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Biomedical subjects

F Leonetti

Publications and source records attributed to F Leonetti.

At least 19 recordsLinked to original sources
PubMed2001

Coumarins derivatives as dual inhibitors of acetylcholinesterase and monoamine oxidase.

A set of 17 coumarin and 2 chromone derivatives with known inhibitory activity toward monoamine oxidase (MAO) A and B were tested as acetylcholinesterase (AChE) inhibitors. All compounds inhibited AChE with values in the micromolar range (3-100 microM). A kinetic study showed that most compounds acted as noncompetitive AChE inhibitors. This finding may be of interest in the context of Alzheimer's disease because recent observations suggest that MAO and AChE inhibition might decrease beta-amyloid deposition.

Acetylcholinesterase↗
PubMed2001

Ectopic lingual thyroid as unusual cause of severe dysphagia.

Ectopic lingual thyroid is an uncommon embryological aberration characterized by the presence of thyroid tissue located in a site different from the pretracheal region as in the normal. Lingual thyroid is the most frequent ectopic location of the thyroid gland, although its clinical incidence varies between 1:3000 and 1:10,000. We present the case of a 26-year-old woman who presented severe dysphagia caused by a mass located on the base of the tongue in the midline. An endoscopic partial removal of the ectopic tissue allowed her to rapidly regain her swallowing capacity. The literature regarding the incidence and diagnosis of lingual thyroid is reviewed and the possibilities of treatment discussed.

Adult↗
PubMed2001

Genotypic and phenotypic characterization of Staphylococcus aureus strains isolated in subjects with atopic dermatitis. Higher prevalence of exfoliative B toxin production in lesional strains and correlation between the markers of disease intensity and colonization density.

Staphylococcus aureus strains generally colonize eczematous lesions of subjects with atopic dermatitis much more frequently than in the skin of normal individuals. The aim of this study was to provide a detailed genotypic and phenotypic analysis of S. aureus strains colonizing four different sites (lesional and non-lesional skin areas, nasal and pharyngeal mucosas) of 49 patients with atopic dermatitis. The 88 isolates were analyzed in duplicate by pulsed field gel electrophoresis and in their exfoliative toxin A or B production by latex test. The patients were characterized by age, sex, severity scoring of atopic dermatitis and serum eosinophil cationic protein. Fourteen (28.6%) of the patients were completely negative for S. aureus while 35 (71.4%) were positive in at least one site. The severity scores and eosinophil cationic protein levels were significantly correlated variables (P<0.001), linked to the colonization intensity (P ranging between 0.05 and <0.001 depending on the site) and to the number of colonized sites (P at least <0.01). The genotypic patterns, widely heterogeneous, showed no restriction to peculiar patterns. Only eight strains produced exfoliative toxin B which was significantly restricted to the lesional isolates (P=0.012).

Adolescent↗
PubMed2000

Inhibition of monoamine oxidases by functionalized coumarin derivatives: biological activities, QSARs, and 3D-QSARs.

A large series of coumarin derivatives (71 compounds) were tested for their monoamine oxidase A and B (MAO-A and MAO-B) inhibitory activity. Most of the compounds acted preferentially on MAO-B with IC(50) values in the micromolar to low-nanomolar range; high inhibitory activities toward MAO-A were also measured for sulfonic acid esters. The most active compound was 7-[(3, 4-difluorobenzyl)oxy]-3,4-dimethylcoumarin, with an IC(50) value toward MAO-B of 1.14 nM. A QSAR study of 7-X-benzyloxy meta-substituted 3,4-dimethylcoumarin derivatives acting on MAO-B yielded good statistical results (q(2)() = 0.72, r(2)() = 0.86), revealing the importance of lipophilic interactions in modulating the inhibition and excluding any dependence on electronic properties. CoMFA was performed on two data sets of MAO-A and MAO-B inhibitors. The GOLPE procedure, with variable selection criteria, was applied to improve the predictivity of the models and to facilitate the graphical interpretation of results.

Animals↗
PubMed2000

Rapid and general profiling of protease specificity by using combinatorial fluorogenic substrate libraries.

