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Women at risk of breast and ovarian cancer due to a genetic predisposition may opt for preventive surgery or surveillance. The aim of this study was to determine the effectiveness of surveillance in families with a BRCA mutation. Sixty-eight BRCA-families underwent surveillance using annual mammography, transvaginal ultrasound, and estimation of CA125. Two hundred and two women had at least one breast examination, and 138 at least one examination of the ovaries. After a mean follow-up of 33 months, breast cancer was detected in 21 women, four with lymph node metastases. After a mean follow-up of 37 months, six advanced ovarian cancers were detected. The percentage of metastatic breast cancers in the current study appeared to be acceptable. However, because these women have a high-risk of developing breast cancer, they still have a substantial risk of developing metastatic disease under surveillance. Surveillance for ovarian cancer was not effective.

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The estrogenic activity of compounds was evaluated in a comparative approach both with in vitro and in vivo assays. By comparing simultaneously obtained experimental data, we evaluated the differences in response sensitivity (by EC10) and concentration-response relationships (including EC50) in order to get an idea about the predictive value of in vitro assays for in vivo estrogenic potencies or effects in fish. Two human estrogen receptor-based assays, the MVLN-assay (transformed MCF-7 human breast cancer cell line) and the yeast estrogen screen (YES-screen) were used for the in vitro evaluation of the estrogenic potencies. An in vivo model with the female zebrafish (Danio rerio) with plasma vitellogenin (VTG) as a biomarker for exposure and the ovarian somatic index (OSI) as an effect endpoint was used for the in vivo work. Compounds tested were 17beta-estradiol (E2), estrone (E1), 17alpha-ethynylestradiol (EE2) and the alkylphenolic compound nonylphenol (NP). All compounds were found to be estrogenic in both in vitro assays and were able to induce VTG and to reduce the ovarian somatic index in female zebrafish. The MVLN-assay appeared up to 15 times more sensitive than the YES-screen. Concentration-response relationships, determined by EC10 and EC50 (concentration of test compound causing 10% or 50% effect compared to control) for VTG and OSI were of the same order of magnitude, indicating that VTG induction as an exposure biomarker can be predictive for effects on ovaries in females. We further demonstrated that for E1 and NP, the in vitro observed estrogenic potencies, based on EC50 values, were of the same order of magnitude as the in vivo estrogenic potencies. For EE2, a difference between in vitro and in vivo relative estrogenic potency was observed, being about 25 times more potent in vivo than could be expected based on the in vitro results. These experimental results showed the suitability of in vitro assays for screening purposes with qualitative assessment of estrogenicity, but they meanwhile point to the need of in vivo tests for an accurate hazard assessment for wildlife.

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In this comparative study, the suitability of the commonly used in vivo biomarker for estrogenicity, vitellogenin (VTG), upon waterborne exposure to known environmental estrogens is evaluated in both male zebrafish (Danio rerio) and juvenile rainbow trout (Oncorhynchus mykiss). The results from initial experiments in which both species were exposed to 4-tert-octylphenol (OP) or 17 alpha-ethynylestradiol under semistatic conditions for 3 weeks demonstrated a difference in species sensitivity for OP exposure. Additional dose-response studies (semistatic, 3 weeks) with 4-nonylphenol (20, 100, and 500 microg/L), bisphenol A (40, 200, and 1000 microg/L), dibutylphthalate (40, 200, and 1000 microg/L DBP), and 17beta-estradiol (20 and 100 ng/L E2) were conducted. All these compounds, except for DBP, were found to be estrogenic to both fish species. The results demonstrated a difference in species sensitivity for NP with the zebrafish being about 5 times less sensitive. For the other compounds tested, no indications for a difference in species sensitivity was found. The results from this study demonstrated that both fish species can be used for the detection of VTG as biomarker for estrogenicity, taken into the potential interspecies differences in sensitivity which might be important for the evaluation of fish population effects.

