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Biomedical subjects

F Fanelli

Publications and source records attributed to F Fanelli.

At least 55 records · Page 3Linked to original sources
PubMed1997

[Combined conventional magnetic resonance, magnetic resonance angiography, and magnetic resonance cholangiopancreatography in the diagnosis and staging of pancreatic carcinoma].

PURPOSE: This study was aimed to integrating MR CholangioPancreatography (MRCP) and MR Angiography (MRA) to conventional MR images in the diagnosis and resectability assessment of pancreatic adenocarcinoma. MATERIAL AND METHODS: Twenty-three consecutive patients with pancreatic adenocarcinoma (16 in the head and 7 in the body-tail region) were examined with MR. Conventional MR, 3D MRCP and venous and arterial MRA images were acquired to assess biliary and vascular involvement. Acquisition time never exceeded 40-45 minutes. The images were independently studied by two radiologists and the final reading was decided upon consensus among readers. Sixteen patients underwent surgery. RESULTS: The diagnosis was confirmed at surgery in 16 patients and at percutaneous biopsy in 7. Interreader agreement was considered high, with .83 interobserver variability. Pancreatic adenocarcinoma was found in all patients examined. Unresectability because of vascular involvement was correctly assessed in all patients but 1. Biliary obstruction was demonstrated in 13 patients, involving the biliary and pancreatic ducts in 9 and the biliary ducts only in 4. CONCLUSION: Technical advances now permit the extensive application of MRI to the study of abdominal conditions. The combination of MRI, MRCP and MRA can provide most of the information needed for the diagnosis and resectability assessment of pancreatic adenocarcinoma, which can otherwise be obtained only performing three different exams.

Adenocarcinoma↗
PubMed1997

Theoretical investigation of IL-6 multiprotein receptor assembly.

Interleukin-6 (IL-6) is a multifunctional cytokine that regulates cell growth, differentiation, and cellular functions in many cell lineages. Recently, evidences for the formation of an active hexameric complex with an IL-6:IL-6R alpha:gp130 stoichiometry of 2:2:2 have been obtained by different experimental approaches. Analysis of the electrostatic potential complementarity between IL-6 and its receptors has been used, in this study, to guide the assembly of homology-based 3D models of the components. The results strongly support a mechanism whereby the active cytokine (IL-6: IL-6R alpha) associates with the signal transducing gp130 protein, and the trimeric complex formed further dimerizes to form the hexameric species. Furthermore, computational simulations of the multiprotein complexes provide a rationalization of data from mutation experiments and highlight some key protein-protein interactions which have not yet been the subject of mutagenesis studies.

Amino Acid Sequence↗
PubMed1996

Amino acids of the alpha1B-adrenergic receptor involved in agonist binding: differences in docking catecholamines to receptor subtypes.

Site-directed mutagenesis and molecular dynamics analysis of the 3-D model of the alpha1B-adrenergic receptor (AR) were combined to identify the molecular determinants of the receptor involved in catecholamine binding. Our results indicate that the three conserved serines in the fifth transmembrane domain (TMD) of the alpha1B-AR play a distinct role in catecholamine binding versus receptor activation. In addition to the amino acids D125 in TMDIII and S207 in TMDV directly involved in ligand binding, our findings identify a large number of polar residues playing an important role in the activation process of the alpha1B-AR thus providing new insights into the structure/function relationship of G protein-coupled receptors.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1996

Constitutively active mutants of the alpha 1B-adrenergic receptor: role of highly conserved polar amino acids in receptor activation.

Site-directed mutagenesis and molecular dynamics simulations of the alpha 1B-adrenergic receptor (AR) were combined to explore the potential molecular changes correlated with the transition from R (inactive state) to R (active state). Using molecular dynamics analysis we compared the structural/dynamic features of constitutively active mutants with those of the wild type and of an inactive alpha 1B-AR to build a theoretical model which defines the essential features of R and R. The results of site-directed mutagenesis were in striking agreement with the predictions of the model supporting the following hypothesis. (i) The equilibrium between R and R depends on the equilibrium between the deprotonated and protonated forms, respectively, of D142 of the DRY motif. In fact, replacement of D142 with alanine confers high constitutive activity to the alpha 1B-AR. (ii) The shift of R143 of the DRY sequence out of a conserved 'polar pocket' formed by N63, D91, N344 and Y348 is a feature common to all the active structures, suggesting that the role of R143 is fundamental for mediating receptor activation. Disruption of these intramolecular interactions by replacing N63 with alanine constitutively activates the alpha 1B-AR. Our findings might provide interesting generalities about the activation process of G protein-coupled receptors.

Adrenergic beta-Agonists↗
PubMed1996

Computational simulations of stem-cell factor/c-kit receptor interaction.

