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In PH the measure of pulmonary function tests (PFT) and arterial blood gases (ABG) are used to identify underlying lung disease. We wondered if there could be a relationship among indices of PFT, ABG (paO2, paCO2), gas exchange (A-a DO2, a-ADCO2, VDphy/VT) and haemodynamic variables in a population of PH patients. Methods: Sixteen patients with suspicion of PH underwent PFT, diffusing lung capacity (DLCO), ABG, gas exchange, right heart cath; physiological dead space to tidal volume was measured. Mean values and their SD were calculated. The relationships between the observed variables were evaluated by their mutual information. The global network was reconstructed using the ARACNE algorithm (Margolin A, et al.: ARACNE. BMC Bioinformatics, 2006; 20:1-7). Modules in the network were identified applying a multidimensional scaling procedure to the adjaceny matrix and, succesively, clustering the variables with a model-based bayesian approach (Fraley C, et al. JASA, 2002; 97:611-631). We conducted the analyses with R statistical software. Results: Pulmonary gas exchange was on average impaired with increased A-a DO2; a-A DCO2 as well as physiological dead space were abnormal thus indicating impairment of ventilation perfusion distribution ratio. The three most influential variables in the networks were: PCW (betweeness=20), RAP (betweeness=18) and VDphy/VT (betweeness=14). Three modules were identified: a (RAP, FEV1, VDphy/VT, CI, TLC); b (PCW, PVR, mPAP); g (aADO2, aADCO2, DsbHb, PaCO2). The three modules were well separated. VDphy and PVR were significantly correlated (p: 0,042; R: 0.53). Conclusions: It turns out from our results a narrow relationships between VDphy and RAP, CI and PVR.

A neoprene wetsuit is widely used to reduce thermal dispersion during diving. Recent observations have pointed out that elastic recoil of the wetsuit might have significant compressive effects, able to affect water and electrolyte homeostasis during both dry and immersed conditions. The aim of this study was to evaluate the possible cardiovascular and respiratory effects of the neoprene wetsuit in dry conditions in a sample of experienced divers. Twenty-four (24) healthy divers were evaluated by Doppler-echocardiography and by spirometry in basal conditions and while wearing a full neoprene wetsuit. During wetsuit conditions, we observed a significant decrease in heart rate (-5%; p

Background We previously showed that up to 40% of RA synovial recombinant monoclonal antibodies (RA-rmAbs) generated from germinal center-like structure (GC-LS+) RA synovium recognize citrullinated antigens contained in neutrophils extracellular traps (NET) (1). The cellular source of other potential autoantigens targeted by the majority of locally differentiated B cells remains undefined. Recently, RA-fibroblast-like synoviocytes (RA-FLS) have been implicated in the release of citrullinated antigens (2, 3). However, whether these cells are targeted by RA-rmAbs is still unknown. Objectives Here, we aimed to define the RA-rmAbs immunoreactivity towards i) RA-FLS and ii) identify potential stromal-derived autoantigens. Methods 67 RA-rmAbs were generated from single CD19+ B cells FACS-sorted from fresh synovial cell suspensions following IgVH+VL genes cloning (1). RA-rmAbs were tested by means of i) cell-based immunofluorescence assays with FLS of RA patients and controls (osteoarthritis (OA)-FLS and RA-dermal fibroblast (RA-DF)), ii) co-localization with stromal specific markers and iii) immunoenzymatic tests with co-localizing antigens. Control rmAbs were also used (Sjogren9s syndrome/healthy donor-IgG rmAbs). Results Immunofluorescence on RA-FLS demonstrated reactivity of 21% of RA-rmAbs (14/67 rmAbs) towards cytoplasmic components of FLS. Only 4 rmAbs out of 14 were binding both FLS and NET components. For some rmAbs this reactivity was not specific to RA-FLS since it was also observed for OA-FLS and RA-DF. Interestingly, strong co-localization was observed with calreticulin (CRT) which in its citrullinated (cit-CRT) form has been previously shown to recognize the RA “shared epitope” HLA domain sequence (3). When tested in ELISA for native vs cit-CRT, 57% (8/14 rmAbs) of the FLS-reactive RA clones showed binding to CRT with 4 out of 8 rmAbs displaying increased immunoreactivity towards cit-CRT. Controls rmAbs showed no reactivity to either FLS or CRT. Preliminary data suggest that RA patient serum preferentially recognize the lectin-like N-terminal domain of CRT (4). Conclusions Here, we provide novel evidence that a subset of locally differentiated B cells within RA synovial GC-LS can react towards RA-FLS derived antigens. Preliminary data suggest that part of this reactivity is directed towards CRT. Identification of immunodominant epitopes within CRT is under investigations. References Corsiero et al, ARD 2015. Sorice et al, Rheumatology 2016. Ling et al, AR 2013. Hong et al, JI 2010. Disclosure of Interest None declared

