Basal growth hormone (GH) and insulin-like growth factor I (IGF-I) as well as GH responses to GH-releasing hormone (GHRH) were studied in 22 subjects (7 females, 15 males), aged between 65 and 86 years. The study was aimed at investigating the possible correlations between the age-dependent GH-IGF-I axis decline and the cognitive function – assessed by the Mini Mental State Examination (MMSE). The relationship between hormonal data, cognition and age, body weight, body mass index (BMI), some nutritional indices (triceps skinfolds, TSF, mid-arm circumference, MAC), and physical activity – quantified by the physical functioning index (PFI) – were also analyzed. GH basal levels were within the normal range, while GH responses to GHRH were blunted in most cases. GH peaks after GHRH were directly correlated with GH basal values. IGF-I serum levels were found to be in the lower part of the reference range for adult subjects or below it. GH responses to GHRH, but not GH and IGF-I basal levels, were inversely correlated with subject age. GH secretion areas after GHRH were inversely correlated with BMI, but no further correlations between GH data and clinical or nutritional parameters were found. MMSE values directly correlated with MAC and PFI values. IGF-I levels were directly correlated with MMSE scores, being lowered in patients with more advanced cognitive deterioration, and with MAC values – the decrease of which is thought to reflect protein caloric malnutrition – but not with body weight, BMI, TSF and PFI. MMSE-related protein caloric malnutrition and decreased physical activity possibly take part in affecting IGF- I function in subjects with mild cognitive impairment and, reciprocally, IGF-I decrement might affect neuronal function.

Human keratinocytes isolated from a skin biopsy and cultured in vitro on a feeder-layer of irradiated fibroblasts reconstitute a stratified squamous epithelium suitable for grafting onto patients suffering from large burn wounds. Since conditioned medium from 3T3-J2 cells can partially substitute for the intact feeder-layer, we studied the possible involvement of insulin-like growth factors acting in a paracrine fashion. IGFs were measured (after Sephadex G-50 gel-chromatography in acid conditions) in media conditioned by a feeder-layer of lethally irradiated 3T3-J2 fibroblasts on which keratinocytes were grown. Immunoreactive (IR) IGF-I, IGF-II, and IGF binding activity were present in the medium conditioned by the feeder-layer. The medium conditioned by keratinocytes showed nearly undetectable amounts of IR IGF-I and IGF-II, suggesting that keratinocytes are unable to synthesize IGFs peptides. Recombinant IGF-I and IGF-II, and conditioned medium from 3T3-J2 cells, caused a dose-dependent increase of 3H-thymydine incorporation in cultured keratinocytes. The stimulatory effect of IGF and of 3T3-J2 conditioned medium was inhibited by the MoAb Sm 1.2, which recognizes both IGF-I and IGF-II but not insulin, and by the MoAb alpha IR-3, which is a specific antagonist of type-I IGF receptor. Fetal mouse-derived 3T3-J2 cells and adult human skin fibroblasts were equally able to sustain keratinocyte growth and in both cases addition of Sm 1.2 MoAb causes a 50% decrease in the keratinocyte number. When the non-IGF-producing BALB/c 3T3 cells were used as a feeder-layer, the keratinocytes number was similar to that observed with 3T3-J2 and with human fibroblasts plus the Sm 1.2 MoAb. IGF-I and IGF-II restored the BALB/c 3T3 growth promoting activity to the level of 3T3-J2 and of normal human fibroblasts. Our results suggest that fetal mouse 3T3-J2 and human fibroblasts synthesize IGF peptides, while keratinocytes do not. Fibroblast-derived IGFs stimulate keratinocyte growth in a paracrine fashion, suggesting their role in the regulation of keratinocyte proliferation in skin growth and in wound healing.

To assess the effect of recombinant human growth hormone (rhGH) on muscle protein metabolism in uremic patients with malnutrition, forearm [ 3 H]phenylalanine kinetics were evaluated in six chronically wasted (body weight 79% of ideal weight) hemodialysis (HD) patients in a self-controlled, crossover study. Forearm protein dynamics were evaluated before, after a 6-wk course of rhGH (5 mg thrice weekly) and after a 6-wk washout period. After rhGH: ( a ) forearm phenylalanine net balance-the difference between phenylalanine incorporation into and phenylalanine release from muscle proteins-decreased by 46% ( Ϫ 8 Ϯ 2 vs. Ϫ 15 Ϯ 2 nmol/min·100 ml at the baseline and Ϫ 11 Ϯ 2 after washout,

