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Biomedical subjects

G Ferretti

Publications and source records attributed to G Ferretti.

At least 19 recordsLinked to original sources
PubMed2003

Binding of nicotine and homoazanicotine analogues at neuronal nicotinic acetylcholinergic (nACh) receptors.

A total of 20 substituted analogues of nicotine (1a) and homoazanicotine (3a) were examined in order to determine whether or not they might bind in a similar manner at alpha4beta2 nicotinic acetylcholinergic (nACh) receptors. It was found that parallel structural changes in the two series resulted in parallel shifts in affinity. Evidence suggests that the two series are binding in a comparable fashion.

Humans↗
PubMed2003

Effect of homocysteinylation on human high-density lipoproteins: a correlation with paraoxonase activity.

We investigated the effect of homocysteine (Hcy)-thiolactone on the activity of the enzyme paraoxonase (PON) associated with human high-density lipoprotein (HDL-PON). HDL were isolated from plasma of normolipidemic subjects. The increase in the levels of sulfhydryl groups (-SH) in HDL incubated with Hcy-thiolactone demonstrates that homocysteinylation of HDL occurs. The increase of -SH groups correlated with the basal values of HDL-PON activity (r = -0.73, P <.001, and r = -0.70, P <.002 using 10 micromol/L and 1 mmol/L Hcy-thiolactone, respectively) suggesting a relationship between the susceptibility of HDL to homocysteinylation and HDL-PON activity. A decrease in the activity of the enzyme HDL-PON was observed in homocysteinylated HDL (Hcy-HDL). The negative correlation established between the basal levels of HDL-PON activity and the percentage decrease of HDL-PON activity (r = -0.76, P <.001, and r = -0.86, P <.001 using 10 micromol/L or 1 mmol/L Hcy-thiolactone, respectively) suggests that subjects with higher HDL-PON activity have a lower decrease in PON activity with respect to subjects with lower HDL-PON activity. The positive correlation established between the percentage decrease of PON activity and the percentage increase of -SH groups in Hcy-HDL (r = 0.80, P <.001, and r = 0.76, P <.001 in HDL incubated in the presence of 10 micromol/L and 1 mmol/L Hcy-thiolactone, respectively) suggests that the modifications of HDL-PON activity are likely related to the compositional changes at the lipoprotein surface of Hcy-HDL. The enzyme PON contributes to the protective role of HDL against the oxidative damage and against toxicity exerted by Hcy involved in the development of atherosclerosis. Therefore the significant decrease of the enzyme activity in HDL incubated with Hcy-thiolactone suggests that homocysteinylation could render HDL less protective against oxidative damage and against toxicity of Hcy-thiolactone.

Adult↗
PubMed2003

Early detection of lung cancer: role of biomarkers.

Early detection of lung cancer requires none or few invasive techniques. Distal lung cancer (40% of the cases in most European countries) can be sensitively detected by spiral computed tomography. Theoretically, in 60% of cases, the proximal lesions (main to segmental bronchi, accessible by bronchoscopy) should be able to be detected by sputum cytology. Unfortunately, this very specific technique has a low sensitivity and is time consuming. Fluorescent bronchoscopy increases the detection rate of early or micro-invasive lesions and may be proposed in highly selected populations, but not as a screening test. Biomarkers in blood and sputum have not yet been clinically validated. However, the amount of data generated from studies first on resected tumours, then on early bronchial lesions and more recently on blood and sputum offer a wide field for investigation. Lung carcinogenesis is a multistep process characterised by the accumulation of successive molecular genetic and epigenetic abnormalities, resulting in selection of clonal cells with uncontrolled growth capacities throughout the whole respiratory tract (field cancerisation). Molecular lesions far precede morphological transformation of preneoplastic bronchial lesions (dysplasia) or alveolar lesions (atypical alveolar hyperplasia). Genetic and epigenetic abnormalities in the genes involved in cell cycle, senescence, apoptosis, repair, differentiation and cell migration control may be detected on bronchial biopsies, on respiratory cells from the sputum and even in the circulating deoxyribonucleic acid (DNA). The key genes involved include those in the P53-retinoblastoma (Rb) pathways. The balance between cyclin-dependent kinases and their inhibitors regulates the level of Rb phosphorylation and its function at G1-S transition; P53 plays at least two functions (cell cycle and apoptosis control). The balance of bax-bcl2 is important in the control of apoptosis as well as loss of fragile histidine triad expression. O(6)-methylguanine-DNA methyltransferase seems to be important in DNA repair control, the RARbeta receptor in differentiation, and cadherin H and E and different metalloproteases genes in cell migration. The demonstration of hyperexpression or silencing of these genes needs different validated techniques: immunohistochemistry on biopsies or cytological preparations, molecular biology techniques for mutations, loss of heterozygosity and aberrant methylation abnormalities. Automation and miniaturisation of these techniques will allow early detection and may be widely applied once clinically validated.

