Modestly Increased Incidence of Ketosis in Caloric Restriction Does not Significantly Alter the Effects of Caloric Restriction.

OBJECTIVES: Caloric restriction (CR) has been shown to slow the aging processes in a number of preclinical studies and reduces expression of aging-associated biomarkers in human trials. We hypothesized that CR would lead to increased incidence of ketosis and that ketosis in CR individuals would alter the aging-protective effects of CR or biomarkers thereof. DESIGN/SETTING/PARTICIPANTS: We analyzed data from the "Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE, Phase 2)" Public Use Database available at calerie.duke.edu. In this study, non-obese adults between the ages of 21 and 50 were randomized to 25% CR or control (ad lib) diet groups and extensively monitored for two years. Given our focus on the effect of caloric restriction on ketosis, individuals with detectible ketones during the baseline visit (pre-randomization) and those with missing data for ketone testing were excluded from the analysis, leaving 71 control and 117 CR participants. MEASUREMENTS: We analyzed the incidence of ketosis as well as ketosis free survival in control and CR participants and assessed the effect of ketosis on a number of clinical lab values, functional assessments, and participant survey data related to aging biology. RESULTS: We report that CR was associated with modestly increased incidence of ketosis (4.4% in CR vs 1.9% in control), though CR-associated changes in T3, VO2, SUMPT-WT (weight normalized composite strength score - peak torque), physical functioning, and general health did not appear to be altered by the presence or absence of ketosis. Additional observations of interest include: 1) striking patterns of biomarker expression changes (MCP-1, TNFα, TGF-ß1, GH) in both the control and CR participants between the baseline visit and the 24-month post-randomization visit and 2) pro-growth/anti-inflammatory baseline (pre-randomization) biomarker expression profile in CR individuals that later test ketone positive relative to other CR individuals. CONCLUSIONS: CR modestly increases the incidence of ketosis in healthy adults, yet the increase in ketosis in CR patients did not significantly affect the aging-protective effects of CR. However, given the relatively small number of participants who were ketone positive, further investigation in larger study cohorts is still required for definitive conclusions.

Rapid Communication: Prolactin and hydrocortisone impact TNFα-mediated mitogen-activated protein kinase signaling and inflammation of bovine mammary epithelial (MAC-T) cells.

The objective of this study was to evaluate the effects of the hormones prolactin (PRL) and hydrocortisone (HC) on bovine mammary alveolar (MAC-T) cells mitogen-activated protein kinase (MAPK) inflammatory signaling and inflammatory gene expression. MAC-T cells were cultured in the presence (+PRL +HC; Dulbecco's modified Eagle's medium [DMEM] 10% fetal bovine serum, 10 µg/mL of insulin, 100 IU/mL penicillin, 100 µg/mL streptomycin, 1 µg/mL ovine PRL, 0.5 µg/mL HC, and 10 m sodium acetate) or the absence (-PRL -HC; DMEM 10% fetal bovine serum, 10 µg/mL insulin, 100 IU/mL penicillin , and 100 µg/mL streptomycin) of PRL and HC, and MAPK (extracellular signal-regulated kinase [ERK], c-Jun N-terminal kinase [JNK], and p38) phosphorylation and inflammatory gene expression were examined in response to tumor necrosis factor α (TNFα). Statistical analysis was assessed using 1-way ANOVA, and Tukey's post hoc analysis was used to assess statistical significance when ≤ 0.05. MAC-T cells cultured in +PRL +HC and -PRL -HC were co-stimulated with increasing concentrations of TNFα (0, 10, 30, 100, 300, and 1,000 p). Cell lysates were harvested 15 min after TNFα stimulation and assessed for MAPK phosphorylation using immunoblotting. c-Jun N-terminal kinase and p38 phosphorylation increased in a dose-dependent manner and was greater in cells cultured in -PRL -HC. MAC-T cells cultured in +PRL +HC and -PRL -HC were next stimulated with TNFα (300 p), and lysates were harvested over time (0, 15, 30, 60, 120, and 180 min) after TNFα stimulation. c-Jun N-terminal kinase and p38 phosphorylation was transiently increased in MAC-T cells stimulated with TNFα; however, JNK and p38 signaling was greater in MAC-T cells cultured in -PRL -HC. We next examined inflammatory gene expression in MAC-T cells cultured in +PRL +HC and -PRL -HC. Cells were co-stimulated with (300 p) or without TNFα. Ribonucleic acid was isolated 1 h after TNFα stimulation, and a PCR array was performed to examine the expression of 83 inflammatory genes. Gene expression was increased in MAC-T cells in response to TNFα. Consistent with enhanced MAPK signaling, inflammatory gene expression was increased in MAC-T cells cultured in -PRL -HC. Real-time quantitative PCR of 6 target genes was used to validate the PCR array findings. Collectively, our data demonstrate that -PRL -HC MAC-T cells are more responsive to TNFα stimuli. These findings suggest that cell culture conditions (e.g., treatment with hormones) greatly impact cellular response and should be considered prior to experimental design and hypothesis testing.

Can alcohol price policies be used to reduce drunk driving? Evidence from Canada.

