Staphylococcal enterotoxin A-activated regulatory T cells promote allergen-specific TH2 response to intratracheal allergen inoculation.

BACKGROUND: TH2 responses are implicated in asthma pathobiology. Epidemiologic studies have found a positive association between asthma and exposure to staphylococcal enterotoxins. OBJECTIVE: We used a mouse model of asthma to determine whether staphylococcal enterotoxins promote TH2 differentiation of allergen-specific CD4 conventional T (Tcon) cells and asthma by activating allergen-nonspecific regulatory T (Treg) cells to create a TH2-polarizing cytokine milieu. METHODS: Ovalbumin (OVA)-specific, staphylococcal enterotoxin A (SEA)-nonreactive naive CD4 Tcon cells were cocultured with SEA-reactive allergen-nonspecific Treg or CD4 Tcon cells in the presence of OVA and SEA. The OVA-specific CD4 T cells were then analyzed for IL-13 and IFN-γ expression. SEA-activated Treg cells were analyzed for the expression of the TH2-polarizing cytokine IL-4 and the T-cell activation markers CD69 and CD62L. For asthma induction, mice were intratracheally sensitized with OVA or cat dander extract (CDE) alone or together with SEA and then challenged with OVA or CDE. Mice were also subject to transient Treg cell depletion before sensitization with OVA plus SEA. Asthma features and TH2 differentiation in these mice were analyzed. RESULTS: SEA-activated Treg cells induced IL-13 but suppressed IFN-γ expression in OVA-specific CD4 Tcon cells. SEA-activated Treg cells expressed IL-4, upregulated CD69, and downregulated CD62L. Sensitization with OVA plus SEA but not OVA alone induced asthma, and SEA exacerbated asthma induced by CDE. Depletion of Treg cells abolished these effects of SEA and IL-13 expression in OVA-specific T cells. CONCLUSION: SEA promoted TH2 responses of allergen-specific T cells and asthma pathogenesis by activating Treg cells.

Model-based imputation approach for data analysis in the presence of non-detects.

A model-based multiple imputation approach for analyzing sample data with non-detects is proposed. The imputation approach involves randomly generating observations below the detection limit using the detected sample values and then analyzing the data using complete sample techniques, along with suitable adjustments to account for the imputation. The method is described for the normal case and is illustrated for making inferences for constructing prediction limits, tolerance limits, for setting an upper bound for an exceedance probability and for interval estimation of a log-normal mean. Two imputation approaches are investigated in the paper: one uses approximate maximum likelihood estimates (MLEs) of the parameters and a second approach uses simple ad hoc estimates that were developed for the specific purpose of imputations. The accuracy of the approaches is verified using Monte Carlo simulation. Simulation studies show that both approaches are very satisfactory for small to moderately large sample sizes, but only the MLE-based approach is satisfactory for large sample sizes. The MLE-based approach can be calibrated to perform very well for large samples. Applicability of the method to the log-normal distribution and the gamma distribution (via a cube root transformation) is outlined. Simulation studies also show that the imputation approach works well for constructing tolerance limits and prediction limits for a gamma distribution. The approach is illustrated using a few practical examples.

Treatment approach, delivery, and follow-up evaluation for cardiac rhythm disease management patients receiving radiation therapy: retrospective physician surveys including chart reviews at numerous centers.

In a 2-part study, we first examined the results of 71 surveyed physicians who provided responses on how they address the management of patients who maintained either a pacemaker or a defibrillator during radiation treatment. Second, a case review study is presented involving 112 medical records reviewed at 18 institutions to determine whether there was a change in the radiation prescription for the treatment of the target cancer, the method of radiation delivery, or the method of radiation image acquisition. Statistics are provided to illustrate the level of administrative policy; the level of communication between radiation oncologists and heart specialists; American Joint Committee on Cancer (AJCC) staging and classification; National Comprehensive Cancer Network (NCCN) guidelines; tumor site; patient׳s sex; patient׳s age; device type; manufacturer; live monitoring; and the reported decisions for planning, delivery, and imaging. This survey revealed that 37% of patient treatments were considered for some sort of change in this regard, whereas 59% of patients were treated without regard to these alternatives when available. Only 3% of all patients were identified with an observable change in the functionality of the device or patient status in comparison with 96% of patients with normal behavior and operating devices. Documented changes in the patient׳s medical record included 1 device exhibiting failure at 0.3-Gy dose, 1 device exhibiting increased sensor rate during dose delivery, 1 patient having an irregular heartbeat leading to device reprogramming, and 1 patient complained of twinging in the chest wall that resulted in a respiratory arrest. Although policies and procedures should directly involve the qualified medical physicist for technical supervision, their sufficient involvement was typically not requested by most respondents. No treatment options were denied to any patient based on AJCC staging, classification, or NCCN practice standards.