Effects of the environmental oestrogens bisphenol A,tetrachlorobisphenol A,tetrabromobisphenol A, 4-hydroxybiphenyl and 4,4'-dihydroxybiphenyl on oestrogen receptor binding,cell proliferation and regulation of oestrogen sensitive proteins in the human breast cancer cell line MCF-7

Bisphenol A is extensively used in the manufacturing of epoxy resins and polycarbonate plastics, whereas several brominated and chlorinated analogues are used as flame retardants and intermediates in the plastic industry. Due to the structural relationship between these chemicals and the high production volumes, we wanted to characterize and compare their potential oestrogen-like potency using several end-points in MCF-7 cells: induction of pS2 protein and progesterone receptor, reduction of oestrogen receptor level, and stimulation of cell growth. Bisphenol A, tetrachloro- and tetrabromo-bisphenol A, 4-hydroxybiphenyl and 4,4'-dihydroxybiphenyl all showed oestrogen-like properties in MCF-7 cells. The chemicals tested had affinity to the oestrogen receptor isolated from MCF-7 cells, although their EC50s were 1,000 to 80,000 times higher than the EC50 of 17beta-oestradiol. Bisphenol A and 4-hydroxybiphenyl induced cell growth in MCF-7 cells, and the highest test concentrations induced responses, apparently exceeding the cell growth induced by 17beta-oestradiol. The other chemicals tested induced less than 50% of the maximum 17beta-oestradiol-stimulated cell growth. Bisphenol A, 4-hydroxybiphenyl, tetrabromobisphenol A and tetrachlorobisphenol A all increased the level of the oestrogen-regulated proteins, progesterone receptor and pS2, whereas 4,4'-dihydroxybiphenyl showed no such effect. Bisphenol A was the only chemical tested that clearly mimicked 17beta-oestradiol in its ability to reduce the level of cytosolic oestrogen receptors in MCF-7 cells. By measuring several oestrogen-dependent endpoints it seems that some xeno-oestrogens cause an imbalanced oestrogen-response. Their ability and potency in mimicking 17beta-oestrogen in one parameter is not necessarily accompanied by a similar effect in another oestrogen-linked parameter.     

Allelic variants of cytochromes P450 2C modify the risk for acute myocardial infarction

SUMMARY: Cytochromes P450 (CYP) 2C8 and 2C9 are polymorphic enzymes responsible for the biosynthesis of vasoactive substances from arachidonic acid including endothelium-derived hyperpolarizing factor. Inter-individual differences in the action of these substances might be important in the pathogenesis of cardiovascular diseases such as acute myocardial infarction (AMI) and hypertension. This study describes the relationship between genetic variants of CYP2C8 and CYP2C9, and morbidity in myocardial infarction in a large Swedish patient material. The study included 1172 AMI patients and 1503 control subjects (matched by age, sex and residential area) who participated in the Stockholm Heart Epidemiology Program (SHEEP). Genotyping was performed by allelic discrimination using a 5'-nuclease assay for the CYP2C8 and CYP2C9 variants. To estimate associations to AMI risks, odds ratios (OR) with 95% confidence intervals (CI) were calculated. The frequencies of CYP2C8*1, 2C8*3, 2C9*1, 2C9*2 and 2C9*3 variants in the control group were 0.91, 0.095, 0.83, 0.11 and 0.065, respectively. The risk of AMI in the female individuals carrying the *2 or *3 variant alleles of CYP2C9 and that of all individuals carrying the *3 variant of CYP2C8 was higher [OR (95% CI): 1.3 (1.0-1.9), P = 0.09; 1.5 (1.0-2.2), P = 0.06 and 1.2 (1.0-1.5), P = 0.07, respectively] compared to the groups with CYP2C8*1 and CYP2C9*1. Possession of rare genetic variants of the CYP2C8 and CYP2C9 genes in females is associated with a modest increase in risk of AMI. This might be related to genetic differences in the formation of endogenous vasoregulating eicosanoids.     

Dual effects of nicotine on dopamine neurons mediated by different nicotinic receptor subtypes

