Evaluation of theophylline pharmacokinetics in a pediatric population using mixed effects models

Routine clinical pharmacokinetic data collected prospectively from pediatric patients receiving theophylline were analyzed using the NONMEM (nonlinear mixed effects model) digital computer program. A total of 314 measured serum theophylline concentrations (STCs) were obtained from 84 hospitalized patients ranging in age from 4 months to 15.2 years with the majority of patients between the ages of 1 and 8 years. Fifty-six percent were male. The race/ethnicity distribution was 71.4% Latin, 15.5% black, 11.9% Caucasian, and 1.2% (one subject) Pakistani. Of the total number of observed STCs, 16.2% reflected some degree of outpatient dosing. The pharmacokinetic model used was a one-compartment open model with either zero-order or first-order absorption and first-order elimination. Age was the most important determinant of theophylline clearance (Cl);weight was inferior to age and did not statistically improve the model (p>0.005when combined with age. Total Clincreased by 10%/year over the age range of 1 to 15 years of age. Black race and male gender were associated with higher Clvalues: for a given age, Clwas 34% higher for blacks than the reference population composed of the remaining patients, and Clfor males was 25% higher than that for females. The volume of distribution (Vdfor the population was estimated to be 0.62 L/kg. The interindividual variability in Cland Vdexpressed as coefficients of variation were 19 and 28%, respectively. The residual intraindividual error variance corresponded to a standard deviation of 2.8 g/ml. The STCs that represented some degree of outpatient dosing were 21 % lower than those reflecting only inpatient dosing. Alternate models that include weight as a determinant of theophylline clearance are also provided. The NONMEM method of determining population pharmacokinetics is well suited to the pediatric population since it does not require a large number of STCs per patient. In this study a mean of only 3.7 STCs per patient were utilized to provide information which should prove useful in the design and adjustment of theophylline dosage regimens in children.     

Clinical information technology in hospitals: a comparison between the state of Iowa and two provinces in Canada

Despite the growing interest in adopting information technology (IT) in healthcare, the degree of technology sophistication varies among healthcare organizations. Changes in the health care sector and continuous pressure to improve the quality of care have driven the evolution of IT in hospitals. This paper provides an overview of clinical IT sophistication in a sample of U.S. hospitals, and compares clinical IT capacities in this sample with a sample of Canadian hospitals. The instrument used for the comparison measures three clinical dimensions of IT sophistication: functional sophistication, technological sophistication and integration level. Clinical areas that were considered include patient management, patient care activities and clinical support activities. The comparison between hospitals in Iowa and Canada shows differences in clinical IT sophistication between the two settings. Hospitals in Iowa appear to have more technologies but fewer computerized processes and integration of patient management activities. Technological sophistication however, was low in both samples. Our findings confirm the construct validity of the measurement instrument and show initial evidence of its generalizability. More initiatives using the instrument would lead to enhancement in IT assessment tools that can be used for evaluation of IT in relation to patient management and quality outcomes.     

Calorie restriction extends yeast life span by lowering the level of NADH

Calorie restriction (CR) extends life span in a wide variety of species. Previously, we showed that calorie restriction increases the replicative life span in yeast by activating Sir2, a highly conserved NAD-dependent deacetylase. Here we test whether CR activates Sir2 by increasing the NAD/NADH ratio or by regulating the level of nicotinamide, a known inhibitor of Sir2. We show that CR decreases NADH levels, and that NADH is a competitive inhibitor of Sir2. A genetic intervention that specifically decreases NADH levels increases life span, validating the model that NADH regulates yeast longevity in response to CR.     

Prostate cancer knowledge among multiethnic black men

The purpose of this survey of 528 black men in Miami and Fort Lauderdale, FL, was to assess prostate cancer knowledge among African-American, English-speaking Caribbean, Haitian-American, and African men in America. Knowledge levels were assessed by education, ethnicity, age, income, family history of prostate cancer, and perceived prostate cancer knowledge. Twenty-five barbershops were visited during Fridays, Saturdays, and Sundays over a course of five months. The response rate was 99%. As the black men waited to be seen by their barbers, three interviewers asked them to answer the demographic and knowledge questions. SPSS was used to analyze the data. The main findings were that knowledge levels were adequate, with mean correct responses being 68.4%. Approximately 19.1% of respondents answered 80% of questions correctly, and 7.1% answered 100% of questions correctly. There were no statistically significant differences in knowledge among black men of different ethnicities. There were only two factors which were significantly related to prostate cancer knowledge. Men who earned more than dollars 50,000 and those with a family history of prostate cancer scored significantly higher than lower-income men and men with no family history of prostate cancer. As the percentage of Caribbean-American men and African men in the United States continues to increase, especially in metropolitan centers, those men at highest risk need to be targeted vigorously so that the disproportionate burden of prostate cancer on black men can be relieved.     

