Color Doppler assessment of blood flow in endometrial cancer.

OBJECTIVE: To determine the location and intensity of angiogenesis as well as selected flow parameters by transvaginal color Doppler (TVCD) and to evaluate the relation of myometrial invasion, histological grading, lymph nodes, and omental and adnexal metastasis on blood flow characteristics in endometrial cancer. METHODS: Transvaginal colour Doppler and pulsed Doppler ultrasound were performed on 90 women with endometrial cancer. The degree of invasion as well as adnexal, omental, and pelvic lymph node metastasis was evaluated. Location of the blood vessels (peripheral, central, mixed) and vascular density as well as selected Doppler blood flow indices: PSV, RI of neoplastic infiltration was assessed. RESULTS: The median age of the 90 women was 63.3 +/- 12.3 years (range 32 to 86 years); of these 92.2% were postmenopausal. Cancer concerned only the endometrium (E), with superficial (S) and deep infiltration (D) established in 14.4%, 45.6% and 40%, respectively. The histological maturity was as follows: G1 - 17.6%, G2 - 66.7%, G3 - 16.6% of cases. Adnexal, omental and lymph node metastasis was found in 12.2%, 3.3% and 16.6%, respectively. Abnormal low impedance and high velocity flow (mean RI 0.38 +/- 0.09, PSV 20.45 +/- 9.6 cm/sec) were found in 88.9% of cases. In types E, S, D in 61.5%, 92.7% and 94.4%, respectively (p = 0.003). Differences in RI and PSV between groups with high and low vascular density were statistically significant (p = 0.005 and 0.001, respectively). In all cases peripheral and mixed vascularity were found more frequently (p < 0.05). A positive significant correlation between vascular density increase and surgicopathological stage of cancer was found more frequently (p < 0.005). There were significant differences in vascular density, Doppler blood flow indices and vascular location in each type of histological malignancy (p < 0.05). No significant differences in each flow parameter in hematogenous-adnexal/omental metastatic and non metastatic cases were found, whereas pelvic lymph node involvement and vascular density were shown to be statistically significant (p < 0.02). There were significant differences in vascular density in lymph-node positive cases whereas the remaining flow parameters did not differ. CONCLUSIONS: These results suggest that TVCD evaluation of endometrial cancer is a reliable method for assessing endometrial angiogenesis. Our results indicate that blood flow rates correspond with increased angiogenesis in endometrial cancers, and might potentially be used as a good prediction factor for tumor progression and metastasis in affected women. Preoperative ultrasound examination should be seen as an important tool in the establishment of individualized treatment programs for women with endometrial cancer.

Human lactoferrin in the milk of transgenic mice increases intestinal growth in ten-day-old suckling neonates.

Regulatory roles and a signaling receptor have been proposed for the milk protein lactoferrin (Lf), but none has been definitively characterized. Nichols and colleagues (1987) observed that human lactoferrin (hLf) stimulated thymidine incorporation into the DNA of rat intestinal crypt cells. We tested the hypothesis that chronic Lf administration stimulates intestinal growth by studying neonatal mice suckling transgenic dams secreting about 12 mg/mL hLf in their milk. Specifically, nontransgenic litters were adjusted to eight pups each and cross-fostered to transgenic dams. Controls were pups suckling nontransgenic dams of the same strain. On day 10 postpartum pups were weighed, sacrificed, and the small intestines were weighed, measured, and stored for later determination of enzyme activities. The results indicate that intestinal growth was increased in neonates suckling transgenic dams. The weight of the small intestine was increased about 27% when the pups received milk containing hLf. Intestinal length only increased about 6.5% suggesting that Lf in milk enhanced mucosal growth. The ratio of maltase to lactase in the duodenal segment of the small intestine, an indicator of maturation, was also significantly increased in the pups suckling transgenic milks. Our results imply that chronic oral consumption of human Lf promotes the growth and maturation of the intestinal mucosa, and suggest a possible therapeutic role for the agent in premature infants as well as in patients with bowel damage.

Does human lactoferrin in the milk of transgenic mice deliver iron to suckling neonates?

