Faculty Bibliography

A number of cyclohexenyl chalcone Diels-Alder natural products possess promising biological properties including strong cytotoxicity in various human cancer cells. Herein, we show that natural products in this class including panduratin A and nicolaioidesin C inhibit cysteine cathepsins as indicated by protease profiling assays and cell-free cathepsin L enzyme assays. Owing to the critical roles of cathepsins in the biology of human tumor progression, invasion, and metastasis, these findings should pave the way for development of novel antitumor agents for use in clinical settings.

Male circumcision (MC) reduces penile high-risk human papillomavirus (HR-HPV) on the coronal sulcus and urethra. HR-HPV varies by anatomic site, and it is unknown whether MC decreases HR-HPV on the penile shaft. We assessed the efficacy of MC to reduce HR-HPV on the penile shaft and compared it to known efficacy of MC to reduce HR-HPV on the coronal sulcus. HIV-negative men randomized to receive immediate circumcision (intervention) or circumcision delayed for 24 months (control) were evaluated for HR-HPV at 12 months postenrollment using the Roche HPV Linear Array assay. Among swabs with detectable β-globin or HPV, year 1 HR-HPV prevalence on the coronal sulcus was 21.5% in the intervention arm and 36.3% in the control arm men [adjusted prevalence risk ratios (PRRs) = 0.57, 95% CI 0.39-0.84, p = 0.005]. On the shaft, year 1 HR-HPV prevalence was 15.5% in the intervention and 23.8% in the control arm (adjusted PRR = 0.66, 95% CI 0.39-1.12, p = 0.12). Efficacy of MC to reduce HR-HPV on the shaft was similar to efficacy on the coronal sulcus (p = 0.52). In a sensitivity analysis in which swabs without detectable β-globin or HPV were included as HPV negative, prevalence of HR-HPV on the shaft was lower in the intervention arm (7.8%) than control arm (13.6%; PRR 0.57, 95% CI 0.33-0.99, p < 0.05). HR-HPV was more frequently detected on the coronal sulcus than penile shaft among uncircumcised men (36.3% vs. 23.8%, respectively, p = 0.02) and circumcised men (21.5% vs. 15.5%, respectively, p = 0.24). MC reduced HR-HPV prevalence on both the coronal sulcus and shaft.

BACKGROUND: The effect of atrial pacing on the incidence of atrial fibrillation (AF) is unknown. Furthermore, the threshold of ventricular pacing that is associated with a higher incidence of AF has yet to be determined. Thus, we set out to determine the optimal pacing modality in patients with sinus node dysfunction (SND) for the prevention of AF. METHODS: Individual patient data from four contemporary pacemaker studies were gathered and analyzed. Since AF would inherently lead to a reduction in atrial pacing, percent atrial and ventricular pacing (%AP and %VP) were determined at the first follow-up visit and then used as a surrogate for all endpoints. Patients with >5 minutes of AF at the first visit were excluded. The primary endpoint was defined as 7 consecutive days of AF. RESULTS: A total of 1,507 patients were included. During a mean follow-up of 14.3 +/- 8.7 months, 77 patients developed AF (annual rate of 4.3%). The incidence of AF in the first (0-32%), second (32-66%), third (66-89%), and fourth (89-100%) quartiles of %AP was 1.3%, 5.3%, 5.8%, and 8.0%, respectively (P < 0.001). A multivariable analysis found that pacing above the first quartile was associated with a relative risk of 2.93 (95% confidence interval 1.16-7.39, P = 0.023). The grouping of %VP into first (0-2%), second (2-7%), third (7-84%), and fourth (84-100%) quartiles yielded an AF incidence of 2.4%, 3.4%, 6.6%, and 8.0%, respectively (P = 0.001). CONCLUSION: We demonstrated that in patients with SND both atrial and ventricular pacing are associated with a higher incidence of AF.

OBJECTIVE: To examine associations between 9/11-related exposures, posttraumatic stress disorder (PTSD), and subsequent development of heart disease (HD). METHODS: We prospectively followed 39,324 WTC Health Registry participants aged >/=18 on 9/11 for an average of 2.9 years. HD was defined as self-reported physician-diagnosed angina, heart attack, and/or other HD reported between study enrollment (2003-2004) and a follow-up survey (2006-2008) in enrollees without previous HD. A PTSD Checklist (PCL) score >/=44 was considered PTSD. We calculated adjusted hazard ratios (AHR) and 95% confidence intervals (CI) to examine relationships between 9/11-related exposures and HD. RESULTS: We identified 1162 HD cases (381 women, 781 men). In women, intense dust cloud exposure was significantly associated with HD (AHR 1.28, 95% CI 1.02-1.61). Injury on 9/11 was significantly associated with HD in women (AHR 1.46, 95% CI 1.19-1.79) and in men (AHR 1.33, 95% CI 1.15-1.53). Participants with PTSD at enrollment had an elevated HD risk (AHR 1.68, 95% CI 1.33-2.12 in women, AHR 1.62, 95% CI 1.34-1.96 in men). A dose-response relationship was observed between PCL score and HD risk. CONCLUSION: This exploratory study suggests that exposure to the WTC dust cloud, injury on 9/11 and 9/11-related PTSD may be risk factors for HD.

