Prevention of bronchiolitis obliterans in rat lung allografts by type V collagen-induced oral tolerance

BACKGROUND: We have reported that feeding type V collagen (col(V)) to lung allograft recipients induces immune tolerance that prevents acute lung allograft rejection. Repeated acute rejection is a risk factor for or associated with chronic rejection, known as bronchiolitis obliterans (BO), the leading cause of death in lung allograft recipients. The current study examines if col(V)-induced oral tolerance prevents BO. METHODS: WKY rats (RT1l) were fed either col(V) or diluent before orthotopic transplantation of F344 (RT1lvl) lung allografts. No rats received any immunosuppression. At 10 weeks posttransplantation the time to onset of BO, delayed type hypersensitivity (DTH) responses to donor antigens, and col(V) were examined. In addition, proliferative responses of recipient T lymphocytes to donor antigens, and ability of recipient antigen presenting cells to present alloantigens in lung allografts were evaluated. RESULTS: The data show that recipient rats have sustained DTH responses to donor antigens and col(V). T lymphocytes from col(V)-fed lung allograft recipients were unable to proliferate in response to donor antigens, but feeding col(V) had no effect on the presentation of donor alloantigens by recipient antigen presenting cells. All diluent fed rats developed BO, but only mild acute rejection (grade 2) was present in all rats fed col(V). Transforming growth factor (TGF)-beta production was up-regulated systemically in col(V)-fed, but not diluent fed, lung allograft recipients, and neutralizing TGF-beta [corrected] recovered the DTH response to donor antigens in col(V)-fed rats. CONCLUSIONS: Collectively these data show that col(V)-induces oral tolerance that prevents BO, and that tolerance may be mediated by systemic production of TGF-beta [corrected].     

How correctly does an intramedullary rod represent the longitudinal tibial axes?

In a robot-assisted procedure for preparing the tibia in total knee arthroplasty, developed in the authors' laboratory, an intramedullary rod is used to register the tibia. In 18 formalin-fixed tibias, the difference in orientation was calculated between the intramedullary rod and several longitudinal tibial axes used in clinical practice. This was done using roentgenstereophotogrammetric analysis. Three tibial axes and two insertion techniques were considered. In three-dimensional space, small differences between the axes are observed. The results showed a high standard deviation, indicating the importance of anatomic differences. In the frontal plane, the difference in orientation between rod and tibial axes never exceeded +/- 2 degrees. In the sagittal plane, the observed differences were larger. Significant differences between the considered axes appeared. The results of the two insertion techniques were not significantly different. Because an intramedullary rod frequently is used for alignment of the tibia in conventional surgery, these results also are valuable for conventional surgery. In the current study, the accuracy of the intramedullary alignment is examined, without influences of the sawing procedure. Moreover, the study is not limited to the frontal plane; the total accuracy in three-dimensional space, and the accuracy in the frontal and the sagittal planes were studied.     

A tailored therapy for the metabolic syndrome: the dual peroxisome proliferator-activated receptor-alpha/gamma agonist LY465608 ameliorates insulin resistance and diabetic hyperglycemia while improving cardiovascular risk factors in preclinical models

A novel nonthiazolidinedione dual peroxisome proliferator- activated receptor (PPAR)-alpha/gamma agonist, LY465608, was designed to address the major metabolic disturbances of type 2 diabetes. LY465608 altered PPAR-responsive genes in liver and fat of db/db mice and dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats, with an ED(50) for glucose normalization of 3.8 mg small middle dot kg(-1) small middle dot day(-1). Metabolic improvements were associated with enhanced insulin sensitivity, as demonstrated in female obese Zucker (fa/fa) rats using both oral glucose tolerance tests and hyperinsulinemic-euglycemic clamps. Further characterization of LY465608 revealed metabolic changes distinct from a selective PPAR-gamma agonist, which were presumably due to the concomitant PPAR-alpha agonism, lower respiratory quotient, and less fat accumulation, despite a similar impact on glycemia in male ZDF rats. In addition to these alterations in diabetic and insulin-resistant animals, LY465608 dose-dependently elevated HDL cholesterol and lowered plasma triglycerides in human apolipoprotein A-I transgenic mice, demonstrating that this compound significantly improves primary cardiovascular risk factors. Overall, these studies demonstrate that LY465608 beneficially impacts multiple facets of type 2 diabetes and associated cardiovascular risk, including those facets involved in the development of micro- and macrovascular complications, which are the major sources for morbidity and mortality in these patients.     

