Chrissi Hatzoglou

Comparison of a network of primary care physicians and an open spirometry programme for COPD diagnosis

BACKGROUND Early diagnosis of Chronic Obstructive Pulmonary Disease (COPD) remains the cornerstone for effective management. In this study we compared an open spirometry programme and a case-finding programme providing spirometry to high-risk subjects selected by primary care physicians. METHODS A network of primary care physicians was created after invitation and all participants received training on COPD and spirometry. The study team visited 12 primary care settings in each programme in a 1-year period. Spirometry was performed in all eligible participants. COPD diagnosis and classification was based on GOLD guidelines and evaluation by a chest physician. RESULTS Patients with acceptable spirometry were evaluated (n = 201 in the case-finding and n = 905 in the open spirometry programme). The proportion of newly diagnosed COPD was 27.9% in the case-finding programme compared to 8.4% in the open spirometry programme (p < 0.0001). The number needed-to-screen (NNS) for a new diagnosis of COPD was 3.6 in the case-finding programme compared to 11.9 in the open spirometry programme. The majority of newly diagnosed patients were classified in GOLD stages I an II. The average cost for a new diagnosis of COPD was 173 € in the open spirometry programme and 102 € in the case-finding programme. CONCLUSIONS A case-finding programme involving primary care physicians was more cost-effective for the identification of new cases of COPD compared to an open spirometry programme. The development of networks of primary care physicians with access to good quality spirometry and specialist consultation for early diagnosis of COPD is justified.

Amiloride-sensitive Sodium Channels on the Parietal Human Peritoneum: Evidence by Ussing-type Chamber Experiments

The mesothelium is part of the peritoneal water and ion transport barrier essential for peritoneal dialysis (PD) treatment and has a central role in the pathogenesis of peritoneal fibrosis and ultrafiltration failure observed in many PD patients. We investigated the effect of amiloride on the transmesothelial electrical resistance (RTM) of isolated parietal human peritoneum. Intact sheets were obtained from seven patients (three men, four women; mean age, 64 ± 8 years). Fourteen peritoneal planar sheets were transferred to the laboratory in oxygenated Krebs-Ringer bicarbonate solution at 4°C within 30 minutes after removal and mounted in an Ussing-type chamber. Amiloride (10−3 mol/L) added apically (n = 8) caused a rapid rise of the RTM to 24.15 ± 0.76 &OHgr;H cm2 and a subsequent value persistence (p < 0.05); added basolaterally (n = 6), it increased the RTM to 22.66 ± 0.59 &OHgr;H cm2 within 1 minute, which persisted throughout the experiment. RTM was measured before and serially for 30 minutes after addition of amiloride. Control RTM was 20.29 ± 0.86 &OHgr;H cm2. These results indicate a rapid inhibitory effect of amiloride on the ionic permeability of parietal human peritoneum. The increase in the RTM observed after addition of amiloride clearly indicates the existence of amiloride-sensitive sodium channels on the human parietal peritoneal membrane, which may play some role in the ultrafiltration process and sodium removal during PD.

Physiology of pericardial fluid production and drainage

The pericardium is one of the serosal cavities of the mammals. It consists of two anatomical structures closely connected, an external sac of fibrous connective tissue, that is called fibrous pericardium and an internal that is called serous pericardium coating the internal surface of the fibrous pericardium (parietal layer) and the heart (visceral layer) forming the pericardial space. Between these two layers a small amount of fluid exists that is called pericardial fluid. The pericardial fluid is a product of ultrafiltration and is considered to be drained by lymphatic capillary bed mainly. Under normal conditions it provides lubrication during heart beating while the mesothelial cells that line the membrane may also have a role in the absorption of the pericardial fluid along with the pericardial lymphatics. Here, we provide a review of the the current literature regarding the physiology of the pericardial space and the regulation of pericardial fluid turnover and highlight the areas that need to be further investigated.

Comparison of the electrophysiological properties of the sheep isolated costal and diaphragmatic parietal pleura

1 Pleural permeability may contribute to pleural fluid turnover. The transmesothelial resistance (RTM), is an established surrogate of mesothelial permeability. The aim of the present study was to compare the electrophysiological properties of costal and diaphragmatic parietal pleura. 2 Specimens of the parietal pleura were isolated from 12 adult sheep from the chest wall and the diaphragm. Electrophysiological measurements were conducted with the Ussing system. Specimens of the parietal pleura of both types (diaphragmatic and costal) were compared histologically and total protein content measurements were also made. 3 The RTM of the diaphragmatic parietal pleura was significantly higher than that of the costal parietal pleura throughout the experiment. The diaphragmatic parietal pleura contains more cuboidal cells than the costal parietal pleura and its protein content was higher, however this difference was not statistically significant. 4 The costal parietal pleura consists of a more ‘leaky’ mesothelium than the diaphragmatic pleura. The morphological differences between the two types of parietal pleura may underline the electrophysiological findings.

