Management of large perforations of the sinus mucosa with PRGF-Endoret® platelet concentrate.

The aim of the present study is to describe a new technique through which it is possible to complete the maxillary sinus lift procedure even in case of severe damage or complete removal of the sinus mucosa using the PRGF-Endoret® platelet concentrate. Eighteen patients (ratio F:M=4:5; average age: 58.2 years; DS: 8.85 years) with severe perforation (more than 10 millimetres of diameter) of the sinus mucosa during the maxillary sinus lift procedure were selected. Normally the procedure is interrupted due to impossible stabilization of the graft material inside the subantral cavity. On the contrary, our protocol foreseen the sealing of the perforation using the PRGF autologous gel membranes or the creation of a new sinus pseudomembrane through which the graft material was covered. The PRGF-Endoret were obtained according to the protocol developed by BTI (Biotechnology Institute - Vitoria, Spain). In 14 cases out of 18 implant fixtures were concurrently inserted while in 4 cases the fixture insertion was postponed after 6 months: 37 fixtures were inserted (27 at the same time and 10 after 6 months). 2 months after surgery the CBCT showed a correct pneumatization of the maxillary sinus in 16 patients out of 18 (89% of cases), while after 12 months the radiological normalization of the maxillary sinus was present in 17 patients out of 18, bringing the healing rate to 94% of cases. Regarding implant healing, 2 out of 37 implants inserted were lost in the first month after the surgical phase, whereas 12 months after prosthesis application the other 35 implants were perfectly osteointegrated with a healing rate equal to 94.6% of the fixtures. 36 months after the surgery all the fixtures were osteointegrated (35 of 37 implants with a percentage of 94.6% of success). We may conclude that the use of PRGF allowed to complete the sinus lift even in case of severe perforation of the sinus mucosa or its total removal thanks to its capability to stabilize the graft, its antibacterial and antifungal activity and its anabolic effect and favouring bone regeneration.

Analysis of the foot load in subjects with prevalent unilateral chewing.

The relationship between occlusion and posture has been and is still strongly debated. This study examines 40 male and female healthy subjects, (11 males and 29 females, average age: 26.27 years, st dv: 3.03) aged between 21 and 32. The baropodometric evaluation was performed with the subject in rest position and in usual centric occlusion. The results obtained were analyzed using a baropodometric platform and Freesteps software (Sensor Medica srl, Rome - Italy) analyzing the podalic load, the foot axis and the foot angles. The values reported show that 80% of subjects in rest position (p-value 0.01) and 70% of subjects in centric occlusion (p-value 0.05) have a greater foot load in the contralateral foot compared to the chewing side; moreover, the foot axis values are statistically significant because 77% of subjects in rest position and 72% in centric occlusion have a foot axis more open on the same side than the chewing one. The foot angles values are not significant. These results could be understood analyzing the activation of the body muscular chains: on the chewing side there is an increase of the activity of the flexion chain with side bending of the trunk. This induces a change of the body barycenter compensated by an outer rotation of the homolateral leg and foot; moreover, the body bending creates a false short leg on the same side, explaining the excess of podalic load on the other side. These values show that the hypothesis of a correlation appears to be likely, although obviously it still needs confirmation and further analysis.

Impact of a premature menopause on cognitive function in later life.

OBJECTIVE: To determine whether premature menopause (≤40 years) can have long-lasting effects on later-life cognition and investigate whether this association varies depending on the type of menopause and use of hormone treatment (HT). DESIGN: Population-based cohort study. SETTING: The French Three-City Study. POPULATION: Four thousand eight hundred and sixty-eight women aged at least 65 years. METHODS: Multivariable-adjusted logistic regression models were used to determine the association between age at menopause, type of menopause (surgical, natural), and the use of menopausal HT and later-life cognitive function. MAIN OUTCOME MEASURES: Performance on a cognitive test battery (at baseline and over 7 years) and clinical dementia diagnosis. RESULTS: Menopause at or before the age of 40 years, both premature bilateral ovariectomy and premature ovarian failure (non-surgical loss of ovarian function), was associated with worse verbal fluency (OR 1.56, 95%CI 1.12-1.87, P=0.004) and visual memory (OR 1.39, 95%CI 1.09-1.77, P=0.007) in later life. HT at the time of premature menopause appeared beneficial for later-life visual memory but increased the risk of poor verbal fluency. Type of menopause was not significantly associated with cognitive function. Premature menopause was associated with a 30% increased risk of decline in psychomotor speed and global cognitive function over 7 years. CONCLUSION: Both premature surgical menopause and premature ovarian failure were associated with long-term negative effects on cognitive function, which are not entirely offset by menopausal HT. In terms of surgical menopause, these results suggest that the potential long-term effects on cognitive function should form part of the risk/benefit ratio when considering ovariectomy in younger women.

