Reflections on community-based population health intervention and evaluation for obesity and chronic disease prevention: the Healthy Alberta Communities project

Objectives  

To reflect upon a population health intervention for obesity and chronic disease prevention, with specific attention to the processes of change and developing, implementing and evaluating an intervention in a community–university–government partnership context.     

Challenges of Using In Vitro Data for Modeling P-Glycoprotein Efflux in the Blood-Brain Barrier

The efficacy of central nervous system (CNS) drugs may be limited by their poor ability to cross the blood-brain barrier (BBB). Transporters, such as p-glycoprotein, may affect the distribution of many drugs into the CNS in conjunction with the restricted paracellular pathway of the BBB. It is therefore important to gain information on unbound drug concentrations in the brain in drug development to ensure sufficient drug exposure from plasma at the target site in the CNS. In vitro methods are routinely used in drug development to study passive permeability and p-glycoprotein efflux of new drugs. This review discusses the challenges in the use of in vitro data as input parameters in physiologically based pharmacokinetic (PBPK) models of CNS drug disposition of p-glycoprotein substrates. Experience with quinidine demonstrates the variability in in vitro parameters of passive permeability and active p-glycoprotein efflux. Further work is needed to generate parameter values that are independent of the model and assay. This is a prerequisite for reliable predictions of drug concentrations in the brain in vivo.     

Associations of urban air particulate composition with inflammatory and cytotoxic responses in RAW 246.7 cell line

Epidemiological studies show heterogeneities in the particulate pollution-related exposure–effect relationships among cardiorespiratory patients, but the connection to chemical composition and toxic properties of the inhaled particles is largely unknown. To identify the chemical constituents and sources responsible for the diverse inflammatory and cytotoxic effects of urban air, fine (PM_2.5–0.2) and coarse (PM_10–2.5) particulate samples were collected during contrasting air pollution situations. We exposed mouse RAW 246.7 macrophages for 24?hrs to PM_2.5–0.2 and PM_10–2.5 samples from six European cities. The concentrations of proinflammatory cytokines (IL-6, TNFα), chemokine (MIP-2), and nitric oxide were measured from the cell culture medium, and the cytotoxicity was assayed. Spearman’s correlations between the chemical constituents and cellular responses were analyzed. In the PM_2.5–0.2 size range, the tracers of photo-oxidation of organics in the atmosphere (oxalate, succinate, malonate), some transition metals (Ni, V, Fe, Cu, Cr), and insoluble soil constituents (Ca, Al, Fe, Si) correlated positively with the response parameters. In contrast, the tracers of incomplete biomass (monosaccharide anhydrides) and coal (As) combustion, and polycyclic aromatic hydrocarbons (PAHs), had negative correlations with the inflammatory activity. The compositions of PM_10–2.5 samples were more uniform and there were only occasional high correlations between the chemical constituents, endotoxin, and the response parameters. The present results suggest that the local sources of incomplete combustion and resuspended road dust are important producers of harmful fine particulate constituents that may, however, operate via diverse toxicity mechanisms. The results agree well with our recent findings in the mouse lung.     

COMBINED RESPIRATORY EFFECTS OF COLD AIR WITH SO2 OR NO2 IN REPEATED 10-MINUTE EXPOSURES OF HYPERVENTILATING GUINEA PIGS

Previous studies in asthmatic subjects and guinea pigs have demonstrated attenuation of bronchoconstriction in repeated exposures to clean cold dry air. In the present animal study, we have simulated short-lasting human exposures to subfreezing urban air containing sulfur dioxide (SO2) and nitrogen dioxide (NO2). The anesthetized, paralyzed, and mechanically ventilated guinea pigs had 4 consecutive 10-min exposures either to clean cold dry air or to cold air with graded concentrations of SO2 (0-5 ppm) or NO2 (0-4 ppm). Peak expiratory flow (PEF) and tidal volume (V_T     

Passive oral drug absorption can be predicted more reliably by experimental than computational models—Fact or myth

This study assessed the prediction power of experimental and computational models that are widely used to predict human passive intestinal absorption. The models evaluated included two cell lines, three artificial membrane models, in vivo rat experiments, and seven previously described computational quantitative structure property relationship models based on human absorption values. The data sets used in the assessment of the models were carefully chosen from the literature, and different models were compared using the same compounds to ensure objective results. Three of the computational models were found to be significantly more reliable in predicting human passive intestinal absorption than the artificial membrane models that have been developed for the prediction of passive intestinal absorption. Two of these computational models were found to be as reliable as the Caco-2 and the 2/4/A1 cell lines and, furthermore, one of the models was able to predict the absorption of a set of 65 drugs nearly as well as absorption studies in rats. The unexpectedly good prediction power of the simple computational models with high throughput makes them ideal tools in the early screening of drug candidates, whereas laborious cell culture models and animal studies can be useful in the later phases when detailed information about the transport mechanisms is needed.     

