Maribeth H. Johnson

Inhibition of Indoleamine 2,3-Dioxygenase in Dendritic Cells by Stereoisomers of 1-Methyl-Tryptophan Correlates with Antitumor Responses

Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that contributes to tolerance in a number of biological settings. In cancer, IDO activity may help promote acquired tolerance to tumor antigens. The IDO inhibitor 1-methyl-tryptophan is being developed for clinical trials. However, 1-methyl-tryptophan exists in two stereoisomers with potentially different biological properties, and it has been unclear which isomer might be preferable for initial development. In this study, we provide evidence that the D and L stereoisomers exhibit important cell type-specific variations in activity. The L isomer was the more potent inhibitor of IDO activity using the purified enzyme and in HeLa cell-based assays. However, the D isomer was significantly more effective in reversing the suppression of T cells created by IDO-expressing dendritic cells, using both human monocyte-derived dendritic cells and murine dendritic cells isolated directly from tumor-draining lymph nodes. In vivo, the d isomer was more efficacious as an anticancer agent in chemo-immunotherapy regimens using cyclophosphamide, paclitaxel, or gemcitabine, when tested in mouse models of transplantable melanoma and transplantable and autochthonous breast cancer. The D isomer of 1-methyl-tryptophan specifically targeted the IDO gene because the antitumor effect of D-1-methyl-tryptophan was completely lost in mice with a disruption of the IDO gene (IDO-knockout mice). Taken together, our findings support the suitability of D-1-methyl-tryptophan for human trials aiming to assess the utility of IDO inhibition to block host-mediated immunosuppression and enhance antitumor immunity in the setting of combined chemo-immunotherapy regimens.

Sleep disorders: a risk factor for normal-tension glaucoma?

PurposeTo determine the prevalence of sleep-related symptoms and sleep-related breathing disorders by polysomnography in patients with normal-tension glaucoma (NTG). Patients and MethodsThis comparative case series included 23 patients with NTG, 14 NTG suspects, and 30 comparison patients without NTG. A sleep history was obtained and determined to be positive or negative. Polysomnography was offered for patients with a positive sleep history. Prevalence of a positive sleep history and prevalence of sleep disorders were the main outcome measures. ResultsThe NTG, NTG suspect, and comparison groups did not differ with respect to age, body mass index, systemic disease, gender, or race. Thirteen (57%) of 23 patients with NTG, 6 (43%) of 14 NTG suspects, and 1 (3%) of 30 comparison patients had a positive sleep history (P = 0.001). Nine of 13 patients with NTG and four of six NTG suspects with a positive sleep history chose to undergo polysomnography. Seven (78%) of nine patients with NTG and all four NTG suspects undergoing polysomnography were diagnosed with a sleep disorder. Five patients with NTG had sleep apnea and two had sleep hypopnea. Two NTG suspects had sleep apnea; one had sleep hypopnea; and one had upper airway resistance syndrome. The one comparison patient with a positive sleep history had upper airway resistance syndrome by polysomnography. ConclusionsSleep-disturbed breathing may be a risk factor for NTG. Although we do not provide evidence for a cause-and-effect relationship, various physiologic factors produced by sleep-disturbed breathing may play a significant role in the pathogenesis of this optic neuropathy. We recommend obtaining a sleep history from patients with NTG and performing polysomnography in those patients with sleep disturbance symptoms.

Ten months of exercise improves general and visceral adiposity, bone, and fitness in black girls.

Objective: The goal of this study was to evaluate the impact of a 10‐month after‐school physical activity (PA) program on body composition and cardiovascular (CV) fitness in young black girls.