Lactoferrin is an iron-binding glycoprotein abundantly present in human milk, and has been postulated both to increase and to decrease intestinal iron absorption. To examine this problem, the interaction of milk iron with pup hemoglobin was studied in controls and in transgenic mice overexpressing human lactoferrin in their milk (2 lines expressing 12 mg/mL and 4 mg/mL, respectively). At day 14 of gestation, pregnant mice were switched from a diet of commercial chow containing iron at 300 mg/kg to diets containing 5, 15, or 50mg iron/kg; controls continued on chow. Nontransgenic pups were cross-fostered to transgenic dams to ensure that any results found in the pups were the effect of milk components. The hemoglobin level in the blood of 10-day-old suckling neonates was measured and calculated as total hemoglobin per pup. The total hemoglobin levels were lower in the pups receiving milk high in human lactoferrin, but the difference reached significance (P < 0.02) only at the highest level of dietary iron. Our findings do not support the hypothesis that lactoferrin functions as an intestinal iron scavenger, at least at high doses.

The effect of serum iron concentration on iron secretion into mouse milk.

1. The concentration of iron in mouse milk is approximately 3 times that of the serum. Although there is clear evidence for the presence of the transferrin receptor in the rodent mammary gland, the precise mechanisms of iron transfer into milk are not known. 2. Milk iron was linearly related to the serum iron:transferrin ratio in lactating mice whose serum iron ranged from 8 to 66 microM. 3. Increasing the iron binding capacity of the milk by 340 microM by targeting the lactoferrin transgene to the mammary gland did not alter the relation between milk iron and the serum iron:transferrin ratio. 4. The steady-state distribution ratio of 125I-transferrin between plasma and milk was about 0.2, indicating that transcytosed transferrin contributed a maximum of 6% of the milk iron. 5. Fluorescently labelled transferrin incubated with the in situ gland localized mainly near the basal surface of the mammary alveolar cells. 6. These experiments provide evidence that the initial and rate-limiting step in the transfer of iron into milk is binding to a basal transferrin receptor. 7. A theoretical model of the relation between milk and serum iron suggests that the affinity of apotransferrin for the basal recycling system may be higher than observed in many other cell types.

Regulation of lipoprotein lipase activity and mRNA in the mammary gland of the lactating mouse.

We examined the effects of reproductive stage and fasting on lipoprotein lipase (LPL) activity and mRNA in the mouse mammary gland. Heparin-releasable and cell-associated LPL activity rose immediately after birth, followed 1-2 days later by an increase in LPL mRNA. Fasting decreased LPL activity in the mammary gland at all reproductive stages. During lactation, both milk and heparin-releasable LPL were substantially decreased by an overnight fast, whereas cell-associated LPL was less affected and LPL mRNA did not change. These studies indicate that the extracellular, heparin-releasable, fraction of mammary LPL activity responds most rapidly to alterations in physiological state, usually accompanied by smaller changes in cellular enzyme activity. Changes in the level of LPL mRNA were seen only during the transition from pregnancy to lactation, and these tended to follow, rather than precede, changes in enzyme activity. We conclude that in the mammary gland as in adipose tissue, LPL is regulated primarily at the translational and post-translational level.

Effects of fasting, elevated plasma glucose and plasma insulin concentrations on milk secretion in women.

In order to determine whether short term variations in plasma glucose and/or insulin influence milk lactose secretion in women, the effects of fasting and increased blood insulin and glucose on milk volume and composition were studied with glucose clamp methodology in exclusively and partially breast-feeding women. Twenty hours of fasting had no discernable effect on the output of milk or its macronutrient composition. Four hours of increased plasma insulin, studied under conditions where plasma glucose was maintained at the fasting level, had no effect on milk volume, milk glucose concentration, total fat content or lactose secretion rate. Increased plasma glucose, maintained at twice fasting levels for 4 to 6 h, produced a threefold increase in milk glucose concentration but had no significant effect on the rate of lactose synthesis. In partially breast-feeding women producing no more than 200 ml milk per day, a similar degree of hyperglycaemia increased milk glucose more than fourfold but did not significantly increase the milk secretion rate. It is concluded that human milk production is isolated from the homeostatic mechanisms that regulate glucose metabolism in the rest of the body, in part because the lactose synthetase system has a Km for glucose lower than the concentration available in the Golgi compartment.