Ovarian response to follicle-stimulating hormone (FSH) stimulation depends on the FSH receptor genotype

Because the ovarian response to FSH stimulation in assisted reproduction is variable, ranging from hyporesponse to hyperresponse, with the possible complication of ovarian hyperstimulation, it would be of great benefit to predict the response of the patients to FSH. To date, no clear-cut predictors of ovarian responsiveness to FSH have been identified. In this study, we investigated the role of two distinct FSH receptor (FSHR) variants, Thr307/Asn680 and Ala307/Ser680, in the response to FSH in women undergoing controlled ovarian stimulation. The FSHR polymorphism at position 680 was analyzed by restriction-fragment-length polymorphism in 161 ovulatory women below the age of 40 yr. With reference to the couple, infertility has been diagnosed as being attributable to male causes (76%), tubal factor (11%), or both (13%). The distribution was 29% for the Asn/Asn, 45% for the Asn/Ser, and 26% for the Ser/Ser FSHR variant. Peak estradiol levels, number of preovulatory follicles, and number of retrieved oocytes were similar in the 3 groups. However, basal FSH levels were significantly different among the 3 groups (6.4 +/- 0.4 IU/L, 7.9 +/- 0.3 IU/L, and 8.3 +/- 0.6 IU/L for the Asn/Asn, Asn/Ser, and Ser/Ser groups, respectively, P < 0.01). The number of FSH ampoules required for successful stimulation was significantly different among the 3 groups (31.8 +/- 2.4, 40.7 +/- 2.3, and 46.8 +/- 5.0 for the Asn/Asn, Asn/Ser, and Ser/Ser groups, respectively, P < 0.05). According to multiple linear regression analysis, the number of ampoules needed could be predicted from a linear combination of both the type of polymorphism and basal FSH levels (P < 0.001). These clinical findings demonstrate that the ovarian response to FSH stimulation depends on the FSHR genotype.     

Gender differences in platelet aggregation in healthy individuals

This study evaluated gender variability in platelet aggregation in response to common agonists. Platelet aggregation was measured in 36 healthy men and women free of any antiplatelet medication, aged 22–36 years, of Caucasian (White not of Hispanic origin), Hispanic, and African-American not of Hispanic origin. In this ex-vivo study, we investigated platelet aggregation in response to adenosine-5′-diphosphate (ADP), epinephrine (EPI), arachidonic acid (AA) and collagen (COL), using a platelet ionized calcium aggregometer (Chrono-Log Co.). Platelet aggregation response to all tested agonists was higher in females than in males regardless of ethnicity. The most significant differences were observed with collagen (P < 0.01). Among the ethnic groups, Caucasian women were most prone to platelet aggregation. Gender is a determinant of agonist effects on platelet aggregability in healthy subjects.     

Corticosterone reduces dendritic complexity in developing hippocampal CA1 neurons

Although prolonged stress and corticosteroid exposure induce morphological changes in the hippocampal CA3 area, the adult CA1 area is quite resistant to such changes. Here we addressed the question whether elevated corticosteroid hormone levels change dendritic complexity in young, developing CA1 cells. In organotypic cultures (prepared from P5 rats) that were 14–21 days cultured in vitro, two doses of corticosterone (30 and 100 nM) were tested. Dendritic morphology of CA1 neurons was established by imaging neurons filled with the fluorescent dye Alexa. Application of 100 nM corticosterone for 20 minutes induced atrophy of the apical dendritic tree 1–4 hours later. Fractal analysis showed that total neuronal complexity was reduced twofold when compared with vehicle‐treated neurons. Exposing organotypic slices to 30 nM corticosterone reduced apical length in a more delayed manner: only neurons examined more than 2 hours after exposure to corticosterone showed atrophy of the apical dendritic tree. Neither dose of corticosterone affected the length of basal dendrites or spine density. Corticosterone was ineffective in changing morphology of the apical dendrites when tested in the presence of the glucocorticoid receptor antagonist RU38486. These results suggest that high physiological levels of corticosterone, via activation of the glucocorticoid receptor, can, during the course of only a few hours, reduce the dendritic complexity of CA1 pyramidal neurons in young, developing hippocampal tissue. These findings suggest that it is relevant to maintain plasma corticosterone levels low during hippocampal development. © 2009 Wiley‐Liss, Inc.     