Tuberculosis screening among foreign-born persons applying for permanent US residence

OBJECTIVES: This study sought to determine adherence of physicians to tuberculosis (TB) screening guidelines among foreign-born persons living in the United States who were applying for permanent residency. METHODS: Medical forms of applicants from 5 geographic areas were reviewed, along with information from a national physician database on attending physicians. Applicant and corresponding physician characteristics were compared among those who were and were not correctly screened. RESULTS: Of 5739 applicants eligible for screening via tuberculin skin test, 75% were appropriately screened. Except in San Diego, where 11% of the applicants received no screening, most of the inappropriate screening resulted from the use of chest x-rays as the initial screening tool. CONCLUSIONS: Focused physician education and periodic monitoring of adherence to screening guidelines are warranted.     

Avoiding the boomerang: testing the relative effectiveness of antidrug public service announcements before a national campaign

OBJECTIVES: This study examined the relative perceived effectiveness of 30 antidrug public service announcements (PSAs) and assessed the extent to which judgments of effectiveness are related to judgments of realism, amount learned, and positive and negative emotional responses. METHODS: Data were obtained from 3608 students in grades 5 through 12 in 10 schools. The ethnically diverse sample was 50.8% male. Students in 5 experimental conditions viewed sets of 6 antidrug PSAs and filled out a brief evaluation questionnaire following each PSA. Those in the control condition viewed a non-drug-related television program. RESULTS: The relative perceived effectiveness of the 30 PSAs varied considerably. Sixteen were rated as significantly more effective, and 6 as significantly less effective, than the control program. Relative rated effectiveness was highly related to realism (r =.87), amount learned (r =.88), negative emotion (r =.87), and positive emotion (r = -.35). CONCLUSIONS: Evaluative research is necessary to prevent broadcast of PSAs that could have a negative impact. PSAs should point out the negative consequences of drug use behavior rather than telling adolescents to "just say no."     

Levels of household mold associated with respiratory symptoms in the first year of life in a cohort at risk for asthma

We assessed prospectively the risk of increased incidence of respiratory symptoms after exposure to particular fungal genera in a susceptible population--namely, infants (n = 880) at high risk for developing asthma. Days of wheeze or persistent cough, information on maternal allergy and asthma, socioeconomic variables, and housing characteristics were collected over the course of the infant's first year of life. Exposure to mold was assessed by airborne samples collected at one time early in the infant's life. Fungi were identified to genus level, recorded as colony-forming units per cubic meter (CFU/m3), and then categorized into four levels: 0 (undetectable), 1-499 CFU/m3 (low), 500-999 CFU/m3 (medium), and greater than or equal to 1,000 CFU/m3 (high). Effects of mold on wheeze and persistent cough, adjusting for potential confounding factors, were examined with Poisson regression analyses. The two most commonly found genera were Cladosporium (in 62% of the homes) and Penicillium (41%). Cladosporium was associated with reported mold (p < 0.02) and water leaks (p < 0.003). Rate of persistent cough was associated with reported mold [Rate ratio (RR) = 1.49; 95% CI, 1.18-1.88]. The highest level of Penicillium was associated with higher rates of wheeze (RR = 2.15; 95% CI, 1.34-3.46) and persistent cough (RR = 2.06; 95% CI, 1.31-3.24) in models controlling for maternal history of asthma and allergy, socioeconomic status, season of mold sample, and certain housing characteristics. We conclude that infants in this high-risk group who are exposed to high levels of Penicillium are at significant risk for wheeze and persistent cough.     

Retinoic acid enhances the T helper 2 cell development that is essential for robust antibody responses through its action on antigen-presenting cells

Previously we reported that vitamin A-deficient (-A) mice had a profound reduction in T helper 2 (Th2) cells, accounting for their depressed T-dependent antibody responses. Providing vitamin A or its active metabolites reversed this defect. The current experiments utilized splenocytes from T cell receptor transgenic mice to investigate how all-trans retinoic acid (atRA) augments Th2 development. These cells were stimulated in vitro in the presence or absence of atRA, with or without exogenous cytokines driving Th1 or Th2 development. Without exogenous cytokines, atRA addition significantly inhibited the interferon (IFN)-gamma response but did not alter the interleukin (IL)-4 response. With Th1 polarizing cytokines, atRA enhanced the IFN-gamma response, with no effect on the IL-4 response. Most importantly, with the Th2 polarizing cytokine IL-4, atRA significantly increased the IL-4 secretion (fivefold) and also increased the Th2 cell frequency twofold. The striking Th2 enhancement was also observed when only antigen-presenting cells were treated with atRA before stimulation of untreated CD4(+) transgenic T cells, but not vice versa. Thus, atRA maximized Th2 cell development in an IL-4-dependent manner, through an effect on antigen-presenting cell function.