BACKGROUND: Serious respiratory illnesses have been reported among rescue/recovery workers (RRW) following the World Trade Center (WTC) attacks. METHODS: We studied RRW enrolled in the WTC Health Registry to assess the effects of different respiratory protection equipment (RPE) types on respiratory outcomes, such as recurrent respiratory symptoms and diseases possibly associated with 9/11 exposures. We performed descriptive and multivariate analyses adjusting for demographics and exposure variables. RESULTS: A total of 9,296 RRW met inclusion criteria. The strongest predictors of using adequate RPE were being affiliated with construction, utilities or environmental remediation organizations and having received RPE training. Workers who used respirators were less likely to report adverse respiratory outcomes compared to those who reported no/lower levels of respiratory protection. CONCLUSIONS: Level of respiratory protection was associated with the odds of reporting respiratory symptoms and diseases. Training, selection, fit testing, and consistent use of RPE should be emphasized among emergency responders.

BACKGROUND: Volunteers (non-professional rescue/recovery workers) are universally present at man-made and natural disasters and share experiences and exposures with victims. Little is known of their disaster-related health outcomes. METHODS: We studied 4974 adult volunteers who completed the World Trade Center Health Registry 2006-07 survey to examine associations between volunteer type (affiliated vs. lay) and probable posttraumatic stress disorder (PTSD); new or worsening respiratory symptoms; post-9/11 first diagnosis of anxiety disorder, depression, and/or PTSD; and asthma or reactive airway dysfunction syndrome (RADS). Affiliated volunteers reported membership in a recognized organization. Lay volunteers reported no organizational affiliation and occupations unrelated to rescue/recovery work. Adjusted odds ratios (OR(adj)) were calculated using multinomial regression. RESULTS: Lay volunteers were more likely than affiliated volunteers to have been present in lower Manhattan, experience the dust cloud, horrific events and injury on 9/11 and subsequently to report unmet healthcare needs. They had greater odds of early post-9/11 mental health diagnosis (OR(adj) 1.6; 95% CI: 1.4-2.0) and asthma/RADS (1.8; 1.2-2.7), chronic PTSD (2.2; 1.7-2.8), late-onset PTSD (1.9; 1.5-2.5), and new or worsening lower respiratory symptoms (2.0; 1.8-2.4). CONCLUSIONS: Lay volunteers' poorer health outcomes reflect earlier, more intense exposure to and lack of protection from physical and psychological hazards. There is a need to limit volunteers' exposures during and after disasters, as well as to provide timely screening and health care post-disaster.

BACKGROUND: Self-report of dietary energy and protein intakes has been shown to be systematically and differentially underreported. OBJECTIVE: We assessed and compared the association of diabetes among postmenopausal women with biomarker-calibrated and uncalibrated dietary energy and protein intakes from food-frequency questionnaires (FFQs). DESIGN: The analyses were performed for 74,155 participants of various race-ethnicities from the Women's Health Initiative. Uncalibrated and calibrated energy and protein intakes from FFQs were assessed for associations with incident diabetes by using HR estimates based on Cox regression. RESULTS: A 20% increment in uncalibrated energy consumption was associated with increased diabetes risk (HR) of 1.03 (95% CI: 1.01, 1.05), 2.41 (95% CI: 2.06, 2.82) with biomarker calibration, and 1.30 (95% CI: 0.96, 1.76) after adjustment for BMI. A 20% increment in uncalibrated protein (g/d) resulted in an HR of 1.05 (95% CI: 1.03, 1.07), 1.82 (95% CI: 1.56, 2.12) with calibration, and 1.16 (95% CI: 1.05, 1.28) with adjustment for BMI. A 20% increment in uncalibrated protein density (% of energy from protein) resulted in an HR of 1.13 (95% CI: 1.09, 1.17), 1.01 (95% CI: 0.75, 1.37) with calibration, and 1.19 (95% CI: 1.07, 1.32) with adjustment for BMI. CONCLUSIONS: Higher protein and total energy intakes (calibrated) appear to be associated with a substantially increased diabetes risk that may be mediated by an increase in body mass over time. Diet-disease associations without correction of self-reported measurement error should be viewed with caution. This trial is registered at clinicaltrials.gov as NCT00000611.