Systematic review of evidence for the benefits of telemedicine

A systematic review of telemedicine assessments based on searches of electronic databases between 1966 and December 2000 identified 66 scientifically credible studies that included comparison with a non-telemedicine alternative and that reported administrative changes, patient outcomes, or results of economic assessment. Thirty-seven of the studies (56%) suggested that telemedicine had advantages over the alternative approach, 24 (36%) also drew attention to some negative aspects or were unclear whether telemedicine had advantages and five (8%) found that the alternative approach had advantages over telemedicine. The most convincing evidence on the efficacy and effectiveness of telemedicine was given by some of the studies on teleradiology (especially neurosurgical applications), telemental health, transmission of echocardiographic images, teledermatology, home telecare and on some medical consultations. However, even in these applications, most of the available literature referred only to pilot projects and to short-term outcomes. Few papers considered the long-term or routine use of telemedicine. For several applications, including teleradiology, savings and sometimes clinical benefit were obtained through avoidance of travel and associated delays. Studies of home care and monitoring applications showed convincing evidence of benefit, while those on teledermatology indicated that there were cost disadvantages to health-care providers, although not to patients. Forty-four of the studies (67%) appeared to have potential to influence future decisions on the telemedicine application under consideration. However, a number of these had methodological limitations. Although useful clinical and economic outcomes data have been obtained for some telemedicine applications, good-quality studies are still scarce and the generalizability of most assessment findings is rather limited.     

Extracellular and intracellular factors influencing gene transfection mediated by 1,4-dihydropyridine amphiphiles

Double-charged 1,4-dihydropyridine (1,4-DHP) amphiphiles have been shown to condense DNA and efficiently transfect it into cells in vitro [Hyvönen et al., Biochim. Biophys. Acta 1509 (2000) 451]. Alkyl chain length and buffering capacity at endosomal pH range (5.0–7.4) affected complexation and transfection activity. In this study we examined how those chemical modifications of amphiphile–DNA complexes (amphiplexes) affect their interactions with extracellular polyanions (glycosaminoglycans, albumin) and lipid bilayers, their cellular uptake and intracellular distribution. To evaluate cellular uptake, CV1-P cells were incubated with labeled DNA–amphiphile complexes and analyzed by flow cytometry. Confocal laser fluorescence microscopy was used to investigate the intracellular distribution of amphiplexes. The results showed that biophysical properties of compounds can be changed by slight structural modifications. These factors determine the intracellular kinetics and transfection efficacy of the compounds. Some extracellular glycosaminoglycans and serum interfere with 1,4-DHP-amphiphile-mediated transfection by destabilizing the amphiplexes. Neither high cellular uptake, membrane destabilizing activity nor buffering capacity alone is adequate for high transfection efficacy. The activity results from complex interplay of various factors that determine intracellular kinetics and, consequently, transfection.     

Novel spectral indexes of heart rate variability as predictors of sudden and non-sudden cardiac death after an acute myocardial infarction

BACKGROUND: Various indexes of 24-hour heart rate variability (HRV) have been able to predict all-cause mortality after an acute myocardial infarction (AMI), but their value in predicting specific modes of cardiac death has been limited. AIM: The aim of this study was to assess the role of two novel spectral indexes of HRV as predictors of either sudden (SCD) or non-sudden cardiac death after an AMI. Method. We used two novel methods of spectral analysis of HRV: 1) the high-frequency (HF) spectral component, V(index), calculated as an average HF power from the most linear portion of HF power versus the R-R interval regression curve, and 2) the prevalent low-frequency oscillation of heart rate (PLF). V(index), conventional HRV measures, and PLF were analyzed from 24-hour Holter recordings of 590 patients with a recent AMI. RESULTS: During the mean follow-up of 39+/-14 months, SCD occurred in 3% (n = 17) and non-sudden cardiac death in 5% (n = 28) of the patients. In univariate analysis, V(index) was the most potent predictor of SCD (RR: 6.0, 95% CI: 1.7-20.7, P<0.01), also remaining the most powerful predictor of SCD after adjustment for clinical variables and ejection fraction (RR: 4.2, 95% CI: 1.2-15.2, P<0.05). PLF was a potent predictor of non-sudden cardiac death (RR: 13.9, 95% CI: 5.9-32.5, P<0.001), but it did not predict SCD. CONCLUSIONS: Novel spectral HRV analysis methods, V(index) and PLF, provide significant information of the risk of the specific mode of death after an AMI.