Burst firing of dopaminergic neurons has been found to represent a particularly effective means of increasing dopamine release in terminal areas as well as activating immediate early genes in dopaminoceptive cells. Spontaneous burst firing is largely controlled by the level of activation of NMDA receptors in the ventral tegmental area (VTA) as a consequence of glutamate released from afferents arising mainly in the prefrontal cortex. Nicotine has been found to effectively increase burst firing of dopaminergic cells. This effect of nicotine may be due to an alpha 7 nicotinic receptor-mediated presynaptic facilitation of glutamate release in the VTA. By the use of in-vivo single-cell recordings and immunohistochemistry we here evaluated the role of alpha 7 nicotinic receptors in nicotine-induced burst firing of dopamine cells in the VTA and the subsequent activation of immediate early genes in dopaminoceptive target areas. Nicotine (0.5 mg/kg s.c.) was found to increase firing rate and burst firing of dopaminergic neurons. In the presence of methyllycaconitine (MLA, 6.0 mg/kg i.p.) nicotine only increased firing rate. Moreover, in the presence of dihydro-beta-erythroidine (DH beta E, 1.0 mg/kg i.p.), an antagonist at non-alpha 7 nicotinic receptors, nicotine produced an increase in burst firing without increasing the firing rate. Nicotine also increased Fos-like immunoreactivity in dopamine target areas, an effect that was antagonized with MLA but not with DH beta E. Our data suggest that nicotine's augmenting effect on burst firing is, indeed, due to stimulation of alpha 7 nicotinic receptors whereas other nicotinic receptors seem to induce an increase in firing frequency.     

Modified fatty acids and their possible therapeutic targets in malignant diseases

Fatty acids and other lipids have multiple roles in the cell, functioning as structural components, participating in intracellular signalling and serving as metabolic fuel. Various compounds that influence cellular lipid metabolism can reduce the growth of malignant cells, and dietary as well as pharmacological strategies for modulating lipid metabolism have therefore been suggested as possible approaches for cancer prevention and treatment. By chemically modifying fatty acids (e.g., butyrates, retinoids), new potential anticancer agents have been produced that possess increased metabolic stability and more specific and potent biological activity compared to the natural fatty acids. Possible therapeutic targets for such modified fatty acids include: i) Histone deacetylase; ii) nuclear hormone receptors (retinoid receptors), peroxisome proliferator-activated receptors; iii) cyclooxygenase-2; iv) intracellular signalling involving protein farnesylation and Ras activation; and v) various mitochondrial functions. Although several fatty acid derivatives have been thoroughly investigated in experimental models, clinical data on toxicity and pharmacological interactions are not available for the majority of these agents. However, several promising novel compounds are now being evaluated in preclinical and early clinical studies, and future research will hopefully reveal new formulations and therapy schedules that will improve the outcome of patients with malignant disorders.     

Serum concentrations and effects of gabapentin and vigabatrin: observations from a dose titration study

To explore possible concentration-effect relationships, gabapentin (GBP) and vigabatrin (VGB) serum concentrations were obtained from patients participating in an add-on dose-titration trial comparing GBP and VGB in partial epilepsy. Patients randomized to GBP started on 1800 mg/d and could have their dosage increased stepwise to 2400 and 3600 mg/d if seizures persisted. Those randomised to VGB started on 1000 mg/d, and the dose could be increased to 2000 and 4000 mg/d. Blood samples were obtained at steady state, at a nonstandardized time, from 27 patients randomized to GBP and from 36 randomized to VGB. Serum samples were analyzed using high-performance liquid chromatography. The treatment effect was expressed as percentage reduction in number of seizures from baseline. In addition, patients were classified as responders (>50% reduction in number of seizures from baseline) or nonresponders. There was no significant correlation between serum concentrations of GBP and seizure reduction at the lowest dosage, 1800 mg/d (r = -0.02, P = 0.94, Spearman-rank), nor between VGB serum levels and seizure reduction at 1000 mg/d of VGB (r = -0.14, P = 0.44). The serum GBP concentrations among responders to GBP 1800 mg/d were 26 +/- 12 micro mol/L (mean +/- SD), which was not different from serum concentrations in nonresponders, 28+/-13 micro mol/L. Nor was there a difference between serum concentrations of responders and nonresponders to VGB 1000 mg/d (32 +/- 23 and 44 +/- 36 micro mol/L, respectively). Hence, with the present study design we were unable to identify specific target ranges of GBP and VGB serum concentrations.     