Drunk driving is one of the more serious negative consequences of alcohol consumption. Since consumption of alcohol is sensitive to the price of alcohol, and the occurrence of drunk driving is sensitive to the level of alcohol consumption, the possibility exists for alcohol pricing policies to be used to reduce drunk driving in the population. This paper reviews the evidence on this possibility in the literature and adds results based on data from the Canadian province of Ontario. Multiple regression analysis of time series data for Ontario from 1972 to 1990 indicate that, controlling for income, the proportion of young males in the population, changes in the minimum drinking age, and other confounding variables, increasing the price of alcohol has a significant effect in reducing alcohol-related motor vehicle accidents (elasticity = - 1.2, p < .05) and alcohol-related traffic offenses (elasticity = -0.50, p < .05). Overall, the evidence strongly supports the view that alcohol tax and pricing policies can be used to reduce the extent of drunk driving.

Interpreting the rational addiction model.

The rational addiction (RA) model of Becker and Murphy (Becker GS, Murphy KM. A theory of rational addiction. J Pol Econ 1988; 96(4): 675-700) has rapidly become one of the standard models in the literature on addictive behaviour. This paper reviews some theoretical issues surrounding its use, and indicates areas in which caution should be used in applying this model.

Does allowing the sale of wine in Quebec grocery stores increase consumption?

OBJECTIVE: To determine if allowing wine sales in corner grocery stores, beginning in 1978 for domestic Quebec wines and then in 1983 for imported wines, in addition to sales in government monopoly stores, led to an increase in alcohol consumption. METHOD: Aggregate retail sales data for the period 1953 to 1990 were analyzed using econometric regression techniques. Time series (unit root) analysis and structural modeling were used to take into account the effect of price, income and other social, economic and demographic factors in order to determine the effect of factors underlying consumption behavior in both the long and short term. RESULTS: In the post-intervention period, wine consumption continued along the rising trend established in the pre-intervention period, with an apparent shift in favor of domestic wine consumption. The increase in wine consumption was highest in the period immediately following privatization, but the increase eventually dampened down within a few years. There was no fundamental change in the responsiveness of wine consumption to price. CONCLUSION: Our findings suggest that the level of wine consumption can be controlled through price changes when alcohol availability increases through increased sales outlets.

Community-based facilities may be replacing hospitals for the treatment of alcoholism: the evidence from Ontario.

We examined hospital utilization and use of community facilities for the treatment of alcohol problems in Ontario using Statistics Canada, Hospital Medical Records Institute records, and other administrative records. Between 1974 and 1986 there was a large drop in utilization of hospital services for treatment of alcohol problems. Rates of alcohol inpatient cases in general hospitals dropped by 47% and in mental hospitals by 33%. At the same time, there was an increase in overall availability of hospital beds and bed-days of care for all medical conditions, and no change in the total number of hospital discharges (1.3 million) and occupancy rates (80-85%). Also at the same time, the number of community-based programs for the treatment of alcohol problems increased, as did the number of persons or cases treated by them. This was associated with a drop of inpatient cases treated for alcohol problems in 38 out of 48 counties in Ontario (P < .0005). Multiple regression techniques were used to take into account the effect of the slight decline in overall alcohol consumption in this period. We found that after controlling for changes in alcohol consumption, the addition of one community-based alcohol treatment program was associated with a reduction in the number of cases treated on a hospital inpatient basis for alcohol-related problems, with a short-run drop of 27.1 hospital cases within 1 year of a community facility's availability and a long-run reduction of 52.2 cases. (P < .005).

Comparison of enzyme-linked immunosorbent assay and high-performance liquid chromatography for the analysis of atrazine in water from Czechoslovakia.

Twenty-two water samples from Bohemian Paradise in Czechoslovakia were analyzed for atrazine (2-chloro-4-ethylamino-6- isopropylamino-1,3,5-triazine) by enzyme immunoassay (EIA) and high-performance liquid chromatography (HPLC). Three samples were drinking water, the others were creek water. The amount of atrazine found by EIA ranged from 0.2 to 12,700 ng/ml and 0.10 to 10,300 ng/ml by HPLC. Agreement between the methods was good. Nine samples containing the highest concentrations of atrazine were used to check the day-to-day reproducibility of both methods at high atrazine levels. The percent coefficients of variation (% CVs) ranged from 5.9 to 26.2 for the EIA and 1.5 to 33.2 for the HPLC. Day to day % CV values for each calibrator concentration ranged from 5.7 to 10.9 for EIA and 9.9 to 13.9 for HPLC. Sensitivity of the EIA was 0.2 ng/ml while it was 0.1 ng/ml for solid phase extraction HPLC and slightly less than 60 ng/ml for direct injection HPLC.

Optimal population control with uncertain output.

"This note has shown how the techniques of stochastic control theory can be used to analyze the impact of uncertainty about non-labour inputs on optimal population control expenditure. While we have chosen very simple structure, it has allowed us to isolate the channels through which uncertainty affects the optimal plan, in this case causing expected expenditure on control to rise more slowly or fall more rapidly than its deterministic counterpart. Given the long-term implications of changes in population growth at any instant, and the stochastic nature of the environment in which control decisions are made, it is likely that useful insights could be obtained by extending the stochastic control approach to more complicated population control structures."

Physician objectives and resource allocation.

This paper examines the theoretical incentives affecting physicians input use in the case of fee-for-service practice. It establishes that while the price taking physician, acting as a utility maximizer, may use inputs relating to his own time efficiently, he may not be efficient in his use of other inputs.