Rapid and deep control of inflammation in rheumatoid arthritis with infliximab and its correlation with acute-phase reactants.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with predominant joint involvement and possible systemic compromise, which leads to a handicapped status and poor quality of life. An optimal approach to treat RA requires early and intensive intervention with close monitoring of treatment response. Tumor necrosis factor (TNF) blockers are recommended in cases of active RA after the unsuccessful use of effective disease-modifying antirheumatic drugs (DMARDs); even adding them to treatment or replacing these drugs. Anti-TNF therapies have been demonstrated to reduce significant joint damage and to relieve symptoms during a prolonged time (see Scott and Kingsley, 2006). The efficacy of infliximab in an open-label trial is summarized with respect to speed of onset of action, durability of response, and its correlation between clinical and laboratory parameters. Safety for long-term treatment is also summarized. We studied 105 RA patients with more than 3 years' history of disease during 24 months on i.v. infliximab (75 completed study). We evaluated ACR responses at base line, and at 1, 6, 12, 16, 52, 77, and 104 weeks. Morning stiffness, swollen and tender joints, HAQ, SF-36% (PCS/MCS), polymerase chain reaction (PCR), erythrosedimentation rate (ESR), transaminases, rheumatoid factor (RF) levels, hemogram, and adverse events profile were all assessed. The treatment offered rapid and sustained clinical improvements as revealed by ACR responses and marked changes in the parameters previously described. Important changes were made in functional status and acute-phase reactants. Finally, infliximab was considered well tolerated and did not affect the safety profile of this trial.

Biological and psychological predictors of posttraumatic stress disorder onset and chronicity. A one-year prospective study.

BACKGROUND: Few studies have prospectively examined risk factors for posttraumatic stress disorder (PTSD) in the aftermath of a traumatic exposure. The aim of this study is to identify the concurrent influence of psychological and biological diatheses on PTSD onset and maintenance, taking into account socio-demographic factors and psychiatric antecedents. METHODS: A total of 123 civilians (61.8% of women) recruited in emergency units, were assessed using validated instruments during the first week and then at 1, 4, and 12 months post-trauma. Baseline assessment included evaluation of the psychological diathesis (i.e. psychiatric history and peritraumatic distress and dissociation), and the biological diathesis [i.e. cortisol, norepinephrine, epinephrine, c-reactive protein, total cholesterol, HDL cholesterol, glycosylated haemoglobin, waist-to-hip ratio (WHR), body mass index, diastolic and systolic blood pressure (SBP), and heart rate]. RESULTS: Multivariate logistic regression analyses demonstrated both psychological and biological diatheses to be independent risk factors for PTSD. Peritraumatic distress and dissociation predicted onset (1-month) and mid-term PTSD (4-months), respectively. PTSD risk was associated positively with SBP and negatively with WHR, throughout the follow-up. In addition, a higher level of 12 h-overnight urinary norepinephrine independently predicted mid-term PTSD (4-months). CONCLUSIONS: This prospective study shows that peritraumatic psychological and biological markers are independent predictors of PTSD onset with specificities according to the stage of PTSD development; the psychological diathesis, i.e. peritraumatic distress and dissociation, being a better predictor of short-term dysfunction whereas biological diathesis was also predictive of development and maintenance of PTSD.

Open-label 24-month study evaluating infliximab therapy in patients with psoriatic spondyloarthropathy.