Public health leaders, like physicians, need to make decisions that impact health based on strong evidence. To generate useful evidence for public health leaders, research must focus on interventions that have potential to impact population-level health. Often policy and environmental changes are the interventions with the greatest potential impact on population health, but studying these is difficult because of limitations in the methods typically used and emphasized in health research. To create useful evidence for policy and environmental interventions, other research methods are needed, including observational studies, the use of surveillance data for evaluation, and predictive mathematical modeling. More emphasis is needed on these types of study designs by researchers, funding agencies, and scientific journals.

Objective: Symptomatic vaginal atrophy affects one out of three menopausal women. Hormone therapy, both systemic and local, is effective and indicated for the relief of this problem but may not be acceptable to all patients. DT56a (Femarelle), a selective estrogen receptor modulator derived from botanical source, was found to be effective at decreasing menopausal hot flushes and increasing bone mass. We performed a pilot study testing the use of DT56a for vaginal atrophy. Design: 12 post-menopausal women with vaginal atrophy (<5% superficial cells on cervical cytology) with at least one moderate-to-severe symptom, were recruited for an TRB-approved 12-week open-label pilot study. DT56a (322mg) was given by mouth 2X/day for 12 weeks. At each visit (0&q4 weeks) subjects had a vaginal atrophy assessment (speculum exam, vaginal pH) and completed questionnaires on atrophy symptoms and quality of life (Utian QoL scale).At weeks 0 and 12, a pap smear with maturation index and vaginal cultures were performed. Results: The main bothersome symptoms were: Dyspareunia- 5 Patients,Vaginal soreness- 3 Patients.Vaginal dryness- 2 Patients.Vaginal irritation-1 Patient and Bleeding with coitus-1 Patient. All patients reported significant improvement in their most bothersome symptom. All women had a significant reduction in vaginal pH. The average pH went from baseline 7.7+/-2.2 to 4.9+/-1.4 on week 12,p<0.0001. The maturation index also improved as shown in the figure below: Parabasal cells that were 100% at entry were 43% following 12 weeks of treatment, Intermediate cells were changed from 0 to 47% and Superficial cells that were 0 at entry, were 10% following 12 weeks of treatment with DT56a (all statistically significant, p<0.001). A significant improvement was found in UQoL index from mean pre-treatment of 75.4+/-22.7 points to mean post-treatment of 88.9+/-26.8, p<0.001.In the sexual domains of the UQoL there was a significant improvement from 6.5+2 points (mean pre-treatment) to 10.6+ 3.2 (mean post-treatment), p<0.001. Conclusion: In this open-label prospective study DT56a was effective against symptomatic vulvo-vaginal atrophy in both subjective and objective measures. The changes in symptoms and pH were prompt and paralleled symptomatic relief. DT56a furnished a significant improvement in UQoL. As the placebo effect on the maturation index and vaginal pH is negligible, this 12 patient study provides an indicative measurement of the positive effect of DT56a for the treatment of vulvo-vaginal atrophy and a large double blind placebo controlled trial is planned. (Table presented)

The accessory gene regulator (agr) locus has been shown to be important for virulence in several animal models of Staphylococcus aureus infection. However, the role of agr in human infections, and specifically in antibiotic treatment, is controversial. Interestingly, agr dysfunction has been associated with reduced vancomycin responses. To systematically investigate the role of agr in virulence and treatment outcome in the context of endovascular infection, 10 well-characterized vancomycin-susceptible methicillin-resistant S. aureus (MRSA) bloodstream isolates (5 agr-I [clonal complex 45, or CC45] and 5 agr-II [CC5]) were studied for (i) agr function, (ii) RNAIII transcriptional profiles, (iii) agr locus sequences, (iv) intrinsic virulence and responses to vancomycin therapy in an experimental infective endocarditis (IE) model, and (v) in vivo RNAIII expression. Significant differences in agr function (determined by delta-hemolysin activity) correlated with the time point of RNAIII transcription (earlier RNAIII onset equals increased agr function). Unexpectedly, four MRSA strains with strong delta-hemolysin activities exhibited significant resistance to vancomycin treatment in experimental IE. In contrast, five of six MRSA strains with weak or no delta-hemolysin activity were highly susceptible to vancomycin therapy in the IE model. agr sequence analyses showed no common single-nucleotide polymorphism predictive of agr functionality. In vivo RNAIII expression in cardiac vegetations did not correlate with virulence or vancomycin treatment outcomes in the IE model. Inactivation of agr in two strains with strong delta-hemolysin activity did not affect virulence or the in vivo efficacy of vancomycin. Our findings suggest that agr dysfunction does not correlate with vancomycin treatment failures in this experimental IE model in two distinct MRSA genetic backgrounds.