2011 Poster Competition Winners
Title: Hyperglycemia Does Not Add to Diabetes Status in Predicting Cognitive Decline: Results from the Atherosclerosis Risk in Communities (ARIC) Study
Introduction: Diabetes is associated with an increased risk of cognitive decline and dementia. It is unclear if hyperglycemia is an independent predictor of cognitive decline in persons with and without diabetes.
Hypothesis: We hypothesized that hyperglycemia, as assessed by glycated hemoglobin (HbA1c), would be positively associated with decline in cognition in persons with and without diabetes.
Methods: Prospective cohort study of 516 participants with and 8,442 without a history of diagnosed diabetes in the ARIC Study. We examined the association of categories of HbA1c (<5.7, 5.7-6.5, ?6.5% in nondiabetics; <7, 7-8, ?8% in diabetics) with 6-year change in three measures of cognition: the Digit Symbol Substitution Test (DSST), Delayed Word Recall Test (DWRT), and Word Fluency Test (WFT). Our primary outcomes were the quintile with the most annual cognitive decline for each test.
Results: Mean age was 56 years; the participants were 56% female and 21% African American. Mean HbA1c was 5.7% overall, and 8.5% in persons with and 5.5% in persons without diabetes. In adjusted logistic regression models, diagnosed diabetes was associated with cognitive decline only as assessed by DSST (OR 1.42, 95% CI (1.14, 1.75), p = 0.002), but HbA1c was not a significant independent predictor of cognitive decline when stratifying by diabetes history (diabetes, p-trend = 0.320; no diabetes, p-trend = 0.566). Similarly, trends were not significant for the DWRT or WFT in either the presence or absence of diabetes.
Conclusions: Over 6 years of follow-up, we found that hyperglycemia, as measured by HbA1c, did not predict cognitive decline beyond diabetes status in this middle-aged, community-based population. These findings are consistent with recent clinical trial data demonstrating that tight glycemic control does not prevent cognitive decline in diabetes. In conclusion, additional work is needed to identify the non-glycemic risk factors by which diabetes may contribute to cognitive decline.
Table. Adjusted* Odds Ratios (95% Confidence Interval) for Top Quintile of Yearly Cognitive Decline.
|Digit Symbol Substitution Test||Delayed Word Recall Test||Word Fluency Test|
|Diagnosed Diabetes (Yes vs. No)||1.42 (1.14, 1.75)||1.13 (0.91, 1.41)||1.20 (0.96, 1.50)|
|HbA1c<5.7||1.00 (ref.)||1.00 (ref.)||1.00 (ref.)|
|HbA1c 5.7-6.5||0.94 (0.81, 1.09)||0.90 (0.77, 1.04)||0.95 (0.82, 1.10)|
|HbA1c?6.5||0.94 (0.69, 1.26)||1.30 (1.00, 1.71)||0.99 (0.73, 1.33)|
|P-Value for Trend||0.566||0.462||0.589|
|HbA1c<7.0||1.04 (0.69, 1.57)||1.01 (0.67, 1.52)||0.93 (0.60, 1.43)|
|HbA1c 7.0-8.0||1.78 (1.15, 2.74)||1.40 (0.90, 2.16)||1.41 (0.90, 2.22)|
|HbA1c?8.0||1.34 (1.00, 1.81)||1.08 (0.80, 1.46)||1.22 (0.90, 1.66)|
|P-Value for Trend||0.320||0.612||0.190|
|P-Value for Overall Trend||0.011||0.235||0.169|
*Adjusted for age, race, sex, education, income, field center, smoking, drinking, body mass index, systolic and diastolic blood pressures, hypertension medication use, LDL- and HDL cholesterol, and triglycerides.
Title: Obesity and Thyroid Cancer Risk
Background: Thyroid cancer incidence has risen dramatically in the U.S. since the early 1980s. Although the prevalence of obesity has doubled during this time period, the relationship between obesity and thyroid cancer is uncertain.