Background Fibroblast-like synoviocytes (FLS) play a crucial role in the pathogenesis of rheumatoid arthritis (RA) directly contributing to local cartilage destruction and synovial inflammation.1 Autophagy, a mechanism whereby damaged proteins are removed from the cells, has been implicated in the pathogenesis of RA by activating the citrullination process in RA-FLS.2 The protein expression pattern of FLS has been also characterised with the identification of >200 proteins which have been involved in the normal or pathological FLS function.3 Among all the proteins identified in the RA-FLS, calreticulin (CRT) has been implicated in the pathogenesis of RA.4,5 In particular, citrullinated-(cit)-CRT has been shown to better recognise the RA ‘share epitope’ HLA domain compared to native CRT.4 Therefore, here we tested the immunoreactivity of RA synovial recombinant monoclonal antibodies (RA-syn-rmAbs) towards RA-FLS and towards cit-CRT. Materials and methods 82 RA-syn-rmAbs were generated from single CD19+B cells FACS-sorted from fresh synovial cell suspensions following IgVH+VL genes cloning (6). RA-syn-rmAbs were tested by means of i) cell-based immunofluorescence assays with FLS of RA patients and controls (osteoarthritis (OA)/healthy donors (HD)-FLS and dermal fibroblast (DF)) and ii) immunoenzymatic tests using native/cit-CRT. Control rmAbs were also used (Sjogren’s syndrome/HD-IgG rmAbs). Results Immunofluoresce on RA-FLS demonstrated reactivity of 21% of RA-syn-rmAbs (14/67 mAbs) towards cytoplasmic/nuclear components of FLS. This reactivity was not exclusively directed against RA-FLS since it was also observed for OA/HD-FLS and DF. When tested in ELISA for native vs cit-CRT, 50% (7/14 mAbs) of the FLS+ RA clones showed to be reactive towards CRT. Interestingly, 4 out of 7 rmAbs displayed an increased reactivity towards cit-CRT. Controls mAbs showed no reactivity towards FLS and CRT. Conclusions Here, we provided evidence that locally differentiated B cells within RA synovial germinal center-like structures can react towards native/cit-CRT likely expressed in RA-FLS. Importantly, this reactivity was disease-specific. The identification of additional cit-antigens such as cit-CRT may provide further insight into the RA pathogenesis. Thus, they might be used as potential new biomarkers in RA diagnosis. References I McInnes and G Schett. N Engl J Med, 2011. M Sorice, et al. Rheumatology, 2016. K Dasuri, et al. Arthritis Res Ther, 2004. J Holoshitz, et al. Ann N Y Acad Sci, 2010. M Ni, et al. J Clin Immunol, 2013. E Corsiero, et al. Ann Rheum Disease, 2015.

3067Background: Nivolumab is the first checkpoint inhibitor approved for the treatment of squamous non small cell lung cancer (Sq-NSCLC) to show a survival benefit in a randomised phase III trial. ...

