Organochlorine exposure and risk of breast cancer

BACKGROUND: Some organochlorine compounds may have weak oestrogenic effects and are, therefore, suspected of increasing the risk of breast cancer. We assessed prospectively the risk of breast cancer in relation to serum concentrations of several organochlorine compounds. METHODS: In 1976, serum samples from 7712 women were obtained from participants in the Copenhagen City Heart Study as part of physical examinations and interviews about lifestyle factors. During 17 years of follow-up, 268 women developed invasive breast cancer. Each woman with breast cancer was matched with two breast-cancer-free women from the remaining cohort. We analysed in 1996-97 the serum samples from 240 women with breast cancer and 477 controls. FINDINGS: Dieldrin was associated with a significantly increased dose-related risk of breast cancer (adjusted odds ratio 2.05 [95% CI 1.17-3.57], p for trend 0.01). Beta-hexachlorocyclohexane increased risk slightly but not significantly (p for trend 0.24). There was no overall association between risk of breast cancer and p,p'-dichlorodiphenyltrichloroethane or metabolites or for polychlorinated biphenyls. Exclusion of women with breast cancer diagnosed within 5 years of blood sampling strengthened the result for dieldrin, but did not affect the other results. INTERPRETATION: These findings support the hypothesis that exposure to xeno-oestrogens may increase the risk of breast cancer.     

A novel class of adenosine A3 receptor ligands. 2. Structure affinity profile of a series of isoquinoline and quinazoline compounds

A series of 3-(2-pyridinyl)isoquinoline derivatives was synthesized as potential antagonists for the human adenosine A3 receptor by substitution of the 1-position. The compounds were obtained by various synthetic routes from 1-amino-3-(2-pyridinyl)isoquinoline. The affinity was determined in radioligand binding assays for rat brain A1 and A2A receptors and for the cloned human A3 receptor. A structure-activity relationship analysis indicated that a phenyl group when coupled by a spacer allowing conjugation on position 1 of the isoquinoline ring increased the adenosine A3 receptor affinity. In contrast, such a phenyl group directly bound to position 1 of the isoquinoline ring decreased affinity. Since the combination of a phenyl group together with a spacer raised adenosine A3 receptor affinity, various spacers were investigated. VUF8501 (N-[3-(2-pyridinyl)isoquinolin-1-yl]benzamidine (15) showed an affinity at the human adenosine A3 receptor of 740 nM. Substituent effects on the phenyl group were investigated by in vitro evaluation of a series of substituted benzamidines. Electron-donating groups at the para position of the benzamidine ring increased adenosine A3 receptor affinity. These investigations led to VUF8505 (4-methoxy-N-[3-(2-pyridinyl)isoquinolin-1-yl]benzamidine(22)), which is a moderately potent and selective ligand for the human adenosine A3 receptor with an affinity of 310 nM in our test system having negligible affinity for rat A1 and A2A receptors.     

Periodontal implications in implant treatment planning for aesthetic results

Insufficient hard and soft tissue height and width can be a repercussion of tooth loss or a result of postoperative healing following implant surgery. Insufficient bone can preclude proper implant positioning, while inadequately treated soft tissue will not exhibit a gingival appearance similar to that of the adjacent teeth. If hard and soft tissue discrepancies are not corrected by regenerative techniques, the replaced tooth appears long or overbulked gingivally. In order to create hard and soft tissue harmony, an understanding of the biological variables and periodontal implications is necessary.     

Prefrontal cortex involvement in selective letter generation: a functional magnetic resonance imaging study

Leech neurons exposed to salines containing inorganic Ca(2+)-channel blockers generate rhythmic bursts of impulses. According to an earlier model, these blockers unmask persistent Na+ currents that generate plateau-like depolarizations, each triggering a burst of impulses. The resulting increase in intracellular Na+ activates an outward Na+/K+ pump current that contributes to burst termination. We tested this model by examining systematically the effects of six transition metal ions (Co2+, Ni2+, Mn2+, Cd2+, La3+, and Zn2+) on the electrical activity of neurons in isolated leech ganglia. Each ion induced bursting activity, but the amplitude, form, and persistence of bursting differed with the ion used and its concentration relative to Ca2+. All ions tested suppressed chemical synaptic transmission between identified motor neurons, consistent with block of voltage-dependent Ca2+ currents in these cells. In addition, a strong correlation between suppression of synaptic transmission and burst amplitudes was obtained. Finally, burst duration was increased and the rate of repolarization decreased in reduced K+ saline, as expected for pump-dependent repolarization. These results provide further support for the hypothesis that a novel form of oscillatory electrical activity driven by persistent Na+ currents and the Na+/K+ pump occurs in leech ganglia exposed to Ca(2+)-channel blockers.     

