"HRCT predictors of GGO surgical resection: Histopathological and molecular correlation in the era of lung sparing surgery".

OBJECTIVES: Ground-glass pulmonary opacities (GGOs) are increasingly encountered in routine clinical practice and an accurate differentiation between benign and malignant lesions is crucial. The aim of this study is to evaluate the relationship between radiological features and the actual biological behavior of these nodules. The secondary endpoint is to identify any radiological predictors able to choose the type of surgical resection and the extent of lymphadenectomy. MATERIALS AND METHODS: This single-center retrospective study included all patients, who underwent high resolution computed tomography (HRCT) and surgical resection for GGOs between 2010 and 2020. Histopathological sampling focused on lesion size, histology, growth pattern, amount of lepidic component, percentage of ground-glass (GG), grade of tumor and proliferation index (Ki67). RESULTS: In 56 patients enrolled, 65 lesions (15 pure GG and 50 part-solid) were resected (44 lobectomies, 9 anatomical segmentectomies, 12 wedge resections). A direct significant correlation was found between: the GG at HRCT and the amount of lepidic component (p < 0.0001; R = 0.305), the tumor grading and the lepidic component at HRCT (p = 0.003), the percentage of GG and the expression of Ki67 (p = 0.016), the lepidic percentage and the expression of Ki67 (p = 0.004; R = 0.223). A total of 609 lymph-nodes were removed (stations N1 and N2) and histopathological analysis was negative for nodal involvement in all cases. CONCLUSION: Pure and part-solid GGOs could benefit from less invasive and lung sparing surgery with just nodal sampling. These would reduce surgical complications and guarantee a better quality of life for the patient. The major limitations are the number of patients and the lack of a longer follow-up.

Pleuroparenchymal fibroelastosis (PPFE) associated with giant cell arteritis: A coincidence or a novel phenotype?

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial lung disease characterized by the fibrotic thickening of subpleural and parenchymal areas of the upper lobes. It may be both idiopathic or secondary to infections, interstitial lung diseases and/or drug exposure. Often PPFE patients report recurrent lower respiratory tract infections, suggesting that repeated inflammatory alterations induced by pulmonary infections may contribute to the development/progression of PPFE. Here, we report for the first time the case of a patient affected by Giant cell Arteritis with histologically proven PPFE. The lung involvement in GCA is rare and interstitial lung diseases are usually reported as an uncommon clinical manifestation of GCA. Our patient is probably the first case presenting PPFE associated with GCA and we wonder if this is a real associative disease or a coincidence perhaps, secondary to drug effects.

Altered gene expression profiles in the lungs of benzo[a]pyrene-exposed mice in the presence of lipopolysaccharide-induced pulmonary inflammation.

Patients with inflammatory lung diseases are often additionally exposed to polycyclic aromatic hydrocarbons like B[a]P and B[a]P-induced alterations in gene expression in these patients may contribute to the development of lung cancer. Mice were intra-nasally treated with lipopolysaccharide (LPS, 20µg/mouse) to induce pulmonary inflammation and subsequently exposed to B[a]P (0.5mg/mouse) by intratracheal instillation. Gene expression changes were analyzed in mouse lungs by RNA microarrays. Analysis of genes that are known to be involved in the cellular response to B[a]P indicated that LPS significantly inhibited gene expression of various enzymes linked to B[a]P metabolism, which was confirmed by phenotypic analyses of enzyme activity. Ultimately, these changes resulted in higher levels of B[a]P-DNA adducts in the lungs of mice exposed to B[a]P with prior LPS treatment compared to the lungs of mice exposed to B[a]P alone. Using principle component analysis (PCA), we found that of all the genes that were significantly altered in their expression, those that were able to separate the different exposure conditions were predominantly related to immune-response. Moreover, an overall analysis of differentially expressed genes indicated that cell-cell adhesion and cell-cell communication was inhibited in lungs of mice that received both B[a]P and LPS. Our results indicate that pulmonary inflammation increased the genotoxicity of B[a]P via inhibition of both phase I and II metabolism. Therefore, inflammation could be a critical contributor to B[a]P-induced carcinogenesis in humans.

