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Cultural heritage governance is undergoing a change related to the roles of the public and private sector and the assessment of heritage as an instrument to achieve broader aims, in terms of social, cultural and economic development as the Council of Europe stated in its 2005 Framework Convention on the Value of Cultural Heritage for Society. These changes have also characterised the Italian institutional framework where the law introduced a series of norms allowing different degrees of involvement of the private sector in the management of heritage sites and museums and/or of the ‘ancillary’ services necessary to favour their fruition (ticket sales, bookshop, cafeteria). The changes in the law facilitated the introduction of Public Private Partnership (PPP) in the heritage sphere, and examples of these are becoming more common. This paper considers one of these cases, where a private organisation, specifically a non-profit association—Officine Culturali—cooperates with a public institution—the University of Catania—to realise the activities necessary to enhance a heritage site which hosts one of the university’s departments and is included in UNESCO's World Heritage List. The association stands out for its focus on participation that is clearly set in its mission. Looking at the activities run by Officine Culturali, two aspects deserve a closer analysis: product differentiation and the use of heritage enhancement as tools to obtain far-ranging social effects. The analysis illustrates the institutional arrangements that made possible the involvement of a private association in the enhancement of a publicly owned heritage site through the creation of a partnership between the association and the university of Catania. The chapter will focus on the activities of Officine Culturali considering, specifically, their focus on social inclusion and their capacity to attain it.

Bronchial hyperresponsiveness (BHR) is a common feature in the majority of asthmatic subjects and methacholine is the most frequently used agent for the test. The influence of 3 or 5 min time intervals between doses steps in a double methacholine challenge test (MCH-3′ or MCH-5′) was investigated. Using the MCH-3′ challenge, 52 intermittent asthmatics were classified as having moderate (BHR-M; 18 subjects), mild (BHR-m; 19 subjects), or bordeline (BHR-B; 15 subjects) BHR. The cumulative dose and the PD20FEV1 were higher for MCH-5′ compared with MCH-3′ in BHR-m (p < 0.05) and BHR-B (p < 0.05) but not in the BHR-M group. Also the dose response slopes, FEV1% decline/cumulative methacholine dose, calculated for the two challenge tests were statistically different only in BHR-m (p < 0.05) and BHR-B (p < 0.01). At MCH-5′, there were 16 subjects with BHR-M, 18 with BHR-m, 12 with BHR-B and 6 subjects with normal reactivity. Results may suggest that in the group of BHR-m and BHR-B subjects, at MCH-5′ compared with MCH-3′, the cumulative effect of the administered drug, quickly metabolized by cholinesterase, is not complete, thus leading to an incorrect estimation of bronchial hyperresponsiveness degree. It is hoped that time interval between doses be standardized to ensure maximum comparability within and between subjects in challenge tests.

The expression of muscarinic cholinergic receptor subtypes was investigated in peripheral blood lymphocytes (PBL) of bronchial asthma patients by a combined kinetic and equilibrium labeling technique for radioligand binding assay of muscarinic cholinergic receptor subtypes and by receptor immunochemistry and immunocytochemistry. An increased expression of M2 and to a lesser extent of M5 receptors and no changes of M4 receptor were observed in PBL of asthmatics compared to control individuals. The increase was related to bronchial hyperresponsiveness detected by methacholine challenge test. Analysis of M3 receptor expression revealed biphasic changes, with a decreased receptor density in patients with normal, mild and moderate responses to methacholine test and a recovery to levels similar to those found in healthy individuals in severe responders to methacholine test. The demonstration of a different expression of lymphocyte muscarinic receptors in asthma suggests that cholinergic system may participate to a molecular framework influencing immune functions in asthma.

