Nitric oxide in acute and chronic inflammation.

PhDNitric oxide (NO) is a signalling molecule formed when L-arginine is converted to L-citrulline by the enzyme NO synthase (NOS. NOS exists as three isoforms, ecNOS is constitutively expressed in endothelial cells and nNOS in neuronal cells, while a third isoform (iNOS) is induced in response to inflammatory stimuli and is capable of sustained production of high levels of NO. NO produced in response to an inflammatory insult, has been shown by use of NOS inhibitors to be detrimental during inflammation by producing the potent oxidising agent peroxynitrite. However, iNOS knockout animals generally produce a similar inflammatory profile to wild type controls. Hence, there is a discrepancy between the effects of phamacological inhibition and gene deletion of iNOS in vivo. Therefore, the aim of this thesis is to use a number of approaches to modulate NO production in acute and chronic inflammatory models and to assess the effects on the NOS pathway and other markers of the inflammatory response. In this thesis, it was established that iNOS protein expression and nitrite formation was significantly elevated after injection of the inflammatory stimulus in the carrageenin-induced pleurisy (RCIP), bovine serum albumin (BSA)-induced pleurisy and methylated BSA-induced pleurisy in the rat, and a murine models of croton oil-induced chronic granulomatous tissue of the air pouch (MCGTAP). The majority of immunostaining was associated with migrating inflammatory cells. NO production was modulated in acute and chronic models of inflammation using NOS inhibitors and NSAIDs. Local injection of NOS inhibitors in the RCIP model caused an increase in pro-inflammatory mediators, including superoxide, histamine and PMN chemoattractants that resulted in an exacerbation of inflammation. This was a result of inhibition of both eNOS and NOS at the inflammatory site. In contrast, systemic inhibition of NOS reduced both inflammatory cell influx and exudation into the pleural cavity. A similar inhibitory ABSTRACT result was obtained after NOS inhibition in the MCGTAP model. This antiinflammatory effect was supported by experiments in mice whose iNOS gene had been genetically deleted. Interestingly, oral aspirin administration significantly elevated nitrite formation in both the RCIP and MCGTAP with a concomitant decrease in inflammation. Further analysis demonstrated that aspirin was able to elevate NO production in lipopolysaccharide induced J774 macrophages and A23187 stimulated EA. hy926 endothelial cells, suggesting that both cell types may be involved in the pharmacological actions of aspirin. In conclusion, NO is a multi-functional free-radical which had advantageous effects in the acute resolving model and detrimental effects in chronic inflammation. Therefore, depending on the levels and micro-environment in which it is produced NO can be either good or ba

Socialist Dandies International: East Europe, 1946-1959

This article maps the looks and lifestyle choices of small groups of young, like-minded people who emerged in the postwar Soviet Union and East Europe in the background of huge political, social, and cultural changes. With their androgynous bodies wrapped in drape jackets and narrow trousers, and their love of jazz and swing, these young men stood in a sharp contrast to the official ideology that promoted socialism as a new, pure, and highly rationalized project, its ideal robust and strong man, and its mass culture that insisted on educational and restrained forms of entertainment. Through the categories of dress, body, and big city, the article investigates the clashes, and the eventual truce, between the socialist streamlined and rationalized master narrative and the young dandies' fragmented and disordered narrative. The article argues that the socialist dandies were not politically minded, and that their challenge to the officially proclaimed values was informed by their adolescent recklessness and a general postwar desolation. They were declared state enemies because the socialist regimes did not allow for alternative types of modernity. Consequently, the authorities condemned the young dandies' looks and interests as cosmopolitan, because they originated in the West, and as artificial, since they belonged to the culture that had preceded a new socialist world

Australian state influenza notifications and school holiday closures in 2019 [version 2; peer review: 2 approved, 1 approved with reservations]

Background: The impact of school holidays on influenza rates has been sparsely documented in Australia. In 2019, the early winter influenza season coincided with mid-year school breaks, enabling us the unusual opportunity to examine how influenza incidence changed during school holiday closure dates. Methods: The weekly influenza data from five Australian state and one territory health departments for the period of week 19 (mid-May) to week 39 (early October) 2019 were compared to each state’s public-school holiday closure dates. We used segmented regression to model the weekly counts and a negative binomial distribution to account for overdispersion due to autocorrelation. The models’ goodness-of-fit was assessed by plots of observed versus expected counts, plots of residuals versus predicted values, and Pearson’s Chi-square test. The main exposure was the July two-week school holiday period, using a lag of one week. The effect is estimated as a percent change in incidence level, and in slope. Results: School holidays were associated with significant declines in influenza incidence in three states and one territory by between 41% and 65%. Two states did not show evidence of declines although one of those states had already passed its peak by the time of the school holidays. The models showed acceptable goodness-of-fit. The first decline during school holidays is seen in the school aged (5-19 years) population, with the declines in the adult and infant populations being smaller and following a week later. Conclusions: Given the significant and rapid reductions in incidence, these results have important public health implications. Closure or extension of holiday periods could be an emergency option for state governments

CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing

Nanoparticle-based therapeutics are being used to treat patients with solid tumors. Whereas nanoparticles have been shown to preferentially accumulate in solid tumors of animal models, there is little evidence to prove that intact nanoparticles localize to solid tumors of humans when systemically administered. Here, tumor and adjacent, nonneoplastic tissue biopsies are obtained through endoscopic capture from patients with gastric, gastroesophageal, or esophageal cancer who are administered the nanoparticle CRLX101. Both the pre- and postdosing tissue samples adjacent to tumors show no definitive evidence of either the nanoparticle or its drug payload (camptothecin, CPT) contained within the nanoparticle. Similar results are obtained from the predosing tumor samples. However, in nine of nine patients that were evaluated, CPT is detected in the tumor tissue collected 24–48 h after CRLX101 administration. For five of these patients, evidence of the intact deposition of CRLX101 nanoparticles in the tumor tissue is obtained. Indications of CPT pharmacodynamics from tumor biomarkers such as carbonic anhydrase IX and topoisomerase I by immunohistochemistry show clear evidence of biological activity from the delivered CPT in the posttreatment tumors

Theology, News and Notes - Vol. 47, No. 02

Theology News & Notes was a theological journal published by Fuller Theological Seminary from 1954 through 2014.https://digitalcommons.fuller.edu/tnn/1140/thumbnail.jp