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Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghrelin is a peptide hormone that stimulates growth hormone (GH) release and positive energy balance through binding to the receptor GHSR-1a. Only acylated ghrelin (AG), but not the unacylated form (UnAG), can bind GHSR-1a; however, UnAG and AG share several GHSR-1a-independent biological activities. Here we investigated whether UnAG and AG could protect against skeletal muscle atrophy in a GHSR-1a-independent manner. We found that both AG and UnAG inhibited dexamethasone-induced skeletal muscle atrophy and atrogene expression through PI3Kβ-, mTORC2-, and p38-mediated pathways in myotubes. Upregulation of circulating UnAG in mice impaired skeletal muscle atrophy induced by either fasting or denervation without stimulating muscle hypertrophy and GHSR-1a-mediated activation of the GH/IGF-1 axis. In Ghsr-deficient mice, both AG and UnAG induced phosphorylation of Akt in skeletal muscle and impaired fasting-induced atrophy. These results demonstrate that AG and UnAG act on a common, unidentified receptor to block skeletal muscle atrophy in a GH-independent manner.

Medicine is a collection of science, technology and human values. Nowadays, the most modern paradigm of medicine is based on the combination of man's vulnerability and his need for healthcare, both in a technical-pharmacological sense, but more importantly, with regard to human relations. Of course, the solidarity perspective must represent the strong relational foundation of the doctor-patient relationship, considering that this perspective is now a clear indicator of the civilization level of a nation. The notion of healthcare must therefore be understood in its twofold and inseparable meaning: firstly, the act of "curing" and secondly, the act of "taking care of". In Italy, the term for both of these acts is unique ("curare" meaning to treat, to cure, to care for). However, it is necessary to encompass all meanings as they are inseparable. The responsibility of the doctor is, therefore, to treat, assist, understand and to be at the service of each human being in their interest and in their centrality.

Increased levels of endogenous and/or exogenous estrogens are one of the well known risk factors of endometrial cancer. Diacylglycerol kinases (DGKs) are a family of enzymes which phosphorylate diacylglycerol (DAG) to produce phosphatidic acid (PA), thus turning off and on DAG-mediated and PA-mediated signaling pathways, respectively. DGK α activity is stimulated by growth factors and oncogenes and is required for chemotactic, proliferative, and angiogenic signaling in vitro. Herein, using either specific siRNAs or the pharmacological inhibitor R59949, we demonstrate that DGK α activity is required for 17-β-estradiol (E2)-induced proliferation, motility, and anchorage-independent growth of Hec-1A endometrial cancer cell line. Impairment of DGK α activity also influences basal cell proliferation and growth in soft agar of Hec-1A, while it has no effects on basal cell motility. Moreover, we show that DGK α activity induced by E2, as well as its observed effects, are mediated by the G protein-coupled estrogen receptor GPR30 (GPER). These findings suggest that DGK α may be a potential target in endometrial cancer therapy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Study Objective: To estimate whether the use of narrow-band imaging (NBI) hysteroscopy increases concordance between visual identification and a histologic diagnosis of endometrial cancer and hyperplasia., Design: Prospective study (Canadian Task Force classification: II-2)., Setting: Department of obstetrics and gynecology, University of Eastern Piedmont, Novara, Italy., Patients: 209 consecutive patients with abnormal uterine bleeding., Interventions: White-light hysteroscopy and NBI hysteroscopy followed by direct biopsy., Measurements and Main Results: The sensitivity and specificity of conventional hysteroscopy in predicting a diagnosis of cancer and hyperplasia were, respectively, 84.21% (95% confidence interval [CI], 79.27-89.15) and 99.47% (95% CI, 98.49-100.0), and 64.86% (95% CI, 58.39-71.34) and 98.77% (95% CI, 97.27-100.0), and of NBI hysteroscopy were 94.74% (95% CI, 91.71-97.76) and 97.89% (95% CI, 95.95-99.84), and 78.38% (95% CI, 72.8-83.96) and 97.67% (95% CI, 96.63-99.72). The concordance of conventional and NBI hysteroscopy with the histopathologic findings (measured using the Cohen kappa) was, respectively, 88.80% (95% CI, 86.2%-96.3%) and 91.78% (95% CI, 89.6%-98.2%), a difference of 2.98% (95% CI, 0-9) in favor of NBI., Conclusion: Narrow-band imaging hysteroscopy can accurately predict a histologic diagnosis of endometrial cancer or hyperplasia., (Copyright © 2010 AAGL. Published by Elsevier Inc. All rights reserved.)

Since the first laparoscopic appendectomy was performed by Semm in 1983, laparoscopic surgery has become the criterion standard surgical route for treatment of several pathologic conditions across disciplines. Attempts to minimize access-related injuries and complications resulted in development of laparoendoscopic single-site surgery (LESS), which, because of the decreased number of ports used, may be the next generation of minimally invasive surgery. Laparoscopic single-site surgery has been reported in nephrectomy, pyeloplasty, radical prostatectomy, cholecystectomy, and colorectal, bariatric, and gynecologic surgery. This technique may increase the benefits of traditional minimally invasive surgery such as decreased blood loss and postoperative pain, faster recovery time, fewer complications, and better cosmetic results, without increasing costs. Herein, we present a case report of single-port laparoscopic ovarian cystectomy and concomitant cholecystectomy performed with a multi-instrument access port (TriPort; Olympus America Inc., Center Valley, Pennsylvania). Single-port surgery eliminates the problem of multiple and different site placement for accessory ports, typical of these procedures when performed simultaneously at conventional laparoscopy., (Copyright © 2010 AAGL. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of study was to investigate factors predicting persistence or relapse of disease after cervical conisation for high-grade squamous intraepithelial lesions (CIN 2 or 3)., Methods: The study involved 78 women with high-grade squamous intraepithelial lesions, conservatively treated with loop electroexcision procedure for cervical conisation and subsequent with CO(2) laser-vaporisation of the cervical bed. Histological specimens were totally included and examined by an experienced pathologist. To evaluate the efficacy of treatment, the patients were examined with colposcopy and Pap smear 4 months after surgery and with PCR to search for and genotyping of HPV, 10 months after treatment., Results: During the post-treatment follow-up, the cytologic examination showed persistent/relapsing disease in six patients (7.6%). In only 1 case, the deep margin of the cone was considered positive for CIN (16%).Ten months after treatment, viral typing revealed the persistence of high-risk HPV in all of these patients. Conversely, the viral follow-up of the other 72 patients without persisting/relapsing disease after treatment disclosed low-risk HPV genotypes in 6 cases, high-risk HPV in 2 cases (2.7%), whereas 7 cases had positive margins for CIN (9.7%). The risk of persistence and relapse of CIN in the group with positive margins was not statistically significant (P = 0.87), whereas it was in the group with HR-HPV positive (P = 0.000048)., Conclusion: HPV testing is the most sensitive mean of identifying persistence or relapse early and is therefore capable of optimising follow-up after the treatment of high-grade CIN.