Body Composition in Severe Refractory Asthma: Comparison with COPD Patients and Healthy Smokers

Background Body composition is an important parameter for patients with chronic obstructive pulmonary disease (COPD) whereas the association between asthma and obesity is not fully understood. The impact of severe refractory asthma (SRA) on fat free mass (FFM) has not been investigated. Methodology and Principal Findings 213 subjects (70 healthy smokers, 71 COPD patients and 72 asthma patients) without significant comorbidities were included in the study. In all patients, body composition assessment (using bioelectrical impendance analysis, skinfold and anthropometric measurements) and spirometry were performed. Differences in fat free mass index (FFMI) between groups were assessed and determinants of FFMI in asthma were evaluated. Patients with SRA had lower values of FFMI compared to patients with mild-to-moderate asthma [18.0(17.3–18.3)–19.5(18.4–21.5), p<0.001], despite the fact that they were more obese. The levels of FFMI in SRA were lower than those of GOLD stage I–III COPD and comparable to those of stage IV COPD patients [18.0(17.3–18.3)–18.8(17.8–20.1), p = ns]. These differences were present even after proper adjustments for sex, age, smoking status, daily dose of inhaled corticosteroids (ICS) and daily use of oral corticosteroids (OCS). In multivariate analysis, independent predictors of FFMI in asthmatic patients were age, use of OCS and the presence of SRA, but not smoking, sex or cumulative dose of ICS used. Conclusions and Significance SRA is related to the presence of low FFMI that is comparable to that of GOLD stage IV COPD. The impact of this observation on asthma mechanisms and outcomes should be further investigated in large prospective studies.

Gene expression profile of aquaporin 1 and associated interactors in malignant pleural mesothelioma

Overexpression of AQP1 has recently been shown to be an independent prognostic factor in pleural mesothelioma favoring survival. This paper presents a data mining and bioinformatics approach towards the evaluation of the gene expression profile of AQP1 in malignant pleural mesothelioma and of AQP1 associated markers in the context of mesothelioma disease phenotype, CDKN2A gene deletion, sex and asbestos exposure. The data generated were thus again subjected to differential expression profile analysis. Here we report that AQP1 is overexpressed in epithelioid mesothelioma and identify TRIP6 and EFEMP2 as candidate genes for further investigation in mesothelioma.

Adrenergic Influence on the Permeability of Sheep Diaphragmatic Parietal Pleura

carefully stripped from the underlying tissue. Pleural specimens were carefully mounted in the Ussing chambers (Dipl.-Ing. K. Mussler Scientific Instruments) with an opening surface area of 1 cm 2 . Caution was taken to avoid touching the surface. The experimental procedure is described in previous studies of ours [6] . The R TM of the pleura specimens is inversely correlated to the pleura permeability. The same number of experiments was performed (n = 12) in control conditions (KRB solution on both membrane sides) as well as when adding adrenaline (10 –7 M ) apically and basolaterally, tracing the effect of adrenaline over time. The following sets of experiments were conducted in order to investigate the type of adrenergic receptors that mediate the action of adrenaline on the diaphragmatic parietal pleura, both apically and basolaterally: adrenaline 10 –7 M + propranolol 10 –5 M ( -adrenergic antagonist, n = 8), adrenaline 10 –7 M + phentolamine 10 –5 M ( -adrenergic antagonist, n = 8), propranolol 10 –5 M (n = 6) and phentolamine 10 –5 M (n = 6). In order to investigate whether the action of adrenaline is mediated through amiloride-sensitive sodium channels, the following sets of experiments were conducted: adrenaline 10 –7 M + amiloride 10 –4 M (sodium channelspecific inhibitor, n = 5) and amiloride 10 –4 M (n = 5). The results presented in this study are the means of the above stated number of different experiments in each instance. Statistical analysis was performed with SPSS for Windows. All data are expressed as SEM. The probability of error for the comparison of the mean values was calculated using the t test for unpaired data. Values of p ! 0.05 were regarded as significant. The control resistance (tissue in KRB solution) across the diaphragmatic pleura was 21.38 8 0.42 · cm 2 (n = 12). The addition of adrenaline both apically and basolaterally resulted in a rapid increase within the first minute (p ! 0.05). This effect was maintained throughout the experimental period of 30 min after the addition of adrenaline apically, whereas the addition of adrenaline basolaterally led to a statistically significant increase in the R TM which lasted for 15 min and declined thereafter ( fig. 1 ). In terms of percentage of R TM after the addition of adrenaline apically, the R TM increased 11.8% (p ! 0.05; fig. 2 a), while basolaterally the R TM increased 8.8% (p ! 0.05; fig. 2 b). On the apical side of the diaphragmatic parietal pleura, the addition of propranolol abolished the effect of adrenaline, while phentolamine did not. Propranolol and phentolamine alone did not have any significant effects. The apical addition of adrenaline plus amiloride and of amiloride alone led to a rapid significant increase in the R TM (p ! 0.05; fig. 2 a). On the basolateral side of the diaphragmatic parietal pleura, the addition of propranolol partly suppressed the effect of adrenaline, while phentolamine abolished the action of adrenaline. Propranolol and phentolamine alone did not have any significant effects. The addition of adrenaline plus amiloride led to a rapid significant increase in the R TM (p ! 0.05), while amiloride alone did not have any effect ( fig. 2 b). The addition of adrenaline on both membrane sides (apical and basolateral) of the diaphragmatic parietal pleura resulted in

