Predicted aquatic and human health risks associated with the presence of metals in the Syr Darya and Shardara Reservoir, Kazakhstan.

Due to the decline of the Aral Sea fishery and recent efforts to expand the fisheries sector in Kazakhstan for both local consumption and global export, there is a need to sustain other fisheries in the area, including the Shardara Reservoir, which lies in the Syr Darya basin. Metals are present in the Syr Darya; yet, their impacts on fishery and consumer health remain unclear. Thus, the objectives of this study were to evaluate: 1) the potential impacts of metals on Syr Darya basin fish and 2) the human health risks posed by consumption of Shardara Reservoir fish. The health of the fishery was assessed by comparing surface water metal concentrations to maximum permissible concentrations (MPCs), calculating water quality index (WQI) and degree of contamination (Cd) values, and evaluating gene expression biomarker responses in wild-caught roach (Rutilus rutilus). To assess the risk to consumers, metal concentrations in roach were used to calculate hazard quotients (HQs) and hazard indices (HIs). Water concentrations of Cu, Fe, Mn, Se, Sr and V exceeded MPCs and all sites were classified as highly polluted based upon WQI and Cd values. This, along with site-specific differences in the expression of genes associated with xenobiotic metabolism and oxidative stress in roach, indicates potential risks to the fishery. Though all HQs and HIs were below 1 indicating a lack of significant risk to consumers, Pb levels in roach exceeded MPCs for safe consumption indicating a potential risk. Given the potential risks to the fishery and consumers, the development of pollution monitoring and management programs are warranted. The work presented here provides initial monitoring data that can be used to aid such efforts and also underscores the need to identify environmental stressors that may thwart the anticipated growth of fisheries in this region.

gamma-Glutamyl transferase and breast cancer risk.

BACKGROUND: It has been reported that there is an increased risk of cancer in individuals with elevated levels of serum gamma-glutamyl transferase (GGT). METHODS: In the Guernsey Breast Cancer Cohort Study, GGT was measured in sera from 1803 normal women. Among these women, 251 subsequently developed cancer, of whom 96 developed breast cancer. RESULTS: After adjustment for age at entry, height, weight, age at menarche and first birth with nulliparity, there was a highly significant relationship between elevated GGT and breast cancer risk. In the highest quartile, the hazard ratio (HR) was 2.17 (95% confidence interval (CI): 1.19, 3.93). When subdivided by menopausal status, there was a reduced non-significant effect in postmenopausal women, whereas for premenopausal women in the highest quartile, HR was 3.81 (95% CI: 1.37, 10.59). Premenopausal women with serum GGT levels above the normal range had a significantly elevated HR of 4.90 (95% CI: 1.86, 12.94). CONCLUSIONS: These results suggest that premenopausal women with high normal (above median) serum GGT or elevated levels (< or =40 IU l(-1)) are at increased risk of breast cancer and might benefit from close surveillance, possibly with breast magnetic resonance imaging scans. Serum GGT may mark previous exposure to carcinogens and lead to the identification of DNA adducts involved in mammary carcinogenesis.

Prognosis of synchronous bilateral breast cancer.

BACKGROUND: The prognosis of patients with synchronous bilateral breast cancer (SBBC) is usually based on the tumour with the worst pathological features. There is little evidence in the literature for this assumption, potentially impairing reasoned decisions on optimal adjuvant therapy. METHODS: This was a case-control study in which 68 women with SBBC were matched with 128 women with unilateral breast cancer. Both the GuysRisk prognostic model and the Nottingham Prognostic Index were used to determine the bilateral tumour with the poorer prognosis. Controls were matched for age, menopausal status, date of diagnosis, histological type and grade, and oestrogen receptor and axillary node status. RESULTS: Both prognostic models indicated the same side tumour with the worst prognosis. Kaplan-Meier survival curves for both disease-free and overall survival showed no significant difference in outcome between the two groups. CONCLUSION: Prognosis was determined by the tumour with the worst prognosis, with no additional worsening of outcome incurred from the second tumour.

Selenium in human mammary carcinogenesis: a case-cohort study.