Xanthines and Phosphodiesterase Inhibitors.

Theophylline is an orally acting xanthine that has been used since 1937 for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, in most treatment guidelines, xanthines have now been consigned to third-line therapy because of their narrow therapeutic window and propensity for drug-drug interactions. However, lower than conventional doses of theophylline considered to be bronchodilator are now known to have anti-inflammatory actions of relevance to the treatment of respiratory disease. The molecular mechanism(s) of action of theophylline are not well understood, but several potential targets have been suggested including non-selective inhibition of phosphodiesterases (PDE), inhibition of phosphoinositide 3-kinase, adenosine receptor antagonism and increased activity of certain histone deacetylases. Although theophylline has a narrow therapeutic window, other xanthines are in clinical use that are claimed to have a better tolerability such as doxofylline and bamifylline. Nonetheless, xanthines still play an important role in the treatment of asthma and COPD as they can show clinical benefit in patients who are refractory to glucocorticosteroid therapy, and withdrawal of xanthines from patients causes worsening of disease, even in patients taking concomitant glucocorticosteroids.More recently the orally active selective PDE4 inhibitor, roflumilast, has been introduced into clinical practice for the treatment of severe COPD on top of gold standard treatment. This drug has been shown to improve lung function in patients with severe COPD and to reduce exacerbations, but is dose limited by a range side effect, particularly gastrointestinal side effects.

Novel relaxant effects of RPL554 on guinea pig tracheal smooth muscle contractility.

BACKGROUND AND PURPOSE: We investigated the effectiveness of RPL554, a dual PDE3 and 4 enzyme inhibitor, on airway smooth muscle relaxation and compared it with that induced by salbutamol, ipratropium bromide, glycopyrrolate or their combination on bronchomotor tone induced by different spasmogenic agents. EXPERIMENTAL APPROACH: Guinea pig tracheal preparations were suspended under 1 g tension in Krebs-Henseleit solution maintained at 37°C and aerated with 95% O2 /5% CO2 and incubated in the presence of indomethacin (5 µM). Relaxation induced by cumulative concentrations of muscarinic receptor antagonists (ipratropium bromide or glycopyrrolate), ß2 -adrenoceptor agonists (salbutamol or formoterol), PDE3 inhibitors (cilostamide, cilostazol or siguazodan) or a PDE4 inhibitor (roflumilast) was evaluated in comparison with RPL554. Maximal relaxation was calculated (% Emax papaverine) and expressed as mean ± SEM. KEY RESULTS: Bronchomotor tone induced by the various spasmogens was reduced by the different bronchodilators to varying degrees. RPL554 (10-300 µM) caused near maximum relaxation irrespective of the spasmogen examined, whereas the efficacy of the other relaxant agents varied according to the contractile stimulus used. During the evaluation of potential synergistic interactions between bronchodilators, RPL554 proved superior to salbutamol when either was combined with muscarinic receptor antagonists. CONCLUSIONS AND IMPLICATIONS: RPL554 produced near maximal relaxation of highly contracted respiratory smooth muscle and provided additional relaxation compared with that produced by other clinically used bronchodilator drugs. This suggests that RPL554 has the potential to produce additional beneficial bronchodilation over and above that of maximal clinical doses of standard bronchodilators in highly constricted airways of patients.

Type II congenital pulmonary airway malformation associated with intralobar pulmonary sequestration: report of a case and review of classification criteria.