Background: Serous psammocarcinoma is a rare variant of epithelial neoplasia that can arise from the ovaries or peritoneum. It is characterized by massive psammoma body formation, invasiveness and low grade cytologic features., Case: A 70-year-old woman was admitted to our hospital; a bimanual examination with cervicovaginal smear was performed. The smears revealed neoplastic cells with psammoma bodies; afterward, endocervical curettage revealed microaggregates of epithelial neoplastic cells with psammoma bodies. Computed tomography of the abdomen showed a diffuse peritoneal carcinosis with left ovarian calcification. An exploratory laparotomy was carried out. Final pathologic findings showed peritoneal serous psammocarcinoma with ovarian implants., Conclusion: Our report suggests that a Pap smear can play a role in the detection of peritoneal psammocarcinoma and underlines the significance of psammoma bodies as a cytologic marker of this rare tumor.

Purpose: Minilaparotomic access in spinal anaesthesia represents an example of mininvasive surgery and could be a valid cost-benefit alternative in the surgical treatment of benign gynaecologic diseases., Methods: The study is a randomized study. We analyzed a consecutive series of 80 patients treated for benign gynaecological diseases with spinal (group A) or with general anaesthesia (group B)., Results: The median length of incision was 5 cm. The average operating time was 40.5 +/- 9.39 min, without differences between groups. The average hospital stay was 0.71 days shorter (p < or = 0.0001) and the postoperative pain was lower at 2 and 6 h from the surgery and at 10 p.m. in the group A (p < or = 0.0001)., Conclusions: Minilaparotomy in spinal anaesthesia carries advantages from economic point of view with reduction of length of stay in hospital which is an important parameter for the evaluation of the quality of surgical treatments.

Objectives: The more effective way of transmission of GB virus C (GBV-C) is parenteral, but sexual and vertical transmission seem to be the main way of spreading. We evaluated the prevalence and the effect of GBV-C infection on pregnant women, vertical transmission and viral effects on the newborn., Study Design: This study has consecutively enrolled 879 pregnant women. All patients had blood sampling to determine GBV-C RNA, serologic tests for chronic viral infections and seric tests of hepatic damage. The newborns from infected mothers had blood sampling to detect the presence of GBV-C at birth, and after 3 and 6 months. Positive babies were checked until 18 months., Results: 36 (4.1%) women resulted GBV-C positive. Among the positive patients none presented complications during pregnancy. Neither embryonic-fetal abnormalities nor relevant differences in fetal birth weight and week of gestation at delivery were found. 20 out of 36 babies had a follow-up. At birth, 13 (65%) babies were positive. 4 out of 9 vaginal deliveries (44%) and 9 out of 11 cesarean sections (82%) resulted positive to GBV-C RNA. The risk of GBV-C vertical transmission was not significantly increased by type of delivery (p=0.274). At 3 months, 13 babies were GBV-C positive (65%) and 7 were negative (35%). At the end of the follow-up, 9 babies were positive (45%), while 11 were negative (55%)., Conclusion: The percentage of patients positive to GBV-C RNA was comparatively high (4.1%). This prevalence, in a population without particular risk factors, confirms that common ways of transmission, such as the sexual and vertical ones, might have an important role in viral diffusion. Our data suggest that the infection does not influence the course of pregnancy. The rate of transmission found in our study is high. Type of delivery does not seem to be actually involved in vertical transmission and the protective role of cesarean section has not been confirmed.

Objective: To describe the three-step hysteroscopic endometrial ablation (EA) technique without endometrial preparation, and its long-term outcomes., Study Design: Four hundred and thirty-eight premenopausal women with menorrhagia or menometrorrhagia underwent three-step hysteroscopic EA, which consists of rollerball ablation of the fundus and cornual regions, a cutting loop endomyometrial resection of the rest of the cavity, and rollerball redessication of the whole pre-ablated uterine cavity. The main outcome measures were menstrual status, level of satisfaction with the procedure, and the need for repeat ablation or hysterectomy. Questionnaires were completed for 385 women (87.9%) with a mean follow-up of 48.2 months., Results: One hundred and eighty-four responders (47.8%) reported amenorrhea; 177 (46%) had light to normal flow. One patient (0.3%) underwent repeat ablation and 20 (5.2%) underwent hysterectomy: 15 (3.9%) because of endometrial ablation failure and 5 (1.3%) because of indications unrelated to the ablation (three cases of atypical endometrial hyperplasia and two cases of fibroids). Two hundred and ninety-two patients (75.8%) were very satisfied, and 78 (20.3%) satisfied with the results. No major complications occurred and three women (0.8%) became pregnant during the follow-up period., Conclusions: EA is safe and effective means of treating of menorrhagia and menometrorrhagia in premenopausal women, and helps avoid hysterectomy in 95% of patients suffering from heavy bleeding, with or without uterine fibroids. Women should be informed that the procedure is not contraceptive and that pregnancy is possible after treatment.