Psoriatic spondyloarthropathy (PsSA) is a common and relatively typical form of spondyloarthropathy, affecting the axial skeleton with peripheral synovitis. Also, extraarticular as well as skin manifestations are sometimes difficult to diagnose and to treat. Recent studies demonstrated that anti-tumor necrosis factor therapies are useful in treating and controlling disease activity. We conducted an open-label 2-year study in 16 patients to evaluate the efficacy and safety of long-term compliance with intravenous infliximab therapy in patients with severe skin and refractory PsSA, with an incomplete response to methotrexate, azathioprine, cyclosporine, and/or sulfasalazine. Patients continued to receive only weekly methotrexate therapy during the study that included 16 patients (9 men, 7 women; mean age 38 +/- 12.5 years [SD]) with psoriatic spondyloarthropathy for 16.4 +/- 9.2 years. Each patient underwent complete physical examination before treatment and at each visit until the end of the study. Results of patient global pain assessment (VAS scale), investigator opinion on global assessment of disease activity (100 mm VAS), patient body weight and blood pressure, ACR response (20%, 50%, and 70%), laboratory parameters (CRP, ESR, WBC, RBC, liver enzymes, etc.), and PASI (skin score) were recorded. We conclude that infliximab therapy was effective in controlling joint and skin disease, having an acceptable safety profile and very good compliance when considering this type of patient. However, further long-term, double-blind, placebo-controlled trials are necessary to validate these results.

Tumor progression and oxidant-antioxidant status.

We previously reported on a paradoxical oxidant-antioxidant status in breast cancer patients, more so in pre-menopausal than menopausal women. In this study, measurements were performed on 146 patients with various carcinomas. Vitamin E/total cholesterol increased and plasma malondialdehyde decreased with tumor size and progression. To investigate the difference between young pre-menopausal and aged menopausal breast cancer patients, the same measurements were performed in 365 breast cancer patients according to pathology, tumor size and estrogen receptors. The oxidant-antioxidant status varied with these prognosis factors in the same pattern, and was more pronounced in young than aged women.

Relationship of serum cholesterol, dietary and plasma beta-carotene with lung cancer in male smokers.

It has been hypothesized that beta-carotene mediates the association between low serum cholesterol levels and increased risk of lung cancer. It follows from this assumption that this association should be greater in population strata with a low intake of beta-carotene than in with those with a high intake. To investigate this hypothesis, we analysed dietary beta-carotene, plasma beta-carotene and serum cholesterol levels in 20 male smokers with lung cancer and 103 male smoking controls, a subsample taken from a larger case-control study on oxidant-antioxidant status. As predicted, we found that the association between low serum cholesterol levels and lung cancer risk was greater in subjects with low plasma beta-carotene. Controlling for plasma beta-carotene decreased but did not negate the magnitude of the inverse association between serum cholesterol and lung cancer. A low serum cholesterol level tended to increase the risk associated with low plasma beta-carotene. Our data suggest that a low plasma beta-carotene does not totally explain the association between serum cholesterol and lung cancer.

Profiles of a healthful diet and its relationship to biomarkers in a population sample from Mediterranean southern France.

OBJECTIVES: The failure of single-nutrient supplementation to prevent disease in intervention studies underlines the necessity to develop a holistic view of food intake. The objectives of this study were to devise a diet quality index (DQI) and identify biomarkers of multidimensional dietary behavior. DESIGN: A nutrition survey was conducted in Mediterranean southern France by means of a food frequency questionnaire. The DQI was based on current dietary recommendations for prevention of diet-related diseases such as cardiovascular disease and some cancers. A second DQI included tobacco use. STATISTICAL ANALYSES: performed Spearman rank correlations, cross-classifications and intraclass correlations were computed between the DQI and biomarkers. RESULTS: Of the 146 subjects, 10 had a healthful diet and 18 had a poor diet. Erythrocyte omega-3 fatty acids-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-beta carotene, and vitamin E concentrations were lower and cholesterol concentrations were higher in the poor diet; the difference was significant for EPA and DHA and borderline significant for vitamin E. Significant correlation was found between the DQI and vitamin E (-0.12), EPA (-0.30), and DHA (-0.28), and beta carotene (-0.17) when tobacco use was considered, but not between the DQI and cholesterol. The correlation coefficient reached 0.58 (P0.01) for a composite index based on all biomarkers except cholesterol. CONCLUSIONS: Subjects with a beta carotene levels greater thanl micromol/L, vitamin E greater than 30 micromol/L and EPA greater than 0.65% and DHA greater than 4% of fatty acids in erythrocytes were likely to have a healthful diet. Each biomarker indicated the quality of diet, but correlation was higher with a composite index.