Development of water soluble derivatives of <Emphasis Type="Italic">cis</Emphasis>-3, 4′, 5-trimethoxy-3′-aminostilbene for optimization and use in cancer therapy

Summary  Colchicine site tubulin inhibitors are currently developed as vascular disrupting agents (VDAs). However, they were found to have cardiotoxicity in clinical trials. To overcome the problem, we developed a stilbene derivative, cis-3, 4′, 5-trimethoxy-3′-aminostilbene (stilbene 5c), which is highly potent and has no bone marrow and cardiac toxicity in mice. Here we attempt to optimize stilbene 5c using computer-based drug design and synthesize derivatives with benzimidazole or indole group. Biological evaluation showed that they are weaker than stilbene 5c without better water solubility. Alternative approach was thus adopted to make prodrugs of stilbene 5c. A water-soluble prodrug PD7 was synthesized by addition of a morpholino group with carbamate linkage to the amino group of stilbene 5c. In vitro studies show that PD7 induces mitotic arrest and disrupts microtubule similar to stilbene 5c. The cell signaling events in Cdc2, p53, Akt, and aurora kinase are similar in cells treated with stilbene 5c, CA4 or PD7, suggesting that they share the same mechanism. Although PD7 is less effective than stilbene 5c in vitro, the biological activity of PD7 as a single agent is similar to that of stilbene 5c. Combination of PD7 with VEGF inhibitor bevacizumab significantly enhances the therapeutic efficacy of PD7 in mouse xenograft model. These data suggest that PD7 could be a good candidate for further pre-clinical and clinical development as a new VDA for cancer therapy.     

Respiratory symptoms/diseases and environmental tobacco smoke (ETS) in never smoker Italian women

AIM: To study the relationship between respiratory/allergic disorders and chronic environmental tobacco smoke (ETS) exposure to husband or at workplace among non-smoking women of a general population in Italy. METHODS: Analyses regard 2195 married or employed women. Information was collected through a self-administered questionnaire. ETS exposure was validated by salivary cotinine. RESULTS: Exposure both to husband and at work resulted a significant risk factor for current dyspnoea (odds ratio (OR) 1.61, 95% confidence interval (CI) 1.20-2.16), any shortness of breath at rest (OR 2.81, 95% CI 1.83-4.30), recent wheeze (OR 1.71, 95% CI 1.04-2.82), recent attacks of shortness of breath with wheeze (OR 1.85, 95% CI 1.05-3.26), asthma diagnosis/symptoms (OR 1.50, 95% CI 1.09-2.08), diagnosis of asthma or bronchitis/emphysema (obstructive lung diseases (OLD)) (OR 2.24, 95% CI 1.40-3.58), current cough/phlegm (OR 1.52, 95% CI 1.07-2.15), and rhino-conjunctivitis (OR 1.48, 95% CI 1.13-1.94). Exposure only at work yielded higher adjusted odds ratios for all health conditions, except for rhino-conjunctivitis. Overall, about 24% of shortness of breath at rest, 16% of dyspnoea, 17% of rhino-conjunctivitis, 12% of OLD, and 10% of asthma diagnosis/symptoms are attributable to the effect of exposures to both husband and at work. Twelve percent of shortness of breath at rest and 10% of rhino-conjunctivitis cases might be avoided by eliminating exposure only at work and only to husband, respectively. CONCLUSIONS: Lifetime ETS exposure, especially at work, is associated with respiratory symptoms/diseases, and it accounts for a sizeable proportion of such disorders. The combined effect of both exposures is higher than the separate effects.     

Reference equations for spirometry from a general population sample in central Italy

Aim of this study was to derive new lung function reference equations and compare the predicted values with those from three sets of existing reference equations: one derived from a Northern Italy population and the two others widely used in European (ECCS) and American (NHANES III) clinical practice. Reference equations for flow-volume curve indexes and VC were derived on 497 normal subjects, aged 8-74, from the epidemiological survey in Pisa, Central Italy (1991-1993). By applying natural cubic splines, one single smooth and continuous equation for the entire age range was provided for each index, separately by gender. Along with age and height, reference values also depended on BMI. Differences among the four reference equations for FEV(1), FVC, VC were quantified for average subjects. The magnitude largely varied over the age range in both genders, reaching up to half litre of air volume at specific ages. Age-gender-specific prevalence rates of airway obstruction, as defined by the ERS criterion, largely varied by applying the considered equations, the differences ranging from -3% to 28%. The observed discrepancies confirm that reference equations should be derived from a population most similar to that for which the equations are to be used and based on measurements obtained by the same instrument and testing procedures, in order to minimize technical variability in lung function both for clinical and epidemiological purposes.