Sintesi: Nel 2009 i Comuni di Viggiano e Grumento Nova hanno deciso di istituire una Commissione per la Valutazione di impatto sulla salute (VIS) per avviare studi sugli effetti della presenza del Centro Olio Val d'Agri (COVA) nel loro territorio. Nel febbraio 2014 è stato avviato il progetto VIS_VG_VdA. Il territorio dei due comuni ricade nell'alta Val d'Agri, in provincia di Potenza, in un'area che da oltre 20 anni è fortemente interessata da attività petrolifere. L'indagine ha riguardato in particolare l'impatto su salute e ambiente del Centro Oli Val d'Agri (COVA), un impianto di primo trattamento del greggio situato nella zona industriale di Viggiano, al confine col territorio di Grumento Nova. Questo tipo di impianti è caratterizzato dall'emissione di diverse sostanze inquinanti che devono essere costantemente monitorate. La sorveglianza sanitaria e gli studi epidemiologici hanno il compito di verificare gli effetti sulla salute, e l'esperienza maturata negli anni recenti sui siti contaminati permette di svolgere studi avanzati. L'indagine ha messo in luce l'impatto ambientale e sanitario dell'impianto sul territorio dei due comuni. Lo studio ha visto la partecipazione di un team di circa trenta ricercatori e della collaborazione di tre istituti del CNR, dell'Università di Bari e del Dipartimento di Epidemiologia del Servizio sanitario della Regione Lazio. La VIS ha seguito un approccio multidisciplinare. Per definire un quadro chiaro della situazione ambientale sono state fatte analisi di aria, acqua e suolo ed è stata studiata la diffusione per via aerea delle emissioni provenienti dai camini del COVA. Sul piano sanitario è stata svolta un'approfondita indagine epidemiologica che ha permesso di conoscere lo stato di salute della popolazione e di quantificare gli effetti dovuti all'impianto petrolifero, tenendo conto della statale di fondovalle. Il quadro è stato integrato con l'analisi diretta di un campione di popolazione adulta residente nei due comuni mediante indagini su funzionalità e sintomi respiratori. Si è infine indagata con un questionario la percezione del rischio e la fiducia nell'informazione ricevuta su ambiente e salute. Dalla VIS emerge che nei due comuni la mortalità e i ricoveri ospedalieri tra il 2000 e il 2014 sono superiori alla media regionale e dei 20 comuni della Concessione Val d'Agri, sebbene la popolazione studiata sia di piccole dimensioni. Uno studio microgeografico ha consentito di stabilire una associazione di rischio fra l'aumento di mortalità e/o ricoveri per malattie del sistema circolatorio, in particolare ischemiche, per malattie dell'apparato respiratorio e l'esposizione alle emissioni del COVA, in particolare nelle donne. Dal punto di vista ambientale si sono studiati i composti organici volatili (COV) presenti intorno all'impianto e potenzialmente dannosi per l'uomo. È emerso inoltre come le sostanze inquinanti emesse dai camini, come l'idrogeno solforato o gli ossidi di azoto, si diffondano fino a molti chilometri di distanza andando a impattare sui comuni limitrofi in direzione est e nord-est. Le analisi su metalli effettuate su campioni di acqua e suoli superficiali non hanno mostrato anomalie di rilievo, ma consegnato informazioni utili per la sorveglianza. L'analisi della percezione del rischio e dell'informazione su ambiente e salute ha evidenziato una marcata preoccupazione sui rischi connessi alla prossimità dell'impianto, nonché un livello di fiducia mediobasso nei confronti di attori istituzionali, media e associazioni. Come specificato in dettaglio nelle raccomandazioni finali, i risultati della VIS indicano con chiarezza la necessità: o di attuare standard di protezione della salute basati sulle conoscenze scientifiche più avanzate, che spesso suggeriscono un approccio di precauzione più severo rispetto a quello basato semplicemente su limiti di legge, peraltro non esistenti per tutte le sostanze emesse o di proseguire lo studio della situazione ambientale e sanitaria della popolazione dei due comuni.