Comparison of dietary assessment methods in a southern French population: use of weighed records, estimated-diet records and a food-frequency questionnaire.

OBJECTIVE: The main objective of the study was to develop appropriate dietary assessment instruments for the French Mediterranean region and to validate the measurements they provide. SUBJECTS AND METHODS: Three different assessment methods were submitted to a sample of 150 male and female volunteers. 98 completed the protocol, which consisted of a 4 d weighed dietary record (PETRA) and a 7 d estimated-diet record (S7) based on a check list and a set of photographs, both these records being completed once in each season of the year, and a semi-quantitative (standard portion) food-frequency questionnaire (FFQ) including questions eliciting socio-demographic and anthropometric data, which was completed once only. The days when PETRA was used to evaluate food consumption coincided with the first 4 d of S7 (S4). RESULTS: Validation was based on nutrients and foods. Energy-adjusted Pearson correlation coefficients between S4 and PETRA ranged from 0.32 for vitamin E to 0.81 for vitamin C (mean: 0.65 for 21 nutrients). There was practically no misclassification in opposite extreme quartiles. Spearman correlation coefficients ranged from 0.63 for fish and sea-food to 0.90 for wine (mean: 0.76 for 16 food groups). There was practically no misclassification in opposite extreme quartiles. De-attenuated energy-adjusted Pearson correlation coefficients between FFQ and S7 ranged from 0.22 for proteins and monounsaturated fatty acids to 0.80 for iron (mean: 0.45). 10% or less of subjects were misclassified in opposite extreme quartiles (except for vitamin C, 12%). Spearman correlation coefficients ranged from 0.25 for green-yellow-red raw vegetables to 0.76 for wine (mean: 0.42). 8% or less of subjects were misclassified in opposite extreme quartiles (except for citrus fruit, 11%). CONCLUSIONS: Portion estimation using the set of photographs was validated by the correlation between S4 and PETRA for both nutrients and foods. The FFQ provides a reasonably reliable measure of macronutrient intake and a good measure of micronutrient intake when compared with the data in the literature. It performs less well for food intake. Better results can be achieved for FFQ: (i) by using the set of photographs instead of standard portions and (ii) by adding further questions on foods which are insufficiently covered.

A comparison of dietary behaviour in Central England and a French Mediterranean region.

UNLABELLED: BJECTIVEe: The investigation involves comparison of dietary behaviour between UK and Mediterranean France by characterizing the pattern of the current French Mediterranean diet compared with the current British diet. DESIGN: The findings of two dietary surveys, one in the UK and one in France, are compared. An interviewer-administered questionnaire was used in both countries. Questions on food frequency were used to assess dietary behaviour, which were regrouped in the French survey to correspond with UK groupings. Dietary indices were constructed to describe dietary behaviour in relation to cancer recommendations for intake of fat, fibre, meat, fruit and vegetables. SETTING: The UK study was conducted in Leicestershire, central England and the French study was carried out in Hérault, southern France. SUBJECTS: UK: n=418 subjects (57.9% female and 42.1% male; mean age=45.0 y); France: n=635 subjects (50.1% female and 40.9% male; mean age=49.8 y). Age range of both samples: 20-74 y. RESULTS: There were positive and negative trends in food consumption in each country. UK respondents reported eating more beans and pulses (P=0.000), less cheese (P=0. 000), red meat (P=0.001), and processed meats (P=0.000) than French respondents. However, on the negative side, they ate less fruit and vegetables (P=0.000), fish and poultry (P=0.000), cereals (P=0.000), and more sweets and chocolates (P=0.000), and cakes, pastries, biscuits and puddings (P=0.000). Women had healthier diets in both countries. CONCLUSIONS: Overall the southern French diet was healthier as French respondents scored significantly better for indices for fat, dietary fibre, fruit and vegetables (P=0.000 in all cases). However, the French sample scored poorer for the meat index (P=0.000). SPONSORSHIP: This study was supported by a grant from l'Association de la Recherche contre le Cancer (ARC) awarded to M Holdsworth.