A method is presented for the preparation and use of fluorogenic peptide substrates that allows for the configuration of general substrate libraries to rapidly identify the primary and extended specificity of proteases. The substrates contain the fluorogenic leaving group 7-amino-4-carbamoylmethylcoumarin (ACC). Substrates incorporating the ACC leaving group show kinetic profiles comparable to those with the traditionally used 7-amino-4-methylcoumarin (AMC) leaving group. The bifunctional nature of ACC allows for the efficient production of single substrates and substrate libraries by using 9-fluorenylmethoxycarbonyl (Fmoc)-based solid-phase synthesis techniques. The approximately 3-fold-increased quantum yield of ACC over AMC permits reduction in enzyme and substrate concentrations. As a consequence, a greater number of substrates can be tolerated in a single assay, thus enabling an increase in the diversity space of the library. Soluble positional protease substrate libraries of 137, 180 and 6,859 members, possessing amino acid diversity at the P4-P3-P2-P1 and P4-P3-P2 positions, respectively, were constructed. Employing this screening method, we profiled the substrate specificities of a diverse array of proteases, including the serine proteases thrombin, plasmin, factor Xa, urokinase-type plasminogen activator, tissue plasminogen activator, granzyme B, trypsin, chymotrypsin, human neutrophil elastase, and the cysteine proteases papain and cruzain. The resulting profiles create a pharmacophoric portrayal of the proteases to aid in the design of selective substrates and potent inhibitors.

Combinatorial Chemistry Techniques↗
PubMed2000

Synthesis of positional-scanning libraries of fluorogenic peptide substrates to define the extended substrate specificity of plasmin and thrombin.

We have developed a strategy for the synthesis of positional-scanning synthetic combinatorial libraries (PS-SCL) that does not depend on the identity of the P1 substituent. To demonstrate the strategy, we synthesized a tetrapeptide positional library in which the P1 amino acid is held constant as a lysine and the P4-P3-P2 positions are positionally randomized. The 6,859 members of the library were synthesized on solid support with an alkane sulfonamide linker, and then displaced from the solid support by condensation with a fluorogenic 7-amino-4-methylcoumarin-derivatized lysine. This library was used to determine the extended substrate specificities of two trypsin-like enzymes, plasmin and thrombin, which are involved in the blood coagulation pathway. The optimal P4 to P2 substrate specificity for plasmin was P4-Lys/Nle (norleucine)/Val/Ile/Phe, P3-Xaa, and P2-Tyr/Phe/Trp. This cleavage sequence has recently been identified in some of plasmin's physiological substrates. The optimal P4 to P2 extended substrate sequence determined for thrombin was P4-Nle/Leu/Ile/Phe/Val, P3-Xaa, and P2-Pro, a sequence found in many of the physiological substrates of thrombin. Single-substrate kinetic analysis of plasmin and thrombin was used to validate the substrate preferences resulting from the PS-SCL. By three-dimensional structural modeling of the substrates into the active sites of plasmin and thrombin, we identified potential determinants of the defined substrate specificity. This method is amenable to the incorporation of diverse substituents at the P1 position for exploring molecular recognition elements in proteolytic enzymes.

Amino Acid Sequence↗
PubMed2000

Timing of nephrology referral: influence on mortality and morbidity.

To assess the influence of the timing of nephrology referral on the short- and long-term outcome of hemodialysis patients, we retrospectively studied 309 patients who had end-stage renal failure and entered the chronic hemodialysis program in Sainte-Marguerite University Hospital between January 1, 1989, and December 31, 1996. We excluded from the analysis five patients without available data on referral pattern and 34 patients with irreversible acute renal failure. Of the remaining 270 patients, 177 patients (58%) had an early referral (ER) 16 or more weeks before the start of dialysis, and 93 patients (31%) had a late referral (LR) of less than 16 weeks before dialysis. Short-time morbidity (initial emergent dialysis, pulmonary edema, severe hypertension, temporary vascular access placement for first dialysis, prolonged initial hospitalization) was significantly more frequent in LR patients. Long-term evolution (mean follow-up, 26.5 +/- 26 months) did not differ between the two groups. The number of days of hospitalization per patient-year at risk beyond the third month was 21.5 +/- 33.7 days for ER and 21.1 +/- 36 days for LR patients. Survival analysis showed no difference between the two groups: 3-month survival rates were 96% in both groups, 1-year survival rates were 90% in the ER and 89% in the LR group, and 5-year survival rates were 52% in the ER and 56% in the LR group. In a Cox hazards regression model, referral pattern was not associated with a greater risk for death. In conclusion, delayed nephrology referral generated strikingly greater initial morbidity, but long-term outcome of hemodialysis patients was not modified by delayed nephrological care.