Pulmonary congenital abnormalities are rare disorders including congenital pulmonary airway malformations (CPAM) and pulmonary sequestration (PS). CPAM is a lesion characterized by the presence of anomalous bronchiolar or acinar structures, variable in size, either cystic or not cystic. PS is generally defined as nonfunctioning lung tissue that is not in normal continuity with the tracheobronchial tree and that derives its blood supply from systemic vessels. We describe a case of a baby girl with a very rare association between CPAM type 2 and intralobar pulmonary sequestration (IPS) focusing on the cystic lesions typical of CPAM and on the lymphatic and blood vessels. The cells lining the cysts often were positive for D2-40 (oncofetal protein M2A). Lymphatic endothelial cells, positive for D2-40, were widely present in the lung parenchyma and dilated lymphatic vessels were present also in the inter-alveolar septa. Moreover, we discuss the pathogenesis of CPAM and its classification criteria.

Inflammation-associated extracellular ß-glucuronidase alters cellular responses to the chemical carcinogen benzo[a]pyrene.

Neutrophils infiltrate tissues during inflammation, and when activated, they release ß-glucuronidase. Since inflammation is associated with carcinogenesis, we investigated how extracellular ß-glucuronidase changed the in vitro cellular response to the chemical carcinogen benzo(a)pyrene (B[a]P). For this we exposed human liver (HepG2) and lung (A549) cells to B[a]P in the presence or absence of ß-glucuronidase. ß-Glucuronidase reduced B[a]P-induced expression of CYP1A1 and CYP1B1 at 6 h after exposure, which did not depend on ß-glucuronidase activity, because the inhibitor D-saccharic acid 1,4-lactone monohydrate did not antagonize the effect of ß-glucuronidase. On the other hand, the inhibitory effect of ß-glucuronidase on CYP expression was dependent on signalling via the insulin-like growth factor receptor (IGF2R, a known receptor for ß-glucuronidase), because co-incubation with the IGF2R inhibitor mannose-6-phosphate completely abolished the effect of ß-glucuronidase. Extracellular ß-glucuronidase also reduced the formation of several B[a]P metabolites and B[a]P-DNA adducts. Interestingly, at 24 h of exposure, ß-glucuronidase significantly enhanced CYP expression, probably because ß-glucuronidase de-glucuronidated B[a]P metabolites, which continued to trigger the aryl hydrocarbon receptor (Ah receptor) and induced expression of CYP1A1 (in both cell lines) and CYP1B1 (in A549 only). Consequently, significantly higher concentrations of B[a]P metabolites and DNA adducts were found in ß-glucuronidase-treated cells at 24 h. DNA adduct levels peaked at 48 h in cells that were exposed to B[a]P and treated with ß-glucuronidase. Overall, these data show that ß-glucuronidase alters the cellular response to B[a]P and ultimately enhances B[a]P-induced DNA adduct levels.

Bradykinin and capsaicin induced airways obstruction in the guinea pig are platelet dependent.

INTRODUCTION: Airways obstruction induced by intravenously administered bradykinin is abolished in guinea pigs treated with indomethacin, which has been shown to be, at least in part thromboxane dependent. As thromboxane is primarily generated from circulating platelets, we investigated whether airways obstruction induced by bradykinin, and other spasmogens, is platelet dependent and the role platelet aggregation played in this response. METHODS: Guinea pigs were chronically treated with busulfan to induce thrombocytopenia. Total lung resistance was measured in anaesthetised and mechanically ventilated control and thrombocytopaenic animals to various stimuli that induce airways obstruction. In other experiments, platelet aggregation was assessed in vitro in response to the same stimuli: guinea pigs were anaesthetized, blood was collected and centrifuged to generate firstly platelet-rich plasma and then platelet-poor plasma. Platelets were resuspended in HEPES buffer and platelet aggregation was assessed. RESULTS: Busulfan treatment significantly reduced the number of circulating platelets in guinea-pigs by 85.5%, but had no significant effect on the number of circulating leukocytes. Treatment with busulfan had no significant effect on bronchoconstriction induced by the direct acting spasmogens histamine or methacholine. However, platelet depletion significantly increased airways obstruction induced by Substance P, but caused a significant reduction in airways obstruction induced by bradykinin, bombesin or capsaicin (P < 0.05). None of these stimuli however were able to exhibit a direct effect on platelet aggregation in vitro. Moreover, busulfan did not significantly alter the contractility of guinea-pig isolated trachea in response to capsaicin. CONCLUSION: Airways obstruction induced by bombesin, capsaicin and bradykinin is platelet dependent, but not secondary to platelet aggregation.