Various studies have suggested that the phytoestrogen genistein has beneficial cardioprotective and vascular effects. However, there has been scarce information regarding the primary effect of genistein on coronary blood flow and its mechanisms including estrogen receptors, autonomic nervous system, and nitric oxide (NO). The present study was planned to determine the primary effect of genistein on coronary blood flow and the mechanisms involved. In anesthetized pigs, changes in left anterior descending coronary artery caused by intracoronary infusion of genistein at constant heart rate and arterial pressure were assessed using ultrasound flowmeters. In 25 pigs, genistein infused at 0.075 mg/min increased coronary blood flow by about 16.3%. This response was graded in a further five pigs by increasing the infused dose of the genistein between 0.007 and 0.147 mg/min. In the 25 pigs, blockade of cholinergic receptors (iv atropine; five pigs) and alpha-adrenergic receptors (iv phentolamine; five pigs) did not abolish the coronary response to genistein, whose effects were prevented by blockade of beta(2)-adrenergic receptors (iv butoxamine; five pigs), nitric oxide synthase (intracoronary N(omega)-nitro-L-arginine methyl ester; five pigs) and estrogenic receptors (ERs; ERalpha/ERbeta; intracoronary fulvestrant; five pigs). In porcine aortic endothelial cells, genistein induced the phosphorylation of endothelial nitric oxide synthase and NO production through ERK 1/2, Akt, and p38 MAPK pathways, which was prevented by the concomitant treatment by butoxamine and fulvestrant. In conclusion, genistein primarily caused coronary vasodilation the mechanism of which involved ERalpha/ERbeta and the release of NO through vasodilatory beta(2)-adrenoreceptor effects.

Objective: The primary aim of this study was to investigate the role of angiogenesis and inflammatory cell response in cervical carcinogenesis., Methods: Formalin-fixed tissue specimens from 58 uterine cervical specimens (8 CIN1, 14 CIN2, 28 CIN3, and 8 SCC), representing the different stages of cervical carcinogenesis, were immunohistochemically analyzed. Normal cervical tissue specimens were also included as controls. The present study assessed the expression of CD31 and CD105 to evaluate microvessel density (MVD), the macrophage marker CD68 and the panleukocyte marker CD45. In addition, expression of iNOS (inducible Nitric Oxide Synthase) was also evaluated., Results: MVD, measured by either CD31 or CD105, increased along the continuum from normal epithelium to squamous cell carcinoma, and a significant correlation between the CD105-MVD and the CD31-MVD was observed (r=0.8735; p<0.0001). Furthermore, the number of infiltrating macrophages was significantly associated with progression to malignancy. Interestingly, there was a close positive correlation between macrophage counts and CD105-MVD (r=0.7525; p<0.0001). In striking contrast to the other angiogenic and inflammatory markers tested, iNOS expression was significantly reduced as cervical lesion grade progressed from low to high., Conclusions: Our findings demonstrated a positive correlation between neovascularity and macrophage counts, whereas iNOS expression displayed an inverse relationship with macrophage density and tumor progression. Low iNOS expression may modify the function of tumor-infiltrating macrophages toward a malignant phenotype that promotes tumor progression rather than an anti-tumor response.

Prolactin has been associated with many effects and has been implicated in the pathogenesis of pregnancy-related hypertensive disorders, although little is known about its vascular effects. The present study was designed to determine the primary effect of prolactin on regional vascular beds and the mechanisms involved. In 37 anesthetized pigs, the infusion of 0.17 mug/kg min of prolactin at constant heart rate and arterial pressure decreased coronary, mesenteric, renal, and iliac blood flow. This response was graded in further five pigs by increasing the infused dose of the hormone between 0.017 and 1 mug/kg min. In 22 of the 37 pigs, blockade of cholinergic receptors (five pigs) and of alpha-adrenoceptors (five pigs) did not affect the prolactin-induced vascular response, which was abolished by blockade of beta(2)-adrenoceptors (five pigs) and by blockade of vascular nitric oxide (NO) synthase (seven pigs). In 15 of the 37 pigs the increases in measured blood flows caused by iv infusion of isoproterenol (five pigs) and by intraarterial administration of acetylcholine (five pigs) and of sodium nitroprusside (five pigs) were significantly reduced by infusion of prolactin. Moreover, the treatment of porcine aortic endothelial cells by prolactin caused a reduction of NO production and of the phosphorylation of ERK, Akt, and p38, which was prevented by the concomitant treatment by the beta(2)-adrenergic agonist albuterol. The present study showed that iv infusion of prolactin primarily caused coronary, mesenteric, renal, and iliac vasoconstriction. These effects were brought about by the inhibition of a vasodilatory beta(2)-adrenergic receptor-mediated effect related to the NO intracellular pathway.

Background: Estrogen receptor (ER)-negative breast cancers have a worse prognosis than ER-positive cancers, being more aggressive and overexposed to stimuli leading to their progression. Hepatocyte growth factor (HGF) has been associated with proliferation, migration and invasion of tumor cells, and several tumors, including those of breast cancer, produce HGF and overexpress its receptor. Diacylglycerol kinases (Dgks), which phosphorylate diacylglycerol to phosphatidic acid, are key regulators of cell signaling. Our research was focused on their role in HGF-induced invasion of MDA-MB-231 cells, a model of ER-negative breast cancer., Materials and Methods: Dgk activity was evaluated with a kinase assay, MDA-MB-231 cell invasion via culturing of cells in matrigel-coated transwells, and anchorage-independent growth was assessed using a soft agar assay., Results: HGF induces Dgk activation in MDA-MB-231 cells that is required for cell invasiveness. Moreover, Dgks are involved in MDA-MB-231 anchorage-independent growth., Conclusion: Dgks could be a target for ER-negative breast cancer therapy.