Methods: We examined the association between body mass index (BMI) and thyroid cancer risk in a pooled analysis from five prospective U.S. studies, including 413,979 women and 434,953 men. Original data from each study were categorized using standardized exposure, covariate, and outcome definitions. Proportional hazards models with attained age as the time metric were adjusted for education, race, marital status, smoking, alcohol intake, and (where appropriate) cohort and sex.
Results: Over follow-up (mean=10.3 years), 768 women and 388 men were diagnosed with thyroid cancer. The risk of thyroid cancer was greater with increasing BMI (per 5 kg/m2: hazard ratio [HR] in women, 1.16 [95% confidence interval (CI), 1.08-1.24]; HR in men, 1.21 [95% CI, 0.97-1.49]). There was no significant heterogeneity between studies (both P>0.05). For women and men combined, the HRs for overweight (25.0-29.9 kg/m2) and obesity (?30 kg/m2) compared to normal-weight (18.5-24.9 kg/m2) were 1.20 (95% CI, 1.04-1.38) and 1.53 (95% CI, 1.31-1.79), respectively. We found no significant effect modification by other factors, and the results did not differ significantly by histologic type. A significant positive association for BMI in young adulthood (ages 18-20) with thyroid cancer risk was also observed (per 5-kg/m2 increase: HR, 1.18 [95% CI, 1.03-1.35]).
Conclusion: These results provide strong evidence that obesity is an independent risk factor for thyroid cancer.
Title: Current and Former Smokers' opinions of potential tobacco regulatory actions by the FDA
The Surgeon General acknowledged the health risks associated with smoking in 1964; however, it was not until 2009 that the government claimed regulatory power over tobacco products with the Family Smoking Prevention and Tobacco Control Act. While the intent of the Tobacco Control Act is to reduce tobacco’s negative impact on the public’s health, the effect of this legislation on smokers’ attitudes, intentions, and behaviors is unclear. This study reports on characteristics of current and former smokers endorsing the following three FDA-related items: 1) Government regulation of cigarettes will make cigarettes safer; 2) The government should reduce the amount of nicotine in cigarettes to help smokers quit; and 3) Menthol cigarettes should be banned. A total of 3638 current and former smokers in 8 cities were surveyed, of which 432 were African American, 256 were Hispanic, and 249 were of another racial/ethnic background. Results indicate that 30% of current and former smokers believe that regulation with yield a safer cigarette. In all cases, former smokers were more supportive of FDA regulation than current smokers. Whites and African Americans vary considerably when asked if menthol should be banned (22% v. 34% p<0.001) and if nicotine should be reduced (53% vs. 67%, p<0.001). Multivariate results demonstrated that smokers who agreed that regulation would yield a safer cigarette were more likely to have graduated high school, feel social pressure to quit, and have a desire to quit. In comparison to smokers who disagreed that the government should decrease nicotine, smokers who agreed were more likely to be female, African American, intend to quit in the next 6 months, believe that smoking is a serious health risk, have a desire to quit, and feel social pressure to quit. Smokers who agreed that menthol should be banned were less likely to have graduated high school, and more likely to be African American, older, intend to quit in the next 6 months, want to quit smoking, and recently tried to quit. Findings suggest that smokers who are interested in quitting are open to government regulation of cigarettes.
Title: Targeting Plasmodium sporozoite-Kupffer cell interactions with a phage display library
After inoculation by the bite of an infected mosquito, Plasmodium sporozoites enter the blood stream and infect the liver with unique specificity. Previous evidence suggests that specific sporozoite-Kupffer cell interactions are required for liver invasion to occur but the molecular determinants of these interactions are unknown. By use of a phage display library we identified three peptides that bind to the surface of Kupffer cells. Importantly, these peptides strongly inhibited Plasmodium berghei sporozoite invasion of Kupffer cells in vitro and of the mouse liver in vivo. In a separate set of experiments we determined that antibodies against one of the peptides binds to the surface of sporozoites and protects mice from Plasmodium infection. The results suggest that the candidate peptides interact with specific Kupffer cell surface receptor(s) and structurally mimic sporozoite ligands of liver invasion. These findings may lead to the development of novel protective vaccines.