Adolescent↗
PubMed2000

Association between lesional or non lesional S. aureus strains from patients with impetigo and exfoliative toxin production. No association with SmaI PFGE patterns.

Contrasting data are reported in the literature on the percent positivity rates (13.5%-100%) of exfoliative toxin (ET) production by S. aureus strains isolated from impetigo patients in Japan and in France. In the present study, by means of a recently available latex-test, toxin-A (ETA) or toxin-B (ETB) production was found in 67.6% of the 34 S. aureus strains isolated from 19 lesional (63.2%) and 15 non-lesional (nose or pharynx, 73.3%) areas of patients with impetigo (with no significant difference between the lesional and non-lesional isolates). ETA + ETB were produced by 44.1% of the strains, while 32.4% were non-producers. In contrast, the percent positivity rate observed in 40 [20 lesional and 20 non-lesional (nose or pharynx)] strains isolated in patients with atopic dermatitis was 15.0% (p < 0.001 both for the lesional and non-lesional strains versus impetigo, with no significant difference between lesional and non lesional strains). Finally, 26 strains from other types of specimens (abscesses, hemocultures, urine, central venous catheters, bronchoalveolar lavages) showed an 11.5% production rate of ETA or ETB (p < 0.001 versus impetigo strains, no significance versus atopic dermatitis). These data point to a significant association between exfoliative toxin production and S. aureus strains isolated in impetigo, both in lesional areas and in nasal/pharyngeal reservoirs. An attempt to correlate SmaI pulsed-field gel electrophoresis (PFGE) restriction patterns and exfoliative toxin production showed no significant association in either group.

Adolescent↗
PubMed2000

S. aureus PFGE patterns of lesional or non lesional strains from patients with impetigo: association of individual bands with lesional or non lesional areas.

PFGE has been extensively used to obtain a reliable intra-species differentiation, although this technique has not been completely standardized. In this study, PFGE was applied to analyze in detail the patterns of 19 lesional S. aureus strains isolated from patients with impetigo, compared with 15 non-lesional strains isolated from nasal or pharyngeal swabs of the same patients. The strain DNA was extracted and processed as previously reported, using the strictest protocol to limit the variations between different analytical sets. To obtain maximum sensitivity and comparability, the electrophoresis patterns were analyzed by an automated and computerized reader (GelDoc1000). The DNA fragments (range 12-15 bands) obtained for each individual strain were then divided into 39 zones including from 1 to 4 bands for a total of at least 91 possible different gel positions. The positivity for each zone (and/or the positivity for the individual bands contained) was associated with the lesional/non-lesional origin and with the face localization of the strains.

DNA, Bacterial↗
PubMed1999

Glucose intolerance and insulin resistance in cirrhosis are normalized after liver transplantation.