Within-subjects seasonal variation and determinants of inter-individual variations of plasma beta-carotene.

We studied determinants of plasma beta-carotene in a sample of 98 normal volunteers. Blood samples were collected and 4-day weighed dietary records kept for each season of the year. Information on tobacco use and demographic and socio-economic data was elicited at the first interview. There was a peak of plasma beta-carotene in the fall, whereas the dietary beta-carotene peak occurred in summer. In a regression analysis involving a variety of independent variables, the only statistically significant determinants of plasma beta-carotene for non-smokers were dietary beta-carotene, sex, serum cholesterol and triglycerides. The number of cigarettes/day was introduced into the model for smokers and a significant negative coefficient was obtained for this variable. Interaction between dietary beta-carotene and tobacco use was shown to be a significant determinant of plasma beta-carotene for the total sample.

[Alcohol consumption by young adults from three cities in Southern France]. / La consommation d'alcool de jeunes adultes dans trois villes du Sud de la France.

AIM: To identify potential factors of change in alcohol consumption and regional differences which could explain why and how habits are evolving. SUBJECTS AND METHODS: Four hundred and thirty three subjects aged 20 to 34 years, were recruited by random sampling in Marseilles, Montpellier and Toulouse. A quantitative food frequency questionnaire was used to collect data on alcohol consumption. A stepwise logistic regression was applied to the total sample, to the sub-sample of drinkers, and to the sub-samples of drinkers of each type of alcoholic beverage. Factors associated with each type of alcoholic consumption were analyzed by city. RESULTS: Montpellier and Toulouse samples were pooled because of the similarity in alcoholic consumption, which was different from that in Marseilles. There are significantly more drinkers in Montpellier/Toulouse than in Marseilles (74.4% versus 53.8%; p=0.001) and also more binge drinking subjects (31.1% versus 10.3%; p=0.001). Age, tobacco, leisure physical activity are independently associated with alcoholic consumption, female sex and Marseilles, being inversely associated. These two last factors are similarly associated with binge drinking, as well as age. CONCLUSION: The study of the factors for alcoholic consumption by site suggests that differences in behavior could explain these results. These distinct characteristics should be considered when implementing anti-alcoholic prevention in youth.

Angiotensin-converting enzyme gene variants are associated with both cortisol secretion and late-life depression.

Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis, which shows hyperactivity in depressed patients. ACE could thus be a promising candidate gene for late-life depression but this has not been examined previously. Depression was assessed in 1005 persons aged at least 65 years, at baseline and over the 10-year follow-up. A clinical level of depression (DEP) was defined as having a score of > or =16 on the Centre for Epidemiology Studies-Depression scale or a diagnosis of current major depression based on the Mini International Neuropsychiatric Interview and according to DSM-IV criteria. Seven single-nucleotide polymorphisms (SNPs) in the ACE gene were genotyped and diurnal cortisol secretion, as an index of HPA axis activity, was measured. Multivariable analyses were adjusted for socio-demographic and vascular factors, cognitive impairment, and apolipoprotein E. Strong significant associations were found between all seven SNPs and DEP and, in particular, first-onset DEP in persons without a past history of depression (P-values ranging from 0.005 to 0.0004). These associations remained significant after correction for multiple testing. The genotypes that were associated with an increased risk of DEP were also significantly associated with an increase in cortisol secretion under stress conditions. Variants of the ACE gene influence cortisol secretion and appear as susceptibility factors for late-life depression in the elderly population. Whether this could represent a common pathophysiological mechanism linking HPA axis and late-life depression remains to be explored.