Title: IL-33 Increases Inflammation and Impairs Heart Function During Viral Myocarditis
Rationale: Cardiovascular disease is the foremost cause of death in the U.S., accounting for 34% of all deaths in 2006. The IL-33/ST2 axis has been identified as a signaling pathway of great importance in the progression of heart disease and the ST2 receptor is considered a biomarker for heart disease. ST2 levels increase due to inflammation and mechanical strain associated with failing hearts. IL-33 binds and activates ST2, which has been shown to be cardioprotective by reducing remodeling and improving function in models of heart injury. However, IL-33/ST2 signaling can also enhance inflammation in autoimmune disease models. Infectious myocarditis, which progresses to dilated cardiomyopathy (DCM) is an instance where both a prolonged inflammatory response with possible autoimmune involvement and heart injury and remodeling occur. In a patient with infectious myocarditis, IL-33 could deleteriously promote inflammation, beneficially prevent heart remodeling and improve heart function, or both. This study was designed to test the effect of increased IL-33 on the development of CVB3-induced myocarditis.
Methods: Exogenous rIL-33 or PBS vehicle was given I.P. to CVB3-infected mice every other day from day 1 to 9 post infection (pi). Heart function was examined by in-vivo catheterization at day 10 pi – the time when mice have previously been determined to develop fulminant myocarditis. Tissue was then harvested for molecular and histological analysis.
Results: Mice that received IL-33 had three times more myocardial inflammatory cell infiltration than PBS controls, which was prominent along the pericardium. Levels of IL-33 were significantly increased in the hearts of mice receiving rIL-33, and levels of sST2 were increased in sera. Viral replication in the heart and pancreas remained unaltered by rIL-33. In-vivo hemodynamic assessment suggests that rIL-33 administration impairs systolic function during acute myocarditis. rIL-33 treated mice demonstrated an 11% decrease in systolic pressure, 40% decline in ventricular power, and 23% drop in contractility (dP/dT max) when compared to PBS treated controls. rIL-33 treated mice also demonstrated a lack of beta adrenergic sensitivity as measured by isoproterenol challenge compared to controls.
Conclusion: Activation of IL-33/ST2 signaling exacerbates myocarditis in two ways: 1) IL-33 increases the amount of inflammation entering the heart. 2) IL-33 impairs heart function by decreasing the heart’s ability to respond to B-adrenergic stimulants like adrenaline and isoproterenol – a common problem seen in human patients with heart failure. The results of this study suggest that IL-33/ST2 signaling is not merely associated with changes in heart function, but is directly involved in the pathophysiology of heart disease development and progression. Further study of this pathway leading to novel therapeutic targets may help treat or prevent cardiovascular diseases in the future.
Title: Successful respiratory immunization with dry powder live-attenuated measles vaccine
Measles remains an important cause of childhood mortality worldwide. Sustained high vaccination coverage is the key to preventing measles deaths. Because measles vaccine is delivered by injection, hurdles to high coverage include the need for trained medical personnel, waste of vaccine in multi-dose vials and risks associated with needle use and disposal. Respiratory vaccine delivery could lower these barriers and facilitate sustained high coverage. We developed a novel single unit dose, dry powder live-attenuated measles vaccine (MVDP) for respiratory delivery without reconstitution. We tested the immunogenicity and protective efficacy in rhesus macaques of one dose of MVDP delivered either with a mask or intranasally with two dry powder inhalers, PuffHaler® and Solovent®. MVDP induced robust measles virus (MeV)-specific humoral and T-cell responses, without adverse effects, which completely protected the macaques from infection with wild type MeV. Respiratory delivery of MVDP was safe and effective and could aid in measles control.