Long-term “protective” effect of aromatase inhibitors on the endometrium of postmenopausal breast cancer patients

Background Decrement of endometrial thickness was recorded following short-term aromatase inhibitor treatment in breast cancer patients previously treated with tamoxifen. It is necessary to verify if long-term aromatase inhibitor treatment can maintain this phenomenon. Methods Prospective long-term comparison of the last ultrasonographic endometrial thickness measurement taken before discontinuation of long-term tamoxifen treatment in 64 postmenopausal breast cancer patients, with further repeated measurements, performed following administration of aromatase inhibitors. Results There was a significant decrement of endometrial thickness, following 36.5 ± 15.7 months of tamoxifen treatment, from a mean value of 8.7 ± 5.2 mm, measured at the last ultrasonographic measurement performed before discontinuation of tamoxifen treatment, down to a mean value of 6.2 ± 4.6 mm, measured following 5.3 ± 4.8 months of aromatase inhibitor therapy (P < 0.001). Further ultrasonographic studies revealed the same significant trend. In the first ultrasonographic study performed during aromatase inhibitor treatment, five (7.8%) patients demonstrated a significant increase of endometrial thickness. Hysteroscopy revealed a benign endometrial polyp in three patients and atrophic endometrium in the other 2. In 35 patients (54.7%), endometrial thickness was reduced following the administration of aromatase inhibitors and in 24 patients (37.5%) there was no change in endometrial thickness. With longer duration of aromatase inhibitor therapy, more patients showed decrement of endometrial thickness. Conclusions Reversal of endometrial thickening induced by long-term tamoxifen treatment in postmenopausal breast cancer patients is maintained throughout long-term aromatase inhibitor treatment.     

Mutation spectrum in HNPCC in the Israeli population

Hereditary non-polyposis colon cancer is caused by mutations in DNA mismatch repair genes. The mutation spectrum in the Israeli population is poorly documented except for the c.1906G>C Ashkenazi founder mutation in the hMSH2 gene. To report our experience in HNPCC screening, the mutations detected and the clinical features among a cohort of Israeli patients. Diagnostic work-up was done in a multi-step process guided by clinical and ethnic information. Tumors of suspected patients were tested for microsatellite instability and immunohistochemistry. Based on tumor analyses, we proceeded to mutation screening by DHPLC followed by sequence analysis and multiplex ligase dependent probe amplification. Ashkenazi Jews were first tested for the c.1906G>C founder mutation. Of the 240 families, 24, including Arabs and Jews from different ethnic origins, were tested positive. All tumors that lost expression of mismatch repair proteins also showed microsatellite instability. There was evidence for involvement of hMSH2 (15) hMLH1 (6) and hMSH6 (3) genes. Mutations were identified in 17/24 (71%) patients: 6 Ashkenazi families harbored the c.1906G>C mutation. Eleven other mutations (2 nonsense, 3 splice site and 6 small deletions) were detected. Three of the mutations are novel. No gross deletions or insertions were detected. This is the first report that characterizes the profile of HNPCC in a cohort of patients in Israel. Tumor testing indicated that the 3 main MMR genes are involved, and that mutation spectrum is broad.

The association between iron-deficiency anemia and recurrent acute otitis media

PURPOSE: This study was designed to examine the association between iron-deficiency anemia and the frequency of recurrent acute otitis media in children, and to evaluate the effect of restoring normal hemoglobin levels on the frequency of acute otitis media attacks. MATERIALS AND METHODS: A total of 680 children with frequent episodes of acute otitis media were enrolled in the study. The levels of the hemoglobin were measured in both these children and in 200 healthy children with no history of infections. The correlation between hemoglobin level and the frequency of middle ear infections was studied and analyzed. All children with hemoglobin levels lower than 9.5 g/dL received iron supplementation until they reached a level of at least 11 g/dL, and the subsequent frequency of middle ear infections was recorded. RESULTS: The 680 children had an average of 8.3 +/- 2.7 episodes of acute otitis media per year per child, and an average hemoglobin level of 11.4 +/- 2.7 g/dL, whereas the controls had an average hemoglobin level of 13.1 +/- 2.5 g/dL. Twenty percent had hemoglobin levels below 9.5 g/dL. These children had more episodes of acute otitis media when compared with children with average levels. By increasing the hemoglobin level in these children, the frequency of the episodes of acute otitis media decreased significantly. CONCLUSIONS: This study confirms that anemic children have higher prevalence of episodes of acute otitis media in comparison to healthy, nonanemic children, and shows that there is a direct relationship between the degree of the anemia and the number of the episodes.     

