Estrogens need insulin-like growth factor I cooperation to exert their neuroprotective effects in post-menopausal women.

BACKGROUND: The abrupt fall in estrogens levels during the menopausal transition may connote an hormonal state predisposing to neurodegenerative disorders, e.g. Alzheimer's disease (AD). Reportedly, the neurotrophic activity of estrogen involves an interaction with IGF-I. AIM: To evaluate the leukocyte gene expression of progesterone receptor (PR-A/B) and interleukin 6 (IL-6), two parameters under the control of estrogens and involved in the pathogenesis of AD. SUBJECTS: The study was conducted in non-demented women divided into two groups according to their pre- or post-menopausal state; each group being further divided into two subgroups based on their circulating levels of IGF-I (normal or low). An additional sample of AD-affected women served as a comparison group. RESULTS: Estrogens maintained their full activity only when IGF-I levels were in the range of normalcy. On the contrary, if the concentrations of one or both hormones were reduced, estrogens were not anymore capable to control the gene expression of PR-A/B or IL-6. CONCLUSIONS: Before administering hormone-based replacement therapy, characterization of the somatotropic function should be performed in the early phase of the menopause.

Menopausal transition: a possible risk factor for brain pathologic events.

BACKGROUND AND OBJECTIVE: Incidence and prevalence of Alzheimer's disease (AD) are higher in postmenopausal women than in age-matched men. Since at menopause the endocrine system and other biological paradigms undergo substantial changes, we thought to be of interest studying whether (and how) the balance between some biological parameters allegedly neuroprotective (e.g. related to estrogen, dehydroepiandrosterone and CD36 functions) and others considered pro-neurotoxic (e.g. related to glucocorticoid and interleukin-6 activities) vary during lifespan in either sex in either normalcy or neurodegenerative disorders. SUBJECTS AND METHODS: Along with this aim, we evaluated the gene expression levels of estrogen receptors (ERs), glucocorticoid receptors (HGRs), interleukin-6 (IL-6) and CD36, a scavenger receptor of class B allegedly playing a key role in the proinflammatory events associated with AD, in a population of 209 healthy subjects (73M, 106F, 20-91-year old) and 85 AD patients (36M, 49F, 65-89-year old). Results obtained were related to plasma titers of estrogens, cortisol and dehydroepiandrosterone sulfate (DHEAS). Studies were performed in peripheral leukocytes, since these cells (1) are easily obtainable by a simple blood sampling, (2) express many molecules and multiple receptors which are under the same regulatory mechanisms as those operative in the brain and (3) some of them, e.g. monocytes, share many functions with microglial cells. RESULTS: In healthy men all the study parameters were quite stable during lifespan. In women, instead, at menopausal transition, some changes that may predispose to neurodegeneration occurred. In particular, there was (1) an up-regulation of ERs, and a concomitant increase of IL-6 gene expression, events likely due to the loss of the inhibitory control exerted by estradiol (E(2)); (2) an increase of HGR alpha:HGR beta ratio, indicative of an augmented cortisol activity on HGR alpha not sufficiently counteracted by the inhibitory HGR beta function; (3) a reduced CD36 expression, directly related to the increased cortisol activity; and (4) an augmented plasma cortisol:DHEAS ratio, widely recognized as an unfavorable prognostic index for the risk of neurodegeneration. In AD patients of both sexes, the expression of the study parameters was similar to that found in sex- and age-matched healthy subjects, thus indicating their unrelatedness to the disease, and rather a better correlation with biological events. CONCLUSIONS: Menopausal transition is a critical phase of women's life where the occurrence of an unfavorable biological milieu would predispose to an increased risk of neurodegeneration. Collectively, the higher prevalence of AD in the female population would depend, at least in part, on the presence of favoring biological risk factors, whose contribution to the development of the disease occurs only in the presence of possible age-dependent triggers, such as beta-amyloid deposition.

Structural and functional characterization of plasma fibronectin in patients with essential mixed cryoglobulinaemia.

Experimental studies suggest that plasma fibronectin may be involved in the cryoprecipitation of cryoglobulins in essential mixed cryoglobulinaemia; reduced plasma concentrations of the glycoprotein have been shown in the disease. The present work was undertaken in order to verify this latter finding and to detect a possible structural alteration of plasma fibronectin as result of enzymatic digestion of the molecule in vivo. This could, in turn, induce a decreased reactivity of the protein in immunometric assays and a reduced opsonic activity, which is normally due to the affinity of fibronectin to the C1q component of complement. Moreover, since a polymorphic variant of fibronectin has been described in plasma during experimental vascular injury and in patients with autoimmune vascular diseases, the aim of this study was also to verify the presence of a polymorphism of the glycoprotein in cryoglobulinaemic vasculitis. Twenty seven patients with essential mixed cryoglobulinaemia and 26 normal subjects were included in the study. Significantly reduced concentrations of plasma fibronectin, as assessed by ELISA, were found in patients when compared with controls (231.7 +/- 15.3 vs 316.1 +/- 16.6 mg/l, P less than 0.0002). In contrast, when affinity-purified plasma fibronectin from 10 patients with essential mixed cryoglobulinaemia and 8 healthy subjects were analysed by western blotting, employing a panel of five monoclonal antibodies to different regions of the molecule, no differences were observed between patients and controls, suggesting integrity of the glycoprotein in the disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical significance of cross-linked fibrin degradation products in essential mixed cryoglobulinemia.

Cross-linked fibrin degradation products (XDP) were measured with a highly sensitive and specific ELISA in 21 patients with essential mixed cryoglobulinemia (EMC) and in 16 controls. Patients had significantly increased levels of XDP, together with abnormalities in routine coagulation tests. Moreover, XDP were higher in patients with more severe disease. These results support the hypothesis that EMC patients have a chronic disseminated intravascular coagulation (DIC), and underline the significance of XDP measurement in the evaluation of these patients.