In vivo biocompatibility, clearance, and biodistribution of albumin vehicles for pulmonary drug delivery.

The development of clinically acceptable albumin-based nanoparticle formulations for use in pulmonary drug delivery has been hindered by concerns about the toxicity of nanomaterials in the lungs combined with a lack of information on albumin nanoparticle clearance kinetics and biodistribution. In this study, the in vivo biocompatibility of albumin nanoparticles was investigated following a single administration of 2, 20, and 390µg/mouse, showing no inflammatory response (TNF-α and IL-6, cellular infiltration and protein concentration) compared to vehicle controls at the two lower doses, but elevated mononucleocytes and a mild inflammatory effect at the highest dose tested. The biodistribution and clearance of (111)In labelled albumin solution and nanoparticles over 48h following a single pulmonary administration to mice was investigated by single photon emission computed tomography and X-ray computed tomography imaging and terminal biodistribution studies. (111)In labelled albumin nanoparticles were cleared more slowly from the mouse lung than (111)In albumin solution (64.1±8.5% vs 40.6±3.3% at t=48h, respectively), with significantly higher (P<0.001) levels of albumin nanoparticle-associated radioactivity located within the lung tissue (23.3±4.7%) compared to the lung fluid (16.1±4.4%). Low amounts of (111)In activity were detected in the liver, kidneys, and intestine at time points >24h indicating that small amounts of activity were cleared from the lungs both by translocation across the lung mucosal barrier, as well as mucociliary clearance. This study provides important information on the fate of albumin vehicles in the lungs, which may be used to direct future formulation design of inhaled nanomedicines.

A miniature microcontroller curve tracing circuit for space flight testing transistors.

This paper describes a novel miniature microcontroller based curve tracing circuit, which was designed to monitor the environmental effects on Silicon Carbide Junction Field Effect Transistor (SiC JFET) device performance, while exposed to the low earth orbit environment onboard the International Space Station (ISS) as a resident experiment on the 7th Materials on the International Space Station Experiment (MISSE7). Specifically, the microcontroller circuit was designed to operate autonomously and was flown on the external structure of the ISS for over a year. This curve tracing circuit is capable of measuring current vs. voltage (I-V) characteristics of transistors and diodes. The circuit is current limited for low current devices and is specifically designed to test high temperature, high drain-to-source resistance SiC JFETs. The results of each I-V data set are transmitted serially to an external telemetered communication interface. This paper discusses the circuit architecture, its design, and presents example results.

A role for mitogen kinase kinase 3 in pulmonary inflammation validated from a proteomic approach.