In a prospective study conducted on the island of Guernsey a cohort of 5162 ostensibly healthy women was enrolled between 1967 and 1976. Blood samples were drawn from each participant, who also completed a questionnaire, which provided information on established risk indicators in human mammary carcinogenesis. Plasma selenium levels were measured in 46 breast cancer cases diagnosed a mean of 11 (S.D. 4) years after entry into the study cohort and in an age-stratified sample of 138 women drawn from the study base. Plasma selenium level in the cases was 109 (28) micrograms/l and in the base sample 103 (22) micrograms/l (95% confidence interval for the overall difference, -2 to 14 micrograms/l). The adjusted relative risk of developing breast cancer in the different quartiles of the selenium distribution was 0.80, 0.79, 0.72 and 1.00, respectively. Thus, in the present study selenium was not a strong indicator of human breast cancer risk.

A prospective study of obesity, lipids, apolipoproteins and ischaemic heart disease in women.

The aim of the study was to examine the relationships of obesity, lipids and apolipoproteins with the risk for subsequent ischaemic heart disease in middle-aged women, using a case-control study nested within a cohort study. A total of 3634 women aged 26-88 were recruited in Guernsey between 1977 and 1985 and followed until June 1986 by abstraction of their general practitioners' records. Fifty-one cases of incident ischaemic heart disease (11 myocardial infarction, 40 angina) were identified. For each case up to 4 controls were selected, matched for age and date at recruitment. Odds ratios for the development of ischaemic heart disease in the middle and upper thirds of the distribution for each variable in the controls, relative to the lowest third (and two-sided P-values for linear trends), were: 3.0, 2.6 (0.015) for Quetelet's index; 3.3, 5.1 (0.003) for total cholesterol; 0.5, 0.6 (0.102) for apolipoprotein A-I; 1.8, 2.4 (0.015) for apolipoprotein B; 1.3, 2.1 (0.155) for apolipoprotein(a). The increased risks associated with increased Quetelet's index and total cholesterol were independent of each other and these variables were more strongly related to myocardial infarction than to angina. The relationships of risk with serum cotinine, fatty acids, dehydroepiandrosterone sulphate and sex hormone binding globulin were weak and did not approach statistical significance.

Serum prolactin levels and their relationship to survival in women with operable breast cancer.

The prognostic value of serum prolactin levels was assessed in a sequential series of 739 patients who were initially treated at Guy's Hospital, London, between 1975 and 1980. Prolactin was measured in 472 patients 1 day before (Hpr1) and in 457 patients 10 days after (Hpr2) mastectomy. Follow-up of the patients was up to August 1992 giving 6139 women-years with a median follow-up time of 11.5 years (13.7 for patients still living and 5.1 for those dead). The association between the three prolactin variables and reproductive and clinical factors was examined before assessing the prognostic value of prolactin levels in terms of overall, disease-specific and disease-free survival. Multivariate survival models were used in order to adjust for the effect of other prognostic variables. These were found to be: tumour size, degree of nodal involvement, tumour grade and age at diagnosis. The results showed that high Hpr2 or high postoperative increase in prolactin (i.e. Hpr2-Hpr1) were significantly related to shorter disease-specific survival (p = 0.04 and 0.01, respectively) in postmenopausal women. In addition there was some indication, which did not attain formal significance, for this association to occur for disease-free survival. Thus the rise in blood prolactin levels after surgery may be a weak indicator of poor prognosis of breast cancer in postmenopausal women.

Relationship of blood prolactin levels and the risk of subsequent breast cancer.