Dopamine is known to play a role in the modulation of aldosterone and catecholamine secretion from the adrenal gland, where dopamine receptors (DR), in particular the DR type 2 (D 2 ), have been found to be expressed. DR expression has also been demonstrated in some types of benign adrenal tumors.The aims of the current study were to evaluate DR expression and D 2 localization in the normal adrenal gland and in different types of benign and malignant adrenal tumors, as well as to evaluate the in vitro effects of the dopamine agonists bromocriptine and cabergoline on hormone secretion in nontumoral adrenal cells.Adrenal tissues from 25 patients, subjected to adrenal surgery for different diseases, were studied. These included three normal adrenals; five adrenal hyperplasias; four aldosteronesecreting, two cortisol-secreting, and two clinically nonfunctioning adrenal adenomas; two aldosterone-secreting, two cortisol-secreting, and two androgen-secreting adrenal carcinomas; and three pheochromocytomas. The dopaminergic system is known to regulate the reninangiotensin-aldosterone system (2). D 1 -like receptors are expressed in the renal juxtaglomerular apparatus, where D 1 -selective dopamine agonists stimulate renin secretion (3, 4). Both D 1 -and D 2 -like receptors have been reported to be expressed in the adrenal medulla, where they modulate catecholamine release (5-7). Conversely, DR expression and function in the normal adrenal cortex are still a matter of debate. Indeed, the administration of the D 2 antagonist

Up to a 75% reduction in the conventional dose of tamoxifen (i.e., 20 mg/day) does not affect the activity of the drug on a large number of biomarkers, most of which are surrogate markers of cardiovascular disease. This study was hypothesis generating, and larger studies are warranted to assess the efficacy of tamoxifen at low doses.

(SSR and DR, respectively), we characterized the expression of SSR and DR subtypes in the non-small-cell lung cancer line Calu-6, and then we evaluated the effect on cell proliferation of SS/D chimeric molecules (BIM-23A387 and BIM-23A370), which bind with high affinity both sst2 and D2R, and compared the results with those obtained by using SS-14 and subtype-selective SS analogs (SSA) and D agonists (DA). Because Calu-6 cells produce insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) peptides, which play a role in the autocrine/paracrine control of cell growth, we also investigated the effects of chimeric compounds on secretion and expression of IGF system components. Relative high levels of sst2 and the long isoform of the D2R were detected by real-time RT-PCR and Western blot in Calu-6, together with sst5 and to a lesser extent sst3 and D4R. BIM-23A387 and BIM-23A370 significantly inhibited growth of Calu-6, whereas IGF-IGFBP secretion or expression was unaffected, suggesting a direct inhibitory effect. The inhibition of cell growth, measured by both [ 3 H]thymidine incorporation and cell count, was significantly lower when individual SSA and DA control peptides or subtype-specific SSA and DA were tested. BIM-23A370 was more potent than BIM-23A387 (P Ͻ 0.001). These findings show that SS/D chimeras can inhibit Calu-6 proliferation in an IGF-independent manner and suggest that this enhanced potency might be because of the induction of SSR/DR dimerization. The Calu-6 cell line, constitutively expressing SSR and DR, provides a suitable model to elucidate the mechanism of action of SSA and DA on regulation of cell growth and to characterize the interaction between SSR and DR.

Stunted growth is a common complication of childhood diseases characterized by chronic inflammation or infections.We previously demonstrated that NSE/hIL-6 transgenic mice, overexpressing the inflammatory cytokine IL-6 since early phase of life, showed a marked growth defect associated with decreased IGF-I levels, suggesting that IL-6 is one of the factors involved in stunted growth complicating chronic inflammation in childhood. Here we show that NSE/hIL-6 mice have normal liver IGF-I production, decreased levels of IGF bind-

Changes in the hypothalamus-pituitary-adrenal axis (HPAA) function, entailing elevated cortisol circulating titres, occur in aging and in some neurological conditions, such as Alzheimer's disease (AD). Excess cortisol has neurotoxic effects which affect hippocampal neurones. Dehydroepiandrosterone sulphate (DHEAS) has an antiglucocorticoid activity and neuroprotective effects, but its levels decrease with aging. Glucocorticoids influence the production of insulin-like growth factor-I (IGF-I) and modify its systemic and neurotrophic biological activity by inducing changes in IGF-binding proteins (IGFBPs). We looked for relationships between cortisol, DHEAS levels, and IGF-I - IGFBPs system in AD. Cortisol, DHEAS and GH levels at 02:00, 08:00, 14:00, 20:00 h, basal IGF-I, IGFBP-1 and IGFBP-3 levels were determined by RIAs or IRMA in 25 AD patients, aged 58-89 yr, and in 12 age-matched healthy controls. AD subjects had higher cortisol, lower DHEAS levels and increased cortisol/DHEAS ratio (C/Dr) than controls. In AD cases, total IGF-I, IGFBP-3, and IGF-I/IGFBP ratios were significantly lowered, while IGFBP-1 levels were significantly higher than in controls. We found a significant inverse correlation between IGF-I and IGFBP-3 levels vs C/Dr, and between both IGF-I/IGFBPs ratios vs mean cortisol levels. IGFBP-3 correlated directly with DHEAS. Cortisol was directly and IGF-I inversely correlated with cognitive impairment. In AD patients we found that alterations in HPAA function and elevated C/Dr are related to lowered total and free IGF-I levels. These findings and their relationship to cognitive impairment suggest that changes in hormonal set-up might influence the clinical presentation of the disease.