Proteomics is a powerful tool to ascertain which proteins are differentially expressed in the context of disease. We have used this approach on inflammatory cells obtained from patients with asthma to ascertain whether novel drugs targets could be illuminated and to investigate the role of any such target in a range of in vitro and in vivo models of inflammation. A proteomic study was undertaken using peripheral blood mononuclear cells from mild asthmatic subjects compared with healthy subjects. The analysis revealed an increased expression of the intracellular kinase, mitogen activated protein kinase (MKK3), and the function of this protein was investigated further in preclinical models of inflammation using MKK3 knockout mice. We describe a 3.65 fold increase in the expression of MKK3 in CD8(+) T lymphocytes obtained from subjects with asthma compared with healthy subjects using a proteomic approach which we have confirmed in CD8(+), but not in CD4(+) T lymphocytes or human bronchial epithelial cells from asthmatic patients using a Western blot technique. In wild type mice, bacterial lipopolysaccharide (LPS) caused a significant increase in MKK3 expression and significantly reduced airway neutrophilia in MKK3(-/-) mice (median, 25, 75% percentile; wild/LPS; 5.3 (0.7-9.9) × 10(5) cells/mL vs MKK3(-/-)/LPS; 0 (0-1.9) × 10(5) cells/mL, P < 0.05). In contrast, eosinophilia in sensitized wild type mice challenged with allergen (0.5 (0.16-0.65) × 10(5) cells/mL) was significantly increased in MKK3(-/-) mice (2.2 (0.9-3.5) × 10(5) cells/mL, P < 0.05). Our results suggest that asthma is associated with MKK3 over-expression in CD8(+) cells. We have also demonstrated that MKK3 may be critical for airway neutrophilia, but not eosinophilia, suggesting that this may be a target worthy of further consideration in the context of diseases associated with neutrophil activation such as severe asthma and COPD.

Outcome in excised thymomas: role of prognostic factors and impact of additional malignancies on survival.

BACKGROUND AND AIMS: Although the management of thymomas has been extensively evaluated, the value of prognostic factors in the outcome of these patients remains unclear. METHODS AND RESULTS: The medical records of all patients who underwent resection of thymoma between January 1985 and September 2010 at a single thoracic unit were reviewed. Patients were followed up with reference to disease recurrence and development of additional malignancies (AM). Total thymectomy was performed in all 68 cases. Mean follow-up time was four years. Mean survival was 63.9 months. Mean disease-free interval was 13 months. Factors affecting prognosis were Masaoka staging and WHO histological sub-type. Patients with thymomas had a higher risk of developing AM when compared with a control population of individuals with other tumours (p = 0.0002). Among thymomas, the cortical subtype was associated with a higher risk of AM (p = 0.047) and mortality (p = 0.001). CONCLUSIONS: This data confirms that Masaoka staging and WHO histologic sub-type are the most important prognostic factors in patients with thymoma. Moreover, thymomas predominantly arising from the thymic cortex are associated with a higher risk of developing other malignancies and with poorer survival. The cortical origin of thymoma could therefore be considered as a significant prognostic factor.

Regulating cough through modulation of sensory nerve function in the airways.

Whilst local anaesthetics when applied directly to laryngeal nerves or topically to the lung can suppress cough, their chronic use is constrained because of dose limiting side effects. However, the effectiveness of local anaesthetics suggests that selectivity targeting nerves in the airway may provide novel approaches for the treatment of cough in the future. There is a considerable wealth of evidence showing that there are different afferent nerve subtypes in the airways. Traditionally C-fibres have been the focus of much research in the cough field since the stimulation of these afferents by capsaicin is able to elicit cough in guinea-pigs and in man, and drugs targeting various proteins expressed in these nerves (e.g. mu-opioid, NOP1, TRPV1, sodium channels) have been shown to be anti-tussive in preclinical models of cough. However, interest in Aδ fibres has increased recently in light of the discovery of a specific cough receptor in the guinea-pig that is provoked by citric acid and punctate stimulation, but not capsaicin and which has been anatomically linked to Aδ fibres. There is also some evidence that as a result of inflammation in the airways, Aδ fibres can begin to express neuropeptides and TRPV1 receptors so that they can become responsive to endogenous activators of this ion channel and to irritants like capsaicin. Consequently, there is considerable interest in targeting either one or both afferent nerve types for the treatment of chronic cough. However, to date the translation of preclinical studies into man has largely been disappointing and certainly there is a need for better preclinical models in this field. There also remain many challenges to overcome at a clinical level, such as what patient group(s) should be used to assess anti-tussive drugs and whether the use of irritants that induce cough in healthy volunteers (such as citric acid or capsaicin) is of any value in the assessment of novel anti-tussive drugs. The development of several continuous monitoring methodologies for measuring cough will hopefully allow better evaluation of treatments in patients with chronic cough. Nonetheless, cough remains a major unmet clinical need in respiratory medicine where new drugs are urgently required.