Characteristics of hormone therapy, cognitive function, and dementia: the prospective 3C Study.

OBJECTIVES: To examine the association between hormone therapy (HT) and cognitive performance or dementia, focusing on the duration and type of treatment used, as well as the timing of initiation of HT in relation to the menopause. METHODS: Women 65 years and older were recruited in France as part of the Three City Study. At baseline and 2- and 4-year follow-up, women were administered a short cognitive test battery and a clinical diagnosis of dementia was made. Detailed information was also gathered relating to current and past HT use. Analysis was adjusted for a number of sociodemographic, behavioral, physical, and mental health variables, as well as APOE epsilon4. RESULTS: Among 3,130 naturally postmenopausal women, current HT users performed significantly better than never users on verbal fluency, working memory, and psychomotor speed. These associations varied according to the type of treatment and a longer duration of HT appeared to be more beneficial. However, initiation of HT close to the menopause was not associated with better cognition. HT did not significantly reduce dementia risk over 4 years but current treatment diminished the negative effect associated with APOE epsilon4. CONCLUSIONS: Current hormone therapy (HT) was associated with better performance in certain cognitive domains but these associations are dependent on the duration and type of treatment used. We found no evidence that HT needs to be initiated close to the menopause to have a beneficial effect on cognitive function in later life. Current HT may decrease the risk of dementia associated with the APOE epsilon4 allele.

Lipid levels and cardiovascular risk in elderly women: a general population study of the effects of hormonal treatment and lipid-lowering agents.

OBJECTIVE: To evaluate plasma lipid levels in elderly women in the general population as a function of use of lipid-lowering agents (LLA) and hormone therapy (HT). METHODS: A total of 4271 women aged over 65 years were recruited from three French cities. Analyses were performed after stratification by LLA treatment and HT and adjusting for a large range of sociodemographic and clinical factors. RESULTS: Fifteen percent of women currently used HT (78% transdermal estradiol), and 30% were taking LLA. In this population, 4.6% of women were taking both HT and LLA (fibrate for 2.4% and statin for 2.2%). In non-LLA-treated women, current HT was associated with lower total cholesterol, low density lipoprotein cholesterol (LDL-C), and non-high density lipoprotein cholesterol (non-HDL-C) compared to never users. Women treated with LLA also had lower total cholesterol, LDL-C, and non-HDL-C compared to non-LLA users, whereas triglyceride levels were the highest in statin users and lowest in fibrate users. Fibrate use was associated with a more favorable lipid pattern than statin treatment independently of HT use. In women without coronary heart disease or diabetes, HT, statin or fibrate use were associated with lower LDL-C level risk based on National Cholesterol Education Program guidelines (adjusted odds ratio (OR) = 0.67 (95% confidence interval (CI) = 0.53-0.85), 0.38 (95% CI = 0.29-0.47), and 0.32 (95% CI = 0.25-0.42), respectively) with a possible interaction between fibrate and HT (0.18 (95% CI = 0.10-0.30)). CONCLUSIONS: Estradiol-based HT may lower atherogenic lipoproteins in postmenopausal women. In primary prevention of coronary heart disease, combining HT and a fibrate may provide additional benefits compared to fibrate use.

Differential inhibition of estrogen and antiestrogen binding to the estrogen receptor by diethylpyrocarbonate.