Between 1968 and 1976 a total of 5162 women volunteers were enrolled into a prospective study conducted on the Island of Guernsey. Up to February 1990 145 women subsequently developed breast cancer. Blood samples were taken at the time of enrollment and prolactin levels were known for 85% of the volunteers. In calculating the relationship between blood prolactin levels and subsequent breast cancer risk, women were excluded if they had a hysterectomy or an oophorectomy or had cancer at any site before enrollment. The final analysis was based on 2596 premenopausal and 1180 naturally postmenopausal women and, of these respectively, there were 71 and 40 volunteers who subsequently developed breast cancer. The total follow-up for these two groups was 49,941 and 22,360 woman-years, respectively. In assessing the relationship between blood prolactin levels and risk of subsequent breast cancer the cohort was divided into quintiles according to prolactin concentration and relative risks (RR) were estimated. In calculating these values possible confounding by age at entry, age at menarche, parity, age at first birth, years since menopause, body build, history of benign breast disease and family history of breast cancer were taken into consideration. There was no significant relation between risk of breast cancer and prolactin in either pre- or postmenopausal women. Hence prolactin appears not to be an important determinant of breast cancer risk.

Relationship of mammographic parenchymal patterns with breast cancer risk factors and risk of breast cancer in a prospective study.

A prospective study has been conducted on 4954 female volunteers from the Island of Guernsey between 1977 and 1985 to examine risk factors for breast cancer and their relationship to mammographic parenchymal patterns as assessed by Wolfe's method of grading. Up to September 1988, 69 women had developed breast cancer, 11 of whom were prevalent cases being diagnosed within six months of mammography. The remaining incident cases were diagnosed six to 126 months (median 65 months) after entry to the study. Univariate analysis showed that the distribution of Wolfe grades in the population was significantly associated with menopausal status, age, parity, adiposity, age at menarche, age at first childbirth and use of oral contraception, but not with a family history of breast cancer. Multivariate analysis of the data for these variables from either pre- and/or post-menopausal women indicated that age, parity and adiposity were significantly related to Wolfe grade pattern. Age had an opposite effect in pre- compared with postmenopausal women thus the probability of either a P2 or DY pattern increased with increasing age in premenopausal but decreased in postmenopausal women so that incidence peaked around the menopause. Other variables did not achieve significance in the multivariate analysis. Odds ratios (ORs) were calculated for women with P2 or DY patterns using those with N1 or P1 grades as the reference group. The ORs were determined at two censoring times; one at five years and the other to include the most recent follow-up of this cohort. The ORs were adjusted for years of follow-up, age and adiposity and in postmenopausal women adjustment was also made for age at menarche.(ABSTRACT TRUNCATED AT 250 WORDS)

Sex-hormone-binding globulin and breast cancer risk.

We have measured serum concentrations of SHBG in 5000 women over the age of 35. In both premenopausal and postmenopausal women who were not suffering from cancer or other diseases or taking drugs likely to affect SHBG, the protein decreased with increasing weight and was lower in single nulliparous women than in married nulliparous women or parous women. In premenopausal women, SHBG was higher in women with late menarche. These findings suggest that diminished SHBG concentrations may be associated with the increased risk for breast cancer conferred by nulliparity and early menarche.

The relationships of SHBG with current and previous use of oral contraceptives and oestrogen replacement therapy.

Sex hormone binding globulin (SHBG) concentration was measured in serum samples from 2077 premenopausal and 901 naturally postmenopausal women who had no history of disease or of recent drug use likely to affect SHBG. Current users of oral contraceptives (OCs) and of oestrogen replacement therapy had higher mean SHBG values than non-current users. Both premenopausal and postmenopausal women who had previously used OCs had a lower mean SHBG concentration than never users of OCs. Previous use of oestrogen replacement therapy was not related to SHBG.

Factors influencing loco-regional relapse in older breast cancer patients treated with tumour resection and tamoxifen.