Cirrhosis is often associated with insulin resistance and glucose intolerance. We evaluated if these alterations are restored by liver transplantation (LT). Glucose tolerance (oral glucose tolerance test [OGTT]), peripheral insulin sensitivity (euglycemic insulin clamp technique), glucose oxidation (indirect calorimetry), nonoxidative glucose disposal, and insulin secretion (hyperglycemic clamp technique) were measured in 6 patients (Group 1) before and 6 months after LT, in 12 patients (Group 2) who underwent LT 6 to 30 months previously, and in 6 healthy individuals (controls). In Group 1, glucose tolerance and insulin sensitivity (3.24 +/- 0.37 mg/kg/min) were normalized after LT (8.6 +/- 0.77 mg/kg/min; P <.0001; P = not significant vs. controls). The improved insulin-mediated glucose uptake was the result of a normalization of nonoxidative glucose disposal. Fasting insulin and C-peptide decreased from 24.6 +/- 3.3 microU/mL and 4.37 +/- 0.46 ng/dL, respectively, to 12.7 +/- 1.9 microU/mL and 2.46 +/- 0.5 ng/dL (controls: 10.0 +/- 3 microU/mL and 1.45 +/- 0.34 ng/dL). The glucose-induced increase of insulin concentration, which was higher before LT, showed a significant reduction, although the first phase of beta-cell secretion remained significantly higher compared with that of controls. All these findings were also confirmed in Group 2. The present data indicate that LT normalizes glucose tolerance and insulin sensitivity in cirrhotic patients through an improvement of both hepatic glucose clearance and the peripheral glucose disposal. The latter effect may be the result of the correction of chronic hyperinsulinemia. An increased first-phase beta-cell insulin secretion in response to high glucose levels persists, suggesting that a memory of previous insulin resistance is maintained.

Adult↗
PubMed1998

Posttransplantation acute tubular necrosis: risk factors and implications for graft survival.

Previous studies aimed at identifying the causes, risk factors, and outcome of kidney transplant recipients with delayed graft function (DGF) have yielded controversial results. We retrospectively analyzed the causes and risk factors for DGF in 263 cadaveric kidney transplantations from November 1988 to March 1997 in one center. Causes of DGF were assessed by postoperative graft evolution and graft biopsy. Univariate and multivariate analysis were used to investigate the risk factors for DGF induced by acute tubular necrosis (ATN). Seventy-six patients (29%) had DGF, which was caused by ATN in 70 patients (92.1%) and acute rejection (AR) in 6 patients (7.9%). Therefore, we focused on risk factors and consequences for ATN-induced DGF. In monofactorial analysis, ATN was significantly associated with greater weight and presence of an atheromatous disease in both donor and recipient. Other risk factors for ATN were older age of donor, recipient American Society of Anesthesiology (ASA) physical status category IV, cold ischemia time (CIT), and transplantation using the right kidney. The multivariate analysis showed that donor and recipient weight, donor age, transplantation using the right kidney, preservation in Eurocollins solution, ASA score, and CIT were associated with ATN. The incidence of rejection and renal function were not different at 3 months or 1 and 5 years. ATN is the main cause of DGF in kidney transplant recipients. ATN is caused by donor and recipient vascular background, grafting the right kidney, and CIT. ATN does not appear to have an adverse effect on long-term kidney function.

Adult↗
PubMed1998

Ligand binding to I2 imidazoline receptor: the role of lipophilicity in quantitative structure-activity relationship models.

A series of 2-trans-styryl-imidazoline (tracizoline) congeners were designed and tested to develop 2-D and 3-D QSAR models for their binding to imidazoline (I2) receptor. The important role of lipophilicity was assessed by classical 2-D QSAR study (Hansch approach) and by comparative molecular field analysis (CoMFA) with the inclusion of the molecular lipophilicity potential (MLP), as an additional descriptor, besides standard steric and electrostatic fields. Results from these studies were compared to those obtained in a previous modeling study of I2 receptor ligands and integrated into a new, comprehensive model, based on about sixty I2 receptor ligands. This model revealed, at the three-dimensional level, the most significant steric, electrostatic, and lipophilic interactions accounting for high I2 receptor affinity.

Animals↗
PubMed1998

Dietary and urinary risk factors for stones in idiopathic calcium stone formers compared with healthy subjects.

