Publications

Methionine-choline-deficient (MCD) diets cause steatohepatitis in rodents and are used to study the pathophysiology of fatty liver disease in human beings. The most widely used commercial MCD formulas not only lack methionine and choline but also contain excess sucrose and fat. The objective of this study was to determine whether dietary sucrose in the MCD formula plays a role in the pathogenesis of MCD-related liver disease. We prepared two custom MCD formulas, one containing sucrose as the principal carbohydrate and the other substituting sucrose with starch. Mice fed the sucrose-enriched formula developed typical features of MCD-related liver disease, including hepatic steatosis, hepatocellular apoptosis, alanine aminotransferase elevation, lipid peroxidation, and hepatic inflammation. In contrast, mice fed MCD-starch were significantly protected against liver injury. MCD-sucrose and MCD-starch mice displayed identical diet-related abnormalities in hepatic fatty acid uptake and triglyceride secretion. Hepatic de novo lipogenesis and triglyceride synthesis, however, were 2 times higher in MCD-sucrose mice than MCD-starch mice (P < 0.01). Hepatic lipid analysis revealed accumulation of excess saturated fatty acids in MCD-sucrose mice that correlated with hepatocellular injury. Overall, the results indicate that dietary sucrose is critical to the pathogenesis of MCD-mediated steatohepatitis. They suggest that saturated fatty acids, which are products of de novo lipogenesis, are mediators of hepatic toxicity in this model of liver disease.

BACKGROUND

Life space is a measure of where a person goes, the frequency of going there, and the dependency in getting there. It may be a more accurate measure of mobility in older adults because it reflects participation in society as well as physical ability.

OBJECTIVE

To assess effects of hospitalization on life space in older adults, and to compare life-space trajectories associated with surgical and nonsurgical hospitalizations.

DESIGN

Prospective observational study.

SETTING

Central Alabama.

PARTICIPANTS

687 community-dwelling Medicare beneficiaries at least 65 years of age with surgical (n = 44), nonsurgical (n = 167), or no (n = 476) hospitalizations.

MEASUREMENTS

Life-Space Assessment (LSA) scores before and after hospitalization (range, 0 to 120; higher scores reflect greater mobility).

RESULTS

Mean age of participants was 74.6 years (SD, 6.3). Fifty percent were black, and 46% were male. Before hospitalization, adjusted LSA scores were similar in participants with surgical and nonsurgical admissions. Life-space assessment scores decreased in both groups immediately after hospitalization; however, participants with surgical hospitalizations had a greater decrease in scores (12.1 more points [95% CI, 3.6 to 20.7 points]; P = 0.005) than those with nonsurgical hospitalizations. However, participants with surgical hospitalizations recovered more rapidly over time (gain of 4.7 more points [CI, 2.0 to 7.4 points] per ln [week after discharge]; P < 0.001). Score recovery for participants with nonsurgical hospitalizations did not significantly differ from the null (average recovery, 0.7 points [CI, -0.6 to 1.9 points] per ln [week after discharge]).

LIMITATION

Life space immediately before and after hospitalization was self-reported, often after hospital discharge.

CONCLUSION

Hospitalization decreases life space in older adults. Surgical hospitalizations are associated with immediate marked life-space declines followed by rapid recovery, in contrast to nonsurgical hospitalizations, which are associated with more modest immediate declines and little evidence of recovery after several years of follow-up.

PRIMARY FUNDING SOURCE

National Institute on Aging.

OBJECTIVES

To determine whether the survival benefit associated with moderate alcohol use remains after accounting for nontraditional risk factors such as socioeconomic status (SES) and functional limitations.

DESIGN

Prospective cohort.

SETTING

The Health and Retirement Study (HRS), a nationally representative study of U.S. adults aged 55 and older.

PARTICIPANTS

Twelve thousand five hundred nineteen participants were enrolled in the 2002 wave of the HRS.

MEASUREMENTS

Participants were asked about their alcohol use, functional limitations (activities of daily living, instrumental activities of daily living, and mobility), SES (education, income, and wealth), psychosocial factors (depressive symptoms, social support, and the importance of religion), age, sex, race and ethnicity, smoking, obesity, and comorbidities. Death by December 31, 2006, was the outcome measure.

RESULTS

Moderate drinkers (1 drink/d) had a markedly more-favorable risk factor profile, with higher SES and fewer functional limitations. After adjusting for demographic factors, moderate drinking (vs no drinking) was strongly associated with less mortality (odds ratio (OR)=0.50, 95% confidence interval (CI)=0.40-0.62). When traditional risk factors (smoking, obesity, and comorbidities) were also adjusted for, the protective effect was slightly attenuated (OR=0.57, 95% CI=0.46-0.72). When all risk factors including functional status and SES were adjusted for, the protective effect was markedly attenuated but still statistically significant (OR=0.72, 95% CI=0.57-0.91).

CONCLUSION

Moderate drinkers have better risk factor profiles than nondrinkers, including higher SES and fewer functional limitations. Although these factors explain much of the survival advantage associated with moderate alcohol use, moderate drinkers maintain their survival advantage even after adjustment for these factors.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has recently emerged worldwide. The United States, in particular, is experiencing a serious epidemic of CA-MRSA that is almost entirely caused by an extraordinarily infectious strain named USA300. However, the molecular determinants underlying the pathogenic success of CA-MRSA are mostly unknown. To gain insight into the evolution of the exceptional potential of USA300 to cause disease, we compared the phylogeny and virulence of USA300 with that of closely related MRSA clones. We discovered that the sublineage from which USA300 evolved is characterized by a phenotype of high virulence that is clearly distinct from other MRSA strains. Namely, USA300 and its progenitor, USA500, had high virulence in animal infection models and the capacity to evade innate host defense mechanisms. Furthermore, our results indicate that increased virulence in the USA300/USA500 sublineage is attributable to differential expression of core genome-encoded virulence determinants, such as phenol-soluble modulins and alpha-toxin. Notably, the fact that the virulence phenotype of USA300 was already established in its progenitor indicates that acquisition of mobile genetic elements has played a limited role in the evolution of USA300 virulence and points to a possibly different role of those elements. Thus, our results highlight the importance of differential gene expression in the evolution of USA300 virulence. This finding calls for a profound revision of our notion about CA-MRSA pathogenesis at the molecular level and has important implications for design of therapeutics directed against CA-MRSA.