BACKGROUND: In breast cancer patients (≥70 years), tumour resection plus tamoxifen (T + T) has a higher loco-regional relapse (LR) rate than mastectomy. This study examines factors influencing local recurrence in these cases. METHODS: Clinical records of 71 patients aged ≥70 years, randomised to the T + T arm of 2 randomised trials were reviewed. Cox Proportional Hazards model was used to determine the most significant variables. RESULTS: After 15-years follow-up, LR relapse occurred in 29/71, of whom 5 had synchronous metastatic disease. Most tumours recurred in the index quadrant. Subsequently 21/24 patients with loco-regional recurrence only had salvage mastectomy. Three variables significantly predicted LR: lympho-vascular invasion (LVI) (HR [95% CI]: 11.18 [4.47, 27.95], p < 0.01), ER negative status (HR [95% CI]: 0.27 [0.10, 0.72] p = 0.01), and tumour necrosis (HR [95% CI]: 2.65 [1.10, 6.37], p = 0.03). Final margin status was not associated with LR. CONCLUSIONS: Tumour resection + Tamoxifen in older patients results in long-term local control in the majority with most loco-regional failures being salvageable. Risk factors for LR are lympho-vascular invasion, ER status and tumour necrosis. Negative tumour excision margins did not significantly change local outcome in the absence of radiotherapy. In these older patients LVI significantly reduced survival time.

The impact of the Occupation of Guernsey 1940-1945 on breast cancer risk factors and incidence.

To examine the impact of the German Occupation of Guernsey (1940-1945) on breast cancer risk factors and incidence. Under study were 1019 women who stayed, or whose mothers had stayed, in Guernsey, and 1358 women evacuated or born to evacuated mothers. Amongst those born 1926-1934 who remained in Guernsey, the secular trend of earlier menarche disappeared: menarche was delayed by 12 months for those born in 1930. By March 2006, 97 breast cancers had been diagnosed, 37 in the occupied group. Unusually, higher age at menarche appeared to be associated with increased risk of breast cancer (>or=14 years vs.

Hormone dependency of breast tumours developing in the Guernsey Cohort study.

The aim of this study was to determine whether endogenous estradiol levels in postmenopausal women helped determine the estrogen receptor status of subsequent breast cancers. Within the Guernsey Cohort study of 6127 women, 140 have been diagnosed with breast cancer of whom 59 had estradiol assays performed and ER status available. Estradiol levels in serum and urine were measured by radioimmunoassay and ER status of tumours by immunohistochemistry. Of the individuals in the highest tertile of serum estradiol 35% had ER+ve tumours compared with 27% in the lowest tertile. In terms of 16hydroxyestrone excretion the proportions ER+ve tumours were 22% in the lowest tertile and 38% in the highest tertile. This suggests that endogenous estrogen levels do impact on the phenotype of subsequent breast cancer.

Smoking and prognosis in women with breast cancer.

The hypothesis was that smokers might have more aggressive types of breast cancer because of either delayed diagnosis or higher grade and hence have a worse prognosis. A cohort of breast cancer patients completed a lifestyle questionnaire at the time of diagnosis, including whether they were current smokers, ex-smokers or lifelong non-smokers. Ex-smokers were asked when they had stopped. The participants were 166 women with stage I/II invasive breast cancer diagnosed between October 1984 and March 1987. Participants were divided into three groups: current smokers, ex-smokers and non-smokers. Survival curves were produced by using Cox proportional hazards analysis, with outcome variables for overall and breast cancer-specific survival together with distant relapse-free survival. Smoking was the third most important predictor of distant relapse-free, breast cancer-specific and overall survival after stage and age at diagnosis. These results suggest that smokers are not only more likely to die of other diseases, but also have a higher mortality from breast cancer, compared with those with the disease who have never smoked. The best prognosis, however, was found in those who had given up smoking.

A prospective study of serum insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding protein-3 and breast cancer risk.

The associations between serum concentrations of insulin-like growth factor-I (IGF-I), IGF-II and IGF-binding proteins (IGFBP)-3 and risk of breast cancer were investigated in a nested case-control study involving 117 cases (70 premenopausal and 47 postmenopausal at blood collection) and 350 matched controls within a cohort of women from the island of Guernsey, UK. Women using exogenous hormones at the time of blood collection were excluded. Premenopausal women in the top vs bottom third of serum IGF-I concentration had a nonsignificantly increased risk for breast cancer after adjustment for IGFBP-3 (odds ratio (OR) 1.71; 95% confidence interval (CI): 0.74-3.95; test for linear trend, P=0.21). Serum IGFBP-3 was associated with a reduction in risk in premenopausal women after adjustment for IGF-I (top third vs the bottom third: OR 0.49; 95% CI: 0.21-1.12, P for trend=0.07). Neither IGF-I nor IGFBP-3 was associated with risk in postmenopausal women and serum IGF-II concentration was not associated with risk in pre- or postmenopausal women. These data are compatible with the hypothesis that premenopausal women with a relatively high circulating concentration of IGF-I and low IGFBP-3 are at an increased risk of developing breast cancer.

