Radiation hardening of components and systems for nuclear rocket vehicle applications

The results of the analysis of the S-2 and S-4B components, although incomplete, indicate that many Saturn 5 components and subsystems, e.g., pumps, valves, etc., can be radiation hardened to meet NRV requirements by material substitution and minor design modifications. Results of these analyses include (1) recommended radiation tolerance limits for over 100 material applications; (2) design data which describes the components of each system; (3) presentation of radiation hardening examples of systems; and (4) designing radiation effects tests to supply data for selecting materials

Kinetics Of Egg Production And Egg Excretion By Schistosoma Mansoni And S. Japonicum In Mice Infected With A Single Pair Of Worms

Individual male and female schistosomes approximately three weeks of age were implanted into the portal venous system of C57Bl/6 mice to produce infections with a single pair of Schistosoma mansoni or S. japonicum. Mice were killed between seven and 53 weeks after infection. Worm fecundity was measured by counting eggs accumulating in the tissues and eggs passed in the feces. Schistosoma mansoni worm pairs laid approximately 350 eggs per day with no change in the apparent rate of egg laying between eight and 52 weeks after infection and approximately one-third of the eggs were passed in the feces. Schistosoma japonicum worm pairs laid approximately 2,200 eggs per day initially and this decreased to 1,000 eggs per day by the end of the experiment, with one-third to one-half of the eggs being passed in the feces. Then was marked variability in the fecundity of individual worm pairs, but the number of eggs passed in the feces of individual mice correlated well with the number of eggs in the intestines at all time points in S. mansoni-infected mice and at the seventh and tenth week of S. japonicum infection

A preliminary design study of a microparticle accelerator final report, 30 jan. - 13 apr. 1964

Design study for 2MV microparticle accelerato

Persistence Of Eggs And Hepatic-Fibrosis After Treatment Of Schistosoma Mansoni-Infected Mice

In 1971 we estimated that Schistosoma mansoni eggs in the tissues of mice were destroyed with an approximate half-life of four weeks. Our present results of five experiments suggest that egg destruction is not as rapid, and no significant destruction of eggs was detected for up to 26 weeks after treatment. However, in these experiments, a mean of 60% of the eggs in intestinal tissues were found in the feces at the time of treatment. In previously reported experiments, only 15% of gut eggs were passed in the feces. We now believe that underestimation of the number of eggs passed in the feces led to an overestimation of the number of eggs destroyed in the tissues. We analyzed liver eggs separately because eggs lost from this site are unaffected by eggs passed in the feces. No significant decrease in liver eggs occurred in the present experiments, but reanalysis of previously published data showed significant egg destruction in the liver in several experiments, although at a much slower rate than previously estimated. However, inspection of the data in the previously published and present experiments does not show a convincing difference in the number of eggs in the liver after treatment. The persistence of egg shells is probably not important in the pathogenesis of disease, but is of concern in calculating worm fecundity. Hepatic collagen levels increased markedly two weeks after treatment and subsequently decreased significantly in some, but not all, experiments

Natural History Of Schistosoma Mansoni Infection In Mice: Egg Production, Egg Passage In The Feces, And Contribution Of Host And Parasite Death To Changes In Worm Numbers

Mice, C57B1/6N (B6) and BALB/cAnN (BALB), infected with Schistosoma mansoni were examined 8-26 weeks postinfection (PI) to estimate the fecundity of the worms and the contribution of death of worms and the death of heavily infected mice to the decrease in worm numbers in chronic infections. Portal worms were recovered by perfusion and the lungs were examined for parasites shunted from the portal circulation. Animals that died were more heavily infected than those that survived. Between eight and 12 weeks PI, this loss of worms resulted in a net decrease of approximately 19% of worm Fairs in surviving BALB mice, but of only 4% in B6 mice. Loss of portal worms to the lungs after the eighth week of infection was 9-13% of portal worms in BALB mice and 3-4% in B6 mice. The estimated rates of egg production by S. mansoni decreased slightly with time in both strains of mice. At 12 and 20 weeks PI, tissue eggs per worm pair and eggs passed in the feces per worm pair often decreased as the intensity of infection increased. We do not consider the loss of worms in the murine host relevant to most infections in humans because of the high intensity of infection relative to body size in mice and the high frequency of severe portal obstruction in murine infections