The protective effect of Ipratropium Bromide (IB) in the methacholine-induced bronchospasm is well known from some time. The objective of the present study was to assess whether a pretreatment with IB may influence the subsequent phase of methacholine-induced bronchospasm relief.Sixteen patients with bronchial hyper-reactivity (PD20 FEV1200 microg) were randomly assigned to three methacholine challenge tests at a 48 to 72 hours interval apart. In the first test IB was inhaled before the challenge (pre-IB), in the second IB was administered soon after the PD20 FEV1 (post-IB), and in the third no treatment was given (control).The pre-IB PD20 FEV1 (695 +/- 587.6 microg) was significantly greater (p0.0001) than that of post-IB (82.2 +/- 49.18 microg) and of control (73.9 +/- 41.8 microg). The dose response slope (DRS) (decline percentage of FEV1/cumulative methacholine dose), in pre-IB was greatly lower (p0.0001) than that in post-IB and in control. During the bronchospasm relief phase, the increase of FEV1 measured after 5, 10, 15, 30 and 60 minutes from the PD20 FEV1 was significantly greater in post-IB (p0.05) compared with the other two conditions. Conversely, the recovery slope (RS) (increase percentage of FEV1 at 60 minutes after PD20 FEV1 x cumulative methacholine dose) was significantly more efficient (p0.001) in pre-IB than in post-IB and in control.In conclusion, ipratropium bromide confirmed to have a good protective activity against methacholine-induced bronchospasm; the pre-administration of ipratropium bromide showed also a positive effect on the recovery phase.

Spontaneously hypertensive rats represent a widely used animal model of hypertension. Altered neurotrophin regulation has been related to systemic hypertension. Lung cells synthesize and release neurotrophins(NT) which are involved in several pulmonary disturbances. Our study explored the expression of NT and their receptors using molecular biology and immunohistochemistry. Spontaneously 6-, 20- and 29- weeks hypertensive (SHR) and Wistar Kyoto rat (WKY) lungs were used. SHR and WKY lungs expressed neurotrophin and neurotrophin receptor mRNAs and protein transcripts. Age and hypertension dependent increase was clearly noticeable. Furthermore, immunohistochemistry revealed that their increase was mainly noticeable within bronchial and vascular components of the lung. Although the role of NT in sympathetic hyperinnervation and progression of systemic hypertension is a well established phenomenon, their increase in SHR lungs, strongly suggest that NT may be operative during pulmonary hypertension and in subsequent airway and pulmonary vascular remodeling.

Neurotrophins (NTs) promote survival and differentiation of central and peripheral neurons, and display several activities also in non-neuronal cells. Human lungs synthesize and release NTs, which are probably involved in the pathophysiology of pulmonary disturbances. In this article the expression and anatomic localization of nerve growth factor, brain-derived neurotrophic factor, and NT-3 and of corresponding high-affinity receptors TrkA, TrkB (full-length and truncated [TR-] isoforms), TrkC, and of the low-affinity p75 receptor, were assessed in surgical samples from adult human lung by reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry. NTs and their cognate receptor mRNA and protein transcripts were detected by reverse transcriptase-polymerase chain reaction and immunoblotting, respectively, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) mRNA and corresponding protein transcripts being the most expressed. High levels of TrkB-[TR-] mRNA and of its protein transcript were also demonstrated, whereas a low expression of p75 mRNA and of corresponding protein transcript were found. Microanatomic analysis of immunohistochemical study revealed that bronchial epithelial cells were immunoreactive for different NTs, with a higher intensity of BDNF immune staining compared with other NTs, but did not express NT receptor immunoreactivity. Alveolar cells were immunoreactive for TrkA and TrkC receptor protein, but did not display immunoreactivity for NTs or other receptors investigated. Gland cells expressed NT and high-affinity NT receptor immunoreactivity, but not p75 receptor immunoreactivity. NT and low-affinity receptor immunoreactivity was observed within neurons and satellite cells of parasympathetic ganglia as well as in nerve fiber-like structures supplying the bronchopulmonary tree. An obvious immunoreactivity for NTs and NT receptor protein was also observed in intrapulmonary branches of pulmonary artery. Pulmonary lymphocytes and macrophages express nerve growth factor and high-affinity NT receptor immunoreactivity. The role of NTs in non-neuronal tissue including lung has not been clarified yet. The widespread expression of NTs and their receptors in different components of the lung suggests that these factors may contribute to regulate cell function in human lung.