Neutral lipid storage disease with ichthyosis: Serum apolipoprotein levels and cholesterol metabolism in monocyte-derived macrophages

Summary Neutral lipid storage disease with ichthyosis (NLSDI) is an inherited metabolic disorder characterized by accumulation of neutral lipids, in a wide variety of cells, by a still unknown mechanism. Previous studies have shown normal cholesterol content in NLSDI granulocytes, fibroblasts and skin cells. Monocyte-derived macrophages possess an additional pathway of cholesterol uptake, which is not shared by these cells and which is not regulated by intracellular cholesterol levels. This pathway is thought to play a rôle in the process of atherosclerosis. Three NLSDI patients were studied. The serum levels of triglycerides, cholesterol, high-density lipoprotein cholesterol, and apolipoproteins A-I and B were within normal limits in all three patients. The intracellular levels of free and esterified cholesterol were measured in the monocyte-derived macrophages of one patient and found to be normal, while the triglyceride concentrations were twice as high as normal. The cholesterol esterification rates, which serve as a sensitive indicator of intracellular changes in cholesteryl ester levels, were normal in the monocyte-derived macrophages of all three patients. These findings provide further evidence that cholesterol metabolism is not disturbed in NLSDI, and it may be inferred that in this respect these patients are not at increased risk for atherosclerosis.Correspondence     

The licorice root derived isoflavan glabridin inhibits the activities of human cytochrome P450S 3A4, 2B6, and 2C9.

The potent antioxidants licorice root extract and glabridin, an isoflavan purified from licorice root extract, were tested for their ability to modulate the activities of several cytochrome P450 (P450) enzymes. P450 3A4, the major human drug metabolizing P450 enzyme, was inactivated by licorice root extract and by glabridin in a time-and concentration-dependent manner. The inactivation was NADPH-dependent and was not reversible by extensive dialysis. Further analysis showed that the loss in enzymatic activity correlated with a loss in the P450-reduced CO spectrum and with a loss of the intact heme moiety. In contrast, incubations of P450 3A4 with similar concentrations of 2,4-dimethylglabridin and NADPH did not lead to inactivation of P450 3A4. P450 2B6 was also inactivated by glabridin in a time- and concentration-dependent manner. The majority of the glabridin-inactivated P450 2B6 was able to form a reduced CO spectrum suggesting that the heme was not modified with this isoform. High-performance liquid chromatography analysis of the P450 heme confirmed that incubations with glabridin and NADPH did not result in the destruction of the heme moiety. The activity of P450 2C9 was competitively inhibited by glabridin, whereas P450 2D6 and P450 2E1 were virtually unaffected. The data show that glabridin can serve as a substrate for at least three human P450 enzymes and that depending on the isoform, metabolism of glabridin can lead to mechanism-based inactivation or inhibition of the P450. Heme and reduced CO spectral analysis also indicated that glabridin inactivated P450s 2B6 and 3A4 by different mechanisms.     

Corrosive gastritis: sonographic findings in the acute phase and follow-up

This paper reports our experience with transabdominal ultrasound in both the acute phase and follow-up in a patient with corrosive gastritis. The case presented demonstrates that serial sonography can localise the injury, demonstrate its depth and reveal the presence of peristalsis, thereby reducing the radiation exposure resulting from barium studies. Received: 20 February 1997 Accepted: 16 April 1997     

Effects of postprandial plasma and chylomicrons on endothelial cells. Differences between dietary cream and cod liver oil

The acute effects of fatty meals (900 kcal) rich in saturated (cream) or n-3 polyunsaturated (cod liver oil, CLO) fatty acids on human umbilical vein endothelial cells (ECM) and platelet behavior were studied. The ECM were incubated for 24 hours at 37 degrees C with either plasma or chylomicrons (CM) obtained 3 hours after the meals. The ability of the ECM to inhibit platelet aggregation (PIA) and the release of prostaglandin I2 measured as 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were measured after 24 hours of incubation, after stimulation and after freezing and thawing. Similar studies were done with CM from a patient with type V hyperlipoproteinemia. The release of 6-keto-PGF1 alpha was increased by postprandial plasma and by CM obtained after both meals. Plasma collected after CLO, but not after cream, increased PIA, whereas CM derived from all sources studied stimulated the PIA of ECM. No consistent correlation could be established between the release of 6-keto-PGF1 alpha and PIA. Increased platelet aggregation in platelet-rich plasma was always observed during postprandial hyperlipidemia.