In neutrophils (but also in eosinophils and in mast cells), different inflammatory stimuli induce histone deimination, chromatin decondensation, and NET formation. These web-like structures that trap and kill microbes contain DNA, cationic granule proteins, and antimicrobial peptides, but the most abundant proteins are core histones. Histones contained in NETs have been deiminated, and arginines are converted in citrullines. While deimination is a physiological process amplified in inflammatory conditions, only individuals carrying genetic predisposition to develop rheumatoid arthritis (RA) make antibodies to deiminated proteins. These antibodies, collectively identified as anti-citrullinated proteins/peptides antibodies (ACPA), react with different deiminated proteins and display partially overlapping specificities. In this paper, we will summarize current evidence supporting the role of NETosis as critical mechanism in the breach of tolerance to self-antigens and in supporting expansion and differentiation of autoreactive cells. In fact, several lines of evidence connect NETosis with RA: RA unstimulated synovial fluid neutrophils display enhanced NETosis; sera from RA patients with Felty’s syndrome bind deiminated H3 and NETs; a high number of RA sera bind deiminated H4 contained in NETs; human monoclonal antibodies generated from RA synovial B cells decorate NETs and bind deiminated histones. In RA, NETs represent on one side an important source of autoantigens bearing posttranslational modifications and fueling the production of ACPA. On the other side, NETs deliver signals that maintain an inflammatory milieu and contribute to the expansion and differentiation of ACPA-producing B cells.

Background Estimating COPD occurrence is perceived by the scientific community as a matter of increasing interest because of the worldwide diffusion of the disease. We aimed to estimate COPD prevalence by using administrative databases from a city in central Italy for 2002–2006, improving both the sensitivity and the reliability of the estimate. Methods Multiple sources were used, integrating the hospital discharge register (HDR), clinical charts, spirometry and the cause-specific mortality register (CMR) in a longitudinal algorithm, to reduce underestimation of COPD prevalence. Prevalence was also estimated on the basis of COPD cases confirmed through spirometry, to correct misclassification. Estimating such prevalence relied on using coefficients of validation, derived as the positive predictive value (PPV) for being an actual COPD case from clinical and spirometric data at the Institute of Clinical Physiology of the National Research Council. Results We found that sensitivity of COPD prevalence increased by 37%. The highest estimate (4.43 per 100 residents) was observed in the 5-year period, using a 3-year longitudinal approach and combined data from three sources. We found that 17% of COPD cases were misclassified. The above estimate of COPD prevalence decreased (3.66 per 100 residents) when coefficients of validation were applied. The PPV was 80% for the HDR, 82% for clinical diagnoses and 91% for the CMR. Conclusions Adjusting the COPD prevalence for both underestimation and misclassification of the cases makes administrative data more reliable for epidemiological purposes.

Pulmonary embolism (PE) remains a challenging diagnostic problem because it mimics other cardiopulmonary disorders. Pulmonary angiography is still the reference standard for diagnosing PE but it is costly, invasive and not readily available. Non-invasive diagnostic strategies have therefore been developed to forego pulmonary angiography in patients suspected of having PE. Ventilation/perfusion lung scanning is, at present, the most widely used non-invasive diagnostic test for PE. A high probability ventilation/perfusion scan (segmental or greater perfusion defects with normal ventilation) warrants the institution of anticoagulant therapy especially when paired with high clinical suspicion of PE. Yet, only a minority of patients with confirmed PE have high probability ventilation/perfusion scans. Ventilation/perfusion abnormalities other than those of the high probability scan should be regarded as non-diagnostic. Under these circumstances, documentation of deep vein thrombosis by non-invasive leg testing warrants anticoagulation without the need for angiography. However, a single negative venous study result does not permit to rule out PE in patients with non-diagnostic ventilation/perfusion scans. Results of a recent prospective study indicate that accurate diagnosis or exclusion of PE is possible with perfusion lung scanning alone (without ventilation imaging). Combining perfusion lung scanning with clinical assessment helps to restrict the need for angiography to a minority of patients with suspected PE.

Reportedly, patients with scleroderma-related pulmonary hypertension (SSc-PAH) respond poorly to new vasoactive drugs (NVD). Forty-nine SSc-PAH patients underwent right heart catheterization (RHC) and, according to NVD availability, divided as follows: Group 1 (n = 23, from 1999 to 2004, poor availability), and Group 2 (n = 26, from 2005 to 2010, good availability). Before diagnostic RHC, NVD had been given to 30 % of the patients in Group 1, and 58 % of those in Group 2 (p = 0.049). At diagnosis, patients in Group 1 had greater heart dilatation (p

