Sensitivity and toxic mode of action of dietary organic and inorganic selenium in Atlantic salmon (Salmo salar).

Depending on its chemical form, selenium (Se) is a trace element with a narrow range between requirement and toxicity for most vertebrates. Traditional endpoints of Se toxicity include reduced growth, feed intake, and oxidative stress, while more recent finding describe disturbance in fatty acid synthesis as underlying toxic mechanism. To investigate overall metabolic mode of toxic action, with emphasis on lipid metabolism, a wide scope metabolomics pathway profiling was performed on Atlantic salmon (Salmo salar) (572±7g) that were fed organic and inorganic Se fortified diets. Atlantic salmon were fed a low natural background organic Se diet (0.35mg Se kg-1, wet weight (WW)) fortified with inorganic sodium selenite or organic selenomethionine-yeast (SeMet-yeast) at two levels (∼1-2 or 15mgkg-1, WW), in triplicate for 3 months. Apparent adverse effects were assessed by growth, feed intake, oxidative stress as production of thiobarbituric acid-reactive substances (TBARS) and levels of tocopherols, as well as an overall metabolomic pathway assessment. Fish fed 15mgkg-1 selenite, but not 15mgkg-1 SeMet-yeast, showed reduced feed intake, reduced growth, increased liver TBARS and reduced liver tocopherol. Main metabolic pathways significantly affected by 15mgkg-1 selenite, and to a lesser extent 15mgkg-1 SeMet-yeast, were lipid catabolism, endocannabinoids synthesis, and oxidant/glutathione metabolism. Disturbance in lipid metabolism was reflected by depressed levels of free fatty acids, monoacylglycerols and diacylglycerols as well as endocannabinoids. Specific for selenite was the significant reduction of metabolites in the S-Adenosylmethionine (SAM) pathway, indicating a use of methyl donors that could be allied with excess Se excretion. Dietary Se levels to respectively 1.1 and 2.1mgkg-1 selenite and SeMet-yeast did not affect any of the above mentioned parameters. Apparent toxic mechanisms at higher Se levels (15mgkg-1) included oxidative stress and altered lipid metabolism for both inorganic and organic Se, with higher toxicity for inorganic Se.

Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden.

Nine different germ-line mutations in the BRCA1 breast and ovarian cancer susceptibility gene were identified in 15 of 47 kindreds from southern Sweden, by use of SSCP and heteroduplex analysis of all exons and flanking intron region and by a protein-truncation test for exon 11, followed by direct sequencing. All but one of the mutations are predicted to give rise to premature translation termination and include seven frameshift insertions or deletions, a nonsense mutation, and a splice acceptor site mutation. The remaining mutation is a missense mutation (Cys61Gly) in the zinc-binding motif. Four novel Swedish founding mutations were identified: the nucleotide 2595 deletion A was found in five families, the C 1806 T nonsense mutation in three families, the 3166 insertion TGAGA in three families, and the nucleotide 1201 deletion 11 in two families. Analysis of the intragenic polymorphism D17S855 supports common origins of the mutations. Eleven of the 15 kindreds manifesting BRCA1 mutations were breast-ovarian cancer families, several of them with a predominant ovarian cancer phenotype. The set of 32 families in which no BRCA1 alterations were detected included 1 breast-ovarian cancer kindred manifesting clear linkage to the BRCA1 region and loss of the wild-type chromosome in associated tumors. Other tumor types found in BRCA1 mutation/haplotype carriers included prostatic, pancreas, skin, and lung cancer, a malignant melanoma, an oligodendroglioma, and a carcinosarcoma. In all, 12 of 16 kindreds manifesting BRCA1 mutation or linkage contained ovarian cancer, as compared with only 6 of the remaining 31 families (P<.001). The present study confirms the involvement of BRCA1 in disease predisposition for a subset of hereditary breast cancer families often characterized by ovarian cancers.

[Differentiation of benign and malignant ovarian tumors by transluminal ultrasound scanning]. / Differentiering af benigne og maligne ovarietumorer med transabdominal ultralydskanning.

