Martin D. Slade

Longevity Increased by Positive Self-Perceptions of Aging

This research found that older individuals with more positive self-perceptions of aging, measured up to 23 years earlier, lived 7.5 years longer than those with less positive self-perceptions of aging. This advantage remained after age, gender, socioeconomic status, loneliness, and functional health were included as covariates. It was also found that this effect is partially mediated by will to live. The sample consisted of 660 individuals aged 50 and older who participated in a community-based survey, the Ohio Longitudinal Study of Aging and Retirement (OLSAR). By matching the OLSAR to mortality data recently obtained from the National Death Index, the authors were able to conduct survival analyses. The findings suggest that the self-perceptions of stigmatized groups can influence longevity.

Amelioration of Acute Sequelae of Blast Induced Mild Traumatic Brain Injury by N-Acetyl Cysteine: A Double- Blind, Placebo Controlled Study

Background Mild traumatic brain injury (mTBI) secondary to blast exposure is the most common battlefield injury in Southwest Asia. There has been little prospective work in the combat setting to test the efficacy of new countermeasures. The goal of this study was to compare the efficacy of N-acetyl cysteine (NAC) versus placebo on the symptoms associated with blast exposure mTBI in a combat setting. Methods This study was a randomized double blind, placebo-controlled study that was conducted on active duty service members at a forward deployed field hospital in Iraq. All symptomatic U.S. service members who were exposed to significant ordnance blast and who met the criteria for mTBI were offered participation in the study and 81 individuals agreed to participate. Individuals underwent a baseline evaluation and then were randomly assigned to receive either N-acetyl cysteine (NAC) or placebo for seven days. Each subject was re-evaluated at 3 and 7 days. Outcome measures were the presence of the following sequelae of mTBI: dizziness, hearing loss, headache, memory loss, sleep disturbances, and neurocognitive dysfunction. The resolution of these symptoms seven days after the blast exposure was the main outcome measure in this study. Logistic regression on the outcome of ‘no day 7 symptoms’ indicated that NAC treatment was significantly better than placebo (OR = 3.6, p = 0.006). Secondary analysis revealed subjects receiving NAC within 24 hours of blast had an 86% chance of symptom resolution with no reported side effects versus 42% for those seen early who received placebo. Conclusion This study, conducted in an active theatre of war, demonstrates that NAC, a safe pharmaceutical countermeasure, has beneficial effects on the severity and resolution of sequelae of blast induced mTBI. This is the first demonstration of an effective short term countermeasure for mTBI. Further work on long term outcomes and the potential use of NAC in civilian mTBI is warranted. Trial Registration ClinicalTrials.gov NCT00822263

Longitudinal study of serum lipids and liver enzymes in workers with occupational exposure to ammonium perfluorooctanoate.

Objective: To examine the relationship between serum perfluorooctanoate (PFOA), a biomarker of ammonium perfluorooctanoate exposure, and lipids and liver enzymes. Methods: We conducted a longitudinal study on 454 workers and used mixed models to examine the relationship between serum PFOA and lipids and liver enzymes. Results: One part per million (ppm) increase in serum PFOA was associated with a 1.06 mg/dL increase in total cholesterol, but was not associated with changes in triglycerides or other lipoproteins, after adjusting for potential confounders. Serum PFOA was also associated with total bilirubin (0.008 mg/dL decline/ppm) and serum aspartate aminotransferase (0.35 units increase/ppm) but not with the other liver enzymes. Conclusions: These medical surveillance data collected on workers for up to 25 years contributes useful information on the effects of ammonium perfluorooctanoate exposure on human liver and lipid chemistry.

Proximity to Pollution Sources and Risk of Amphibian Limb Malformation

The cause of limb deformities in wild amphibian populations remains unclear, even though the apparent increase in prevalence of this condition may have implications for human health. Few studies have simultaneously assessed the effect of multiple exposures on the risk of limb deformities. In a cross-sectional survey of 5,264 hylid and ranid metamorphs in 42 Vermont wetlands, we assessed independent risk factors for nontraumatic limb malformation. The rate of nontraumatic limb malformation varied by location from 0 to 10.2%. Analysis of a subsample did not demonstrate any evidence of infection with the parasite Ribeiroia. We used geographic information system (GIS) land-use/land-cover data to validate field observations of land use in the proximity of study wetlands. In a multiple logistic regression model that included land use as well as developmental stage, genus, and water-quality measures, proximity to agricultural land use was associated with an increased risk of limb malformation (odds ratio = 2.26; 95% confidence interval, 1.42–3.58; p < 0.001). The overall discriminant power of the statistical model was high (C = 0.79). These findings from one of the largest systematic surveys to date provide support for the role of chemical toxicants in the development of amphibian limb malformation and demonstrate the value of an epidemiologic approach to this problem.