Objectives: Hypoplastic left heart syndrome (HLHS) with an intact atrial septum (IAS) is a rare finding, reported in only 1% of pathologic specimens with hypoplasia of the aortic tract complex. In newborns with left heart obstruction, the existence of an interatrial communication is very important for oxygenated blood to be distributed to the body and to prevent pulmonary congestion. The ability to predict prenatally restriction of the atrial defect may allow earlier surgery to be planned., Methods: We report a case of prenatal diagnosis of HLHS with a complete premature closure of the foramen ovale that was not detected by prenatal echocardiography., Results and Conclusion: The management of neonates with HLHS in the first days of life is crucial to the results of the first stage of the Norwood procedure. We suggest that delivery of the mother close to surgical centre and avoiding neonatal transfer improve the results, but stabilisation with prostaglandins and balancing of the systemic and pulmonary resistances are also important. A restrictive or closed atrial septal defect may contribute to haemodynamic instability in the first days of life. The ability to predict this complication prenatally may help in the immediate postnatal management of the affected infant.

Ghrelin is an acylated peptidyl gastric hormone acting on the pituitary and hypothalamus to stimulate appetite, adiposity, and growth hormone release, through activation of growth hormone secretagogue receptor (GHSR)-1a receptor. Moreover, ghrelin features several activities such as inhibition of apoptosis, regulation of differentiation, and stimulation or inhibition of proliferation of several cell types. Ghrelin acylation is absolutely required for both GHSR-1a binding and its central endocrine activities. However, the unacylated ghrelin form, des-acyl ghrelin, which does not bind GHSR-1a and is devoid of any endocrine activity, is far more abundant than ghrelin in plasma, and it shares with ghrelin some of its cellular activities. In here we show that both ghrelin and des-acyl ghrelin stimulate proliferating C2C12 skeletal myoblasts to differentiate and to fuse into multinucleated myotubes in vitro through activation of p38. Consistently, both ghrelin and des-acyl ghrelin inhibit C2C12 proliferation in growth medium. Moreover, the ectopic expression of ghrelin in C2C12 enhances differentiation and fusion of these myoblasts in differentiation medium. Finally, we show that C2C12 cells do not express GHSR-1a, but they do contain a common high-affinity binding site recognized by both acylated and des-acylated ghrelin, suggesting that the described activities on C2C12 are likely mediated by this novel, yet unidentified receptor for both ghrelin forms.

We present an analysis of the antitumour effects of a library of ingenol derivatives synthesized in our laboratory and published elsewhere. Fluoro-ingenol (1), ingenol-20-deoxy-20-phtalimido (2), ingenol-3-benzoate-20-deoxy-20-benzamide (3), ingenol-3-benzoate (4), ingenol-3,5-dibenzoate (5), ingenol-3,20-dibenzoate (6), 20-deoxy-20-benylureidoingenol-3-benzoate (7), ingenol-20-deoxy-20-fluoro-3-benzoate (8), ingenol-20-deoxy-20-fluoro-3,5-dibenzoate (9), ingenol-20-phenylcarbamate (10), ingenol-20-benzoate (11), ingenol-3-benzoate-20-phenylcarbamate (12) were tested in vitro on two well characterized breast cancer cell (BCC) lines, namely T47D and MDA-MB-231, as representative of two opposite types of hormone-sensitiveness and differentiation stage. These experiments led us to identify ingenol-20-benzoate (11) as a promising antitumour compound characterized by a relevant inhibition of cell growth and apoptotic cell death involving a p53-mediated pathway.

Steroid hormones bind to their receptors and trans-activate target genes. Rapid non-genomic action of steroid hormones has been proposed in addition to the one at the genomic level. Estrogen has been described to activate c-Src kinase and this activation has been shown to be responsible for estrogen-dependent mitogenicity. A major substrate of c-Src kinase activity is the cytoskeletal protein p130Cas, originally identified in v-Src-transformed cells. We show that in the human breast carcinoma T47D cells, upon estrogen treatment, p130Cas rapidly and transiently associates with the estrogen receptor alpha in a multi-molecular complex containing the c-Src kinase and the p85 subunit of PI 3-kinase. Association of p130Cas with the estrogen receptor alpha occurs within 3 minutes of estrogen treatment and is dependent on c-Src kinase activation. Transient overexpression of p130Cas in T47D cells increases estrogen-dependent Src kinase and Erk1/2 MAPKs activities and accelerates their kinetics of stimulation. A similar effect was detected on estrogen-dependent cyclin D1 expression, suggesting a role for p130Cas in regulating estrogen-dependent cell cycle progression. Double-stranded small RNA interference (siRNA) by silencing endogenous p130Cas protein, was sufficient to inhibit estrogen-dependent Erk1/2 MAPKs activity and cyclin D1 induction, demonstrating the requirement of p130Cas in such events. Therefore, our data show that the adaptor protein p130Cas associates with the estrogen receptor transducing complex, regulating estrogen-dependent activation of c-Src kinase and downstream signaling pathways.

A case of solitary angiomyofibroblastoma of the vulva in a 16-year-old woman was examined by histology and immunohistochemistry. Microscopic examination of the tumor revealed typical features of a mesenchymal neoplasm, composed of bundle spindle cells with low cellular density, rich in collagen fibers and thin-walled blood vessels. Immunohistochemistry revealed immunoreactivity for progesterone receptor, CD34, desmin and vimentin, tumor cells expressing positivity, but not for estrogen receptors. The stains for the muscle-specific actin and S-100 were negative. These results were mostly consistent with those of previous reports and suggest that the tumors cells were derived from primitive mesenchymal cells which occur normally in this region and show the potential for diverse lines of myoid differentiation.

We evaluated whether insulin signaling modulates plasma cell glycoprotein (PC-1) plasma membrane recruitment, posttranslational processing, and gene expression in human cultured cell lines. Insulin induced a fourfold increase (P < 0.01) of membrane PC-1 expression by rapid and sensitive mechanism(s). This effect was reduced (P < 0.05-0.01) by inhibition of phosphatidylinositol 3-kinase (200 nmol/l wortmannin) and S6 kinase (50 nmol/l rapamycin) activities and intracellular trafficking (50 micromol/l monensin) and was not accompanied by PC-1 gene expression changes. Moreover, at Western blot, insulin elicited the appearance, in both plasma membrane and cytosol, of a PC-1-related 146-kDa band (in addition to bands of 163, 117, 106, and 97 kDa observed also in absence of insulin) that was sensitive to endoglycosidase H. Finally, inhibition of PC-1 translocation to plasma membrane, by wortmannin pretreatment, increases insulin-stimulated receptor autophosphorylation. Our data indicate that insulin stimulates PC-1 posttranslational processing and translocation to the plasma membrane, which in turn impairs insulin receptor signaling. Bidirectional cross talk between insulin and PC-1, therefore, takes place, which may be part of the hormone self-desensitization mechanism.