Multimodality treatment for gastric carcinoid tumor with liver metastases

Carcinoid tumors are the most common neuroendocrine tumors in the gastrointestinal tract, and between 10% and 30% of these tumors are gastric in origin. Three types of gastric carcinoid tumors are recognized: type I, associated with chronic atrophic gastritis type A; type II, associated with multiple endocrine neoplasia; and type III, sporadic and the most malignant. We present a patient with an aggressive, sporadic-type gastric carcinoid that metastasized to the liver. Her symptomatic treatment included the somatostatin analog octreotide. Octreotide scintigraphy demonstrated that this tumor avidly bound the peptide. The patient's gastric carcinoid (assessed by endoscopy and endoscopic ultrasound) regressed and she underwent hepatic artery embolization for her liver metastases. After initial partial CT resolution the tumor grew, compressing the inferior vena cava. The patient underwent orthotopic liver transplant with excellent recovery, although she was subsequently found to have two small lung metastases. She has responded well to adjuvant Indium-111 octreotide receptor targeted therapy. This case highlights the therapeutic options for metastatic neuroendocrine tumors, including liver transplantation and adjuvant receptor targeted therapy.     

Sequence comparison of outer membrane phospholipases A: implications for structure and for the catalytic mechanism

OBJECTIVES: The preferences for high-fat foods are believed to be based on their sensory attributes and energy density; however less is known about how such preferences might be weakened, other than in response to deterioration in flavor or textural quality. The aim of the present study was to see whether acceptability of reduced fat/energy foods would wane as the original post-ingestive nutritional benefits are reduced when palatability remains essentially constant. DESIGN: Repeated measures, within-subjects design conducted in two counterbalanced three week trials. SETTING/SUBJECTS: Sixteen normal-weight males (mean age 25.8 +/- 1.2 y) came to our laboratory at the H?pital Hotel Dieu in Paris to eat an afternoon snack on 13 consecutive days (excluding weekends). INTERVENTION/OUTCOME MEASURES: Intake was recorded following repeated exposure to two flavors of standard (10% fat as a percentage of total solids weight), and low (3%) fat ice cream. One group received standard vanilla or low-fat strawberry ice cream on alternate days for two consecutive weeks; these flavor associations were reversed for a second group. The two flavors were rated as equipalatable at the beginning of the experiment at all energy levels. RESULTS: Subjects consumed the same quantity of ice cream throughout the experimental period, independent of energy density or flavor. Consequently, aggregate (summed) energy intake for subjects consuming low-fat ice cream was significantly lower (by 581 kJ (139 kcal), 15.4 g fat). Food intake records for the 24 h period immediately following the test sessions revealed no compensation for fat or energy. Despite the 28% reduction in energy density for the low-fat version, acceptance for the flavors associated with the reduced-energy versions had not declined by the end of the experimental period. CONCLUSIONS: The findings suggest that acceptance of reduced-fat foods may not be critically dependent on the post-ingestive metabolic effects when the reductions in energy density are small. Further tests with more severe reductions, and perhaps over more prolonged time periods, will be necessary to determine at what level of substitution acceptance might begin to deteriorate.     

Role of thrombolytic therapy in the treatment of patients with unstable angina

Thrombolytic therapy (TT) was performed in 39 of 81 patients with unstable angina pectoris (UAP) resistant to conventional treatment. TT was found to improve prognosis of UAP, to quicken UAP stabilization. Predictors of UAP unfavorable course were discovered. TT is indicated in patients suffering from resistant UAP with markers of poor prognosis.     

Hysterectomy in a Danish population. Weight-related factors, psychological factors and life style variables

The aim was to assess risk factors for hysterectomy performed for benign conditions. In a prevalence study, 2301 Danish women were selected at random in 1982. Information about weight and slimming history, life-styles, psychological factors, gynaecological history, and social background were obtained. In an incidence study, the cohort was followed from 1982 to 1990 to assess the incidence of hysterectomy. In the prevalence study, weight cycling (recurrent weight loss and weight gain of more than 5 kg) was associated with hysterectomy for benign disease (adjusted odds ratio 1.77, 95% confidence interval 1.05-2.99) independently of overweight, smoking, oral contraceptives, psychological and social factors. In the incidence study, weight cycling was the only significant weight-related risk factor for hysterectomy performed for benign disease (adjusted relative risk 2.49, 95% confidence interval 1.10-5.60), explaining the relation between hysterectomy and psychological factors. Weight cycling might be an important risk factor for premenopausal hysterectomy performed for benign conditions.     

Measurement of styrene oxide in polystyrenes, estimation of migration to foods, and reaction kinetics and products in food simulants

The concentration of styrene-7,8-oxide has been measured in nine base resins and 16 samples of polystyrene articles intended for food contact. The epoxide was not detected in the resins (limit of detection 0.5 mg/kg) but was found in 11 of the 16 packaging samples at up to 2.9 mg/kg. Assuming that the propensity of styrene oxide to migrate is the same as styrene monomer, and using existing survey data for styrene monomer in packaging and foods, the migration levels expected for styrene oxide were calculated. Estimates were from 0.002 to 0.15 microgram/kg styrene oxide in foods. The stability of styrene oxide in the four standard EU food simulants was studied at 40, 100, 150 and 175 degrees C, to establish the transformation products to be expected following migration testing. The half-life at 40 degrees C in distilled water, 15% aqueous ethanol, 3% aqueous acetic acid and olive oil was 15, 23, < 1, > 2000 hr, respectively. The principal product was the diol from hydrolysis of the epoxide group. Ring opening in aqueous ethanol simulant gave the diol and also the glycol monoethyl ether. It is concluded that this instability of styrene oxide will reduce concentrations in foods, from an already low migration level to even lower levels with the formation of hydrolysis products that are less toxic than the parent epoxide.