Memory Shaped by Age Stereotypes over Time

OBJECTIVES Previous studies showed that negative self-stereotypes detrimentally affect the cognitive performance of marginalized group members; however, these findings were confined to short-term experiments. In the present study, we considered whether stereotypes predicted memory over time, which had not been previously examined. We also considered whether self-relevance increased the influence of stereotypes on memory over time. METHOD Multiple waves of memory performance were analyzed using individual growth models. The sample consisted of 395 participants in the Baltimore Longitudinal Study of Aging. RESULTS Those with more negative age stereotypes demonstrated significantly worse memory performance over 38 years than those with less negative age stereotypes, after adjusting for relevant covariates. The decline in memory performance for those aged 60 and above was 30.2% greater for the more negative age stereotype group than for the less negative age stereotype group. Also, the impact of age stereotypes on memory was significantly greater among those for whom the age stereotypes were self-relevant. DISCUSSION This study shows that the adverse influence of negative self-stereotypes on cognitive performance is not limited to a short-term laboratory effect. Rather, the findings demonstrate, for the first time, that stereotypes also predict memory performance over an extended period in the community.

Association Between Positive Age Stereotypes and Recovery From Disability in Older Persons

OBJECTIVES: To compare restraint-use practices and injuries among children in crashes with grandparent versus parent drivers. METHODS: This was a cross-sectional study of motor vehicle crashes that occurred from January 15, 2003, to November 30, 2007, involving children aged 15 years or younger, with cases identified via insurance claims and data collected via follow-up telephone surveys. We calculated the relative risk of significant child-passenger injury for grandparent-driven versusparent-driven vehicles.Logistic regression modeling estimated odds ratios (ORs) and 95%confidence intervals (CIs), adjusting for several child occupant, driver, vehicle, and crash characteristics. RESULTS: Children driven by grandparents comprised 9.5% of the sample but resulted in only 6.6%of the total injuries. Injuries were reported for 1302 children, for an overall injury rate of 1.02 (95%CI: 0.90–1.17) per 100 child occupants. These represented 161 weighted injuries (0.70%injuryrate) withgrandparent driversand2293injuries (1.05%injury rate) with parent drivers. Although nearly all children werereportedtohavebeenrestrained,childrenincrasheswithgrandparent drivers used optimal restraint slightly less often. Despite this, children in grandparent-driven crashes were at one-half the risk of injuries as those in parent-driven crashes (OR: 0.50 [95% CI: 0.33– 0.75]) after adjustment. CONCLUSIONS: Grandchildren seem to be safer in crashes when driven by grandparents than by their parents, but safety could be enhanced if grandparents followed current child-restraint guidelines. Additional elucidation of safegrandparent drivingpractices whencarrying their grandchildren may inform future child-occupant driving education guidelines for all drivers. Pediatrics 2011;128:289–295 AUTHORS: FredM. Henretig, MD,DennisR. Durbin, MD, MSCE, Michael J. Kallan, MS,and FlauraK. Winston, MD, PhD Division of Emergency Medicine, Center for Injury Research and Prevention, and eDivision of General Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; bDepartment of Pediatrics and dCenter for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and fLeonard Davis Institute for Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania

Ubiquitin-Fused and/or Multiple Early Genes from Cottontail Rabbit Papillomavirus as DNA Vaccines

ABSTRACT Human papillomavirus (HPV) vaccines have the potential to prevent cervical cancer by preventing HPV infection or treating premalignant disease. We previously showed that DNA vaccination with the cottontail rabbit papillomavirus (CRPV) E6 gene induced partial protection against CRPV challenge and that the vaccines effects were greatly enhanced by priming with granulocyte-macrophage colony-stimulating factor (GM-CSF). In the present study, two additional strategies for augmenting the clinical efficacy of CRPV E6 vaccination were evaluated. The first was to fuse a ubiquitin monomer to the CRPV E6 protein to enhance antigen processing and presentation through the major histocompatibility complex class I pathway. Rabbits vaccinated with the wild-type E6 gene plus GM-CSF or with the ubiquitin-fused E6 gene formed significantly fewer papillomas than the controls. The papillomas also required a longer time to appear and grew more slowly. Finally, a significant proportion of the papillomas subsequently regressed. The ubiquitin-fused E6 vaccine was significantly more effective than the wild-type E6 vaccine plus GM-CSF priming. The second strategy was to vaccinate with multiple CRPV early genes to increase the breadth of the CRPV-specific response. DNA vaccines encoding the wild-type CRPV E1-E2, E6, or E7 protein were tested alone and in all possible combinations. All vaccines and combinations suppressed papilloma formation, slowed papilloma growth, and stimulated subsequent papilloma regression. Finally, the two strategies were merged and a combination DNA vaccine containing ubiquitin-fused versions of the CRPV E1, E2, and E7 genes was tested. This last vaccine prevented papilloma formation at all challenge sites in all rabbits, demonstrating complete protection.