Effect of histamine on the electrophysiology of the human parietal pleura

INTRODUCTION Histamine is involved in the pathogenesis of numerous diseases and regulates the permeability of different tissues. The aim of this study is to investigate the effects of histamine on the electrophysiology of human parietal pleura and the underlying mechanisms involved. MATERIALS AND METHODS Pleural specimens were obtained from patients subjected to thoracic surgery and were mounted in Ussing chambers. Histamine solutions (1μM to 1mM) were applied in native and pretreated specimens with dimetindene maleate, cetirizine, ranitidine, amiloride and ouabain. Trans-mesothelial resistance was determined (R(TM)). RESULTS Histamine induced a rapid R(TM) increase on the mesothelial (p = 0.008) and a decrease on the interstitial surface (p = 0.029). This effect was dose-dependent and was totally abolished by dimetindene maleate, cetirizine and amiloride and partially by ranitidine and ouabain. CONCLUSIONS Histamine induces acute electrochemical changes in human pleura mainly via interaction with the H(1) and partially with the H(2) histamine receptors. It also interferes with trans-cellular permeability and therefore may participate in pleural fluid recycling.

Influence of AQP1 on cell adhesion, migration, and tumor sphere formation in malignant pleural mesothelioma is substratum- and histological-type dependent

Malignant pleural mesothelioma (MPM) is an aggressive cancer. MPM cells express aquaporin-1 (AQP1) that in other cancers has been shown to participate in the tumor metastasis processes. However, in MPM patients AQP1 overexpression is an independent prognostic factor favoring survival. In this study we aimed at evaluating the role of AQP1 in cell adhesion, migration, and tumor sphere formation in nonmalignant mesothelial cells (MeT-5A) and in epithelioid (M14K) and sarcomatoid (ZL34) MPM cell lines. We used fibronectin (FN) or homologous cell-derived extracellular martrix (ECM) substratum to investigate the role of AQP1 in these experimental phenotypes, inhibiting AQP1 by 10(-5) M mercury chloride (MC). Deposited ECM during cell culture exhibited significant concentration differences among cell types. ZL34 cell adhesion was significantly higher than MeT-5A or M14K cells on FN and ECM. MeT-5A and M14K cell adhesion on FN was sensitive to AQP1 inhibition, whereas AQP1 inhibition on ECM was limited to M14K cells. Wound healing in ZL34 cells was significantly higher than MeT-5A and M14K cells on FN and ECM. AQP1 inhibition significantly lowered cell migration in ZL34 cells on FN and ECM. Sphere formation was not dependent on FN or ECM in the media. AQP1 inhibition in FN media reduced sphere formation in M14K cells, whereas, in ECM, all three cell types were sensitive to AQP1 inhibition.

Computational genomic analysis of PARK7 interactome reveals high BBS1 gene expression as a prognostic factor favoring survival in malignant pleural mesothelioma

The aim of our study was to assess the differential gene expression of Parkinson protein 7 (PARK7) interactome in malignant pleural mesothelioma (MPM) using data mining techniques to identify novel candidate genes that may play a role in the pathogenicity of MPM. We constructed the PARK7 interactome using the ConsensusPathDB database. We then interrogated the Oncomine Cancer Microarray database using the Gordon Mesothelioma Study, for differential gene expression of the PARK7 interactome. In ConsensusPathDB, 38 protein interactors of PARK7 were identified. In the Gordon Mesothelioma Study, 34 of them were assessed out of which SUMO1, UBC3, KIAA0101, HDAC2, DAXX, RBBP4, BBS1, NONO, RBBP7, HTRA2, and STUB1 were significantly overexpressed whereas TRAF6 and MTA2 were significantly underexpressed in MPM patients (network 2). Furthermore, Kaplan-Meier analysis revealed that MPM patients with high BBS1 expression had a median overall survival of 16.5 vs. 8.7 mo of those that had low expression. For validation purposes, we performed a meta-analysis in Oncomine database in five sarcoma datasets. Eight network 2 genes (KIAA0101, HDAC2, SUMO1, RBBP4, NONO, RBBP7, HTRA2, and MTA2) were significantly differentially expressed in an array of 18 different sarcoma types. Finally, Gene Ontology annotation enrichment analysis revealed significant roles of the PARK7 interactome in NuRD, CHD, and SWI/SNF protein complexes. In conclusion, we identified 13 novel genes differentially expressed in MPM, never reported before. Among them, BBS1 emerged as a novel predictor of overall survival in MPM. Finally, we identified that PARK7 interactome is involved in novel pathways pertinent in MPM disease.