Publications

Tuberculosis (TB) is the major cause of death from infectious diseases around the world, particularly in HIV infected individuals. TB vaccine design and development have been focused on improving Bacille Calmette-Guérin (BCG) and evaluating recombinant and viral vector expressed Mycobacterium tuberculosis (Mtb) proteins, for boosting BCG-primed immunity, but these approaches have not yet yielded significant improvements over the modest effects of BCG in protecting against infection or disease. On March 7-8, 2016, the National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop on "The Impact of Mtb Immune Evasion on Protective Immunity: Implications for TB Vaccine Design" with the goal of defining immune mechanisms that could be targeted through novel research approaches, to inform vaccine design and immune therapeutic interventions for prevention of TB. The workshop addressed early infection events, the impact of Mtb evolution on the development and maintenance of an adaptive immune response, and the factors that influence protection against and progression to active disease. Scientific gaps and areas of study to revitalize and accelerate TB vaccine design were discussed and prioritized. These included a comprehensive evaluation of innate and Mtb-specific adaptive immune responses in the lung at different stages of disease; determining the role of B cells and antibodies (Abs) during Mtb infection; development of better assays to measure Mtb burden following exposure, infection, during latency and after treatment, and approaches to improving current animal models to study Mtb immunogenicity, TB disease and transmission.

Both the history of obesity and weight loss may change how menopause affects metabolic health. The purpose was to determine whether obesity and/or weight loss status alters energy balance (EB) and subsequent weight gain after the loss of ovarian function. Female lean and obese Wistar rats were randomized to 15% weight loss (WL) or ad libitum fed controls (CON). After the weight loss period, WL rats were kept in EB at the reduced weight for 8 weeks prior to ovariectomy (OVX). After OVX, all rats were allowed to eat ad libitum until weight plateaued. Energy intake (EI), spontaneous physical activity, and total energy expenditure (TEE) were measured with indirect calorimetry before OVX, immediately after OVX, and after weight plateau. Changes in energy intake (EI), TEE, and weight gain immediately after OVX were similar between lean and obese rats. However, obese rats gained more total weight and fat mass than lean rats over the full regain period. Post-OVX, EI increased more ( ≤ 0.03) in WL rats (58.9 ± 3.5 kcal/d) than CON rats (8.5 ± 5.2 kcal/d), and EI partially normalized (change from preOVX: 20.5 ± 4.2 vs. 1.5 ± 4.9 kcal/day) by the end of the study. As a result, WL rats gained weight (week 1:44 ± 20 vs. 7 ± 25 g) more rapidly (mean = 44 ± 20 vs. 7 ± 25 g/week;  < 0.001) than CON Prior obesity did not affect changes in EB or weight regain following OVX, whereas a history of weight loss prior to OVX augmented disruptions in EB after OVX, resulting in more rapid weight regain.

UNLABELLED

Using a nonsteroidal anti-inflammatory drug (NSAID) before a single bout of mechanical loading can reduce bone formation response. It is unknown whether this translates to an attenuation of bone strength and structural adaptations to exercise training.

PURPOSE

This study aimed to determine whether nonsteroidal anti-inflammatory drug use before exercise prevents increases in bone structure and strength in response to weight-bearing exercise.

METHODS

Adult female Wistar rats (n = 43) were randomized to ibuprofen (IBU) or vehicle (VEH) and exercise (EX) or sedentary (SED) groups in a 2 × 2 (drug and activity) ANCOVA design with body weight as the covariate, and data are reported as mean ± SE. IBU drops (30 mg·kg BW) or VEH (volume equivalent) were administered orally 1 h before the bout of exercise. Treadmill running occurred 5 d·wk for 60 min·d at 20 m·min with a 5° incline for 12 wk. Micro-CT, mechanical testing, and finite element modeling were used to quantify bone characteristics.

RESULTS

Drug-activity interactions were not significant. Exercise increased tibia cortical cross-sectional area (EX = 5.67 ± 0.10, SED = 5.37 ± 0.10 mm, P < 0.01) and structural estimates of bone strength (Imax: EX = 5.16 ± 0.18, SED = 4.70 ± 0.18 mm, P < 0.01; SecModPolar: EX = 4.01 ± 0.11, SED = 3.74 ± 0.10 mm, P < 0.01). EX had increased failure load (EX = 243 ± 9, SED = 202 ± 7 N, P < 0.05) and decreased distortion in response to a 200-N load (von Mises stress at tibia-fibula junction: EX = 48.2 ± 1.3, SED = 51.7 ± 1.2 MPa, P = 0.01). There was no effect of ibuprofen on any measurement tested. Femur results revealed similar patterns.

CONCLUSION

Ibuprofen before exercise did not prevent the skeletal benefits of exercise in female rats. However, exercise that engenders higher bone strains may be required to detect an effect of ibuprofen.

OBJECTIVES

To define the role of single or serial measurement of endothelin 1 (ET-1) for prognostication beyond traditional and modern markers of risk in heart failure (HF).

METHODS

In total, 115 patients with chronic systolic HF were followed for 10 months. Clinical assessment and ET-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP), highly sensitive troponin I (hsTnI), soluble ST2 (sST2), and galectin 3 were measured at each visit.

RESULTS

Elevated ET-1 was associated with worse HF, lower right ventricular function, higher pulmonary pressure, and higher left atrial volume index despite similar left ventricular function. ET-1 correlated with angiotensin-converting enzyme inhibitor use. A model containing traditional risk factors, ET-1, NT-proBNP, hsTnI, and sST2 best predicted cardiovascular events, and ET-1 improved reclassification. In an adjusted time-integrated model, percent time spent with ET-1 of 5.90 pg/mL or less was predictive of fewer cardiovascular events (odds ratio, 0.75; 95% confidence interval, 0.62-0.91). ET-1 reduction over time was associated with a lower rate of cardiovascular events compared with increasing or stable ET-1 (24.4% vs 50.0%).

CONCLUSIONS

ET-1 may be a unique predictor of HF prognosis, complementing other biomarkers in a multimarker profile. Serial measurement of ET-1 may provide additional prognostic information.