Granulocyte-Macrophage Colony-Stimulating Factor Priming plus Papillomavirus E6 DNA Vaccination: Effects on Papilloma Formation and Regression in the Cottontail Rabbit Papillomavirus-Rabbit Model

ABSTRACT A cottontail rabbit papillomavirus (CRPV) E6 DNA vaccine that induces significant protection against CRPV challenge was used in a superior vaccination regimen in which the cutaneous sites of vaccination were primed with an expression vector encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that induces differentiation and local recruitment of professional antigen-presenting cells. This treatment induced a massive influx of major histocompatibility complex class II-positive cells. In a vaccination-challenge experiment, rabbit groups were treated by E6 DNA vaccination, GM-CSF DNA inoculation, or a combination of both treatments. After two immunizations, rabbits were challenged with CRPV at low, moderate, and high stringencies and monitored for papilloma formation. As expected, all clinical outcomes were monotonically related to the stringency of the viral challenge. The results demonstrate that GM-CSF priming greatly augmented the effects of CRPV E6 vaccination. First, challenge sites in control rabbits (at the moderate challenge stringency) had a 0% probability of remaining disease free, versus a 50% probability in E6-vaccinated rabbits, and whereas GM-CSF alone had no effect, the interaction between GM-CSF priming and E6 vaccination increased disease-free survival to 67%. Second, the incubation period before papilloma onset was lengthened by E6 DNA vaccination alone or to some extent by GM-CSF DNA inoculation alone, and the combination of treatments induced additive effects. Third, the rate of papilloma growth was reduced by E6 vaccination and, to a lesser extent, by GM-CSF treatment. In addition, the interaction between the E6 and GM-CSF treatments was synergistic and yielded more than a 99% reduction in papilloma volume. Finally, regression occurred among the papillomas that formed in rabbits treated with the E6 vaccine and/or with GM-CSF, with the highest regression frequency occurring in rabbits that received the combination treatment.

Subliminal Strengthening Improving Older Individuals’ Physical Function Over Time With an Implicit-Age-Stereotype Intervention

Negative age stereotypes that older individuals assimilate from their culture predict detrimental outcomes, including worse physical function. We examined, for the first time, whether positive age stereotypes, presented subliminally across multiple sessions in the community, would lead to improved outcomes. Each of 100 older individuals (age = 61–99 years, M = 81) was randomly assigned to an implicit-positive-age-stereotype-intervention group, an explicit-positive-age-stereotype-intervention group, a combined implicit- and explicit-positive-age-stereotype-intervention group, or a control group. Interventions occurred at four 1-week intervals. The implicit intervention strengthened positive age stereotypes, which strengthened positive self-perceptions of aging, which, in turn, improved physical function. The improvement in these outcomes continued for 3 weeks after the last intervention session. Further, negative age stereotypes and negative self-perceptions of aging were weakened. For all outcomes, the implicit intervention’s impact was greater than the explicit intervention’s impact. The physical-function effect of the implicit intervention surpassed a previous study’s 6-month-exercise-intervention’s effect with participants of similar ages. The current study’s findings demonstrate the potential of directing implicit processes toward physical-function enhancement over time.

Chitinase 3–Like 1 Suppresses Injury and Promotes Fibroproliferative Responses in Mammalian Lung Fibrosis

Chitinase 3–like 1 protects against lung injury but has a profibrotic role during the repair phase. Two-Face Chitinase Idiopathic pulmonary fibrosis is a devastating—currently incurable—disease where scars develop deep in the lung, making it hard to breathe. Now, Zhou et al. report a breath of fresh air for IPF. They found that the protein chitinase 3–like 1 (CHI3L1) is elevated in IPF patients, and that high levels of CHI3L1 are associated with disease progression. However, things were not as simple as they seemed. CHI3L1 actually played a protective, anti-apoptotic role against lung injury, but contributed to fibrosis during the repair phase, in part through inducing myofibroblast transformation. This insight into the two sides of CHI3L1 provides mechanistic understanding of the pathogenesis of IPF, which is necessary to the development of successful therapeutics. Epithelial injury, alternative macrophage accumulation, and fibroproliferation coexist in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Chitinase 3–like 1 (CHI3L1) is a prototypic chitinase-like protein that has been retained over species and evolutionary time. However, the regulation of CHI3L1 in IPF and its ability to regulate injury and/or fibroproliferative repair have not been fully defined. We demonstrated that CHI3L1 levels were elevated in patients with IPF. High levels of CHI3L1 are associated with progression—as defined by lung transplantation or death—and with scavenger receptor–expressing circulating monocytes in an ambulatory IPF population. In preterminal acute exacerbations of IPF, CHI3L1 levels were reduced and associated with increased levels of apoptosis. We also demonstrated that in bleomycin-treated mice, CHI3L1 expression was acutely and transiently decreased during the injury phase and returned toward and eventually exceeded baseline levels during the fibrotic phase. In this model, CHI3L1 played a protective role in injury by ameliorating inflammation and cell death, and a profibrotic role in the repair phase by augmenting alternative macrophage activation, fibroblast proliferation, and matrix deposition. Using three-dimensional culture system of a human fibroblast cell line, we found that CHI3L1 is sufficient to induce low grade myofibroblast transformation. In combination, these studies demonstrate that CHI3L1 is stimulated in IPF, where it represents an attempt to diminish injury and induce repair. They also demonstrate that high levels of CHI3L1 are associated with disease progression in ambulatory patients and that a failure of the CHI3L1 antiapoptotic response might contribute to preterminal disease exacerbations.