A novel δ-hemolysis screening method for detecting heteroresistant vancomycin-intermediate Staphylococcus aureus and vancomycin-intermediate S. aureus.

We assessed a new screening method, based on δ-hemolysin production in the presence of 6 mg/liter vancomycin, to distinguish heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA) and vancomycin-intermediate S. aureus (VISA) from vancomycin-susceptible S. aureus (VSSA). On 37 clinical methicillin-resistant S. aureus (MRSA) isolates, hVISA and VISA displayed no δ-hemolysis whereas VSSA displayed strong δ-hemolysis, showing 91.6% sensitivity. These data, supported by real-time reverse transcription PCR (real-time RT-PCR) highlighting an hld downregulation, i.e., VSSA>hVISA>VISA, define this new assay as a valid screening method.

TNF-α-induces airway hyperresponsiveness to cholinergic stimulation in guinea pig airways.

BACKGROUND AND PURPOSE: TNF-α is an inflammatory cytokine implicated in the pathogenesis of asthma and it causes airway inflammation, bronchoconstriction and airway hyperresponsiveness to a number of spasmogens following inhalation. EXPERIMENTAL APPROACH: We compared contractions of guinea pig isolated trachea incubated with saline or TNF-α for 1, 2 or 4 days to electrical field stimulation (EFS), 5-HT or methacholine. In addition, we compared bronchoconstriction in anaesthetized guinea pigs 6 h after intratracheal instillation of saline or TNF-α to vagal nerve stimulation, i.v. 5-HT or methacholine. Differential counts were performed on the bronchoalvelolar lavage fluid (BALF). KEY RESULTS: Maximum contractions to methacholine, 5-HT and EFS were not different between freshly prepared and saline-incubated tissues. Exposure to TNF-α concentration-dependently potentiated contractions to 5-HT and EFS, but not methacholine. All contractions were atropine-sensitive, but not hexamethonium-sensitive. 5-HT-evoked contractions were inhibited by ketanserin or epithelial denudation. Only EFS-evoked contractions were tetrodotoxin-sensitive. Vagal stimulation, i.v. 5-HT or MCh caused a significant atropine-sensitive, frequency- and dose-dependent bronchoconstriction and decreased blood pressure similarly in both saline and TNF-α pre-treated animals. TNF-α potentiated the bronchoconstriction to vagal stimulation and 5-HT, but not MCh. The BALF from saline-treated animals contained predominantly macrophages, whereas that from TNF-α-treated animals contained neutrophils. CONCLUSIONS AND IMPLICATIONS: TNF-α caused airway hyperresponsiveness to nerve stimulation in vivo and increased contractility in vitro. However, responsiveness to MCh was unchanged, suggesting a pre-synaptic action of TNF-α on parasympathetic nerves. TNF-α-induced airway hyperresponsiveness to 5-HT suggested an increased 5-HT(2A) receptor-mediated acetylcholine release from epithelial cells.

Airway responsiveness in an allergic rabbit model.