Ghrelin is an acyl-peptide gastric hormone acting on the pituitary and hypothalamus to stimulate growth hormone (GH) release, adiposity, and appetite. Ghrelin endocrine activities are entirely dependent on its acylation and are mediated by GH secretagogue (GHS) receptor (GHSR)-1a, a G protein-coupled receptor mostly expressed in the pituitary and hypothalamus, previously identified as the receptor for a group of synthetic molecules featuring GH secretagogue (GHS) activity. Des-acyl ghrelin, which is far more abundant than ghrelin, does not bind GHSR-1a, is devoid of any endocrine activity, and its function is currently unknown. Ghrelin, which is expressed in heart, albeit at a much lower level than in the stomach, also exerts a cardio protective effect through an unknown mechanism, independent of GH release. Here we show that both ghrelin and des-acyl ghrelin inhibit apoptosis of primary adult and H9c2 cardiomyocytes and endothelial cells in vitro through activation of extracellular signal-regulated kinase-1/2 and Akt serine kinases. In addition, ghrelin and des-acyl ghrelin recognize common high affinity binding sites on H9c2 cardiomyocytes, which do not express GHSR-1a. Finally, both MK-0677 and hexarelin, a nonpeptidyl and a peptidyl synthetic GHS, respectively, recognize the common ghrelin and des-acyl ghrelin binding sites, inhibit cell death, and activate MAPK and Akt.These findings provide the first evidence that, independent of its acylation, ghrelin gene product may act as a survival factor directly on the cardiovascular system through binding to a novel, yet to be identified receptor, which is distinct from GHSR-1a.

Arsenic trioxide (As2O3) is used clinically to treat acute promyelocytic leukemia and has activity in vitro against several solid tumour cell lines, where induction of differentiation and apoptosis are the prime effects. To investigate the potential therapeutic application of As2O3 to breast cancer, we analysed the effects of As2O3 on the growth of four human breast cancer cell lines: MCF7, MDA-MB-231, T-47D and BT-20. Cells were cultured in 0.5, 2 and 5 microM AS2O3, a range of pharmacologically achievable concentrations of AS2O3. At > or = 2 microM, AS2O3 rapidly induced cell death by apoptosis in MCF7 and MDA-MB-231 while T-47D and BT-20 were partially resistant. At 0.5 microM, As2O3 was subapoptotic but induced features of differentiation consisting in upregulation of ICAM-1 (CD54), a marker of mammary epithelial differentiation, and cell cultures appeared morphologically more organized. Furthermore, we demonstrate by standard cytotoxicity assays that As2O3 treatment can augment breast cancer cell lysis by lymphokine-activated killer cells and demonstrate an important role of the ICAM-1/LFA-1 interaction in this process. This additional activity of As2O3 could translate into improved antitumour immunosurveillance in vivo. In conclusion, As2O3 induced varying degrees of differentiation, apoptosis and lysis in these model cell lines, and may be a promising adjuvant to current treatments of breast cancer by virtue of its triple apoptotic, differentiative and immunomodulatory effects.

This study was undertaken to determine the effects of progesterone on the peripheral circulation. In prepubertal female pigs anesthetized with sodium pentobarbitone, changes in the superior mesenteric, left renal and left external iliac flow caused by intravenous infusion of progesterone were assessed using electromagnetic flow meters. Changes in heart rate and arterial blood pressure were prevented by atrial pacing and by connecting the arterial system to a pressurized reservoir containing Ringer solution. In 20 pigs, infusion of 1 mg/kg of progesterone increased mesenteric, renal and iliac flow. In a further 4 pigs, the vasodilatory effects of the hormone were enhanced by graded increases in the dose between 1, 2 and 3 mg/kg. The mechanisms of these responses were studied in the 20 pigs by repeating the experiment after hemodynamic variables had returned to the control values before infusion. In 5 pigs, blockade of adrenergic receptors with propranolol and phentolamine did not affect the responses elicited by progesterone. The increases in mesenteric, renal and iliac flow to progesterone were prevented, respectively, by the injection of N(omega)-nitro-L-arginine methyl ester into the mesenteric (5 pigs), the renal (5 pigs) or the iliac artery (5 pigs). The present study shows that intravenous infusion of progesterone dilated mesenteric, renal and iliac circulations. The mechanism of this response involved the release of nitric oxide., (Copyright 2001 S. Karger AG, Basel)

Neurofibromatosis type 1 could be associated with multiple gastrointestinal stromal tumours, although their presence is not considered among the major diagnostic criteria. We present here a case of a 50-year-old female complaining of abdominal pain, with about 100 small intestinal stromal tumours. This finding prompted us to suspect a neurofibromatosis which was clinically confirmed afterwards. Light microscopy examination revealed a low-grade stromal tumour with skeinoid fibres. Mixed neural-interstitial cells of Cajal origin or, alternatively, neural differentiation of interstitial cells of Cajal are discussed on the basis of immunophenotype (CD117+, CD34+) and ultrastructure. A 2-year follow-up did not indicate an aggressive course in the case of this neoplasm.

In 1995, the Course on Integrated Obstetrical and Gynaecological Techniques was added to the training program of the Obstetrics and Gynaecology Clinic and to the Midwife Diploma School, at the Faculty of Medicine of the A. Avogadro University of East Piemonte. This addition was due to the demand to create a service to train young medical doctors and student midwives on the basis of the requirements of the World Health Organisation, concerning a more natural way of giving birth. In this paper the results obtained after a four years practical application of these clinical techniques are presented. The factors considered were the type of assistance offered in correlation with different outcomes for both mother and child. The study demonstrates a general improvement in the quality of assistance and a decrease of costs for the National Health Service. The data have been compared with those of the neighbour Hospital Division, where deliveries are assisted with traditional techniques.