Biomarkers, Tumor↗
PubMed2002

Homoazanicotine: a structure-affinity study for nicotinic acetylcholine (nACh) receptor binding.

We have recently identified 3-[(1-methyl)-4,5-dihydro-1H-imidazol-2-yl)methyl]pyridine (homoazanicotine, 8) as a novel nicotinic acetylcholinergic (nACh) receptor ligand. In the present investigation, after we determined that 8 binds selectively at nicotinic (K(i) = 7.8 nM) vs muscarinic (K(i) > 10,000 nM) acetylcholinergic receptors, we examined its structure-affinity relationships for nACh receptor binding. The features investigated included the influence of (i) the composition of connector that separates the two rings, (ii) the N-methyl group, (iii) the ring opening of the imidazoline ring, (iv) the pyridine nitrogen atom, and (v) the aromatization of the imidazoline ring on nACh receptor affinity. As with nicotine, the parent structure seems optimal and most structural changes reduce nACh receptor affinity. Also, as with nicotine analogues, alteration of the spacer group influences affinity in a manner that is somewhat different than that seen with the parent structure.

Acetamides↗
PubMed2002

Effect of human Apo AIV against lipid peroxidation of very low density lipoproteins.

Recent studies have demonstrated that Apo AIV exerts a protective effect against atherosclerosis. Moreover, Qin et al. (Am. J. Physiol. 274 (1998) H1836) have demonstrated that Apo AIV, isolated from rat plasma, exerts an inhibitory effect against Cu(2+)-induced lipid peroxidation of intestinal lymph and LDL. The aim of the study was to investigate whether human Apo AIV exerts a protective effect against Cu(2+)-induced lipid peroxidation. Our results demonstrated that human Apo AIV exerted an inhibitory effect against Cu(2+) and AAPH induced lipid peroxidation of VLDL, as shown by the lower increase in the levels of TBARS and conjugated dienes in lipoproteins preincubated with Apo AIV. In addition, the tryptophan (Trp) and probe 2-(dimethylamino)-6-lauroylnaphthalene (Laurdan) fluorescence studies demonstrated that the modifications of spectral properties in both lipoproteins preincubated with Apo AIV were lower with respect to ox-lipoproteins, suggesting that Apo AIV prevents the modification of physico-chemical properties due to peroxidation.

2-Naphthylamine↗
PubMed2002

Recognizing features that are dissimilar in male and female breast cancer: expression of p21Waf1 and p27Kip1 using an immunohistochemical assay.

