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Notes: Abstract:  This article summarizes the conclusions of a meeting of diverse breast cancer experts who discussed issues, controversies, and new clinical trial results relevant to the use of aromatase inhibitors for treating postmenopausal women with breast cancer. The new generation of aromatase inhibitors (anastrozole, letrozole, exemestane) have largely replaced megestrol acetate as a second-line therapy in postmenopausal women with hormone-responsive advanced breast cancer. In addition, anastrozole and letrozole have been shown to be superior to tamoxifen for first-line therapy. Finally, recent results suggest that anastrozole may be superior to tamoxifen as adjuvant therapy for early stage disease in postmenopausal women with hormone-responsive disease.

Notes:  Abstract: It is essential that the epidemiological aspects of breast cancer are understood by clinicians and used humanely in counselling women to compensate for the scare mongering of the media and ill informed agents of public health policy. Examples described in this paper include breast cancer awareness campaigns, the promotion of breast cancer screening, the use of oral contraceptives, and the prescription of hormone replacement therapy. The translation of relative risks into absolute numbers will allow the proper advice necessary for women to make informed choices about risk avoidance and risk management.

Notes: Vaginocervical stimulation of ovariectomized estradiol-primed ferrets (which are reflex ovulators) with a glass rod in the presence of a neck-gripping male induced an increase in plasma luteinizing hormone (LH) from undetectable levels (≤0.50 ng/ml) before stimulation, to 2.4 ± 0.43 ng/ml 75 min after stimulation (stimulated females). Forty-eight h after stimulation plasma LH returned to baseline levels (post-stimulated females). A significant decrease in the number of perikarya containing LH-releasing hormone (LHRH), detected by immunocytochemistry, was associated with the increase in plasma LH following stimulation. Approximately one half of the number of immunoreactive LHRH neurons (243±27) were detected in the forebrain of stimulated females, compared to those detected in the forebrain of post-stimulated animals (436 ± 88) using antiserum AR 744. Equivalent results were obtained with a different antiserum (RM 1076) capable of detecting the extended decapeptide, or precursor, as well as partially or fully processed decapeptide.We conclude that controlled Vaginocervical stimulation of female ferrets evokes the release of LHRH as well as LH, depleting approximately 50% of the LHRH perikarya of detectable LHRH. Additionally, electron microscopy of LHRH perikarya of stimulated females revealed more Golgi complexes/cell compared to baseline females. We propose that Vaginocervical stimulation also augments the processing of extended precursor forms of LHRH to generate the decapeptide.

Notes: The mating-induced preovulatory surge of luteinizing hormone (LH) lasts for at least 12 h in the female ferret. This prolonged increase in circulating LH is presumably accompanied by a corresponding elevation in the activity and output of luteinizing hormone-releasing hormone (LHRH) neurons projecting to the hypothalamic-hypophyseal portal blood vessels and adenohypophysis. We used the protein products of the immediate early genes (IEGs) c-fos, and c-jun as markers of neural activation in order to determine whether a sub-population of LHRH neurons is differentially activated by mating and whether non-LHRH neurons in specific forebrain regions are selectively activated at different times during the mating-induced preovulatory LH surge. In Experiment 1, estrous female ferrets were perfused 0.5, 1.5, 3.0, 6.0 or 12.0 h after receiving one 5-min intromission from a male or after being placed alone in a testing cage for 20 min. Fos-like immunoreactivity (Fos-IR; Oncogene Ab-2 antiserum) and LHRH-like immunoreactivity (LHRH-IR; LR-1 antiserum) were visualized. The percentage of Fos-IR LHRH neurons was significantly augmented 1.5 h after mating but had returned to basal levels by 3.0 h. The double-labeled LHRH neurons were concentrated in the caudal medio-basal hypothalamus. In non-LHRH neurons the number of Fos-IR neural nuclei was significantly increased by mating in the medial preoptic area (MPOA), bed nucleus of the stria terminalis (BNST), medial amygdala (MA), ventrolateral hypothalamus (VLH), and midbrain central tegmental field (CTF) 1.5 h after mating but, as in LHRH neurons, had returned to basal levels by 3.0 h. In Experiment 2, estrous females were perfused 1.5 h or 8.0 h after either receiving one 5-min intromission or being placed alone in a testing cage, and the brains were processed for LHRH and c-Fos-like (DCH-1, Dr Gerard Evan), c-Jun-like (Jun-IR; Oncogene Ab-2) or Egr-1-like (Egr-IR; Santa Cruz) immunoreactivity. The percentage of LHRH neurons colabeled with both Fos-IR and Jun-IR was significantly greater in the 1.5 h group than in the unpaired group. Again, the induction of these IEG products occurred in LHRH neurons in the caudal medio-basal hypothalamus. Mating significantly increased the number of Fos-IR non-LHRH neural nuclei in the MPOA, BNST, MA, VMH and CTF, as well as the number of Egr-IR nuclei in the MPOA, BNST and MA in the 1.5 h group. By contrast, the number of Jun-IR non-LHRH neurons was unaffected by mating. In these Experiments we have identified a sub-population of LHRH neurons which, using Fos and Jun as markers of neural activation, is activated by mating and may be differentially involved in the generation of the preovulatory LH surge. Although the LHRH system is presumably activated throughout the duration of the 12 h preovulatory LH surge, c-Fos and c-Jun immunoreactivity in LHRH neurons is augmented only transiently. Fos-IR and Egr-IR in non-LHRH neurons show a similar time-course. Together, these results suggest that the presence of augmented levels of these proteins is not required for the maintenance or termination of the preovulatory output of LHRH.

Notes: Experiments were conducted to explore the possible relationship between testicular androgen secretion and the development of brain aromatase activity in fetal ferrets. Aromatase activity in the preoptic+mediobasal hypothalamus and temporal lobe was similar in fetuses of both sexes between embryonic Days 26 and 36 even though whole body androgen content was invariably higher in males than females. Whole body androgen content was significantly higher in females located caudally (downstream) from two or more as opposed to zero or one males in the same uterine horn; nevertheless their brain aromatase activity was similar. Finally, maternal treatment with either the androgen receptor antagonist Flutamide or 5α-dihydrotestosterone propionate beginning on gestational Day 24 did not affect brain aromatase activity in fetal offspring of either sex, delivered on embryonic Day 34. Previous studies suggest that the biosynthesis of estrogen in the fetal ferret brain is normally greater in males than females. The present results suggest that this sex difference results primarily from increased androgenic substrate being available to non-saturated aromatizing enzymes and not from an androgen-dependent activation of aromatase.

Notes: Peripheral anosmia was previously found to disrupt sex discrimination and partner preference in male and female ferrets. Here we show directly that volatile anal scent gland odourants from male and female ferrets activated overlapping but distinguishable clusters of glomeruli located in the ventral–caudal portion of the main olfactory bulb (MOB) of breeding ferrets of both sexes. No glomerular activation was seen in the accessory olfactory bulb (AOB). The profile of MOB glomerular activation induced in oestrous females by male anal scents was very similar to that induced by direct contact with a male during mating, and oestrogen treatment failed to alter the profile of glomerular activation induced in ovo-hysterectomized females by male anal scents. In rodents, ‘atypical’ MOB glomeruli, which have dense acetylcholinesterase (AChE) activity in the neuropil, may be activated by body odours from conspecifics. No such AChE-staining ‘atypical’ glomeruli were found in the ferret's MOB, suggesting that in this carnivore they do not constitute a subset of MOB glomeruli that respond to body odourants. In ferrets of both sexes, volatile body odourants that are detected by the main as opposed to the vomeronasal–AOB accessory olfactory system may play a critical role in mate identification.

Notes: This study used transgenic mice, in which expression of a bacterial nitroreductase (ntr) gene was linked to the expression of olfactory marker protein (OMP). The nitroreductase enzyme is thus expressed in mature chemosensory neurons of these OMP-ntr transgenic mice, and converts the pro-drug CB1954 to a cytotoxic form, specifically killing these neurons. Systemic injections of the pro-drug led to the ablation of receptor neurons in both the main olfactory and vomeronasal epithelia. Due to the anatomical separation of the epithelia, however, when the pro-drug was administered by intranasal infusion only the receptors of the main olfactory epithelium were destroyed. This procedure resulted in a profound deficit in olfactory investigation and discrimination in a habituation–dishabituation test, whereas the pregnancy blocking effect of male pheromones, which is mediated via the vomeronasal system was unaffected. OMP-ntr mice receiving intranasal infusion of pro-drug had not recovered any significant main olfactory function at 24 days following treatment. This novel technique could potentially be applied to selectively ablate olfactory receptor neurons expressing a particular olfactory receptor by linking its expression to that of the nitroreductase enzyme.

Notes: Exposure of recently mated female mice to the urinary odours of an unfamiliar male blocks pregnancy (the Bruce effect). The absence of a pregnancy block in response to the stud male's familiar odours depends on an olfactory memory that is formed in the accessory olfactory bulb (AOB) in response to vomeronasal organ (VNO) inputs during mating. Sexually naive Balb/c female mice in pro-oestrus/oestrus were either placed onto soiled bedding (‘bedding-only’ females) from, or allowed to mate with, a Balb/c male (‘recently mated’ females). After 42 h, females were placed for 90 min onto clean bedding (controls) or onto soiled bedding from either a C57BL/6 male (unfamiliar bedding) or a Balb/c male (familiar bedding). Significant increases in Fos-immunoreactivity (Fos-IR, a marker of neuronal activation) occurred in the medial amygdala and the medial preoptic area (MPA) of ‘bedding only’ females exposed to either unfamiliar or familiar bedding and in ‘recently mated’ females exposed to unfamiliar bedding but not to familiar bedding. This suggests that a mating-induced memory prevents the later activation by the familiar stud male's odours of neurons in forebrain regions that receive inputs from the VNO–AOB. ‘Bedding-only’ females later exposed to either familiar or unfamiliar bedding had increased Fos-IR in the Gαo protein-expressing basal zone of the VNO whereas no such effect occurred in ‘recently mated’ females. Familiar, as well as unfamiliar, male odours augmented Fos-IR in significantly more rostral than caudal AOB granule cells in all groups, with the effect being strongest in ‘recently mated’ females exposed to familiar male bedding. This outcome is consistent with the absence of odour-induced Fos-IR in forebrain regions of these females and, presumably, the absence of a pregnancy block.

Notes: Abstract.  According to numerous recent cross-national studies of public support for democracy, citizens of both well-established and newer democracies continue to share a strong commitment to the ideals and principles of representative democracy. Paradoxically, however, these same citizens are increasingly ‘critical’ of and ‘dissatisfied’ with the performance of their national democratic institutions. One response has been to call for the ‘re-invention of government’ through the use of referendums and ballot initiatives. This article explores what happens when the national referendum was introduced in Portugal in 1998 – a polity that only recently consolidated its transition to democracy. We examine in some depth the context under which the referendum was introduced and its results in terms of electoral behaviour. The main goals are to explain both abstention and vote choice in the 1998 Portuguese referendums, analysing the role of political parties, social structural factors and pressure groups on those phenomena.