In addition to its catalytic activities as ecto-NAD+ glycohydrolase (NADase), CD38 displays the ability to transduce signals of biological relevance. Indeed, ligation of CD38 on peripheral blood mononuclear cells (PBMC) by agonistic monoclonal antibodies (mAbs) is followed by the transcription and secretion of a vast array of regulatory cytokines. The present work addresses the issue of whether the signals leading to calcium (Ca2+) mobilization, lymphocyte proliferation and release of cytokines is dependent on the epitopes recognized by the individual mAbs. Competition binding analysis identifies two families of mAbs, namely IB4, IB6 and AT2 on one side and OKT10, SUN-4B7 and AT1 on the other. Each mAb family binds epitopes that are completely or partially common. However, the functional activities of the CD38 molecule can not be simply attributed to the epitopes engaged: for instance, IB4 and OKT10 mAbs, which bind different epitopes, perform as agonistic mAbs in inducing PBMC proliferation and interferon (IFN)-gamma secretion. SUN-4B7 yields intermediate effects, whereas IB6, AT1 and AT2 mAbs are totally ineffective. The effects mediated by IB4 and OKT10 mAbs are apparent in 80% of the healthy individuals studied, whereas the effects of SUN-4B7 mAb operate only in 25% of the donors. Interleukin (IL)-6 secretion was observed in all individuals analyzed, irrespective of the epitopes triggered and of mAbs used to ligate the CD38 molecule. In addition, IB4 is the only mAb able to induce significant intracellular Ca2+ fluxes.

For many years, we and others have reported the efficacy of cervical cerclage in the prevention of miscarriage in patients with uterine malformations. In this paper the experience of 275 cases collected between 1978 and 1998 is reported. Our data indicate that cervical cerclage is effective in preventing miscarriages, prevalently in those pregnancies bearing uterine malformations with simultaneous cervical incompetence.

Background: The aim of this study was to evaluate the possibility of identifying women with a high risk of postmenopausal osteoporosis by using computerised bone mineral analysis (CBMA) associated with markers of bone turnover in order to provide a valid and reliable screening test., Methods: A total of 925 patients were evaluated, 252 of whom had already undergone a preliminary densitometric test six months earlier and were diagnosed as fast bone losers. 225 of them (89%) also showed altered bone turnover markers. CBMA was negative in the remaining 673 patients but 13 patients showed altered bone turnover markers and three of the latter then showed a positive CBMA 18 months later. The 673 patients who, after six months of study, were not fast bone losers were monitored over time., Results: It emerges from these results that fast bone losers are characterised by higher levels of hydroxyprolinuria and calcium, lower levels of oestrone and estradiol, and reduced body weight compared to healthy subjects., Conclusions: This simplified method enabled 79% of the fast bone losers to be identified, whereas densitometry identified 87.5% of the high-risk subjects. The main advantage of our simplified method compared to the measurement of bone mineral content is that it identifies the majority of fast bone losers in the initial postmenopausal period, before a substantial reduction in BMC has taken place.

All-trans retinoic acid (ATRA) is currently used in clinical trials for breast cancer, in virtue of its ability to inhibit cell growth and to promote cell differentiation. Elucidation of the molecular mechanism(s) underlying the pleiotropic pharmacological activity of ATRA is of fundamental relevance for an effective use of the compound in clinics. This paper reports on the effects of ATRA treatment on the cell surface expression of a panel of adhesion molecules known to regulate the interactions between the effectors of the immune system and tumor targets. Results indicate that breast cancer (BC) cell lines exposed to ATRA selectively up-modulate the surface expression of ICAM-1/CD54, a molecule regulating cell/cell contacts. Such effect could be reproduced in all the BC cell lines analyzed, independently of their hormone receptor status, indicating that estrogens and progesterone are irrelevant in this process. The regulatory effects on ICAM-1 expression are time- and dose-dependent and reversible. Moreover, other differentiating and proliferating agents comparatively tested, e.g. dimethyl sulfoxide, estradiol or dexamethas one, are ineffective, indicating that ICAM-1 up-modulation is uniquely featured by ATRA. A second observation is that ATRA treated cells are, only apparently, less sensitive to lysis by lymphocytes activated by IL-2, as determined by means of a standard 51Cr release assay. In fact, notwithstanding this effect, a marked reduction in the ability to form colonies was highlighted in ATRA treated versus control lines after incubation with LAK. Finally, the clonogenic killing effect could be reversed using anti-CD54 mAbs as blocking tools, indicating that ICAM-1 plays a key role in the phenomena.

It has been previously shown in anesthetized pigs that intravenous infusion of 2 microg/h of 17beta-estradiol primarily dilated renal, iliac and coronary circulations, while higher doses of the hormone were required to cause vasodilation also in the mesenteric vascular bed. In the same experimental model, a tonic beta2-adrenoceptor mediated vasodilation, which could be argued to attenuate the vasodilator effect of 17beta-estradiol, has been described. The present study was planned to investigate the role of beta2-adrenergic receptors in the hemodynamic responses of renal and mesenteric vascular beds to 17beta-estradiol. Changes in flow caused by intravenous infusion of 2 microg/h of the hormone at constant heart rate and aortic blood pressure in the left renal and superior mesenteric arteries were assessed using electromagnetic flowmeters. In six pigs, infusion of 17beta-estradiol caused an increase in renal blood flow, which averaged 12.1% of the control values, without affecting mesenteric blood flow. In the same pigs, after hemodynamic variables had returned to the baseline values, blockade of beta2-adrenergic receptors with butoxamine caused an increase in aortic blood pressure and an increase in renal and mesenteric resistance. The subsequent infusion of 17beta-estradiol elicited increases in renal and mesenteric blood flow which respectively averaged 19.6% and 12.8%. Therefore, the present study in anesthetized pigs have shown that the vasodilator responses of the renal and mesenteric circulations to 17beta-estradiol were attenuated and even masked by a tonic beta2-adrenoceptor mediated vasodilation. This indicates that some vasodilator effects elicited by normally used replacement doses of the hormone may not be apparent.