BACKGROUND: The high social-economic cost of nephrolithiasis wholly justifies the attempts to understand its mechanism and avoid recurrences. The influence of dietary habits and urinary risk factors has been evaluated, but the results were discrepant, probably because of differences in the methodologies used to compare patients and controls. METHODS: The aim was to assess dietary and urinary risk factors for urinary stones by comparison between 108 calcium stone formers (SF) and 210 healthy subjects (HS). All subjects were recruited during the same 1 year period. Personal characteristics, dietary habits (evaluated through a food frequency questionnaire) and urinary biochemical parameters were collected. The high predominance of men in the SF group led us to focus on the 79 SF and the 96 HS men. RESULTS: A familial history of stones was reported more frequently in SF than in HS, 42.9% vs 17.6%, P<0.005. Body weight was higher in SF, 76.8+/-12.2 kg vs 72.8+/-9.6 kg, P=0.02; and calcium intake was lower in SF, 794.8+/-294.1 mg vs 943.6+/-345.4 mg, P<0.01. For urinary parameters, calcium and oxalate output were significantly higher in SF. Urinary urea, as a reflection of daily protein intake, and uric acid were also higher in SF. Urinary citrate excretion related to body weight was lower in SF. Calciuria was significantly correlated with urinary urea in both SF and HS, but the correlation was stronger for SF. Calciuria correlated significantly with natriuria only in HS. CONCLUSIONS: The main differences between SF and HS were that SF had a family history of stones, a higher body weight, a lower daily intake of calcium, and a higher urinary output of calcium and oxalate. These results underline the combined role of genetic and nutritional factors in the pathogenesis of urinary stone formation.

Calcium Oxalate↗
PubMed1998

Increased OB gene expression leads to elevated plasma leptin concentrations in patients with chronic primary hyperinsulinemia.

Leptin, a hormone secreted by adipocytes, decreases food intake and increases energy expenditure. The role of insulin in the regulation of leptin secretion is poorly understood and is still a topic of debate. Insulin increases leptin mRNA synthesis in rodents, but in humans, the available data are discordant. To investigate the role of chronic hyperinsulinemia in the regulation of plasma leptin concentrations, we studied 13 patients with surgically confirmed insulinoma before and after tumor removal, along with 15 healthy control subjects matched for sex, age, and BMI. Immunoreactive plasma leptin levels were measured by radioimmunoassay; leptin mRNA levels were also determined by reverse transcription-competitive polymerase chain reaction in a subgroup of six patients with insulinoma and six control subjects. All determinations were made with subjects in the fasting state. Plasma leptin concentrations correlated positively with leptin mRNA levels (r = 0.880, P < 0.001). Leptin levels, both plasma protein and mRNA, were significantly higher in the insulinoma patients than in the control subjects (plasma protein: 17.5 +/- 3.6 vs. 2.9 +/- 0.4 ng/ml, respectively, P < 0.001; mRNA: 0.98 +/- 0.33 vs. 0.19 +/- 0.064 amol/microg RNA, respectively, P < 0.05), and they correlated positively with fasting plasma insulin levels in the patients with insulinoma (plasma protein: r = 0.686, P < 0.01; mRNA: 0.796, P < 0.05). Finally, removal of the insulin-secreting tumor was followed by the normalization of plasma leptin levels. In summary, in patients with insulinoma, 1) plasma leptin levels and leptin mRNA are elevated; 2) a direct relationship exists between leptin, both circulating protein and mRNA, and insulin concentrations; and 3) plasma leptin returns to normal levels after tumor removal. These data, therefore, support a role for insulin in the chronic regulation of leptin gene expression.

Adipose Tissue↗
PubMed1997

Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance.