BACKGROUND: Male breast cancer (MBC) is an uncommon disease, and most of our current knowledge of its biology, natural history and treatment has been extrapolated from data on the disease in women. Information is still needed on the molecular biological properties of male breast tumors and their predictive relevance. Kinase inhibitor proteins (KIPs) p27Kip1 and p21Waf1 negatively regulate cell cycle progression by preventing the passage of cycling cells from G1 to S phase through G1 cyclin-dependent kinase activation. No studies exist on the role of these factors in male breast carcinoma. PATIENTS AND METHODS: We have retrospectively analyzed the immunohistochemical expression of p21Waf1 and p27Kip1 protein in 27 primary MBC and in 101 female breast cancers (FBC) treated at the European Institute of Oncology between 1997 and 2000. We also assessed sex hormone receptors status, p53, bcl-2 and c-erb-B2 protein expression, and Ki-67 labeling index. RESULTS: We observed a statistically significant difference in the immunostaining of KIPs p27Kip1 and p21Waf1 in male patients compared with females. Expression of p21Waf1 was observed in 19 of the 27 (70.3%) primary MBCs versus 29 of 101 FBC (29%). Fourteen of 22 negative c-erbB-2 MBCs cases expressed immunostaining for p21Waf1 (P = 0.05). p27Kip1 immunoreactivity was been detected in 26 of 27 (96.2%) male breast patients versus 39 of 101 FBC (39.3%) (P = 0.000). Highly positive staining for P27Kip1 was found in 21 of 25 androgen receptor-expressing samples. Higher levels of p27Kip1 were expressed in bcl-2-positive samples (17 of 20). Eighteen of 22 c-erbB-2-negative cases were strongly immunoreactive for p27Kip1. CONCLUSIONS: p27Kip1 and p21Waf1 immunoreactivity is higher in MBCs compared with FBCs. The findings of higher p27Kip1 and p21Waf1 immunostaining may be an additional predictive factor in MBC. These biological features could be possible indicators for different biological pathways in the tumorigenesis of MBCs.

Adult↗
PubMed2002

Positive predictive value of 99mTc sestamibi scintimammography in patients with non-palpable, mammographically detected, suspicious, breast lesions.

The purpose of this study was to analyse whether the use of Tc sestamibi scintimammography improves the positive predictive value of X-ray mammography. A series of 73 women (median age 51 years, range 35-79 years) with non-palpable, mammographically suspicious, breast lesions was reviewed. There were 41 (56.2%) pre-menopausal, and 32 (43.8%) post-menopausal women. All patients underwent sestamibi scintimammography prior to open breast biopsy. Definitive histology showed breast cancer (pT1a=1 (1.9%), pT1b=47 (90.4%), pT1c=4 (7.7%)) in 52 (71.2%) patients, and benign breast lesions in 21 (28.8%). Patients with cancer were significantly older (P <0.01), while the greatest dimension (size) of the excised lesion did not differ (8.47+/-1.51 vs 8.30+/-1.53 mm; P =0.66) between the two groups. Overall, the positive predictive values of mammography and sestamibi scintimammography were 71.2% and 95.7%, respectively (P =0.004). Patients with false positive mammography were significantly younger than those in whom cancer was diagnosed correctly (45.35+/-7.56 vs 53.96+/-10.60 years; P =0.001), while age did not affect the sensitivity of sestamibi scintimammography, which reached 100% in patients with breast lesions > or =8 mm in size. In this subgroup the positive predictive value of mammography, sestamibi scintimammography, and mammography+sestamibi scintimammography together were 63.4%, 95.1% (P =0.001), and 97.6%, respectively, and the majority of the patients with benign lesions (13 of 15 (86.7%)) could have avoided biopsy. It is concluded that the use of Tc sestamibi scintimammography in conjunction with mammography may potentially reduce unnecessary surgical procedures, and should be performed in all patients with mammographically suspicious breast lesions of 8 mm or greater in size.

Adult↗
PubMed2002

Glycated low density lipoproteins modify platelet properties: a compositional and functional study.

The interaction between low density lipoproteins (LDL) and platelets might play a central role in the development of atherosclerosis in diabetes. The aim of the present study was to investigate whether the glycation of LDL is associated with modifications of their physico-chemical and functional properties and to study the action of glycated LDL (glycLDL) on platelets. LDL and platelets were isolated from 15 healthy subjects. The content of thiobarbituric acid-reactive substances and the generalized polarization of the fluorescent probe Laurdan were determined in LDL glycated in vitro. Platelets were incubated with native LDL, GlycLDL, and minimally oxidized LDL, and the following parameters were evaluated: platelet aggregation, nitric oxide production, intracellular Ca(2+) concentrations, Na(+)/K(+)-adenosine triphosphatase (Na(+)/K(+)-ATPase), and Ca(2+)-ATPase activities. GlycLDL showed increased thiobarbituric acid-reactive substance levels, a red shift of the Laurdan emission maximum, and a decrease in generalized polarization, indicating a higher polarity and a reduced molecular order compared with native LDL. GlycLDL caused a significant increase in platelet nitric oxide production, intracellular Ca(2+) concentration, and aggregating response to ADP; an inhibition of the platelet membrane Na(+)/K(+)-ATPase activity; and a stimulation of Ca(2+)-ATPase activity. Minimally oxidized LDL did not cause statistically significant changes in the parameters studied. The present work demonstrates that glycation induces compositional and structural changes in LDL and suggests that an altered interaction between glycLDL and platelets might play a role in the vascular complications of diabetes.