BACKGROUND: Animal models of allergy and bronchial hyperresponsiveness (BHR) are useful in researching pulmonary diseases and evaluating drug effects on the airways. Neonatally immunised rabbits exhibit several features of asthma as adults, including early and late airway responses following antigen challenge, oedema and inflammatory cell infiltration into the lung, BHR to inhaled histamine and methacholine (compared with naïve rabbits) and exacerbations of BHR following antigen challenge. Therefore this model can be used to investigate the underlying mechanisms of BHR and for the preclinical evaluation of new drugs for the treatment of asthma. AIM: To describe the characteristics of airway responses in a rabbit model of allergic inflammation and to evaluate the relationship between skin test reactivity to antigen, airway inflammation and BHR. METHODS: New Zealand White rabbits were neonatally immunised against Alternaria tenius. At 3 months of age, airway responsiveness was measured to aerosolised histamine, methacholine or allergen. Bronchoalveolar lavage (BAL) was performed and cell counts recorded. Direct skin tests were performed to assess skin reactivity to allergen and passive cutaneous anaphylaxis (PCA) tests were performed to determine titres of circulating IgE. RESULTS: In a population of allergic rabbits, allergen challenge induced a significant bronchoconstriction, airway inflammation and BHR. Skin test responsiveness to allergen did not correlate with various indices of pulmonary mechanics e.g. baseline sensitivity to methacholine and histamine, or allergen-induced BHR. In contrast, skin test responsiveness did predict airway inflammation as assessed by measurements of eosinophil recruitment to the lung. CONCLUSION: The allergic rabbit is a useful model to further our understanding of allergic diseases. Recording lung function using a minimally invasive procedure allows repeated measurements to be made in rabbits longitudinally, and each animal may thus be used as its own control. Our observations do not support the use of skin responsiveness to allergen as a predictor of airway sensitivity as we observed no correlation between skin sensitivity and airway responsiveness to inhaled histamine, methacholine or allergen. However, skin reactivity did predict airway inflammation as assessed by measurements of eosinophil recruitment to the lung. Our results also further highlight the likely dissociation between airway inflammation and BHR.

Phosphodiesterase inhibitors in the treatment of inflammatory diseases.

Phosphodiesterase 4 (PDE4) belongs to a family of enzymes which catalyzes the breakdown of 3, 5'-adenosine cyclic monophosphate (cAMP) and is ubiquitously expressed in inflammatory cells. There is little evidence that inflammatory diseases are caused by increased expression of this isoenzyme, although human inflammatory cell activity can be suppressed by selective PDE4 inhibitors. Consequently, there is intense interest in the development of selective PDE4 inhibitors for the treatment of a range of inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, and psoriasis. Recent clinical trials with roflumilast in COPD have confirmed the therapeutic potential of targeting PDE4 and recently roflumilast has been approved for marketing in Europe and the USA, although side effects such as gastrointestinal disturbances, particularly nausea and emesis as well as headache and weight loss, may limit the use of this drug class, at least when administered by the oral route. However, a number of strategies are currently being pursued in attempts to improve clinical efficacy and reduce side effects of PDE4 inhibitors, including delivery via the inhaled route, development of nonemetic PDE4 inhibitors, mixed PDE inhibitors, and/or antisense biologicals targeted toward PDE4.

Methicillin resistance and vancomycin heteroresistance in Staphylococcus aureus in cystic fibrosis patients.

Methicillin-resistant Staphylococcus aureus (MRSA) infections are increasingly being reported among cystic fibrosis (CF) populations worldwide. In this paper, we sought to examine at the epidemiology, the molecular characterisation and the antibiotic resistance of MRSA isolates in our cohort of CF patients. All MRSA strains were collected prospectively at the University Hospital of Catania, Italy, during a two-year study between mid 2005 to mid 2007 and underwent molecular, pathotype and susceptibility characterisations. Our study demonstrates persisting infections with both hospital-associated (HA-) and community-associated (CA-)MRSA, including Panton-Valentine leukocidin (PVL)-positive strains, in our CF population with an overall prevalence of 7.8%. We demonstrated that, in these patients, persistence was sustained by either identical clones that underwent subtle changes in their toxin content or by different clones over time. The isolation of MRSA in our CF population aged 7-24 years was associated with an increased severity of the disease even if, due to the small sample of patients included and the paucity of data on the clinical outcome, these results cannot be conclusive. Furthermore, three strains were heteroresistant vancomycin-intermediate S. aureus (hVISA), questioning the use of glycopeptides in the treatment of MRSA infections in these patients.