UNLABELLED: The ability of hyperglycaemia to enhance glucose uptake was evaluated in 9 non-insulin-dependent (NIDDM), 7 insulin-dependent (IDDM) diabetic subjects, and in 6 young and 9 older normal volunteers. Following overnight insulin-induced euglycaemia, a sequential three-step hyperglycaemic clamp (+ 2.8 + 5.6, and + 11.2 mmol/l above baseline) was performed with somatostatin plus replacing doses of basal insulin and glucagon, 3-3H-glucose infusion and indirect calorimetry. In the control subjects as a whole, glucose disposal increased at each hyperglycaemic step (13.1 +/- 0.6, 15.7 +/- 0.7, and 26.3 +/- 1.1 mumol/kg.min). In NIDDM (10.5 +/- 0.2, 12.1 +/- 1.0, and 17.5 +/- 1.1 mumol/kg.min), and IDDM (11.2 +/- 0.8, 12.9 +/- 1.0, and 15.6 +/- 1.1 mumol/kg.min) glucose disposal was lower during all three steps (p < 0.05-0.005). Hepatic glucose production declined proportionally to plasma glucose concentration to a similar extent in all four groups of patients. In control subjects, hyperglycaemia stimulated glucose oxidation (+4.4 +/- 0.7 mumol/kg.min) only at +11.2 mmol/l (p < 0.05), while non-oxidative glucose metabolism increased at each hyperglycaemic step (+3.1 +/- 0.7; +3.5 +/- 0.9, and +10.8 +/- 1.7 mumol/kg.min; all p < 0.05). In diabetic patients, no increment in glucose oxidation was elicited even at the highest hyperglycaemic plateau (IDDM = +0.5 +/- 1.5; NIDDM = +0.2 +/- 0.6 mumol/kg.min) and non-oxidative glucose metabolism was hampered (IDDM = +1.8 +/- 1.5, +3.1 +/- 1.7, and +4.3 +/- 1.8; NIDDM = +0.7 +/- 0.6, 2.1 +/- 0.9, and +7.0 +/- 0.8 mumol/kg.min; p < 0.05-0.005). Blood lactate concentration increased and plasma non-esterified fatty acid (NEFA) fell in control (p < 0.05) but not in diabetic subjects. The increments in blood lactate were correlated with the increase in non-oxidative glucose disposal and with the decrease in plasma NEFA. IN CONCLUSION: 1) the ability of hyperglycaemia to promote glucose disposal is impaired in NIDDM and IDDM; 2) stimulation of glucose oxidation and non-oxidative glucose metabolism accounts for glucose disposal; 3) both pathways of glucose metabolism are impaired in diabetic patients; 4) impaired ability of hyperglycaemia to suppress plasma NEFA is present in these patients. These results suggest that glucose resistance, that is the ability of glucose itself to promote glucose utilization, is impaired in both IDDM and NIDDM patients.

Adult↗
PubMed1997

Impaired nonoxidative glucose metabolism in patients with liver cirrhosis: effects of two insulin doses.

Glucose intolerance is encountered in the majority of cirrhotic patients. This alteration has been attributed to a defective insulin-mediated glucose uptake in peripheral tissue, where nonoxidative glucose disposal seems to be chiefly impaired. To further investigate insulin action under euglycemic conditions, we studied how physiological (100 microU/mL) and pharmacological (1,000 microU/mL) plasma insulin concentrations affect whole-body insulin-mediated glucose uptake, as well as oxidative and nonoxidative glucose disposal, in cirrhotic patients and controls. To this aim, a sequential two-step insulin euglycemic clamp combined with indirect calorimetry was performed in eight cirrhotic patients and six control subjects. During the first step of the clamp, total glucose uptake was reduced by 40% in cirrhotic patients versus controls (4.42 +/- 1.39 v 7.63 +/- 1.60 mg/kg/min, P = .002). By increasing insulin to pharmacological levels, glucose disposal increased in both groups. However, the maximum rate of glucose metabolism achieved in cirrhotic patients was lower than in controls at all times (10.29 +/- 2.04 v 12.82 +/- 0.51 mg/kg/min, P = .012). Glucose oxidation was lower in cirrhotics in the basal state, but similar in both groups during insulin/glucose infusion. On the other hand, the reduced nonoxidative glucose disposal observed in cirrhotic patients was not normalized even by increasing insulin to pharmacological levels. In conclusion, in liver cirrhosis a reduced insulin sensitivity is associated with a reduced insulin responsiveness that is mainly caused by defective nonoxidative glucose disposal.

Adult↗
PubMed1997

2-D and 3-D modeling of imidazoline receptor ligands: insights into pharmacophore.

A 3-D quantitative structure-activity relationship (3-D QSAR) study was carried out using comparative molecular field analysis (CoMFA) on both imidazoline (I2R) and alpha 2 receptor binding affinities of a large series of 2-substituted imidazolines. Significant cross-validated correlations, having promising predictive ability, were obtained along with 3-D pharmacophore models that defined the spatial regions where steric and electrostatic interactions may modulate the in vitro binding affinities and indicated possible physicochemical and structural requirements for I2/alpha 2 receptor selectivity.

Computer Simulation↗