Changes in monocyte functions have been described in several human malignancies. The monocyte/macrophage system is known to play a crucial role in the rejection of tumor cells and phagocytosis represents an important defense mechanism used by these cells. This paper reports the adherence power and phagocyting ability (latex beads) of circulating monocytes in 20 patients with unresectable non-small cell lung cancer (NSCLC), stage IIIB or stage IV, before and after multiagent chemotherapy (carboplatin + etoposide + ifosfamide or cisplatinum + etoposide). We demonstrated that both monocyte adherence and phagocytosis were not affected in lung cancer patients before chemotherapy in comparison with healthy controls. After chemotherapy, a statistically significant decrease in monocyte count on day 4 (p0.05) and in their phagocyting ability on day 4 and 15 (p0.001 and p0.05 respectively) was showed. In addition, a statistically reduced monocyte adherence was found on day 4 (p0.05). The described impairment was prolonged but reversible. These changes in monocyte functions after chemotherapy could be due to a direct effect of the chemotherapy on these cells or to functionally immature cells circulating after myelodepression. The in vitro assessment of monocyte functions may be useful to better clarify mechanisms by which anti-neoplastic agents may act on immune functions and prevent adverse side effects.

Forty-eight patients suffering from intermittent bronchial asthma underwent methacholine challenge test. Response was stronger in 29 patients and less pronounced in 19. The two groups had the same characteristics except for the cumulative methacholine dose which was lower in severe hyperresponsiveness. The patients were studied both in the phase of induced bronchospasm and in the subsequent phase of spontaneous recovery. Dose-response curves to methacholine were analyzed as FEV1% decline/methacholine dose for the induction phase of bronchoconstriction and as FEV1% increase*methacholine dose/time after PD20FEV1 for the recovery phase. The phase of induced bronchospasm as well as spontaneous recovery had a linear pattern in severe hyperresponsiveness; in patients with moderate response, induced bronchoconstriction had a curvilinear pattern whereas spontaneous recovery had a linear pattern. This latter group had to break down an amount of methacholine that was fivefold greater than the former, therefore the mechanism of local homeostasis recovery may be more efficient in moderate hyperresponsiveness. However, in both groups recovery after the bronchospasm was not complete after 60 min (p < 0.01 versus baseline). Furthermore, recovery was faster in the first 15 min than in the remaining time. In conclusion the behavior of methacholine-induced bronchospasm and its spontaneous recovery in both severe and moderate hyperresponsiveness seem to be different although several and not well-established mechanisms may be responsible for this phenomenon.

The expression of dopamine receptors by human platelets was investigated by Western blot analysis and immunocytochemical techniques using antibodies raised against dopamine D1–D5 receptor protein. The influence of dopamine D1-like and D2-like receptor agonists on adrenaline-induced platelet aggregation was also investigated. Western blot analysis revealed that platelet membranes bind anti-dopamine D3 or D5 receptor protein antibodies, but not anti-D1, D2 or D4 receptor protein antibodies. Cytospin centrifuged human platelets exposed to anti-dopamine D3 or D5 receptor protein antibodies developed a specific immune staining, whereas no positive staining was noticeable in platelets exposed to other antibodies tested. Both the D1-like receptor agonist 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF 38393) and the D2-like receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) dose-dependently inhibited adrenaline-induced platelet aggregation. These effects were decreased respectively by the D1-like and D2-like receptor antagonists R(+)-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrochloride (SCH 23390) and (-)sulpiride. The above findings indicate that human platelets express dopamine D3 and D5 receptors probably involved in the regulation of platelet function.