It has recently been shown that distension of the uterus in anaesthetized pigs causes reflex haemodynamic responses through efferent sympathetic mechanisms. The present study was undertaken to determine whether these mechanisms include activation of the renin-angiotensin system. The same methods were used in 14 pigs which were anaesthetized with alpha-chloralose and artificially ventilated. Balloons positioned within the uterus were distended for periods of 30 min by injecting 20 ml of warm Ringer solution. The responses of arterial blood pressure and heart rate were respectively prevented by blockade of alpha-adrenergic receptors with phentolamine and atrial pacing. Changes in plasma renin activity (PRA) were assessed during the last minute of distension by radioimmunoassay of angiotensin I. In each of 10 pigs, distension of the uterus (mean uterine transmural pressure of 17 mmHg) caused an increase in PRA in the absence of changes of interfering haemodynamic variables. In the remaining four pigs, this response was graded by step increments of the distension. The increase in PRA caused by uterine distension was abolished by bilateral section of the renal nerves (five pigs) or by blockade of beta-adrenergic receptors with propranolol. The present study showed that distension of the uterus in anaesthetized pigs primarily caused a reflex increase in PRA. This reflex response was mediated by renal nerves and involved beta-adrenergic receptors.

Normal bone mass is one of the principal factors in the prevention of osteoporosis for women in advanced age. Therefore, it is necessary to have efficacious serum and urinary markers available to screen the bone development and the bone resorption. Even if we are also far from identifying an ideal marker, the measurement of some substances such as pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) seems to be a first progress for efficacious and rather simple techniques.

The present study was undertaken in anaesthetised pigs to determine the primary reflex effects of distension of the uterus on the peripheral circulation. Experiments were performed in seven pigs anaesthetised with alpha-chloralose and artificially ventilated. Blood flow in the superior mesenteric, left renal and left external iliac arteries was assessed using electromagnetic flowmeters. Distension of the uterus was performed whilst preventing changes in heart rate and aortic blood pressure by injecting 20 ml of warm Ringer solution in a balloon positioned within the viscus (mean transmural pressure of about 18 mmHg). In each pig, distension of the uterus caused decreases in all measured blood flows. In four pigs, these decreases were graded by step increments of distension. In the seven pigs, the responses of decrease in mesenteric, renal and iliac blood flows were not affected by blockade of beta-adrenergic receptors with propranolol, but were abolished by the subsequent blockade of alpha-adrenergic receptors with phentolamine. The present study showed that distension of the uterus in anaesthetised pigs primarily caused reflex vasoconstriction in the mesenteric, renal and iliac vascular beds. This reflex response was mediated by sympathetic mechanisms which involved alpha vascular adrenergic receptors.

The Kasumi-Kamio parameters (margins, peripheral echoes, internal echoes, posterior echoes, lateral shadow cones) and the ratio between the longitudinal and transverse diameter of the breast lump form the basis for a list of standardised diagnostic criteria on which to base an analysis of breast disease that assesses the specificity and sensitivity of ultrasonography as a valid, reliable initial step in the diagnosis of breast tumours. The study was based on a series of 129 tumour cases and produced correct diagnosis in 89.28% of benign, 83.33% of malignant cases.

The present study was undertaken in anaesthetized pigs to determine whether distension of the uterus reflexly affects the aortic blood pressure, heart rate, left ventricular inotropic state and the coronary circulation. Experiments were performed in 17 pigs anaesthetized with alpha-chloralose and artificially ventilated. Coronary blood flow was measured with an electromagnetic flowmeter positioned around the origin of the left circumflex coronary artery. The uterus was distended by injecting 20 ml warm Ringer solution into a balloon positioned within the uterus (mean transmural pressure of about 17 mmHg). Distension of the uterus without controlling any haemodynamic variable caused an increase in aortic blood pressure. When this response was prevented, an increase in heart rate was obtained in each animal. When the heart rate and blood pressure responses were prevented, the distension did not cause significant changes in the maximum rate of change of left ventricular pressure, but always caused a decrease in mean coronary blood flow. In five pigs, the increase in heart rate and the decrease in mean coronary blood flow were graded by step increments of distension. In six pigs, the haemodynamic responses to distension of the uterus were not affected by the administration of atropine. In 12 pigs, which included the six given atropine, the increase in heart rate was abolished by the administration of propranolol and the increase in aortic blood pressure and the decrease in mean coronary blood flow were abolished by the subsequent administration of phentolamine. In the remaining five pigs, the haemodynamic responses caused by uterine distension were abolished by the administration of bretylium tosylate. The present study showed that distension of the uterus in anaesthetized pigs primarily caused reflex increases in heart rate and aortic blood pressure and coronary vasoconstriction. These reflex responses were mediated by efferent sympathetic mechanisms.

A homogeneous group of 45 patients, aged between 19 and 37 years was considered in relationship to metabolic response during oral contraceptive use. A free endocrinological-metabolic pathology control group, formed by 30 patients, aged between 22 and 35, who were not treated with any therapy in the six months before, was also considered. We also considered any other factors like smoking, height, and weight in all women of our study. Study-trial was comprehensive of a 12 months follow-up, with some periods of study at 0, +6, +12 months. Metabolic responses of lipoprotein(a) and apolipoprotein A and B during the different follow-up steps were determined. Total and fractionated cholesterol and triglycerides were also determined. Positive correlations were shown between Lipo(a) and Apo B and also between total cholesterol and LDL. Negative correlations were shown between Lipo(a) vs HDL and Apo A. Lipoprotein(a) was determined by the ELISA technique and turbidimetric technique. The aim of our study was to verify the importance of the new markers of atheroma risk; even if the oral estrogen-progestin contraception little interferes with this biohumoral marker synthesis, it improves atheroma risk protection through the lipidic metabolism complexity.