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In this study, the impact of an exposure of zebrafish embryos (Danio rerio) until 3 months post fertilization to 17alpha-ethynylestradiol (EE2: 0; 0,1; 1; 10; 25 ng/l) was evaluated for growth and development, gonad development and body vitellogenin (VTG) content. After a recovery period of 5 months, the female reproductive success was evaluated. The results demonstrated a significant reduction in total body length, body weight, whole body Ca and P content and an increase in morphological abnormalities for fish exposed to 25 ng/l EE2 as a function of exposure time. An increase in total body VTG content was observed for fish exposed for a period of 3 months down to levels of 1 ng/l EE2. At the age of 3 months, a dose-dependent increase of the number of fish with no macroscopic recognizable gonads was observed (up to 100% at 25 ng/l EE2). After a recovery period on clean tap water for 5 months, all fish had developed either ovaries or testis with a gonadosomatic index not different from control fish and the sex ratio was similar in EE2 treatment groups and controls. Nevertheless, a reduced number of spawning females and a reduced egg production were found for the female fish exposed to 10 or 25 ng/l EE2 for 3 months and which were allowed to recover for 5 months. Although the underlying mechanism could not be elucidated, these findings did indicate that the reproduction potential of fish populations might be disturbed by a long-term exposure to EE2 (> or =10 ng/l) from fertilization until sexual maturity.

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In this study, the impact of ethynylestradiol (EE2) and 4t-octylphenol (OP) on reproduction in zebrafish (Danio rerio) was evaluated using spawning and fertilization success, gonadosomatic index, and plasma vitellogenin (VTG) levels as endpoints. Adult male and female zebrafish were exposed under semi-static conditions to 5, 10, 25 and 50 ng/L EE2 and to 12.5, 25, 50 and 100 microg/L OP for 3 weeks. A dose-related reduction in the number of females capable of spawning was observed at 10 ng/L EE2 with a complete inhibition of spawning at levels of 25 ng/L EE2. The ovaries of these nonspawning females were regressed and mean ovary somatic index (OSI) was significantly below the reference OSI determined in nonexposed females prior to spawning. Our results suggest an adverse impact of EE2 on male fertilization capacity and demonstrate a significant reduction in testis somatical index after exposure to 10 and 25 ng/L EE2. For both males and females, a dose dependent VTG induction was measured. Levels of VTG in fish plasma were significantly correlated with measured gonadosomatic indices. Minor effects were observed for OP. No significant effects on spawning or fertilization success were observed in this study, though OSI of nonspawning females was reduced at levels of 25 microg/L OP and higher. No changes in plasma protein levels were measured in male and female fish exposed to OP. The results from this study demonstrate that OP and especially EE2 can adversely affect the normal reproduction success of male and especially female zebrafish, with relevance for population effects.

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Three spined sticklebacks (Gasterosteus aculeatus) were sampled from five different watercourses in Flanders (Belgium). Concentrations of cadmium, lead, copper, and zinc were measured in water, sediment, food, and fish tissues. Considered as food was the taxonomic groups of macroinvertebrates predominately present in the stomach of the sticklebacks at the different sites. Analyzed tissues were gill, liver, and muscle. To determine the relative importance of the different uptake routes, multiple linear regression models were constructed. Accumulated metal levels in the tissues were related to metal levels in sediment, water, and food. Generally, the amount of variation in accumulated metal levels that could be explained by these models was limited, with coefficients of determination not exceeding 0.57. Cadmium levels in the three tissues were solely related to levels in invertebrates. The same was true for copper in liver. In the other cases the tissue levels could be related only to sediment and/or water levels. Depending on the metal, levels were highest in gill or in liver. In all cases lowest metal levels were measured in muscle.

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Although there are abundant data on heavy metal contamination in the feathers of seabird species and birds of prey, relatively few studies have addressed the use of passerine birds as indicators of point-source contamination. Concentrations of three essential elements (Al, Zn, and Cu) and two toxic metals (Cd and Pb) were determined in the outer tail feathers of great and blue tits (Parus major and Parus caeruleus), two small insectivorous passerines, at a presumed polluted site (in an urban area close to household waste incinerators) and at a reference site (in a nature reserve). For the great tit, both Cd and Cu levels were significantly higher at the polluted site than in the nature reserve. For the blue tit, Cd, Pb, and Cu levels were significantly higher at the polluted site than at the reference site. There were striking differences in metal levels between blue and great tits inhabiting the same polluted site: lead, zinc, and copper were significantly higher in the smaller blue tit than in the great tit. We suggest that tit (Parus) species, which have been important models in behavioral and ecological research, may be very useful as biomonitors for local contamination.