Diethylpyrocarbonate differentially inhibited the specific binding, in lamb uterine cytosol, of estradiol (inhibition approximately 90% with 4 mM reagent) and 4-hydroxytamoxifen (inhibition approximately less than 50% with 4-16 mM reagent), a potent triphenylethylene antiestrogen. Saturation analysis experiments indicated that the effects of diethylpyrocarbonate were due to progressive but differing decreases in the concentration of binding sites for the two ligands, with no apparent change in the affinity constants. However, competitive binding and dissociation experiments evidenced that steroidal and nonsteroidal estrogens still bound, but with very low affinities, to diethylpyrocarbonate-modified receptor (greater than 1000-fold decrease in affinity) whereas the affinities of triphenylethylene antiestrogens were much less affected (less than 10-fold decrease). Both ligands prevented the inactivation of the estrogen receptor by diethylpyrocarbonate, estradiol being more efficient than 4-hydroxytamoxifen. These data indicate that the action of diethylpyrocarbonate results in the formation of two populations of estrogen receptor that are quantitatively nearly equivalent: the first does not bind estrogens or antiestrogens; the second does not bind estrogens significantly but still interacts with antiestrogens at a high affinity. The simplest interpretation is that these two populations arise from mutually exclusive modifications by diethylpyrocarbonate of at least two aminoacid residues located at or close to the ligand binding site; modification of one residue totally prevents the binding of estrogens and antiestrogens; the modification of the second impairs only the binding of estrogens. Considering that (i) hydroxylamine, which specifically reverses the diethylpyrocarbonate-induced modification of histidine and tyrosine residues, restored a large part (greater than 80%) of the estradiol- and 4-hydroxytamoxifen-binding capacity of diethylpyrocarbonate-inactivated cytosol, and that (ii) similar differential inhibition of estrogen and antiestrogen binding was observed following the action of tetranitromethane, it is likely that these residues are histidine(s) and/or tyrosine(s). These results evince a marked difference in the interaction of estrogens and triphenylethylene antiestrogens with the estrogen receptor, which could account for the altered activation of the receptor by triphenylethylene antiestrogens. Consequently, the screening of ligands with modified steroid receptors could be a useful method for distinguishing between potential hormone agonists and antagonists.

Differential interactions of estrogens and antiestrogens at the 17 beta-hydroxy or counterpart function with the estrogen receptor.

The action of diethylpyrocarbonate on lamb uterine estrogen receptor produced an homogeneous population of the receptor (approximately 55%) which still bound triarylethylene antiestrogens such as 4-hydroxytamoxifen with a high affinity but bound classical potent estrogens such as estradiol or diethylstilbestrol with a very low affinity. To specify the structural features of the ligands involved in the decrease of ligand affinity upon modification of the estrogen receptor, we determined the relative affinity constants of 17 steroidal estrogens or antiestrogens (deriving from estradiol by a 7 alpha- or 11 beta-substitution) and 14 nonsteroidal estrogens or antiestrogens (all including the 1,2-trans-diphenylethylene structure of diethylstilbestrol) for native and diethylpyrocarbonate-modified estrogen receptors. Then the ratio of the relative affinity constant for the native receptor to that for the modified receptor (rho) was calculated for each ligand, to compare the variation in the affinity of the ligand upon modification of the receptor to that of 4-hydroxytamoxifen (rho = 1). The results showed that the strong decrease of ligand affinity upon modification of the receptor displayed by classical estrogens (rho greater than or equal to 200) is strictly dependent on the presence of the 17 beta-hydroxyl group in steroidal compounds or its alpha-4- and beta-4-counterparts in diethylstilbestrol-related compounds. However, for the 7 alpha- or 11 beta-derivatives of estradiol displaying potent antiestrogenic properties, the relative decrease in affinity was much more limited (rho less than or equal to 19). For 11 beta-derivatives displaying a relative estrogenic activity weaker than that of estradiol itself, an average decrease in affinity was observed (23 less than or equal to rho less than or equal to 62). With the diethylstilbestrol-related compounds, bearing or not the alpha-4-hydroxyl and/or the beta-4-hydroxy functions and showing either weak relative estrogenic or antiestrogenic properties, the relative variation in affinity was weak (0.6 less than or equal to rho less than or equal to 24). These results indicate that the interaction of 7 alpha- or 11 beta-substituted steroidal antiestrogens and of 1,2-trans-diphenylethylene or triphenylethylene derivatives, displaying either weak relative estrogenic or antiestrogenic properties with the receptor, differs at the 17 beta-hydroxy or at the alpha-4-/beta-4-hydroxy functions from that of potent estrogens. They suggest that the strong decrease in the relative affinity of ligands upon receptor modification may reflect the high efficiency of the ligands to activate the receptor properly.(ABSTRACT TRUNCATED AT 400 WORDS)