Stem-cell factor (SCF) is a noncovalent homodimeric cytokine that exhibits profound biological function in the early stages of hematopoiesis by binding to a cell surface tyrosine kinase receptor that is encoded by the c-Kit proto-oncogene. The results obtained from a combined implementation of homology-based molecular modeling and computational simulations in the study of species-specific SCF/ c-Kit interactions are reported. The structural models of the human and rat SCF ligands are based on the close structural similarity to the cytokine M-CSF, whose C alpha structure has recently become available. The constant domains of the human Fc fragment are used as a template for the ligand binding domains of the c-Kit receptor. The factors responsible for the stabilization of the SCF quaternary structure and the molecular determinants for ligand recognition and ligand specificity have been identified by assessing the conformational, topographical, and dynamic features of the isolated ligands and of the ligand-receptor complexes.

Animals↗
PubMed1996

2-(Substituted)amino-2,8-diazaspiro[4,5]decan-1,3-diones as potential muscarinic agonists: synthesis, modeling and binding studies.

A series of 2-(acyl)amino-8-substituted-2,8-diazaspiro[4,5]decan-1,3-diones (5a-j), structurally related to the muscarinic agonist RS-86, was synthesized and compounds tested for their affinity towards muscarinic receptors. Though all compounds proved to be less active than the model in binding studies, only three derivatives (5a, b, c) being able to significantly displace 3H-QNB at mM concentration, their behaviour could be interpreted in terms of theoretical molecular descriptors computed on the basis of the suggestions coming from Molecular Dynamics simulations of ligand-receptor complexes.

Animals↗
PubMed1996

[Usefulness of the new sequences of magnetic resonance in the study of hepatic hydatidosis].

We investigated the role of new MR Imaging techniques for the diagnosis, characterization and staging of hepatic hydatid disease. We examined 21 patients (30 hydatid cysts), 7 men and 14 women, ranging in age 26 to 74 years, with known hydatid disease. MR examinations were carried out on a 0.5T superconductive magnet (Philips Gyroscan T5, Philips Medical System) with the following imaging protocol: T1w (TR/TE/NEX: 300/10/4) SE, T2w (TR/TE/NEX: 3000/120/6) TSE and fat suppressed (SPIR technique) T2w (TR/TE/NEX: 3000/120/6) sequences. MR Angiography examinations were performed with 2D Time of Flight sequences (TR = 33 ms; TE = 6.9 ms; flip angle = 60 degrees; slice thickness = 4.0 mm with 2.0 mm overlapping; matrix = 256 x 256; number of slices = 45-50; acquisition time = 4 min 19 s), while MR cholangiography was performed with 3D, fat suppressed (SPIR) Turbo Spin-echo (TSE) sequences (TR = 3000 ms, TE = 700 ms, ETL = 12, acq. time = 5 min 48 s). MRI correctly detected all the hydatid cysts on both T1- and T2-weighted images. Characterization was correct in all the cysts larger than 3 cm, where typical signs consistent with hydatid disease were detected. MRA images always showed the inferior vena cava and the splenoportal system. The portal vessels were demonstrated only up to the first branches. In 3 cases an extrinsic compression of the inferior vena cava was diagnosed. MRC, performed in 7 cases, showed normal main bile duct caliber in 6 cases, while in another case, where a cyst ruptured inside the bile ducts, the communication between the cyst and the bile ducts was clearly demonstrated. In conclusion, MR Imaging is a valuable tool in the study of liver hydatid disease. Moreover, the availability of such new MR techniques as MRC and MRA, greatly improves the diagnostic role of MR imaging, especially when studying complications and before surgery.

Adult↗
PubMed1996

[Quantification of mesenteric flow with magnetic resonance imaging before and after a meal: results in healthy volunteers].

Several literature studies showed that total intestinal blood flow approximates superior mesenteric vein flow. Today, new accurate techniques can be used to measure blood flow. We investigated MR capabilities in measuring mesenteric vein flow, to assess total intestinal blood flow. Nine healthy volunteers were examined before and after a meal with a phase-contrast technique to measure blood flow. Flow speed and quantity can be measured positioning a ROI inside the vessel for speed evaluation and around the vessel for flow quantitation. Superior mesenteric blood flow exhibited a three-fold increase after a meal relative to pre-meal values. Cine phase-contrast MRI was a useful tool to measure mesenteric flow in healthy volunteers both before and after a meal and can therefore be suggested for the noninvasive examination of patients with a suspected chronic mesenteric blood supply deficiency.

Adult↗
PubMed1996

[Cholangiography with magnetic resonance in the diagnosis of main common bile duct calculi in candidates to laparoscopic cholecystectomy].