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Surficial sediments, midge larvae (Chironomidae, Diptera) and tubificid worms (Tubificidae, Oligochaeta) were collected at 65 sampling sites located in four different river basins in Flanders (Belgium). Concentrations of the trace metals Cu, Zn, Cd and Pb were measured in organisms and sediments by atomic absorption spectrophotometry. Sediments were subjected to a simultaneous extraction scheme to identify trace metal partitioning among various geochemical phases. Three geochemical characteristics of the sediment were analysed; Total Organic Carbon (TOC), Fe oxides and Mn oxides. Non-linear regression models were constructed to determine the relative importance of the different sediment factors contributing to the variation in metal accumulation by the tubificid worms and chironomids. Generally, the amount of variation that could be explained by these models was limited, with coefficients of determination ranging from 0.05 to 0.66. In most cases, metal levels in organisms were positively related to the easily reducible and reducible metal fractions, and negatively related to the TOC and Fe sediment content. The correlations between metal concentrations in tubificid worms and chrinomid larvae were also rather poor, with coefficients of determinations ranging from 0.01 to 0.52. This indicates that understanding the chemistry of the environment does not suffice to predict the concentrations in organisms. Differences in the structural and functional organisation of the organisms, which among others determine the route of exposure, are at least equally important causes of variability in metal availability and accumulation.

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The effect of temperature (5 to 25 degrees C) was studied on the uptake of cadmium and zinc by larvae of the midge Chironomus riparius, using artificial chemically defined solutions. The influence of prior acclimation of midge larvae at five temperatures on metal uptake was examined. At all acclimation temperatures metal uptake in organisms increased with increasing exposure temperature. Among the different temperature exposure groups the effect of temperature acclimation on metal uptake is rather variable and a general pattern can not be distinguished. The integration of the different temperature effects explains 69% of the total variation in cadmium uptake and 68% of the total variation in zinc uptake by midge larvae. The factor that accounts for respiration explained 59% of the cadmium uptake and 60% of the zinc uptake by midge larvae. The apparent activation energies for larval metal uptake are much higher than the activation energy for the free diffusion of the cadmium or zinc ion but close to the activation energy for respiration, showing that metal uptake by midge larvae is largely controlled by active physiological rather than by passive diffusional processes.

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The impact of an industrial effluent containing high loads of calcium, cadmium, lead chloride and sulphate, on a river ecosystem was assessed using a combination of an effluent toxicity test, an ambient toxicity test and an ecological survey. Only this combination of techniques made it possible to discriminate between the effects of the discharge and those of the background pollution. Each of the individual techniques detected essential effects which the other failed to reveal. With the physical and chemical measurements, important increases of several components were measured at all sampling sites downstream of the discharge. With the ecological survey, however, no large changes in water quality could be determined at the sampling sites, due to the high degree of pollution present upstream of the discharge. Reproduction of Daphnia magna, exposed to sublethal effluent dilutions, was followed over two generations. The offspring of the first generation were shown to have an increased sensitivity to the effluent, compared to the first generation that was born from previously unexposed mothers. Besides the toxicity of the effluent, the acute and chronic toxicity of its main component, CaCl(2), was also determined. The results of the CaCl(2)-tests and toxicity data from literature for the suspected toxicants were transformed to Toxic Units (TU). Using the sum of the TUs we investigated the possibility of predicting effluent toxicity to Daphnia magna. Effluent toxicity was under-estimated by calculating the sum of the TUs of the individual components. Dilution of the effluent to a level at which the measured toxicant concentrations comply with European regulations still showed significant effects on Daphnia reproduction.

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The alleged clinically observed association between the use of seclusion and the luteal phase of the menstrual cycle was studied in 113 consecutively admitted female psychiatric patients by means of a monitoring of oestrogen and progesterone levels, the use of seclusion, age, drug use, regularity of menses, and a history of hysterectomy. Twenty-one patients (18.6%) were in the luteal phase. During the study period, 14 patients (12.4%) had to be secluded. No significant difference in the frequency of seclusion between luteal patients and patients in the other phases could be demonstrated. The findings indicate that the luteal phase of the menstrual cycle is not associated with an increased occurrence of seclusion in female psychiatric patients.