Inhaled corticosteroids are first-choice drugs in the treatment of chronic asthma. A metered dose inhaler (MDI) equipped with a spacer device is easier to use for patients with a poor inhalatory technique; it favors a reduction in the size of the particles delivered to the patient and thus a reduction in the incidence of local and systemic side effects of these drugs. The aim of this study was to determine the particle characteristics of fluticasone propionate (FP), flunisolide (FLUN), and beclomethasone dipropionate (BDP), each administered at a rate of 250 micrograms per puff and at inspiratory flow rates of 30 and 60 L/min in vitro, to estimate the particle characteristics of these drugs aspirated via an MDI alone and via a large-volume holding chamber (Volumatic). Compared with the MDI alone, at 30 L/min, the Volumatic (Glaxo Wellcome, Ware, UK) significantly reduced the mass median aerodynamic diameter (MMAD) and increased the fine particles (5 microns and2 microns) generated by all three drugs. At 60 L/min, the MMAD increased and the generation of fine particles decreased with both devices. These data suggest that the inspiratory flow applied by means of the devices may be a determinant for the deposition of the drug in the lower airways in that by increasing the inspiratory flow, the MMAD increases and the percentage of fine particles decreases, probably because of the reaggregation favored by the higher flows.

Aim of the study was to discover whether the recovery phase after methacholine challenge might be influenced by the administration of an antimuscarinic drug and to verify the mode and timescale of restored receptor activity. 16 patients with severe bronchial hyperreactivity were selected and subjected to methacholine test in order to assess: the preventive bronchodilatory effect of ipratropium bromide (40 mcg) inhaled before the test and the bronchial spasm spontaneous recovery after PD20 at 15, 30 and 60 minutes. Data were subjected to variance and Tukey test analysis. The results confirm that ipratropium bromide raises the methacholine dose response threshold by a factor of about 10 and also demonstrate that the anti-muscarinic drug modified the FEV1 PD20 and influenced the recovery phase by intensifying and making the bronchial spasm resolution faster. Thus results moreover suggest that the receptor activity restoration depends also on the elimination of the muscarinic mediator.

Analysis of lymphocyte muscarinic cholinergic receptors using quantitative techniques such as radioligand binding assay is made difficult due to the low density of these sites and the lack of subtype-specific selectivity of most available muscarinic ligands. In this study, a combined kinetic and equilibrium labeling technique recently developed for brain tissue was used for labeling the five muscarinic cholinergic receptor subtypes in intact human peripheral blood lymphocytes. No specific muscarinic M1 receptor binding was detectable in human peripheral blood lymphocytes using [3H]-pirenzepine as a ligand. Labeling of M2-M5 muscarinic receptors using [3H]N-methyl-scopolamine (NMS) by occluding various receptor subtypes with muscarinic antagonist and mamba venom resulted in the labeling of M2-M5 receptors in brain as well as in human peripheral blood lymphocytes. The relative density of different receptor subtypes was M3 > M5 > M4 > M2. The development of a reproducible technique for assaying muscarinic cholinergic receptor subtypes expressed by human peripheral blood lymphocytes may contribute to clarify their role in lymphocyte function.

1 Muscarinic cholinergic receptors were assayed in human peripheral blood lymphocytes of healthy control and airway hyperresponsive subjects using a radioligand binding assay technique and the muscarinic cholinergic receptor antagonist [3H]-quinuclidinyl benzilate (QNB) as a radioligand. Subjects investigated were divided in four different groups based on threshold responses to methacholine inhaled as challenge test. 2 [3H]-QNB was bound to human peripheral blood lymphocytes in a manner consistent with the labelling of muscarinic cholinergic receptors. Dissociation constant (Kd) values of [3H]-QNB binding were similar in the different groups examined, whereas maximum density of binding sites (Bmax) was increased in airway hyperresponsive subjects in comparison with healthy controls. 3 The above findings indicate that the density of muscarinic cholinergic receptors is increased in peripheral blood lymphocytes of airway hyperresponsive subjects. 4 This suggests that airway hyperresponsiveness is associated with cholinergic hyperreactivity and is probably a systemic cholinergic dysfunction since it is accompanied by changes in the density of muscarinic cholinergic receptors expressed by peripheral blood lymphocytes.