2-Naphthylamine↗
PubMed2001

Accuracy of technetium-99m sestamibi scintimammography and X-ray mammography in premenopausal women with suspected breast cancer.

The aim of this study was to evaluate the usefulness of technetium-99m sestamibi scintimammography (SSM) and combined use of SSM and X-ray mammography (MG) in premenopausal patients with small (< or =2 cm) suspicious breast lesions. Eighty-seven premenopausal women (median age 47 years, range 32-52) with breast lesions ranging from 4 to 20 mm in greatest diameter (median 12 mm) and detected by MG, underwent SSM prior to open breast biopsy. A planar camera and single-photon emission tomography (SPET) technique were used in 23 (26.4%) and 64 (73.6%) patients, respectively. At histological examination, 72 (82.8%) breast cancers (pT1a=3, pT1b=27, pT1c=42) and 15 (17.2%) benign masses were found. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of MG and SSM were 80.6% vs 80.6%, 60.0% vs 93.3% (P<0.05), 90.6% vs 98.3%, 39.1% vs 50.0% and 77.0% vs 82.8%, respectively. MG + SSM together had a sensitivity of 94.4% (P<0.05 vs SSM alone) and an accuracy of 82.8% for the detection of breast cancer. Tumours undetected by both MG and SSM were significantly (P<0.05) smaller than those correctly diagnosed. Patients with false-negative MG were younger (P<0.05) than those with tumours correctly detected, while SSM sensitivity was independent (P=NS) of age. In conclusion, in premenopausal patients with small breast lesions, the sensitivity of SSM and MG is similar (P=NS), whereas the specificity of SSM is significantly higher (P<0.05) than that of MG. Furthermore, the combination of MG and SSM offers significantly improved sensitivity and accuracy in comparison with the individual techniques, suggesting a complementary role of SSM in the detection of breast cancer in younger patients.

Breast↗
PubMed2001

Extreme human breath-hold diving.

In this paper, the respiratory, circulatory and metabolic adjustments to human extreme breath-hold diving are reviewed. A survey of the literature reveals that in extreme divers, adaptive mechanisms take place that allow prolongation of apnoea beyond the limits attained by non-diving subjects, and preservation of oxygen stores during the dives. The occurrence of a diving response, including peripheral vasoconstriction, increased arterial blood pressure, bradycardia and lowered cardiac output, is strongly implicated. Some peripheral regions may be excluded from perfusion, with consequent reliance on anaerobic metabolism. In addition, extreme breath-hold divers show a blunted ventilatory response to carbon dioxide breathing, possibly as a consequence of frequent exposure to high carbon dioxide partial pressures during the dives. These mechanisms allow the attainment of particularly low alveolar oxygen (< 30 mmHg) and high alveolar carbon dioxide (> 50 mmHg) partial pressures at the end of maximal dry breath-holds, and reduce oxygen consumption during the dive at the expense of increased anaerobic glycolysis (rate of blood lactate accumulation > 0.04 mM.s-1). The current absolute world record for depth in breath-hold diving is 150 m. Its further improvement depends upon how far the equilibrium between starting oxygen stores, the overall rate of energy expenditure, the fraction of energy provided by anaerobic metabolism and the diving speed can be pushed, with consciousness upon emersion. The ultimate limit to breath-hold diving records may indeed be imposed by an energetic constraint.

Adaptation, Physiological↗
PubMed2001

Oxygen delivery and oxygen return in humans exercising in acute normobaric hypoxia.

At a given steady O2 consumption (VO2) in normoxia, cardiac output (Q) is inversely proportional to arterial O2 concentration (CaO2), so that O2 delivery (QaO2=QCaO2) is kept constant and adapted to VO2. The matching between QaO2 and VO2 keeps O2 return (QvO2=QaO2-VO2) constant and independent of VO2 and haemoglobin concentration ([Hb]). This may not be so in hypoxia: in order for QvO2 to be independent of the inspired O2 fractions (FIO2), the slopes of the Q versus VO2 lines should be greater the lower the CaO2, which may not be the case. Thus, we tested the hypothesis of constant QvO2 by determining QaO2 and QvO2 in acute hypoxia. Thirteen subjects performed steady-state submaximal exercise on the cycle ergometer at 30, 60, 90 and 120 W breathing FIO2 of 0.21, 0.16, 0.13, 0.11 and 0.09. VO2 was measured by a metabolic cart, Q by CO2 rebreathing, [Hb] by a photometric technique and arterial O2, saturation (SaO2) by infrared oximetry. CaO2 was calculated from [Hb], SaO2 and the O2 binding coefficient of haemoglobin. The VO2 versus power relation was independent of FIO2. The relations between Q and VO2 were displaced upward and had higher slopes in hypoxia than in normoxia. However, the Q changes did not compensate for those in CaO2. The slopes of the QaO2 versus VO2, lines tended to decrease in hypoxia. QVO2 was lower the lower the FIO2. A significant relationship was found between QvO2 and SaO2 (QvO2= 1.442 SaO2+0.107, r=0.871, n=24, P<10(-7)), which confutes the hypothesis of constant QvO2 in hypoxia.

Adult↗
PubMed2001

Effect of glycation of high density lipoproteins on their physicochemical properties and on paraoxonase activity.

We investigated the effect of incubation of high density lipoprotein (HDL) under hyperglycaemic conditions on lipid composition, physicochemical properties and activity of paraoxonase (PON), a calcium-dependent enzyme associated with HDL that contributes to the antiatherogenicity of this lipoprotein. HDL incubated for three days with various glucose concentrations (0-100 mM) had significant increases in thiobarbituric acid-reactive substances (TBARS) and conjugated dienes with respect to control HDL. These results suggest that lipid peroxidation accompanies HDL glycation in vitro. The susceptibility to lipid peroxidation was higher in HDL isolated from subjects with low HDL-paraxonase activity with respect to subjects with higher HDL-PON activity. The lipid compositional changes were associated with modifications of apoprotein conformation as shown by the red-shifted position of the maximum emission of tryptophan in treated HDL. The decrease in the Gp (generalized polarization) value and the red-shifted position of the maximum emission of Laurdan incorporated in treated HDL demonstrate modifications of order and polarity with respect to control HDL. The negative correlation established between the Gp value and TBARS demonstrates that the modifications in molecular order are likely related to the increase in lipid peroxidation products. The activity of paraoxonase was significantly decreased in HDL incubated at 37 degrees C; a greater decrease occurred in the presence of 50 mM and 100 mM glucose. This study demonstrates modifications of lipid composition, apoprotein conformation and physicochemical properties of HDL incubated in the presence of glucose. These modifications affect the activity of HDL-associated paraoxonase. The physicochemical properties of lipoproteins play a regulatory role in lipoprotein function. The modification of order and polarity of glycated HDL and the alterations in paraoxonase activity could potentially contribute to the accelerated atherosclerosis in diabetic patients.

2-Naphthylamine↗
PubMed2001

Usefulness of 99m-Tc-sestamibi scintimammography in suspected breast cancer and in axillary lymph node metastases detection.

AIMS: To evaluate the usefulness of 99m-Tc-sestamibi scintimammography (SSM) in the detection of T1-2, N0-1, M0 breast cancer (BC) and axillary node (AN) metastases. PATIENTS AND METHODS: A series of 239 women (median age 55 years) who had already been selected for breast biopsy underwent both mammography (MG) and SSM before surgery. The final diagnosis confirmed in 207 (86.6%) patients, and benign breast lesions in 32 (13.4%). RESULTS: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of MG and SSM in BC detection were 88.9% vs 87.9%, 62.5% vs 93.8% (P<0.01), 93.9% vs 98.9%, 46.5% vs 54.5%, and 85.4% vs 88.7%, respectively. Age did not affect (P=NS) SSM sensitivity, and in premenopausal patients (n=80 (33.5%)) its specificity was 100%. Overall sensitivity and specificity of SSM for assessing AN involvement were 82.3% and 94.1%, respectively. In patients with <3 AN metastases (n=33 (53.2%)) SSM sensitivity was 69.7%, and only one out of six patients with a single AN metastasis had a positive scan. CONCLUSIONS: In patients with suspicious MG undergoing biopsy, SSM should be considered before surgery because of its high specificity, especially in younger patients. At present, its usefulness in detection of AN metastases is still modest and does not allow a correct pre-operative staging of patients with BC.

Adult↗
PubMed2001

Maximal instantaneous muscular power after prolonged bed rest in humans.

A reduction in lower limb cross-sectional area (CSA) occurs after bed rest (BR). This should lead to an equivalent reduction in maximal instantaneous muscular power (W(p)) if the body segments' lengths remain unchanged. W(p) was determined during maximal jumps off both feet on a force platform before and on days 2, 6, 10, 32, and 48 after a 42-day duration BR. CSA of thigh muscles was measured by magnetic resonance imaging before and on day 5 after BR. Before BR, W(p) was 3.63 +/- 0.43 kW or 48.6 +/- 3.3 W/kg. On days 2 and 6 after BR, W(p) was reduced by 23.7 +/- 6.9 and 22.7 +/- 5.4% (P < 0.01), respectively. Thigh extensors CSA (CSAEXT) was 16.7 +/- 4.7% (P < 0.01) lower than before. When normalized per CSAEXT, W(p) was reduced by only 4.8 +/- 4.5% (P < 0.05). By day 48 of recovery, W(p) had returned to baseline values. Therefore, if W(p) is appropriately normalized for CSA of the extensor muscles, the reduction in CSAEXT explains most of the decrease in W(p) decrease after BR. Other factors such as a deficit in neural activation or a decrease in fiber-specific tension may account for only 5% of the W(p) loss after BR.

Adult↗
PubMed2001

Progress report on the palliative therapy of 100 patients with neoplastic effusions by intracavitary low-dose interleukin-2.

OBJECTIVE: Several cytokines, particularly IL-2 and interferons, are thought to be effective in the palliative therapy of neoplastic effusions. We report on the activity and toxicity of intracavitary administration of low-dose IL-2 in a case series of 100 cancer patients with neoplastic effusions. METHODS: One hundred patients with advanced solid tumors and neoplastic effusions underwent IL-2 intracavitary injection as first-line treatment. The most common sites of fluid accumulation were pleura (n = 68), peritoneum (n = 21) and pericardium (n = 11). Breast cancer, lung cancer and mesothelioma were the most frequent neoplasms in our series. One cycle consisted of intracavitary IL-2 at 6,000,000 IU on days 1 and 7. RESULTS: According to Paladine's criteria, an objective clinical response was achieved in 72% (complete response in 27% and partial response in 45%), with a median duration of 5 months (range: 1-11 months). The peritoneum was the least responsive site for neoplastic effusion reduction. IL-2 intracavitary injection was well tolerated in all patients; the only toxicity observed was fever >38 degrees C in 6% of the patients. CONCLUSION: This study shows that intracavitary injection of IL-2 represents a feasible, well-tolerated and effective therapy of neoplastic fluid accumulation. Further studies are needed in order to compare the effectiveness of intracavitary IL-2 with other standard treatments.

Adult↗
PubMed2001

Sleep apnoea and Turner's syndrome.

A 32-yr-old female with Turner's syndrome and anatomical craniofacial abnormalities, presented with obstructive sleep apnoea syndrome. This was initially treated by nasal continuous positive airway pressure and secondarily cured by maxillomandibullar advancement osteotomy. Anatomical upper airway abnormalities and hormonal factors, which predispose Turner patients to develop obstructive sleep apnoea syndrome, are discussed. A systematic assessment and treatment of sleep-disordered breathing is probably of interest in these patients.

Adult↗