The aim of our work was to investigate Magnetic Resonance Cholangiography (MRC) capabilities in detecting common bile duct (CBD) stones in patients to be submitted to laparoscopic cholecystectomy. MRC was performed as the only preoperative imaging modality in 45 selected patients (16 men and 29 women; age range: 28-72 years, mean age: 54.4 years) before laparoscopic cholecystectomy. MRC images were obtained with 3D Turbo Spin-Echo sequences (TR = 3000 ms, TE = 700 ms, echo train length = 128) with an acquisition time of 5 min 48 sec. Diagnostic confirmation was obtained in all the patients at intraoperative cholangiography. When a stone was detected, it was removed by transcystic or transcholedochal approach. Eighteen of 45 patients (40%) had CBD stones. MRC correctly demonstrated 16 of 18 stones, with 88.9% sensitivity, 100% specificity, 100% positive predictive value, 90% negative predictive value and 95.6% accuracy. Despite the good results we obtained with MRC, this technique cannot be proposed as a screening method to be performed in all the patients candidate to laparoscopic cholecystectomy because of its high cost and of the limited number of MR units available. In conclusion, only selected patients should be submitted to MRC before laparoscopic cholecystectomy.

Adult↗
PubMed1995

Molecular dynamics simulations of m3-muscarinic receptor activation and QSAR analysis.

Molecular dynamics simulations of the rat m3-muscarinic seven-helix-bundle receptor models were performed on the free, agonist-bound and antagonist-bound forms. A comparative structural/dynamics analysis was performed in order to explain the perturbations induced by the functionally different ligands when binding to their target receptor. Theoretical quantitative structure-activity relationship models were developed; a good correlation was obtained between the interaction energies of the minimized average ligand-receptor complexes and the pharmacological affinities of the considered ligands. The consistency obtained between the structural rearrangement of the transmembrane seven-helix-bundle models considered and the experimental pharmacological efficacies and affinities of the ligands constitutes an important validation of the 3-D models proposed and allows the inference of the mechanism of ligand-induced or mutation-induced receptor activation at the molecular level.

Animals↗
PubMed1995

Computer simulations of signal transduction mechanism in alpha 1B-adrenergic and m3-muscarinic receptors.

Molecular dynamics simulations of the hamster alpha 1B-adrenergic and the rat m3-muscarinic seven-helix bundle receptor models have been carried out. The free, agonist-bound and antagonist-bound forms have been considered. Moreover, three mutant forms of the m3-muscarinic receptor (N507-->A, N507-->D and N507-->S) have also been simulated; among these, the N507-->S mutant shows a constitutive activity. A comparative structural/dynamics analysis has been performed to elucidate (i) the perturbations induced by the functionally different ligands upon binding to their target receptor, (ii) the features of the three single-point mutants with respect to the receptor wild type and (iii) the properties shared by the agonist-bound forms of the alpha 1B-adrenergic receptor and the m3-muscarinic receptor and by the constitutively active mutant N507-->S. The consistency obtained between the structural rearrangement of the transmembrane seven-helix bundle models considered, and the experimental pharmacological efficacies of the ligands and of the mutants, constitute an important validation of the 3-D models obtained and allow the inference of the mechanism of ligand- or mutation-induced receptor activation at the molecular level.

Adrenergic alpha-Agonists↗
PubMed1994

Sonohysterography versus hysteroscopy for diagnosing endouterine abnormalities in fertile women.

OBJECTIVES: To evaluate the usefulness of abdominal and vaginal sonohysterography (SHG) (considered both singly and in combination) for the diagnosis of intrauterine abnormalities. METHODS: At the Department of Obstetrics and Gynecology, University of Bari, Italy, the results of the abdominal and vaginal SHG were retrospectively compared with those of conventional transvaginal sonography and hysteroscopy in 35 fertile women in whom a hysteroscopy was indicated. The sensitivity and specificity for the diagnosis of intrauterine abnormalities of both kinds of SHG (considered both singly and in combination), transvaginal sonography and hysteroscopy were compared; the predictive values of abnormal and normal SHG were determined by a 2 x 2 table relating the test results to the patients' abnormalities shown at hysteroscopy. RESULTS: The combination of both abdominal and vaginal SHG had a sensitivity of 95% and a specificity of 100%; the predictive value of an abnormal test was 100% and that of a normal test 94%. CONCLUSIONS: SHG provides a reliable diagnosis of intrauterine abnormalities. However, hysteroscopy and guided biopsies remain the decisive diagnostic test for investigating intrauterine abnormalities.

Adult↗
PubMed1994

Theoretical quantitative structure-activity relationship analysis on three dimensional models of ligand-m1 muscarinic receptor complexes.