Retnla (Relmα/Fizz1) Suppresses Helminth-Induced Th2-Type Immunity

Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. However, the role of Retnla in Th2-type immunity is unknown. Here, using Retnla−/− mice and three distinct helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Moreover, when chronically infected with S. mansoni cercariae, Retnla−/− mice displayed significant increases in granulomatous inflammation in the liver and the development of fibrosis and progression to hepatosplenic disease was markedly augmented. Finally, Retnla−/− mice infected with the gastrointestinal (GI) parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla−/− mice developed stronger Th2 responses, which could be reversed by exogenous rRelmα treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-γ, while tissue localization and cell isolation experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses

Arginase-1–Expressing Macrophages Suppress Th2 Cytokine–Driven Inflammation and Fibrosis

Macrophage-specific expression of Arginase-1 is commonly believed to promote inflammation, fibrosis, and wound healing by enhancing L-proline, polyamine, and Th2 cytokine production. Here, however, we show that macrophage-specific Arg1 functions as an inhibitor of inflammation and fibrosis following infection with the Th2-inducing pathogen Schistosoma mansoni. Although susceptibility to infection was not affected by the conditional deletion of Arg1 in macrophages, Arg1−/flox;LysMcre mice died at an accelerated rate. The mortality was not due to acute Th1/NOS2-mediated hepatotoxicity or endotoxemia. Instead, granulomatous inflammation, liver fibrosis, and portal hypertension increased in infected Arg1−/flox;LysMcre mice. Similar findings were obtained with Arg1flox/flox;Tie2cre mice, which delete Arg1 in all macrophage populations. Production of Th2 cytokines increased in the infected Arg1−/flox;LysMcre mice, and unlike alternatively activated wild-type macrophages, Arg1−/flox;LysMcre macrophages failed to inhibit T cell proliferation in vitro, providing an underlying mechanism for the exacerbated Th2 pathology. The suppressive activity of Arg1-expressing macrophages was independent of IL-10 and TGF-β1. However, when exogenous L-arginine was provided, T cell proliferation was restored, suggesting that Arg1-expressing macrophages deplete arginine, which is required to sustain CD4+ T cell responses. These data identify Arg1 as the essential suppressive mediator of alternatively activated macrophages (AAM) and demonstrate that Arg1-expressing macrophages function as suppressors rather than inducers of Th2-dependent inflammation and fibrosis

Regulation and Function of the Interleukin 13 Receptor α 2 During a T Helper Cell Type 2–dominant Immune Response

Highly polarized type 2 cytokine responses can be harmful and even lethal to the host if they are too vigorous or persist too long. Therefore, it is important to elucidate the mechanisms that down-regulate these reactions. Interleukin (IL)-13 has emerged as a central mediator of T helper cell (Th)2-dominant immune responses, exhibiting a diverse array of functional activities including regulation of airway hyperreactivity, resistance to nematode parasites, and tissue remodeling and fibrosis. Here, we show that IL-13 receptor (R)α2 is a critical down-regulatory factor of IL-13–mediated tissue fibrosis induced by the parasitic helminth Schistosoma mansoni. IL-13Rα2 expression was induced after the onset of the fibrotic response, IL-10, IL-13, and Stat6 dependent, and inhibited by the Th1-inducing adjuvant IL-12. Strikingly, schistosome-infected C57BL/6 and BALB/c IL-13Rα2–deficient mice showed a marked exacerbation in hepatic fibrosis, despite displaying no change in granuloma size, tissue eosinophilia, or mastocytosis. Fibrosis increased despite the fact that IL-13 levels decreased significantly in the liver and serum. Importantly, pathology was prevented when IL-13Rα2–deficient mice were treated with a soluble IL-13Rα2-Fc construct, formally demonstrating that their exacerbated fibrotic response was due to heightened IL-13 activity. Together, these studies illustrate the central role played by the IL-13Rα2 in the down-regulation of a chronic and pathogenic Th2-mediated immune response

New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer

A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines. T cell subsets with more naïve and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies