Reproductive factors and breast cancer: An overview

Summary Despite extensive research, there is still uncertainty on the separate effects of parity and age at first birth on breast cancer risk. Thus, information on these variables from formal epidemiological articles published in English since 1970 is reviewed in the present article. Among 26 studies considered, one found no significant association with either variable, seven showed an association between age at first birth but not parity and breast cancer risk, six an association with parity but not age at first birth, and in twelve studies both variables appeared to be independently related with breast cancer risk. Various reasons for these apparent differences can be considered, including heterogeneity between various populations (for instance, the proportion of multiparous women in studies showing no association with parity tended to be higher than in studies finding an inverse relation with parity), criteria for selection of cases and controls, influence of age and other covariates (among which the interval between pregnancies is of particular interest) and, of course, the role of chance. The data reviewed suggest, from an aetiological viewpoint, that both parity and age at first birth have some independent effect on breast carcinogenesis. From a public health viewpoint, however, it appears that the importance of age at first birth is greater, since the trend is linear across subsequent age levels, while the protection of parity seems to be quantitatively relevant only for women with four or five births or more.

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Fortpflanzungsfaktoren und Brustkrebs: eine Übersicht

Zusammenfassung Trotz intensiver Forschung bestehen immer noch Zweifel über die einzelnen Auswirkungen von Parität und Alter bei der Erstgeburt auf das Brustkrebsrisiko. Deshalb werden in diesem Artikel die Arbeiten, welche seit 1970 in Englisch veröffentlicht worden sind, analysiert. Von den 26 berücksichtigten Studien fand eine keine eindeutige Beziehung zu diesen beiden Variablen. Sieben wiesen eine Beziehung mit dem Alter bei der Erstgeburt nach, jedoch nicht mit der Parität. Sechs fanden einen Zusammenhang mit der Parität, aber nicht mit Alter bei Erstgeburt und aus 12 Studien ging hervor, dass beide Faktoren unabhängig voneinander mit dem Brustkrebsrisiko verbunden sind. Es gibt verschiedene Hypothesen, diese Diskrepanzen zu erklären, darunter auch die Verschiedenartigkeit in den untersuchten Bevölkerungen (so lag z.B. die Proportion der Frauen mit mehreren Geburten in jenen Studien, die nicht mit Parität verbunden sind höher, als in jenen, welche eine Verbindung zur Parität fanden), die Auswahlkriterien für Fälle und Kontrollen, der Einfluss des Alters und von anderen Variablen (wobei der Zeitabstand zwischen den Schwangerschaften besonders interessant ist) und natürlich die Rolle des Zufalls. Die gesichteten Resultate deuten vom ätiologischen Sichtpunkt darauf hin, dass Parität und Alter bei der Erstgeburt unabhängig voneinander das Brustkrebsrisiko beeinflussen. Die Beziehung zwischen dem Alter bei der Erstgeburt und der Brustkrebshäufigkeit scheint, vom Standpunkt der Sozialmedizin aus, jedoch von grösserer Bedeutung zu sein, da das Risiko in jeder Altersklasse linear ansteigt. Der Schutzeffekt der Parität hingegen ist erst von der vierten oder fünften Geburt an nachzuweisen.

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Les facteurs reproductifs et le cancer du sein: un résumé

Résumé Malgré des recherches approfondies, des doutes subsistent quant aux effets de parité et d'âge à la première naissance sur le risque du cancer du sein. Différents travaux parus en anglais depuis 1970 sont analysés dans cet article. Des 26 études analysées, une seule ne démontrait pas d'association. Sept ont montré une association avec l'âge à la première naissance mais pas avec la parité. Six ont démontré une association avec la parité mais non avec l'âge à la première naissance et 12 études ont montré une influence indépendante de ces deux facteurs sur le risque de cancer du sein. Différentes hypothèses peuvent être considérées pour ces différences apparentes, y compris l'hétérogénéité entre les populations étudiées (par exemple la proportion de femmes multipares est plus élevée dans les études démontrant une association avec la parité que dans celles avec une relation inverse), la sélection des cas et des témoins, la structure de l'âge, ainsi que d'autres facteurs comme par exemple l'intervalle entre les grossesses et bien sûr le hasard. Ces données laissent apparaître que la parité, ainsi que l'âge à la première naissance, peuvent influencer d'une manière indépendante le risque du cancer du sein. La corrélation entre l'âge à la première naissance et le cancer du sein est très importante pour la santé publique, étant donné que le risque augmente avec chaque classe d'âge, tandis que la parité n'a un effet protecteur qu'à partir de la quatrième ou de la cinquième naissance.

     

Human isolated small intestine: motor responses of the longitudinal muscle to field stimulation and exogenous neuropeptides

Summary (1) Longitudinal muscle strips from the human small intestine (jejunum/ileum) responded to electrical field stimulation (1–50 Hz) with frequency-related primary contractions which were largely atropine- (3 M) sensitive. When the tone was raised by addition of galanin (0.3 – 1 M), prostaglandin (PG) E₂ (1–10 M) or neurokinin A (NKA, 0.1 M), a frequency-related relaxation was evident which was potentiated by atropine. All the responses to field stimulation were abolished by tetrodotoxin (1 M), thus indicating their neural origin. (2) The atropine-sensitive primary contraction to field stimulation was virtually abolished by omega conotoxin fraction GVIA (CTX, 0.1–0.3 M) while the relaxations were CTX-resistant. The field stimulation-induced relaxations, which were observed in the presence of atropine and guanethidine (3 M), were also unaffected by apamin (0.1 M). (3) NKA and substance P (SP) produced a concentration- (1 nM–1 M for both peptides) related contraction, NKA being about 53 times more potent than SP. [Pro⁹]SP sulphone and [MePhe⁷]-NKB, selective agonists of the NK-1 and NK-3 receptor, respectively, were barely effective. On the other hand, [\Ala⁸]NKA(4–10), a selective NK-2 receptor agonist, had a potent contractile activity, similar to that of NKA. (4) Galanin (1 nM–1M) produced an atropine- and tetrodotoxin-resistant concentration-related contraction of longitudinal muscle of human isolated small intestine. The response to galanin did not show any sign of fading and was particularly suitable to study the evoked relaxations. (5) Calcitonin gene-related peptide (CGRP) (10–100 nM) consistently inhibited the nerve-mediated contractions of strips from the ileum while the effect on the jejunum was less pronounced. Vasoactive intestinal polypeptide (VIP, 0.1–1 M) inhibited nerve-mediated contractions both in the ileum and the jejunum. (6) These experiments indicate that both cholinergic excitatory and non-adrenergic non-cholinergic nerves affect motility of the longitudinal muscle of the human small intestine. Furthermore, several neuropeptides produce potent motor effects, the contractile response to tachykinins being apparently mediated by activation of NK-2 receptors.     

Rapid leukocyte integrin activation by chemokines

Summary: Chemokines control selective targeting of circulating leukocytes to the microvasculature by triggering inside-out signal transduction pathways leading to integrin-dependent adhesion. Integrin activation by chemokines is very rapid, is downmodulated within minutes and appears to involve both enhanced heterodimer lateral mobility on the plasma membrane, facilitating encounters with dispersed ligand, as well as induction of a high-affinity state. These two modalities of integrin activation by chemokines involve distinct signaling pathways in the cell, yet complement each other functionally, allowing binding of rolling cells under conditions of low as well as high ligand density. Recent data show that chemokines generate both pro- and anti-adhesive intracellular signaling events, whose equilibrium is likely to be relevant to the kinetics of adhesion and de-adhesion, and to cell movement during diapedesis and chemotaxis. Importantly, chemokines utilize different signaling mechanisms to modulate the activity of distinct integrin subtypes. These recent advances suggest that chemokines may regulate adhesive responses of immune cells based not only on patterns of chemokine receptor expression, but also on variable signaling pathways that can modulate the pro-adhesive responses of leukocytes as a function of their differentiated state, and of the local microenvironment.     

MEG Characterization of Spontaneous Alpha Rhythm in the Human Brain

The present piece of research studied the spontaneous alpha rhythm of the human brain by combining the use of a whole-cortex neuromagnetometer and Magnetic Resonance Imaging. Single trials of spontaneous brain activity were recorded from ten human subjects asked to rest, with their eyes either closed or open, in relaxed wakefulness. MEG measurements were conducted over a period of one and a half years. The replicability of the results was confirmed for eight subjects out of ten. For three subjects, the alpha rhythm did not show any reductions due to the opening of the eyes. Both field map pattern and location of the estimated source were persistently stationary during each of the bursts of oscillations of the alpha rhythm. Dipoles were concentrated in clusters, indicating the existence of several spatially distributed sources. The calcarine fissure, the parieto-occipital sulcus and the surrounding occipital and parieto-occipital areas were identified as cortical sites of the brain where the alpha rhythm may originate. For four subjects, the majority of the sources were located near or in the calcarine fissure, while for five subjects, they were located near or in the parieto-occipital sulcus and for the remaining subject they were equally divided between the two generation sites.     

Peripheral cytokine release in Alzheimer patients: correlation with disease severity

Various studies suggested that inflammation is involved in the pathogenesis of Alzheimer's disease (AD). We investigated cytokine release from LPS-stimulated blood cells of 32 AD patients, with different disease severity, compared to 16 age-related controls. A significant decrease of IL-1beta and IL-6 secretion was observed in severely demented patients; TNF-alpha release was also decreased, but not significantly. By contrast, mild and moderate patients showed a cytokine release similar to controls. IL-1beta, IL-6 and TNF-alpha secretion was negatively correlated with the severity of dementia, quantified by the MMSE. Our data suggest that alterations of the immune profile are associated with AD progression.     

Relative growth of adenomatous polyps of the colon

Summary The volume of the adenomatous mucosa (V), the area of the surface epithelium (Ss), the area of the glandular epithelium (Sg), and theSg:Ss ratio were calculated in a series of 14 adenomatous polyps (APs) of a case of multiple polyposis of the colon. The equation of simple allometry was used to study the relative growth of the four series of values.Ss grew isometrically with size;Sg overgrewSs and accounted for most of the increase inV. TheSg:Ss ratio increased withSg andV.     

Comparison of intranasal and transdermal estradiol on nasal mucosa in postmenopausal women

OBJECTIVE: To compare nasal symptomatology and function and local concentrations of estradiol (E2), estradiol receptor (ERalpha), vasoactive intestinal peptide (VIP), substance P (SP) and neuropeptide Y (NPY) in nasal biopsies of 20 postmenopausal women complaining of paradoxical nasal stuffiness before and after treatment with intranasal or transdermal E2. DESIGN: Twenty healthy postmenopausal women willing to start hormone therapy (HT) were allocated to one of two groups, using a computer-generated randomization list.Ten postmenopausal women were treated with transdermal 17beta-estradiol 50 microg daily plus nomegestrole acetate 5 mg/day for 12 days per 28-day cycle for 6 months (Group A). Ten postmenopausal women were treated with intranasal 17beta-estradiol 300 microg/day (one spray delivery of 150 microg per nostril) plus nomegestrole acetate 5 mg/day for 12 days per 28-day cycle for 6 months (Group B). Fourteen fertile women undergoing nasal mucosa biopsy during plastic surgery were used as controls for the immunohistochemical evaluation (Group C).All women in groups A and B underwent evaluation of nasal stuffiness score, mucociliary transport time, rhinoscopy, and active anterior rhinomanometry at the beginning of the study and after, VIP, SP, and 6 months of HT. Nasal biopsies and evaluation of local concentrations of E2, ERalpha NPY were performed in groups A and B before and after 6 months of HT and in group C. RESULTS: Both intranasal and transdermal HT improve nasal symptomatology and nasal mucosa appearance and reduce mean mucociliary transport time. The effectiveness of intranasally administered therapy at improving nasal function is significantly better than transdermal therapy. In comparison with premenopausal controls, untreated postmenopausal women of group A and B showed significantly decreased immunopositivity for E2, ERalpha, and SP. HT induced a significant increase in E2, ERalpha, VIP, and SP and a decrease in NPY immunopositivity. Intranasal therapy was associated with a significantly higher immunopositivity for VIP and SP. CONCLUSIONS: HT improves nasal function and symptomatology in postmenopausal women with paradoxical nasal stuffiness, modulating nasal mucosa function through an action on cholinergic, adrenergic, and sensory peptides. Intranasally administered HT is more effective at improving nasal function than transdermal HT.