A homogeneous group of 37 patients, aged between 52 and 61 years was considered in relationship to the metabolic response during hormonal replacement therapy (HRT). A free endocrinological-metabolic pathology control group, formed by 40 patients, who were not treated with any therapy, was also considered. Study-trial was comprehensive of a 123 months follow-up, with some periods of study at 0, +6, +12 months. Metabolic responses of lipoprotein(a) and apolipoprotein A and B during the different follow-up steps were determined. Total and fractioned cholesterol and triglycerides were also determined. Significant correlations were shown between Lipo(a) and Apo B and also between Lipo(a) and LDL in both groups considered Lipoprotein(a) was determined by ELISA methodic and turbidimetric methodic. The aim of our study was to verify the importance of the new markers of the atheromatous risk. The reduction of lipoproteins middle value observed in the HRT group shows a little, but however present, estrogens action to the Lipo(a) itself. This fact testifies to the benefit of the use of HRT in post-menopause also as reg ards an evaluated cardiovascular risk inhibition.

We tried to identify a correlation between bacterial vaginosis and PROM with the aim of proposing a future screening for pregnant women at risk for premature rupture of membranes. We made two vaginal bacteriological tests on women pregnant at 24th and 34th week, and we repeated the same test when it proved positive for infection after therapy. We did 375 tests and our study group was composed of 249 pregnant women, aged between 24 and 35. We also evaluated some variable factors as ultrasonographic gestational age redetermination, number pregnancies of oral contraceptives or IUD use, presence of risk factors presence (recurrent abortion, previous PROM, glucose metabolism alteration, immunosuppression, condylomatosis). 171 tests proved positive (total positivity percentage: 47.2%). The most common micro-organism was Ureaplasma urealyticum (49.1%) that was related to PROM in 66.7%. This result contracts with affirmations of some England authors who think that Ureaplasma hasn't an important role in PROM. This fact, if related to the other data we obtained with our study, actually current, shows a strict correlation between PROM and bacterial vaginosis, but also a different distribution of vaginal infections in our country in comparison with English countries.

We report the topography of integrins and some basement membrane zone (BMZ) proteins in normal vulvar skin and in seven cases of vulvar squamous carcinoma (VSC). In vulvar epidermis integrin chains alpha 2, alpha 3 and beta 1 lined the lateral surface of basal cells, while the heterodimer alpha 6 beta 4 was detected only at their basal domain. The location of alpha 6 beta 4 exactly matched BMZ identified by kalinin, laminin and collagen type IV. In VSC this pattern was subverted since both beta 1 integrins and alpha 6 beta 4 became pericellular. In particular, alpha 6 beta 4 lost its coherence with the residual organization of BMZ. In fact, BMZ components displayed their normal pattern were this was preserved, and so were fibronectin and tenascin in the stroma underlying the tumor. Furthermore, alpha 5 beta 1, the prototype fibronectin receptor that is not normally exposed in vulvar epidermal cells, became detectable pericellularly in VSC tumor cells. Alteration of integrin polarized topography appears to be typical of VSC cells as well as of other tumor epidermal cells. This alteration may be easily shown by immunohistochemistry on routinely collected frozen biopsies. It may then represent a tool for the early diagnosis of VSC that provides a quick and easy complement of traditional histology.

The intrinsic characteristics of LH and prolactin (PRL) episodic secretion were evaluated in a group of 18 children (8M and 10F). The children were divided into two groups according to the Tanner stage: Group A (Tanner < or = 1, N = 7, 3M and 4F, 6-10 years of age) and group B (Tanner 2-3, N = 11, 5M and 6F, 9-11 years of age). A pulsatility study of 4 h, sampling every 10 min, was carried out in all children. LH and PRL plasma levels were assayed by IFMA and RIA respectively. LH and PRL secretory episodes were then identified on plasma determinations using the program DETECT. Instantaneous secretory rates (ISR) were then computed for both LH and PRL using the specific algorithm within the DETECT program. Plasma LH levels were different between the two groups of children. Group A children showed undetectable LH plasma levels (below the minimal detectable dose of 0.1 mIU/ml), while group B demonstrated LH plasma levels in the normal range of values for age and sexual development (1.5 +/- 0.3 mIU/ml, mean +/- SEM). LH pulse frequency for group B was 3.2 +/- 0.4 peaks/4 h. No significant differences in mean plasma PRL levels, pulse frequency and pulse amplitude were observed between the two groups of children. Computation of ISR for LH (group B only) and PRL (both groups) identified the intrinsic episodic characteristics of the two hormones. No significant differences in LH and PRL pulse frequencies were observed when comparing the results estimated on ISR with those estimated on plasma concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

The intrinsic secretory characteristics of prolactin (PRL) have been investigated using newly developed algorhythms for instantaneous secretory rate (ISR) computation. PRL secretory rate, its intrinsic pulsatile characteristics and their possible dependance from gonadal steroids were investigated in five groups of subjects: a) 11 women during the follicular and luteal phase of the same menstrual cycle; b) 5 healthy postmenopausal women; c) 6 women affected by functional hyperprolactinemia; d) 5 normal men; e) 4 agonadal subjects before and during testosterone replacement therapy. All subjects underwent a 6 hours pulsatility study, from 08:00 to 14:00, sampling every 10 minutes. PRL plasma concentrations were determined using a RIA system and the presence of PRL secretory pulses was evaluated with program DETECT, both on plasma time series and after ISR computation. A distinct PRL episodic release was observed in all groups (follicular phase: 5.5 +/- 0.5, luteal phase: 6.5 +/- 0.6, postmenopause: 5 +/- 1, hyperprolactinemic women: 4.2 +/- 0.8, men: 4.8 +/- 0.4, agonadal before testosterone: 6 +/- 1, agonadal during testosterone administration: 5.3 +/- 0.3 peaks/6h), but mainly the computation of ISR allowed to demonstrate that the duration of the lactotropes secretory events was constant in all groups studied. PRL secretory bursts duration ranged between 23.1 +/- 1.8 and 25.4 +/- 2.5 minutes independently both on PRL or on sex steroid plasma levels. In conclusion, the present report shows that in different physiological conditions the intrinsic secretory bursts from lactotropes are constant in duration independently from the functional state, sex and the steroid hormone levels.