The effect of indomethacin on the cytokine cascade and body temperature following burn injury in rats.

This study investigates the hypothesis that indomethacin's ability to prevent "fever" following burn injury in rats is mediated via decreased plasma concentrations of IL-6, the putative mediator of increased body temperature. Sprague-Dawley rats had radio transmitters and osmotic pumps containing indomethacin placed in the peritoneal cavity. Seven days later full thickness scald burns to 50% of the body surface area were produced. Following burn injuries, daily blood samples were obtained from a carotid catheter for assay of lipopolysaccharide (LPS), interleukin-1alpha (IL-1alpha), IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and IL-6. In addition, body temperature (T(B)) and activity index were obtained every five minutes by telemetry. There were four experimental groups: burn + indomethacin (B-In); burn + polyethylene glycol (Peg) (B-Peg); control + indomethacin (C-In); and control + Peg (C-Peg). Burned animals demonstrated a significant two-fold increase in plasma IL-1alpha levels (p=0.004) and a seven-fold increment in IL-6 (p=0.0001) through the 7th PBD, and indomethacin administration had no significant effect upon the cytokine plasma levels. There were no significant increases in IL-1beta, TNF-alpha or LPS in any group. Indomethacin eliminated the chronic increase in T(B) following burn injury, and this effect was not produced by changes in plasma levels of the endogenous pyrogens IL-1alpha and IL-6.     

Characterisation of a myofibroblast-like cell line from an angiosarcoma

We have isolated a cell line (ASMM) by serial passage of cells from explant cultures of an angiosarcoma resected from the calf of a 62 year old female. ASMM has been in continuous culture for over eighteen months (>150 population doublings) and has a Fibroblast-like morphology with a doubling time of approximately 72 h. ASMM has a normal diploid karyology and is unable to generate tumors in nude mice or produce colonies in soft agar. Examination of the cytoskeletal proteins shows both desmin and vimentin and a low level of alpha-smooth muscle actin, which can be upregulated by treatment with TGF beta. Low levels of basal VCAM-1 are significantly upregulated with TNF alpha and reduced by the presence of TCF beta. Basal ICAM-1 is also upregulated with TNF alpha and we show an additional upregulation through TGF beta. ASMM expresses high levels of the hyaluronate receptor CD44, including the variant exons 6, 8 and 10. In addition, ASMM synthesises high levels of hyaluronate (HA), as did the original tumor. Unlike human umbilical vein endothelial cells (HUVECs) these cells were unable to generate capillary-like tubes when seeded onto basement membrane gels, and generated cords of cells containing many synthetic organelles and intermediate filaments. We were unable to detect the expression of factor VIII-related antigen, von Willebrand factor (vWF), CD31 or CD34, and were not able to induce expression of E-selectin after TNF alpha stimulation. In conclusion, this cell line represents a partially transformed population of cells which show characteristics consistent with myofibroblast-like cells. The production of high levels of HA and expression of CD44 may help to explain the high degree of agressiveness of the tumor from which ASMM was derived, as these molecules have been shown to play a role in cell motility and adhesion.     

Breast tumor-derived factors stimulate reduction of estrone to estradiol in nonmalignant breast tissue

Summary This study examines the paracrine influence by human breast carcinoma cells (UISO-BCA-1) on nonmalignant breast tissuein vitro. The 17-OH-SDH-mediated reductive pathway (estroneestradiol) was significantly increased in nonmalignant breast tissue coincubated with human breast carcinoma cells, compared to control tissues incubated in the media alone. No influence on the enzyme activity was noticed in coincubated breast cancer cells. Preincubation of breast cancer cells with estradiol (10^–8 M) significantly decreased the enzyme activity in coincubated nonmalignant breast tissue, which was restored to control levels by addition of R5020 (10^–8 M), tamoxifen (10^–6 M), or a combination of both. In nonmalignant tissues incubated in the presence of growth factor TGF, enzyme activity was reduced to between 46% and 76%. No other growth factors (IGF I, IGF II, PDGF) influenced enzyme activity. In nonmalignant tissues incubated with malignant tumor cytosol, enzyme activity was increased in 16% cases, inhibited in 21%, and not significantly changed in 63%.The data from the present study suggest that factors produced by breast carcinoma cells may influence interconversion of estradiol in nonmalignant tissue. In patients, factors produced by malignant tumor mass may have paracrine influence on surrounding nonmalignant breast tissue and, thereby, may influence the estrogen availability to tumor mass.     

