Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation.

Addback of donor T cells following T cell-depleted stem cell transplantation (SCT) can accelerate immune reconstitution and be effective against relapsed malignancy. After haploidentical SCT, a high risk of graft-versus-host disease (GVHD) essentially precludes this option, unless the T cells are first depleted of alloreactive precursor cells. Even then, the risks of severe GVHD remain significant. To increase the safety of the approach and thereby permit administration of larger T cell doses, we used a suicide gene, inducible caspase 9 (iCasp9), to transduce allodepleted T cells, permitting their destruction should administration have adverse effects. We made a retroviral vector encoding iCasp9 and a selectable marker (truncated CD19). Even after allodepletion (using anti-CD25 immunotoxin), donor T cells could be efficiently transduced, expanded, and subsequently enriched by CD19 immunomagnetic selection to >90% purity. These engineered cells retained antiviral specificity and functionality, and contained a subset with regulatory phenotype and function. Activating iCasp9 with a small-molecule dimerizer rapidly produced >90% apoptosis. Although transgene expression was downregulated in quiescent T cells, iCasp9 remained an efficient suicide gene, as expression was rapidly upregulated in activated (alloreactive) T cells. We have demonstrated the clinical feasibility of this approach after haploidentical transplantation by scaling up production using clinical grade materials.

Design of mixed-longitudinal studies

Cross-sectional designs, longitudinal designs in which a single cohort is followed over time, and mixed-longitudinal designs in which several cohorts are followed for a shorter period are compared by their precision, potential for bias due to age, time and cohort effects, and feasibility. Mixed longitudinal studies have two advantages over longitudinal studies: isolation of time and age effects and shorter completion time. Though the advantages of mixed-longitudinal studies are clear, choosing an optimal design is difficult, especially given the number of possible combinations of the number of cohorts and number of overlapping intervals between cohorts. The purpose of this paper is to determine the optimal design for detecting differences in group growth rates.^ The type of mixed-longitudinal study appropriate for modeling both individual and group growth rates is called a "multiple-longitudinal" design. A multiple-longitudinal study typically requires uniform or simultaneous entry of subjects, who are each observed till the end of the study.^ While recommendations for designing pure-longitudinal studies have been made by Schlesselman (1973b), Lefant (1990) and Helms (1991), design recommendations for multiple-longitudinal studies have never been published. It is shown that by using power analyses to determine the minimum number of occasions per cohort and minimum number of overlapping occasions between cohorts, in conjunction with a cost model, an optimal multiple-longitudinal design can be determined. An example of systolic blood pressure values for cohorts of males and cohorts of females, ages 8 to 18 years, is given. ^

FEASIBILITY OF CORRELATING INCIDENCE OF DIARRHEA WITH CHARACTERISTICS OF RURAL EGYPTIAN HOUSEHOLDS BY MEANS OF AN ENVIRONMENTAL SURVEY

Few, if any studies, have attempted to identify the specific environmental factors associated with the incidence of diarrheal disease and to rank these by their contribution to the total incidence of diarrheal illness. Potentially those factors with the greatest contribution are the variables on which intervention could be expected to have the greatest impact on the incidence of diarrhea.^ In 317 rural Egyptian households participating in a longitudinal study of diarrheal disease, selected environmental characteristics were observed and recorded on a questionnaire. Characteristics of the environment were classified into seven categories including water usage, proximity of animals to the house, waste management, food preparation area, toilet area, the household structure and hygiene. The variables from each of the seven major groupings most associated with the incidence of diarrhea in infants were selected through the application of stepwise multiple regression. Each area was then ranked by the portion of the incidence of diarrhea in infants that each composite group of area-specific variables alone would explain. The groups of household structure and water usage variables were found to be more associated with the incidence of diarrhea in infants than variables describing the toilet area, proximity to animals or others. It was also found that 24.7% of the total variance in incidence of diarrheal illness was explained by environmental variables. ^

A feasibility study for assessing building occupants' indoor air quality expectations compared to nationally recognized standards

Indoor Air Quality (IAQ) can have significant implications for health, productivity, job performance, and operating cost. Professional experience in the field of indoor air quality suggests that high expectations (better than nationally established standards) (American Society of Heating, Refrigerating, and Air-conditioning Engineers (ASHRAE)) of workplace indoor air quality lead to increase air quality complaints. To determine whether there is a positive association between expectations and indoor air quality complaints, a one-time descriptive and analytical cross-sectional pilot study was conducted. Area Safety Liaisons (n = 330) at University of Texas Health Science Center – Houston were asked to answer a questionnaire regarding their expectations of four workplace indoor air quality indicators i.e., (temperature, relative humidity, carbon dioxide, and carbon monoxide) and if they experienced and reported indoor air quality problems. A chi-square test for independence was used to evaluate associations among the variables of interest. The response rate was 54% (n = 177). Results did not show significant associations between expectation and indoor air quality. However, a greater proportion of Area Safety Liaisons who expected indoor air quality indicators to be better than the established standard experienced greater indoor air quality problems. Similarly, a slightly higher proportion of Area Liaisons who expected indoor air quality indicators to be better than the standard reported greater indoor air quality complaints. ^ The findings indicated that a greater proportion of Area Safety Liaisons with high expectations (conditions that are beyond what is considered normal and acceptable by ASHRAE) experienced greater indoor air quality discomfort. This result suggests a positive association between high expectations and experienced and reported indoor air quality complaints. Future studies may be able to address whether the frequency of complaints and resulting investigations can be reduced through information and education about what are acceptable conditions.^