension. Exposure of amorphous NiS particles to the vigorously reducing environment of a LiAlH(,4) solution under an inert atmosphere resulted in the particles' acquisition of a more negative surface charge. Amorphous NiS particles thus treated were phagocytosed by CHO cells to an extent similar to that of untreated crystalline NiS particles and likewise were shown to induce morphological transformation of primary Syrian hamster embryo cells with a similar potency. The potentiation of uptake characteristic of LiAlH(,4)-treated amorphous NiS was lost gradually upon storage of particles in ambient oxygenated atmosphere and was lost rapidly by apparent particle surface oxidation in aerated distilled water suspensions aged for up to 7 days. Concomitant with this loss of uptake there occurred a loss of negative surface charge. These results suggest the predominant role of particle surface charge rather than adsorbed serum components or particle dissolution as a determinant of selective phagocytosis among particulate nickel compounds. ^

Adherence to medication regimen among children with persistent asthma in Houston, Texas

An estimated 5.6 million children under the age of 18 suffer from asthma in the United States making asthma one of the most common chronic diseases in children. Because of the nature of the disease, the treatment regimen necessary to manage asthma has considerably changed as new drugs are developed and improved. The complexity of the treatment regimen recommended by the physician, however, has been linked with problems in adherence. Accordingly, the purpose of this cross-sectional study is to determine the prevalence of adherence to medication regimens among children between 9 to 15 years of age with physician-diagnosed asthma in Houston, Texas. The study used a set of data from a sample of children who participated in a pilot, panel asthma study to investigate the association between exposure to oxygenated air toxics and asthma health outcomes, conducted between 2002 and 2003. Data on daily intake of medication and onset of asthma-related symptoms were collected for each child per 10-day sampling period. Information was gathered through telephone or personal interviews for the 28 study participants who completed the study. The prevalence of adherence was calculated based on the number of times the participant reported taking his or her maintenance medication. The Fisher's Exact test and the Student's t-test were used to compare the level of adherence between the first and the last sampling cycle (Cycle 1 and Cycle 4) among the study participants by age, gender, and ethnicity. ^

Factors affecting ozone related asthma responses among middle school students with asthma

Outdoor environmental risk factors for asthma have been extensively researched, even though the majority of a person's daily activity occurs indoors. There is limited evidence linking personal exposure concentrations of ozone, pollen, mold, temperature, and humidity to childhood asthma. ^ The current study consisted of a secondary, more complex analysis of the data from the Houston Air Toxics and Asthma in Children (ATAC) Study to further investigate the association of personal ozone exposure on asthma outcome variability among middle school children with asthma. The ATAC Study primarily investigated the association between selected oxygenated air toxics and indicators of asthma variability (PEFR, FEV1, asthma symptoms, and rescue medication usage) among 30 labile and persistent Houston middle-school children with diagnosed asthma. This panel study used a repeated measurements design of four separate 10-day sampling periods that extended over a 20 month period. The secondary analysis included aggregate regression models that were constructed with two different estimates of ozone exposure (daily maximum hourly outdoor concentration and daily maximum hourly personal exposure), with three different estimates of personal environmental temperature and humidity exposures (daily average, intraday difference, and interday difference), and for thee different time periods [same day of exposure (lag 0), one day after initial exposure (lag 1), and two days after initial exposure (lag 2)]. ^ Overall, the models using daily maximum hourly personal ozone exposures in combination with intraday and interday personal temperature and humidity differences produced more significant plausible associations than models using daily maximum hourly personal ozone exposures with personal average temperature and humidity exposures. Significant associations were identified between daily maximum hourly personal ozone exposure and clinical indicators of asthma variability. The increasing effect on rescue medication usage from daily maximum hourly personal ozone exposure were identified as soon as the same day of exposure (lag 0; p=0.0072), and the same effects were delayed until the second next day (lag 2; p= 0.0026). The increasing effect on asthma symptoms were identified on the second next day after initial exposure (lag 2; p= 0.0024). There was a consistent inverse relationship between personal relative humidity exposure and indicators of asthma variability. Decreasing effects on daily FEV1 variability from personal relative humidity exposure were identified on the same day of exposure (lag 0; p= 0.034), increasing effects on morning PEFR were identified on the next day after initial exposure (lag 1; p= 0.0001), and decreasing effects on overnight PEFR variability were identified on the second next day after the initial exposure (lag 2; p= 0.007). With the conclusion of this research, there are opportunities for future similar studies in the preventive management of asthma in children living in high-ozone areas.^

Altered cholesterol metabolism in a hypercholesterolemia -resistant rabbit colony

A colony of rabbits has been developed at the University of Texas Medical School at Houston that is resistant to dietary-induced hypercholesterolemia. The liver of resistant rabbits had higher levels of ($\sp{125}$I) $\beta$-VLDL binding and 3-hydroxy-3-methylglutaryl (HMGCoA) reductase activity, but lower acyl coenzyme A:cholesterol acyltransferase (ACAT) activity than normal rabbits. Direct quantitation of intracellular cholesterol content of the liver revealed that the resistant rabbits had $<$10% of the intracellular free cholesterol present in normal rabbits. Fibroblasts isolated from normal and resistant rabbits exhibited differences in ($\sp{125}$I) LDL binding, HMGCoA reductase activity and ACAT activity that were similar to those found in the liver. No structural differences were found in the LDL receptor of normal and resistant fibroblasts that would account for the increased binding capacity of the resistant cells. The regulation of LDL receptor levels by exogenous oxygenated sterols was similar in normal and resistant fibroblasts. The regulation of LDL receptor binding capacity by LDL was attenuated in the resistant compared to normal fibroblasts, suggesting that the resistant fibroblasts have an alternate pathway for processing lipoprotein-derived cholesterol. Sterol-balance studies revealed that the cholesterol-fed resistant rabbits increased lithocholic acid excretion compared to the basal state, and had higher levels of deoxycholic acid excretion than cholesterol-fed normal rabbits. In addition, the specific activity and mRNA levels of cholesterol 7$\alpha$-hydroxylase (C7$\alpha$H) were higher in resistant rabbits than normal rabbits, suggesting that the increased bile acid excretion was due to an increase in bile acid synthesis. Increased clearance of cholesterol relieves the negative feedback inhibition cholesterol exerts on expression of the LDL receptor. The number of cell surface LDL receptors is then increased in resistant rabbits and allows rapid clearance of lipoproteins from the plasma compartment, thereby reducing plasma cholesterol levels. The low intracellular cholesterol level also relieves the negative feedback inhibition cholesterol exerts on HMGCoA reductase. Increased synthesis of cholesterol from acetate provides cells with cholesterol for bile acid synthesis and/or homeostasis. The activity of ACAT is then decreased due to the flux of cholesterol through the bile acid synthetic pathways. ^