(Teicher et al., 1981). Even more recently, the profound effects that hypoxia can have on the actions of cytokines, including interleukin 2 (IL-2), tumour necrosis factor alpha (TNF-a) and interferon (IFN), have been described (Aune and Pogue, 1989;Ishizaka et al., 1992;Sampson and Chaplin, 1994).It has been known for many years that radiobiologicaly hypoxic cells exist in experimental rodent and xenografted human tumours. The recent availability of the Eppendorf Po2 histograph has enabled the demonstration of hypoxic regions in primary human tumours (Vaupel et al., 1991;Hockel et al., 1993). Despite our knowledge of the existence of hypoxic cells in tumours and the undoubted importance of hypoxia to therapeutic response, relatively little attention has been focused on how hyponia arises within a solid tumour mass. Knowledge as to how hypoxic cells occur has important impi;cations for the approaches that can be used to improve the oxygenation status of cells and ultimately therapeutic response. Moreover, in order to mimic more closely in vitro the nutritional and physiological status of hypoxic cells in vivo, knowledge of how they occur and how long they remain hypoxic represents important information.On a theoretical basis, hypoxic cells can result from two distinct processes: firstly from diffusion limitations in a system with a constant blood flow and oxygen delivery capacity; cell division and oxygen ultilisation by those cells closest to the blood vessel result in a gradual decline in the oxygenation and nutritional status of cells further away.
Summary The DNA-binding fluorescent dye Hoechst 33342 (H33342) has been used in a series of investigations of the vascular parameters of two murine tumours. This dye has been shown, to have a short half-life in the circulation (T-less than 2min), but is stably bound for at least 2h after it enters cells. It can be used in morphometric studies on frozen sections to determine the effective vascular volume, the capillary fraction and the size distribution of blood vessels in each tumour. These latter two parameters cannot be deduced from the less labour intensive techniques using radioactive isotopes.The effective vascular volume perfused in 1 min by H33342 was compared with the volume perfused in 30 min with 5"Cr labelled erythrocytes. Similar volumes were estimated with the two techniques in a murine carcinoma and in a sarcoma. Both techniques showed that the vascular volume decreased in larger tumours. The H33342 analysis of vessel size showed the decrease in capillary vessels in the carcinomas was even greater, falling from 70% in small tumours to 20% in larger tumours. The deteriorating vascular network in larger tumours is associated with an increasing fraction of necrotic tissue.Experiments in which the isotopes and dye were co-injected suggest that at 40mg kg' the dye may rapidly lead to a partial shutdown of the tumour vascular bed. This is less marked with 20mg kg-1. In spite of this effect there is in general a close correlation between the volumes perfused by labelled red blood cells and the fluorescent dye.
The metastasis along peritoneal surfaces of serous cystadenocarcinoma, the most common ovarian malignancy, occurs early and is present in most patients at the time of clinical diagnosis. In many patients, however, computed tomography (CT) is unable to demonstrate peritoneal metastases because of their small size and similarly has been unable to demonstrate metastases in normal sized lymph nodes. Serous cystadenocarcinoma contains histologic calcification in approximately 30% of cases; thus, CT scans were retrospectively reviewed in 15 patients with pathologically proved stage III or IV disease to detect calcified peritoneal metastases. Six patients had calcified peritoneal implants, five of which had perihepatic calcifications. One of the five also had calcified lymphatic metastases, some of which were in normal sized nodes. In three of these five, the examination was otherwise normal. Search for these calcifications should improve the sensitivity of CT in diagnosing metastases from ovarian carcinoma.
We investigated the effect of a single oral dose of the selective noradrenaline reuptake inhibitor, reboxetine (4 mg), on plasma and salivary cortisol in 24 healthy volunteers in a randomized, placebo-controlled, parallel-group design. Reboxetine significantly increased both plasma and salivary cortisol, although the correlation between the responses in plasma and saliva was modest. Our results are consistent with previous neuroendocrine challenge studies showing that potentiation of brain noradrenaline function stimulates the hypothalamic-pituitary-adrenal axis. Reboxetine-induced salivary cortisol release appears to be a simple and relatively non-invasive test of hypothalamic noradrenaline function. However, placebo-controlled, within-subject designs are likely to yield a more valid measure of noradrenaline-mediated cortisol release.
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