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1.  A 48-year-old man with a pleural-based consolidation 
PMCID: PMC3761011  PMID: 23754107
2.  Prognostic value of alveolar volume in systolic heart failure: a prospective observational study 
Ventilatory impairment is known to occur in patients with heart failure (HF). Alveolar volume (VA) is measured by the dilution of an inert gas during a single breath-hold maneuver. Such measurement is sensitive to ventilatory disturbances. We conducted a prospective, observational study to establish the prognostic value of VA in systolic HF.
We studied 260 consecutive patients who were hospitalized for systolic HF. All patients were evaluated under stable clinical conditions, before hospital discharge. Lung function studies included spirometry and determination of the lung diffusing capacity for carbon monoxide (DLCO) by the single-breath method. We also measured the cardiothoracic ratio on frontal chest radiographs, and the circulating levels of N-terminal pro-hormone of B-type natriuretic peptide (NT-proBNP). The hazard ratio (HR) of death was estimated with Cox regression, and the percentiles of survival time with Laplace regression. For survival analysis, VA was categorized as < 80% (n = 135), or ≥ 80% of the predicted value (n = 125).
Follow-up had a median duration of 2.7 years (interquartile range, 1.1 to 4.2 years). The crude mortality rate was 27% in the whole sample, 36% in patients with VA < 80%, and 16% in those with VA ≥ 80%. The HR of death was 2.3-fold higher in patients with VA < 80% than in those with VA ≥80% (p = 0.002). After adjusting for age, New York Heart Association class III-IV, cardiothoracic ratio >0.5, NT-proBNP, persistent atrial fibrillation, DLCO, COPD comorbidity, use of beta-blockers and angiotensin converting enzyme inhibitors, the HR decreased to 1.9 but remained statistically significant (p = 0.039). Two percent of the patients with VA < 80% died about 0.9 years earlier than those with VA ≥ 80% (p = 0.033). The difference in survival time at the 20th percentile was 0.8 years.
VA is a significant, independent predictor of reduced survival in patients with systolic HF.
PMCID: PMC3840733  PMID: 24267007
Systolic heart failure; Alveolar volume; Prognosis; Survival
3.  Clinical Presentation of Acute Pulmonary Embolism: Survey of 800 Cases 
PLoS ONE  2012;7(2):e30891.
Pulmonary embolism (PE) is a common and potentially fatal disease that is still underdiagnosed. The objective of our study was to reappraise the clinical presentation of PE with emphasis on the identification of the symptoms and signs that prompt the patients to seek medical attention.
Methodology/Principal Findings
We studied 800 patients with PE from two different clinical settings: 440 were recruited in Pisa (Italy) as part of the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis (PISAPED); 360 were diagnosed with and treated for PE in seven hospitals of central Tuscany, and evaluated at the Atherothrombotic Disorders Unit, Firenze (Italy), shortly after hospital discharge. We interviewed the patients directly using a standardized, self-administered questionnaire originally utilized in the PISAPED. The two samples differed significantly as regards age, proportion of outpatients, prevalence of unprovoked PE, and of active cancer. Sudden onset dyspnea was the most frequent symptom in both samples (81 and 78%), followed by chest pain (56 and 39%), fainting or syncope (26 and 22%), and hemoptysis (7 and 5%). At least one of the above symptoms was reported by 756 (94%) of 800 patients. Isolated symptoms and signs of deep vein thrombosis occurred in 3% of the cases. Only 7 (1%) of 800 patients had no symptoms before PE was diagnosed.
Most patients with PE feature at least one of four symptoms which, in decreasing order of frequency, are sudden onset dyspnea, chest pain, fainting (or syncope), and hemoptysis. The occurrence of such symptoms, if not explained otherwise, should alert the clinicians to consider PE in differential diagnosis, and order the appropriate objective test.
PMCID: PMC3288010  PMID: 22383978
4.  Soluble receptor for advanced glycation end products in COPD: relationship with emphysema and chronic cor pulmonale: a case-control study 
Respiratory Research  2011;12(1):37.
The receptor for advanced glycation end products (RAGE) is a multiligand signal transduction receptor that can initiate and perpetuate inflammation. Its soluble isoform (sRAGE) acts as a decoy receptor for RAGE ligands, and is thought to afford protection against inflammation. With the present study, we aimed at determining whether circulating sRAGE is correlated with emphysema and chronic cor pulmonale in chronic obstructive pulmonary disease (COPD).