Bergmann's rule near the equator: latitudinal clines in body size of an Andean passerine bird

Critical correlative support for Bergmann's ecogeographic rule is provided by symmetrical patterns of size variation in Diglossa carbonaria, a tropical passerine bird whose geographic range in the Andes Mountains of South America straddles the equator. Body size is positively correlated with latitude both north and south of the equator. Moreover, parapatric taxa that exhibit either partial (north-western Bolivia) or complete (northern Peru) reproductive isolation converge in body size. Relative uniformity in the length of the highly modified flower-piercing bill among populations of D. carbonaria that differ significantly in body size suggests that character displacement or interspecific competition is not responsible for these patterns. These findings support the hypothesis that climate, particularly temperature seasonality, is an important environmental determinant of geographic size variation in homeotherms. In addition they demonstrate that clinal variation correlated with subtle climatic gradients can occur in tropical environments.     

Comparing sulindac with indomethacin for closure of ductus arteriosus in preterm infants

Objectives: A prospective study comparing the efficiacy and side-effects of oral sulindac with intravenous indomethacin in clinically stable preterm infants (<1750 g) requiring non-invasive closure of haemodynamically significant patent ductus arteriosus.
Methodology: As maturity and birthweight are the two major determinants of ductal closure, infants were matched as closely as possible for these parameters. An eligible patient was first assigned to the sulindac group and a subsequent patient with similar gestational age (± 1 week) and birthweight (±100 g) to the previously recruited infant would automatically receive indomethacin. A total of eight infants were enrolled in each group.
Results: The ductus arteriosus was successfully closed in all eight infants receiving indomethacin, and in seven of eight infants receiving sulindac. No significant differences were found with regards to the ductal size between the two groups at diagnosis or on each of the consecutive days of treatment ( P >0.25). More renal adverse effects were encountered in the indomethacin group. Significant differences in changes from baseline value for urine output, plasma sodium, urea and creatinine concentrations were noted at 24, 48 and 72 h after commencement of treatment between the two groups ( P <0.05). All the parameters returned to normal or pre-treatment levels 48 h after stopping therapy. Unexpectedly, severe gastrointestinal complications were encountered in the sulindac group.
Conclusions: Sulindac is capable of promoting ductal constriction in clinically stable preterm infants without compromising the renal function. The spectrum of gastrointestinal complications observed in sulindac treated infants were similar to those described for indomethacin. The use of sulindac for ductal closure in the preterm infant should remain experimental.     

Aberrant crypt focus promotion and glucose intolerance: correlation in the rat across diets differing in fat, n-3 fatty acids and energy

McKeown-Eyssen (Cancer Epidemiol. Biomarkers Prevent., 3, 687-695, 1994) and Giovannucci (Cancer Causes Control, 6, 164-179, 1995), noting the striking similarity in lifestyle risk factors for colorectal cancer and insulin resistance, proposed that the hyperinsulinemia, glycemia and hypertriglyceridemia associated with insulin resistance promotes colon cancer. To compare the effect of diet on colon cancer promotion and insulin resistance in the F344 rat, we assessed the effect of fat, n-3 fatty acids and energy in pairwise comparisons on average size of aberrant crypt foci (ACF) and on glucose intolerance in the same animals in a single experiment. Diets high in fat and energy increased and diets with increased n-3 fatty acids and calorie restriction decreased both ACF growth and glucose intolerance compared with control diets. The measures of promotion of colon cancer and insulin resistance were strongly correlated (n = 98, r = 0.67, P < 0.001). In addition, both were highly correlated with daily energy intake (r = 0.62 and 0.66) and were also correlated with basal (post-prandial) insulin, glucose and triglycerides (r = 0.31-0.53, P < 0.01). We concluded that ACF growth and glucose intolerance are correlated for a wide range of diets and that increased circulating energy (glucose and triglycerides) may lead to both colon cancer promotion and insulin resistance.