The heuristic-direct QSAR (quantitative structure-activity relationships) approach has been applied to a series of 34 muscarinic receptor ligands, including antagonists, weak partial agonists, partial agonists and full agonists, interacting with the human ml-muscarinic receptor subtype. The first step of this procedure consists of the computer-aided 3D-model building of the receptor. The second step involves docking simulations with selected ligands, maximizing the complementarity between ligand and receptor. In the third step, a detailed and extensive correlation analysis between the computed interaction energies, their components and the experimental pharmacological affinity and action is accomplished in order to evaluate the consistency of the QSAR model proposed and to provide a quantitative tool for comparisons among the different complexes considered. In this context, good linear correlations have been obtained between ad hoc theoretical intermolecular interaction descriptors and the pharmacological action, which allow one to classify quantitatively and predict the pharmacological action of new ligands. Finally, according to the ml-receptor model proposed, it has been possible to speculate on the amino acid residues which are mainly involved in the interaction with the ligands, and on the nature of the prevailing intermolecular interactions which are responsible for the different behaviour of antagonists, weak partial agonists, partial agonists and full agonists.

Amino Acid Sequence↗
PubMed1992

Further data on the development of SRIF-like immunoreactive nerve cell populations in the chick embryo brain stem. I. Medulla and pons.

Further immunocytochemical analysis of the neuroblasts with SRIF-like immunoreactivity (ir) was carried out on the chick embryo medulla and pons. 5 or 100 microns rombencephalon sections were obtained from 60 White Leghorn chick embryos at stages (E = Embryonic days) ranging from E4 1/2 to E18 and incubated with rabbit polyclonal antibodies against synthetic cyclic Somatostatin-14, according to PAP-DAB technique. In the medulla and pons the ir appeared as from E12. From E12 to E13 1/2-E14 the ir distribution gradually changed. From E14 to E18 numbers and spatial arrangement of the positive neuroblast groups did not show substantial changes; in these respects the ir distributional pattern proved to be markedly different from the one observed by the Authors in adult animals. Moreover, from E13 to E15 the positive neuroblast density appeared to be higher than that of positive neurons in adults. These results are consistent with a possible SRIF local regulative role.

Animals↗
PubMed1992

Further data on the development of SRIF-like immunoreactive nerve cell populations in the chick embryo brain stem. II. Midbrain tegmentum.

Further immunocytochemical analysis of the neuroblasts with SRIF-like immunoreactivity (ir) was carried out on the chick embryo midbrain tegmentum. 5 or 100 microns mesencephalon sections were obtained from 60 White Leghorn chick embryos at stages (E = Embryonic days) ranging from E4 1/2 to E18 and incubated with rabbit polyclonal antibodies against synthetic cyclic Somatostatin-14, according to PAP-DAB technique. In the midbrain tegmentum the ir appeared as from E12. From E12 to E13 1/2-E14 the ir distribution gradually changed. From E14 to E18 numbers and spatial arrangement of the positive neuroblast groups did not show substantial changes; in these respects the ir distributional pattern proved to be similar to the one observed by the Authors in adult animals. From E17 to E18 a decrease in the positive neuroblast density appeared to occur, particularly in a ventrally placed group. These results are consistent with a possible local regulative role of the SRIF.

Animals↗
PubMed1991

Nasally-administered progesterone: comparison of ointment and spray formulations.

The aim of the study was to compare the bioavailability and clinical usefulness of progesterone (P) administered nasally in spray or ointment form. Twenty healthy post-menopausal women were randomly allocated to treatment by either intranasal spray (4 doses of an oil-based P solution at a concentration of 2 mg/0.1 ml, corresponding to a total dose of approximately 11 mg of P) or an ointment (quantity 0.1 ml, P concentration 20 mg/0.1 ml). Circulating P levels were calculated at various time intervals following administration. The spray formulation yielded a mean maximum concentration (CMax) of 3.75 ng/ml after 60 min (TMax) and the area under the curve (AUC) 0-720 min was 1481.6 +/- 343 ng.h/ml. The ointment yielded a mean CMax of 1.19 ng/ml at TMax = 30 min, the AUC 0-720 value being 404.35 +/- 148 ng.h/ml. The study findings confirmed that the intranasal route is a potentially useful alternative for the administration of natural sex steroid hormones, making it possible to avoid first-pass liver metabolism. P administered by spray showed greater bioavailability than it did when administered in ointment form, while both formulations seemed to be acceptable to patients and were probably clinically safe.

Administration, Intranasal↗
PubMed1991

Progesterone administration by nasal spray.

The bioavailability and the clinical usefulness of the P administered by nasal spray were investigated. Ten healthy menopausal women received an IN spray administration (4 doses of an oleic P solution 20 mg/mL, corresponding to nearly 11.2 mg of P) and the circulating P levels were calculated. Sixty minutes after administration, the maximum concentration (CMax, 3.75 +/- 0.214 ng/mL) was reached. High P levels (greater than 2 ng/mL) lasted until 360 minutes, and the AUC 0 to 720 was 1,481.6 +/- 343 ng.h/mL. Progesterone administration by spray formulation has proven to be effective in reaching therapeutic levels and to be acceptable to patients and, probably, clinically safe.

Absorption↗