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The effect of posture on hand preferences was examined in an experiment with 5 bonobos (Pan paniscus). To obtain a food reward, the animals had to adopt 1 out of 7 different postures. These postures represented an increasing problem to the maintenance of body equilibrium. It was expected that an increasing demand for equilibrium maintenance would elicit individual preferences and a population-level bias. All animals showed an increasing trend toward left-handedness while shifting to a bipedal posture from a seated posture by way of a quadrupedal posture. The importance of bipedalism in the evolution of left- and right-handedness is discussed briefly.

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Infant-carrying behaviour was observed in two families of captive golden-headed lion tamarins. Although the young were raised in almost identical social situations, we found a reversed involvement of mother-father pairs in the amount of time they carried their offspring. In one case, the parental division of carrying behaviour was consistent with the standard description for callitrichids in that the adult male was the primary carrier. In the other family, the mother carried the infant considerably more than the male. Comparison of transfer initiations and transfer times showed that maternal choice operated. It is suggested that maternal behavior may depend primarily on the female's physical and hormonal condition.

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Mouse monoclonal antibodies (OV-TL 3) were raised against human ovarian tumor-associated antigens for diagnostic purposes. A cloned hybridoma cell line was obtained by fusion of murine myeloma cells with spleen lymphocytes from BALB/c mice immunized with a tumor cell suspension prepared from an ovarian endometrioid carcinoma. The antibodies were initially screened for their ability to bind on frozen sections of human ovarian carcinoma tissue and a negative reaction on gastric carcinoma tissue by indirect immunofluorescence. The reactivity of the selected OV-TL 3 clone (IgG1 subclass) was studied on normal and neoplastic tissues as well as on a cell line derived from the original tumor cell suspension used for immunization. OV-TL 3 antibodies stained frozen sections of human ovarian carcinomas of the following histological types: serous, mucinous, endometrioid, and clear cell. No reaction was found with breast cancers or other nongynecological tumors. No differences in staining pattern were observed between primary and metastatic ovarian carcinomas. OV-TL 3 antibodies brightly stained ovarian carcinoma cell clusters in ascitic fluids and left unstained mesothelial cells and peripheral blood cells. The OV-TL 3-defined antigen also remained strongly expressed on a cell line derived from the endometrioid ovarian carcinoma originally used for generation of OV-TL 3 clone. Reactivity was weak and irregular in a few ovarian cysts, while traces of fluorescence were sometimes detected in epithelial cells lining the female genital tract. In only 3 specimens of 15 endometrium carcinomas was weak focal reactivity with OV-TL 3 antibodies observed. The results of the immunofluorescence study were confirmed by the more sensitive avidin-biotin method and by 125I-labeled OV-TL 3 antibodies. Thus OV-TL 3 recognizes a common antigen for most ovarian carcinomas and may be a useful tool for rapid diagnosis of ovarian carcinomas.

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This paper describes a new automated system to prepare slides of cytological material from suspension. The system collects material on a filter tape by filtration and transfers it to glass slides by means of pressure-fixation. Using cervical cells as a model, results show that a well-defined cell number is evenly deposited over a standardized area, while a small number of cells is retained on the tape and a negligible number lost in the filtrate. Contamination is very small. Application of the system to other cytological material (fine needle aspirations, monolayer and cell suspension cultures, agar cultures, and isolated nuclei) is shown. In general, more than one slide can be made from one sample. Several histological staining procedures as well as immunofluorescence labeling protocols can be applied to the preparations obtained in this way. This system thus introduces a method that will standardize specimen preparation, is quick, saves operator time, and can be used for both diagnostic and research applications.

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Two-layer soft agar cultures from 26 patients with renal cell carcinoma, 21 renal primary lesions and 5 metastatic lesions, were evaluated for tumor colony formation using both dynamic growth curves and static single time point colony counting. Dynamic growth curves markedly increased the number of evaluable tumor cultures. There was no relationship between colony formation and TNM stage of the tumor or renal vein invasion. However, there was a significantly (p less than 0.02) higher rate of colony formation from younger (less than 50 y.) patients than from older patients. Only 2 of 5 tumors tested showed response to one or more cytostatic agents in vitro, both tumors showing response to Adriamycin and one to Cis-platin. Dynamic evaluation of tumor colony formation in soft agar may increase the clinical applicability of the human tumor cloning system both by increasing the number of evaluable cultures and by providing more information about the processes involved in tumor colony formation in vitro.

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