In 200 COPD patients and 201 age- and sex-matched controls, we measured lung function by spirometry, and sRAGE by ELISA method. We also measured the plasma levels of two RAGE ligands, N-epsilon-carboxymethyl lysine and S100A12, by ELISA method. In the COPD patients, we assessed the prevalence and severity of emphysema by computed tomography (CT), and the prevalence of chronic cor pulmonale by echocardiography. Multiple quantile regression was used to assess the effects of emphysema, chronic cor pulmonale, smoking history, and comorbid conditions on the three quartiles of sRAGE.
sRAGE was significantly lower (p = 0.007) in COPD patients (median 652 pg/mL, interquartile range 484 to 1076 pg/mL) than in controls (median 869 pg/mL, interquartile range 601 to 1240 pg/mL), and was correlated with the severity of emphysema (p < 0.001), the lower the level of sRAGE the greater the degree of emphysema on CT. The relationship remained statistically significant after adjusting for smoking history and comorbid conditions. In addition, sRAGE was significantly lower in COPD patients with chronic cor pulmonale than in those without (p = 0.002). Such difference remained statistically significant after adjusting for smoking history, comorbidities, and emphysema severity. There was no significant difference in the plasma levels of the two RAGE ligands between cases and controls.
sRAGE is significantly lower in patients with COPD than in age- and sex-matched individuals without airflow obstruction. Emphysema and chronic cor pulmonale are independent predictors of reduced sRAGE in COPD.
PMCID: PMC3072955  PMID: 21450080
5.  The role of IREB2 and transforming growth factor beta-1 genetic variants in COPD: a replication case-control study 
BMC Medical Genetics  2011;12:24.
Genetic factors are known to contribute to COPD susceptibility and these factors are not fully understood. Conflicting results have been reported for many genetic studies of candidate genes based on their role in the disease. Genome-wide association studies in combination with expression profiling have identified a number of new candidates including IREB2. A meta-analysis has implicated transforming growth factor beta-1 (TGFbeta1) as a contributor to disease susceptibility.
We have examined previously reported associations in both genes in a collection of 1017 white COPD patients and 912 non-diseased smoking controls. Genotype information was obtained for seven SNPs in the IREB2 gene, and for four SNPs in the TGFbeta1 gene. Allele and genotype frequencies were compared between COPD cases and controls, and odds ratios were calculated. The analysis was adjusted for age, sex, smoking and centre, including interactions of age, sex and smoking with centre.
Our data replicate the association of IREB2 SNPs in association with COPD for SNP rs2568494, rs2656069 and rs12593229 with respective adjusted p-values of 0.0018, 0.0039 and 0.0053. No significant associations were identified for TGFbeta1.
These studies have therefore confirmed that the IREB2 locus is a contributor to COPD susceptibility and suggests a new pathway in COPD pathogenesis invoking iron homeostasis.
PMCID: PMC3047296  PMID: 21320324
6.  Bayes pulmonary embolism assisted diagnosis: a new expert system for clinical use 
Emergency Medicine Journal : EMJ  2007;24(3):157-164.
The diagnosis of pulmonary embolism demands flexible decision models, both for the presence of clinical confounders and for the variability of local diagnostic resources. As Bayesian networks fully meet this requirement, Bayes Pulmonary embolism Assisted Diagnosis (BayPAD), a probabilistic expert systems focused on pulmonary embolism, was developed.
To quantitatively validate and improve BayPAD, the system was applied to 750 patients from a prospective study done in an Italian tertiary hospital where the true pulmonary embolism status was confirmed using pulmonary angiography or ruled out with a lung scan. The proportion of correct diagnoses made by BayPAD (accuracy) and the correctness of the pulmonary embolism probabilities predicted by the model (calibration) were calculated. The calibration was evaluated according to the Cox regression–calibration model.
Before refining the model, accuracy was 88.6%. Once refined, accuracy was 97.2% and 98%, respectively, in the training and validation samples. According to Cox analysis, calibration was satisfactory, despite a tendency to exaggerate the effect of the findings on the probability of pulmonary embolism. The lack of some investigations (like Spiral computed tomographic scan and Lower limbs doppler ultrasounds) in the pool of available data often prevents BayPAD from reaching the diagnosis without invasive procedures.
BayPAD offers clinicians a flexible and accurate strategy to diagnose pulmonary embolism. Simple to use, the system performs case‐based reasoning to optimise the use of resources available within a particular hospital. Bayesian networks are expected to have a prominent role in the clinical management of complex diagnostic problems in the near future.