The aim of this study was to assess the granulometric characteristics and the deposition probabilities of particles and drug, in the respiratory tract, following one puff of salbutamol delivered by a metered-dose inhaler (MDI) and a breath-actuated metered-dose inhaler (BAI-Autohaler). Particle analysis, achieved using an API Aerosizer Mach2, showed that the two devices have similar granulometric characteristics; recording the following data for the mass median aerodynamic diameter (MMAD) and for the geometric standard deviation (GSD): MDI (MMAD 2.29 microns. GSD 1.46); BAI (MMAD 2.41 microns, GSD 1.48). Data on the percentage of drug carried by the single particles suggest a higher probability of deposition of salbutamol delivered by Autohaler in the pulmonary and tracheobronchial tracts (approximately 61 vs 48% for the conventional MDI) and a reduced deposition in the orolaryngeal tract (17 vs 26% for the conventional MDI), with a consequently lower risk of having collateral effects caused by systemic absorption of the drug and an improved effectiveness at the site of action.

The subtypes of muscarinic cholinergic receptors were studied in human peripheral blood lymphocytes with radioligand binding techniques and the non-selective muscarinic cholinergic receptor antagonist [3H]quinuclidinyl benzylate (QNB) as a ligand. [3H]QNB was bound to human peripheral lymphocytes in a manner consistent with the labelling of muscarinic cholinergic receptors. The dissociation constant (Kd) value was 0.60 +/- 0.08 nM and the maximum density of binding sites (Bmax) was 2.33 +/- 0.03 fmol/2.2 x 10(6) cells. The binding was time-, temperature- and concentration-dependent, belonging to a single class of high affinity sites. Analysis of the pharmacological profile of [3H]QNB binding in the presence of compounds specific for the different muscarinic receptor subtypes suggests that human peripheral blood lymphocytes express mainly muscarinic cholinergic M2 and M3 receptor subtypes and to a lesser extent muscarinic M4 receptors. The characterization of the subtypes of muscarinic cholinergic recognition sites expressed by human peripheral blood lymphocytes may represent a tool for investigating the possible relationships between immune and cholinergic systems in normal and pathologic conditions.

Our aim was to asses the association between the decrease of FEV1 and the modifications of the indices (PEF, MEF25, MEF50 and MEF75% of FVC) during methacholine challenge. 105 patients of both sexes with mild bronchial asthma were included in this study and were subjected to methacholine test according to ATS standards. The results were analysed using analysis of variance (MANOVA), discriminant stepwise and multiple regression. The reduction of FEV1 induced by increasing dosage of methacholine was associated with a significant decrease of the other flow-volume curve indices but we can observe a different flow behaviour. The MEF50 was more significant during the first level of variations and the MEF75 and MEF25 being more significant during the subsequent phases. We conclude that the evaluation of the flow volume indices can be important for better study the site of action of methacholine.

We examined the resolution of the bronchial spasm induced by methacholine after administration of a dose sufficient to provoke PD20 to study, in patients with bronchial asthma, how spontaneous resolution (as opposed to bronchodilator-induced resolution) takes place. According to a randomization criterion, the patients were divided into four groups: 1) resolution induced by salbutamol (S), 2) by ipratropium bromide (I), 3) after placebo (P) and 4) spontaneous resolution (R). In brief, we observed that variations in FEV1 after methacholine PD20, reach statistically significant levels after 15 minutes in patients from groups (S) and (I), after 30 minutes in patients from groups (P) and (R) (p0.05). Comparing the phenomenon at various intervals in the four experimental situation, we found a pairing trend: groups (S) and (I) on the one hand, and groups (P) and (R) on the other. On the whole, this phenomenon shows that pharmacological treatment accelerates the process of spontaneous resolution of the bronchial spasm induced by methacholine which, in our experience, beings to show after 15 minutes, and that after 60 minutes, there are no statistically significant differences in the four groups. It is our opinion that closer examination of this phenomenon may provide greater knowledge of the mechanisms that come into play during the phase after stimulation of the muscarinic receptors and that reasonably involve the system to eliminate the muscarinic drug.