Preliminary findings of the effect of a 3-year after-school physical activity intervention on fitness and body fat: The Medical College of Georgia Fitkid Project

OBJECTIVE To evaluate the effect of a 3-year after-school physical activity (PA) intervention on aerobic fitness and percent body fat (%BF). METHODS In total, 18 schools were randomized into intervention or control arms. Measurements were made at the beginning and end of the third, fourth and fifth grades. Fitness was measured with heart rate response to a bench-stepping task.%BF and bone density were measured with dual-energy x-ray absorptiometry. The intervention included 40 min of academic enrichment activities, during which healthy snacks were provided, and 80 min of moderate-to-vigorous PA (MVPA). RESULTS Data analyses were performed on 206 youths who remained in the same schools for the 3-year period, who were measured at all six time points and, for the intervention group, who attended at least 40% of the sessions in each of the 3 years. The group by time interactions were significant for fitness (p < 0.01) and %BF (p < 0.05). Children in intervention schools improved in fitness and %BF during the school years and returned to levels similar to those in control schools during the summers. Over the six measurement points, the intervention group increased more than the control group in bone density (p < 0.01), fat-free soft tissue (p < 0.01), weight (p < 0.01), height (p < 0.01), and body mass index (p < 0.05). CONCLUSIONS An after-school program focusing on MVPA had a beneficial effect on fitness and body composition. During the summers, the beneficial effect of the previous years participation on fitness and %BF was lost. This highlights the importance of year-round programs to promote healthy growth in youths.

The effect of blood transfusion protocol on retinopathy of prematurity: A prospective, randomized study.

Objective. Controversy exists regarding the potential influence of anemia and blood transfusions on the rate of retinopathy of prematurity (ROP) in premature infants. A prospective, randomized, masked trial was performed to determine the influence of red blood cell transfusion protocol on ROP incidence and severity in a population of high-risk infants. Methods. A total of 50 infants with birth weights <1251 g were divided randomly into two groups beginning on day of life 29. Group 1 (n = 24) received red cell transfusions during the 6-week study period, only if certain symptom-based guidelines were met. Group 2 (n = 26) received red cell transfusions to maintain the hematocrit level above 40% for the entire 6 weeks. Infants were monitored for ROP, growth, and associated morbidity. Serial measurements of serum glucose, lactate, ferritin, total iron-binding capacity, and iron were performed. Results. ROP occurred in 83% of infants in group 1, and 73% of infants in group 2. There were no statistically significant differences in ROP severity, intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, or any of the laboratory values except hemoglobin (10.8 vs 13.2 g/dL) and hematocrit (33.9% vs 41.8%) between the groups. Combining data from both groups, there was no association between hemoglobin or hematocrit ratios and ROP incidence or severity. Conclusions. A transfusion policy aimed at limiting the amount of blood given to premature infants (symptom-based) during the neonatal period does not impart a significantly different risk for ROP or other associated conditions, than does a policy in which transfusions are given more liberally for replacement purposes.

Cost-Effectiveness of a School-Based Obesity Prevention Program

BACKGROUND A school-based obesity prevention study (Medical College of Georgia FitKid Project) started in the fall of 2003 in 18 elementary schools. Half of the schools were randomized to an after-school program that included moderate-to-vigorous physical activity, healthy snacks, homework assistance, and academic enrichment. All third graders were invited to enroll. The objective of this study was to assess the cost-effectiveness (CE) of the first-year intervention. METHODS Standard CE analysis methods and a societal perspective were used. Program delivery costs incurred during the first-year intervention and the usual after-school care costs that would occur in the absence of the intervention were estimated (in 2003 dollars). Net intervention costs were calculated by subtracting the usual after-school care costs from the intervention costs. The effectiveness of the intervention was measured as percent body fat (%BF) reduction compared with a control condition. The CE was assessed as the net intervention cost divided by the effectiveness of the intervention. RESULTS The intervention costs totaled

General and visceral adiposity in black and white adolescents and their relation with reported physical activity and diet.

174,070,

Effect of neutrophil depletion on gelatinase expression, edema formation and hemorrhagic transformation after focal ischemic stroke

558/student, or

Remote Ischemic Perconditioning Is Effective Alone and in Combination With Intravenous Tissue-Type Plasminogen Activator in Murine Model of Embolic Stroke

956/student who attended > or = 40% of the intervention sessions. The usual after-school care costs were estimated at

Hypertension after experimental cerebral ischemia: candesartan provides neurovascular protection

639/student. Students who attended > or = 40% of the intervention reduced %BF by 0.76% (95% confidence interval: -1.42 to -0.09) at an additional cost of