Therapeutic drug monitoring of the newer antiepileptic drugs

The aim of the present review is to discuss the potential value of therapeutic drug monitoring (TDM) of the newer antiepileptic drugs (AEDs) felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, and zonisamide. Studies of the relationship between serum concentrations and clinical efficacy of these drugs are reviewed, and the potential value of TDM of the drugs is discussed based on their pharmacokinetic properties and mode of action. Analytical methods for the determination of the serum concentrations of these drugs are also briefly described. There are only some prospective data on the serum concentration-effect relationships, and few studies have been designed primarily to study these relationships. As TDM is not widely practiced for the newer AEDs, there are no generally accepted target ranges for any of these drugs, and for most a wide range in serum concentration is associated with clinical efficacy. Furthermore, a considerable overlap in drug concentrations related to toxicity and nonresponse is reported. Nevertheless, the current tentative target ranges for felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine (10-hydroxy-carbazepine metabolite), tiagabine, topiramate, vigabatrin, and zonisamide are 125 to 250 micromol/L, 70 to 120 micromol/L, 10 to 60 micromol/L, 35 to 120 micromol/L, 50 to 140 micomol/L, 50 to 250 nmol/L, 15 to 60 micromol/L, 6 to 278 micromol/L, and 45 to 180 micromol/L, respectively. Further systematic studies designed specifically to evaluate concentration-effect relationships of the new AEDs are urgently needed. Although routine monitoring in general cannot be recommended at present, measurements of some of the drugs is undoubtedly of help with individualization of treatment in selected cases in a particular clinical setting.     

Investments in social capital--implications of social interactions for the production of health

This paper develops a theoretical model of the family as producer of health- and social capital. There are both direct and indirect returns on the production and accumulation of health- and social capital. Direct returns (the consumption motives) result since health and social capital both enhance individual welfare per se. Indirect returns (the investment motives) result since health capital increases the amount of productive time, and social capital improves the efficiency of the production technology used for producing health capital. The main prediction of the theoretical model is that the amount of social capital is positively related to the level of health; individuals with high levels of social capital are healthier than individuals with lower levels of social capital, ceteris paribus. An empirical model is estimated, using a set of individual panel data from three different time periods in Sweden. We find that social capital is positively related to the level of health capital, which supports the theoretical model. Further, we find that the level of social capital (1) declines with age, (2) is lower for those married or cohabiting, and (3) is lower for men than for women.     

Induced abortion and risk of subsequent miscarriage

BACKGROUND: To evaluate the impact of surgically induced first-trimester abortion on the risk of miscarriage in a subsequent pregnancy. METHODS: The study is a pregnancy cohort study. It was conducted among 15 general hospitals or maternity and infant health institutes in Shanghai, China from November 1993 to March 1998. The abortion cohort consisted of pregnant women whose previous pregnancies were terminated by vacuum aspiration (98%). The reference cohort consisted of primigravidae. Subjects were recruited at 35-63 days of gestational age. A total of 2953 pregnant women were enrolled; 1502 in the abortion cohort, 1451 in the reference cohort. RESULTS: There were only 62 women lost to follow-up. The remaining 2891 women had 2732 live births, and 137 miscarriages. About 5.5% of pregnancies in the abortion cohort were miscarried and 4.0% in the reference cohort. Once potential confounders were controlled for by logistic regression, odds ratio (OR) of miscarriage between the abortion cohort and the reference cohort was 1.55 (95% CI: 1.08-2.23). The adjusted OR were 2.44 (95% CI: 1.16-5.15) among women who were recruited within 49 days of gestational age, and 1.72 (95% CI: 1.09-2.72) for the first-trimester miscarriage. CONCLUSIONS: Induced abortion by vacuum aspiration is associated with an increased risk of first-trimester miscarriage in the subsequent pregnancy.     

Annoyance and performance during the experimental chemical challenge of subjects with multiple chemical sensitivity

OBJECTIVES: This study explored the subjective reactions and psychological test performance of smell-intolerant subjects during consecutive challenges to chemicals with contrasting neurotoxic properties. METHODS: Women with symptoms compatible with multiple chemical sensitivity (N=10) and healthy referents (N=20) were individually challenged in an exposure chamber. All the subjects attended two separate 2-hour sessions of exposure to n-butyl acetate and toluene, in counterbalanced sequence. After an initial phase without exposure, air concentrations were increased in steps ranging from 3.6 to 57 mg/m3 for n-butyl acetate and from 11 to 180 mg/m3 for toluene. The response measures comprised ratings of annoyance and smell intensity and also neurobehavioral test performance. RESULTS: Both groups showed an increase in annoyance ratings and a decrease in test performance in the initial unexposed chamber phase and also in the first phase of the chemical exposure, these results indicating slight immediate expectancy or "suggestion" effects. During the six chamber phases, the ratings of mucous membrane irritation and fatigue showed a steeper increase in the group with multiple chemical sensitivity than among the referents, while the ratings of smell intensity and smell annoyance were similar in the two groups. A reduction in test performance was observed during the chamber phases, particularly in the group with multiple chemical sensitivity. No relation was found between the ratings or performance and chemical substance. CONCLUSIONS: Stronger immediate expectancy or "suggestion" reactions than normal did not characterize the group with multiple chemical sensitivity. This group showed a stronger than normal gradual build-up of fatigue, mucous membrane irritation, and reduced performance during chemical exposure. The results offer the most support to an irritative basis for multiple chemical sensitivity.