AIMS: Radiological inappropriateness in medical imaging leads to loss of resources and accumulation of avoidable population cancer risk. Aim of the study was to audit the appropriateness rate of different cardiac radiological examinations. METHODS AND PRINCIPAL FINDINGS: With a retrospective, observational study we reviewed clinical records of 818 consecutive patients (67 ± 12 years, 75% males) admitted from January 1-May 31, 2010 to the National Research Council - Tuscany Region Gabriele Monasterio Foundation cardiology division. A total of 940 procedures were audited: 250 chest x-rays (CXR); 240 coronary computed tomographies (CCT); 250 coronary angiographies (CA); 200 percutaneous coronary interventions (PCI). For each test, indications were rated on the basis of guidelines class of recommendation and level of evidence: definitely appropriate (A, including class I, appropriate, and class IIa, probably appropriate), uncertain (U, class IIb, probably inappropriate), or inappropriate (I, class III, definitely inappropriate). Appropriateness was suboptimal for all tests: CXR (A = 48%, U = 10%, I = 42%); CCT (A = 58%, U = 24%, I = 18%); CA (A = 45%, U = 25%, I = 30%); PCI (A = 63%, U = 15%, I = 22%). Top reasons for inappropriateness were: routine on hospital admission (70% of inappropriate CXR); first line application in asymptomatic low-risk patients (42% of CCT) or in patients with unchanged clinical status post-revascularization (20% of CA); PCI in patients either asymptomatic or with miscellaneous symptoms and without inducible ischemia on non-invasive testing (36% of inappropriate PCI). CONCLUSION AND SIGNIFICANCE: Public healthcare system--with universal access paid for with public money--is haemorrhaging significant resources and accumulating avoidable long-term cancer risk with inappropriate cardiovascular imaging prevention.

To evaluate pulmonary alveolar-capillary membrane integrity and ventilation/perfusion mismatch after breath-hold diving.Pulmonary diffusing capacity to carbon monoxide (DLCO) and nitric oxide (DLNO), haemoglobin (Hb) and haematocrit (Hct) were measured in six elite divers before and at 2, 10 and 25 minutes after a maximal breath-hold dive to a depth of 10 metres' sea water.Compared to pre-dive, DLCO showed a slight increase at 2 minutes in five subjects and a tendency to decrease at 25 minutes (P0.001) in all subjects. DLNO showed an increase at 10 minutes in three divers and a slight decrease at 25 minutes in five subjects. There was a small but significant (P0.001) increase in Hb and Hct at 2 minutes, possibly affecting the DLCO measurements.An early but transient increase in DLCO in five divers may reflect the central shift in blood volume during a breath-hold dive. The late parallel decrease in DLCO and DLNO likely reflects alveolar-capillary distress (interstitial oedema). The DLNO increase in three subjects at 10 minutes may suggest ventilation/perfusion mismatch.

Patients with inoperable chronic thromboembolic pulmonary hypertension (Inop-CTEPH) treated with conventional therapy have a poor survival. We compare the 3-year survival between those treated with conventional therapy and those treated with conventional therapy and a combination of novel drugs. We also evaluate the clinical course. A total of 34 Inop-CTEPH consecutive patients were evaluated from 1991 to 2009 including right heart catheterization (RHC) and perfusion lung scan (PLS): 7 underwent surgical treatment while 27 were confirmed inoperable. Of these 27 patients, 12 evaluated from 1991 to 2003 (Group 1) were treated with conventional therapy and 15 evaluated from 2004 to 2009 (Group 2) were treated with conventional and novel therapies. At baseline, no group difference emerged at RHC. Based on clinical course, novel drugs and oxygen supplementation were given to patients of Group 2. Seven of these who had worse clinical course repeated RHC and four of them also PLS during therapy. Those without repeat RHC had baseline pulmonary artery mean pressure and brain natriuretic peptide (NT-proBNP) lower and mixed venous saturation (SvO2) and exercise test higher (p = 0.022, 0.015, 0.044 and 0.003, respectively). During therapy, those with repeat RHC had total pulmonary vascular resistance reduced (p = 0.012), base excess increased (p = 0.002) and significant redistribution of pulmonary blood flow at PLS. At the 3-year follow-up, survival was 86% in Group 2 and 31% in Group 1 (p = 0.031). In Inop-CTEPH patients, the clinical course may help to select drugs and the level of oxygen supply that can improve hemodynamics, gas exchange and long-term survival.