Myocardial ANP expression in Pompe's disease: An immunohistochemical study

The expression of atrial natriuretic peptide (ANP) was analyzed in the atrial and ventricular myocardium in three cases of Pompe's disease (glycogen storage disease of the myocardium), using an immunoperoxidase technique. The cytoplasm of almost all atrial myocytes and some subendocardial myocytes from the right and left ventricles were ANP-positive, excluding the typical central vacuole, which was occupied by glycogen. Ventricular ANP expression was usually more prominent in left ventricular samples, and its distribution was similar to that described in dilated, hypertrophic, restrictive, or ischemic heart disease; however, the enlargement of the myocytes in Pompe's disease is not caused by hypertrophy. We conclude that the atrial myocytes in Pompe's disease maintain ANP expression, despite severe cytoplasmic vacuolization. These results suggest that ventricular ANP expression may be related to mechanical stimuli, such as the increase in wall stress, and not directly related to myocyte hypertrophy.     

The outcome of T-cell costimulation through intercellular adhesion molecule-1 differs from costimulation through leucocyte function-associated antigen-1

Optimal T-cell activation requires both an antigen-specific and a costimulatory signal. The outcome of T-cell activation can be influenced by the nature of the costimulatory signal the T cell receives. We recently demonstrated the ability of stimulation through intercellular adhesion molecule-1 (ICAM-1), resident on the T-cell surface, to provide a second signal for T-cell activation, and have extended that work here to begin an examination of the functional outcome of this set of signals. Costimulation through ICAM-1 resulted in a greater percentage of cells having undergone more than three divisions when compared to costimulation through leucocyte function-associated antigen-1 (LFA-1). Costimulation through ICAM-1 also had an effect similar to costimulation through CD28 in its ability to down-regulate the cyclin dependent kinase inhibitor p27kip1. Costimulation through ICAM-1 provided greater protection from apoptosis than costimulation through LFA-1, especially in cells having divided more than three times. This was supported by the ability of costimulation through ICAM-1 to up-regulate the anti-apoptotic protein Bcl-2. Finally, costimulation through ICAM-1 or CD28 produced a greater number of T cells with a memory phenotype than costimulation through LFA-1.     

The Role of Sialic Acid in Opsonin-Dependent and Opsonin-Independent Adhesion of Listeria monocytogenes to Murine Peritoneal Macrophages

The adhesion of listeriae to host cells employs mechanisms which are complex and not well understood. Listeria monocytogenes is a facultative intracellular pathogen responsible for meningoencephalitis, septicemia, and abortion in susceptible and immunocompromised individuals. Subsequent to colonization and penetration of the gut epithelium, the organism attaches to resident macrophages and replicates intracellularly, thus evading the humoral immune system of the infected host. The focus of these studies was to investigate the attachment of the organism to murine peritoneal macrophages in an opsonin-dependent and opsonin-independent fashion. Assessment of competitive binding experiments by immunofluorescence and enzyme-linked immunosorbent assays showed that adhesion of the organism to macrophages in the presence or absence of opsonins was inhibited (90%) by N-acetylneuraminic acid (NAcNeu). In addition, the lectin from Maackia amurensis, with affinity for NAcNeu-α(2,3)galactose, blocked binding of L. monocytogenes to host cells. Oxidation of the surface carbohydrates on the organism by using sodium metaperiodate resulted in a dose-dependent reduction (up to 98%) in adherence to macrophages. Monoclonal antibody to complement receptor 3 did not prevent listeriae from binding to mouse macrophages or from replicating within the infected cells whether or not normal mouse serum was present. Based on our results, we propose the involvement of NAcNeu, a member of the sialic acid group, in the attachment of L. monocytogenes to permissive murine macrophages.