We intended to evaluate ultrasonographic criteria for differentiation of benign and malignant ovarian tumours, and to estimate the risk of malignancy in unilocular ovarian cysts. The files of 186 women aged 40 or above, who had undergone surgery in the department of gynaecology and obstetrics at Hillerød hospital between 01.01.1988-31.12.1990 and where pathological ovarian histology was found were reviewed. Preoperative ultrasonographic examination concerning size and morphology was compared to histological diagnosis. Tumours were classified according to the ultrasonographic internal structure into a) unilocular cysts, b) unilocular cysts with solid areas, c) multilocular cysts, d) multilocular cysts with solid areas and e) solid tumours. Criteria for suspicion of malignancy were unilocular cysts > 10 cm and complex and solid tumours, whereas smaller unilocular cysts were thought to be benign. Twenty-one tumours, diagnosed by ultrasound as unilocular cysts were all histologically benign, independently of size. For complex and solid tumors there was an increased risk of malignancy, and a statistically significant correlation between tumour size and risk of malignancy was found. Using the ultrasonographic criteria for malignancy a sensitivity of 97% and a specificity of 28% was found. The suggested criteria for ultrasonographic suspicion of malignancy were found usable in differentiating benign and malignant ovarian tumours. The risk of malignancy for unilocular cysts seems to be low, independently of size.

Altered progesterone/estrogen receptor ratios in endometriosis. A comparative study of steroid receptors and morphology in endometriosis and endometrium.

In a comparative study of endometriosis and endometrium, specimens were taken from both endometriotic and endometrial tissue in 14 patients. Receptor assays and histological examinations were performed on both specimens. Cytosolic estrogen receptors (ERc) as well as cytosolic progesterone receptors (PRc) were detected in 9/14 and 12/12 cases of endometriosis respectively. Nuclear estrogen receptors (ERn) were detected in 4/4 cases of endometriosis. Expressed as fmol/mg cytosol protein, significantly higher values of both ERc and PRc were found in endometrium than endometriosis (p less than 0.01). However, when the ratio between PRc and ERc was considered, significantly higher PRc/ERc ratios were found in the cytosol of endometriotic tissue (p less than 0.01). Thus the lower receptor concentrations found in endometriosis cannot be explained solely as ectopic endometrium being diluted by nonreceptor-containing tissue. In spite of high PRc/ERc ratios in endometriosis, secretory changes similar to those found in endometrium were observed in only one of 7 cases (p less than 0.05).

[Peroral treatment with natural human estrogens in the climacteric]. / Peroral behandling med naturlige, humane østrogener i klimakteriet.

PIP: Various aspects of climacteric treatment with natural human estrogens are discussed. Estradiol, estradiol valerate, estron sulfate, or estriol are used separately or together in various preparations to treat the symptoms of approaching menopause. Estrogen treatment causes proliferation of the endometrium and causes a decrease in LHRH, FSH, and LH secretion. Treatment can take the form of continuous or cyclic treatment with estrogens alone, or sequential estrogne/gestagen preparations can be used. Ovarian function decreases as menopause approaches and results in the cessation of ovulation. Then the hypolutein phase begins, during which the secretion of progesterone is reduced and menstrual bleeding irregularities begin to occur. Eventually, estrogen production decreases so much that menstruation ceases completely, and symptoms such as heat flashes are experienced. Women who want treatment for climacteric symptoms but who want no regular menstrual bleeding can be administered low doses of pure estrogen. Regular abrasio control of endometrial development should be performed, however. Pure estrogen treatment can also be used in the case of hysterectomized women. Otherwise, a sequential treatment is generally indicated. Possible side effects of estrogen substitution therapy are changes in the genitalia, breasts, menstrual bleeding, blood pressure, and weight. There is also an indication that estrogen use can induce endometrial cancer. Besides the definite contraindication of endometrial cancer, relative contraindications of estrogen therapy include breast cancer, reduced liver function, thromboembolic disease, and serious hypertension. Estrogen therapy is to be used to solve acute climacteric symptoms; women should be well informed about possible side effects and that the therapy is no panacea for all menopausal problems.^ieng

Oestrogen treatment and subsequent pregnancy in two patients with severe hypergonadotrophic ovarian failure.

This report describes in detail the histological and hormonal findings in a patient with Turner's syndrome (45,XO) and a patient with premature menopause (46,XX), who both conceived after withdrawal or reduction of substitution therapy with oestrogens. The aetiology of severe hypergonadotrophic ovarian failure is discussed, and theories regarding a possible relationship between the oestrogen treatment and subsequent pregnancy are hypothesized.