Positive symptoms and the organization within and between ideas in schizophrenic speech.

The study examined the performance of positive symptom schizophrenics vis à vis that of demographically well-matched negative symptom schizophrenics and normals in organizing words into ideas and ideas into integrated spoken discourse. This involved applying a series of analyses to speech produced when describing pictures in an unconstrained way. The results showed that, for the most part, positive symptom schizophrenics organized their speech, both within and between ideas, as well as negative symptom schizophrenics and normals. The results did, however, show an increased tendency by the positive speech disordered schizophrenics to omit referents for noun phrases requiring referents. This constitutes a specific failure to connect ideas and does, at least in part, explain what makes positive speech disorder (incoherence of speech) unintelligible. However, taken altogether, the results do not support the extant view that positive symptom schizophrenics suffer from a general loss of control in producing speech.

Pregnancy and menstrual hormone levels in mothers of twins compared to mothers of singletons.

This study examined the hormonal differences between premenopausal mothers of twins and other premenopausal parous women during and after pregnancy. Serum concentrations of oestradiol and testosterone between 6 and 20 weeks of gestation were measured for 11 mothers of twins and 115 mothers of singletons selected from the controls in a case-control study of cryptorchidism. Serum concentrations of oestradiol, progesterone, testosterone, follicle stimulating hormone and sex hormone-binding globulin during the menstrual cycle were measured for 25 mothers of twins and 38 mothers of singletons recruited as a part of a prospective study of breast cancer risk. During pregnancy, women carrying twins had a 58% higher geometric mean oestradiol concentration (p = 0.02) and a 50% higher testosterone concentration (p = 0.03) than women carrying singletons. Women who had previously had twins demonstrated a 49% higher mean concentration of follicle stimulating hormone (p = 0.02) and a 42% higher concentration of sex hormone-binding globulin (p = 0.03) than women who had singletons only, but no significant differences in oestradiol, progesterone and testosterone concentrations. The increased concentrations of follicle stimulating hormone during the menstrual cycle of mothers of twins, which has also been reported in two previous studies suggests that follicle stimulating hormone level may be an important determinant of dizygotic twinning.

An immunohistochemical evaluation of c-erbB-2 expression in human breast carcinoma.

The c-erbB-2 gene codes for a putative transmembrane protein, similar in structure to the epidermal growth factor (EGF) receptor. Amplification of the gene has been described in a variety of human adenocarcinomas and is particularly well documented in breast carcinoma. It has been suggested that amplification is indicative of poor prognosis and, as such, is comparable with lymph node status as a predictor of clinical outcome. This study examines the suggestion indirectly by an immunohistochemical technique. Archival tissue from 195 patients with primary breast carcinoma was stained with the polyclonal antibody 21N, raised to amino acids 1243-1255, the C-terminus of the predicted amino acid sequence of the c-erbB-2 protein. Up to 10 year verified follow-up data were available on all patients. Staining compatible with significant amplification was observed in 17 patients. Using the chi-squared test for trend a significant correlation was found between staining and grade (P = 0.04) but not with either node or receptor status. No significant association was found between staining and clinical outcome although there was a tendency for patients with stained tumours to have a worse prognosis. A Cox regression analysis was used to adjust for node status and grade and still no correlation was revealed between staining and prognosis. However a study of this size in which only a small number of patients have been found to have stained tumours does have wide confidence limits. Comparable staining observed in in situ and infiltrating components of tumours suggests that amplification is an early event in carcinogenesis. Similar staining in primary and subsequent metastatic lesions was also noted. It is considered that further studies at both the DNA/mRNA and protein levels are required to confirm the significance of c-erbB-2 amplification in human breast carcinoma.