PMCID: PMC2660017  PMID: 17351217
7.  Association of MMP - 12 polymorphisms with severe and very severe COPD: A case control study of MMPs - 1, 9 and 12 in a European population 
BMC Medical Genetics  2010;11:7.
Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease - antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies.
To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history.
Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV.
Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity.
PMCID: PMC2820470  PMID: 20078883
8.  Diagnostic value of gas exchange tests in patients with clinical suspicion of pulmonary embolism 
Critical Care  1999;3(4):111-116.
To assess the value of parameters derived from arterial blood gas tests in the diagnosis of pulmonary embolism.
We measured alveolar-arterial partial pressure of oxygen [P(A–a)O2] gradient, PaO2 and arterial partial pressure of carbon diaxide (PaCO2) in 773 consecutive patients with suspected pulmonary embolism who were enrolled in the Prospective Investigative Study of Acute Pulmonary Embolism.
The study design required pulmonary angiography in all patients with abnormal perfusion scans.
Of 773 scans, 270 were classified as normal/near-normal and 503 as abnormal. Pulmonary embolism was diagnosed by pulmonary angiography in 312 of 503 patients with abnormal scans. Of 312 patients with pulmonary embolism, 12, 14 and 35% had normal P(A–a)O2, PaO2 and PaCO2, respectively. Of 191 patients with abnormal scans and negative angiograms, 11, 13 and 55% had normal P(A–a)O2, PaO2 and PaCO2, respectively. The proportions of patients with normal/near-normal scans who had normal P(A–a)O2, PaO2 and PaCO2 were 20, 25 and 37%, respectively. No differences were observed in the mean values of arterial blood gas data between patients with pulmonary embolism and those who had abnormal scans and negative angiograms. Among the 773 patients with suspected pulmonary embolism, 364 (47%) had prior cardiopulmonary disease. Pulmonary embolism was diagnosed in 151 (41%) of 364 patients with prior cardiopulmonary disease, and in 161 (39%) of 409 patients without prior cardiopulmonary disease. Among patients with pulmonary embolism, there was no difference in arterial blood gas data between patients with and those without prior CPD.
These data indicate that arterial blood gas tests are of limited value in the diagnostic work-up of pulmonary embolism if they are not interpreted in conjunction with clinical and other laboratory tests.
PMCID: PMC29023  PMID: 11056733
arterial blood gas tests; gas exchange; pulmonary embolism
9.  Impact of ventilation/perfusion single-photon emission computed tomography on treatment duration of pulmonary embolism 
Nuclear Medicine Communications  2014;36(2):162-167.
The aim of the study was to establish whether the duration of anticoagulant (AC) therapy can be tailored, on an objective basis, by using ventilation/perfusion single-photon emission computed tomography (V/P SPECT) and to assess the extent of residual perfusion defects over time. In particular, we addressed the following: (a) is the extent of perfusion recovery at 3 months of initial pulmonary embolism (PE) diagnosis a satisfactory criterion for deciding the duration of oral AC? (b) Is it safe to withdraw AC at 3 months if perfusion recovery is complete?
Patients and methods
Of 269 consecutive patients with suspected PE, 100 patients were diagnosed with PE using V/P SPECT. Sixty-seven patients with acute PE were followed up clinically and with V/P SPECT at 3 months. Sixty-four patients were subject to review and examination using V/P SPECT for a period of 6 months and 33 were followed up only clinically. Therapy was terminated after 3 months if perfusion was normalized, and patients were free of symptoms and the risk of hypercoagulability. Initial extension of PE did not have an impact on decision making.
PE extension varied from 10 to 70% in the acute stage. After 3 months, complete resolution of PE was found in 48 patients. The treating pulmonologist decided to terminate therapy in 35 (73%) patients and to continue AC in 13 patients because of persistent risk factors. Six months later, at the second control stage, 53 patients had complete recovery of pulmonary perfusion. Eleven patients still had perfusion defects at 6 months. No recurrence was identified at 6 months in the 35 patients whose therapy was terminated after 3 months. No bleeding effects were observed in any of the patients during the 6-month follow-up.
This study shows that AC therapy can be tailored, on an objective basis, by using V/P SPECT. Normalization of perfusion at 3 months of initial PE diagnosis was a reliable indicator that AC could be safely withdrawn in patients who were without hypercoagulability risk.
PMCID: PMC4280272  PMID: 25321156
duration of anticoagulant therapy; follow-up; pulmonary embolism; ventilation/perfusion single-photon emission computed tomography

Results 1-9 (9)