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Patients with many recurrences of acute pericarditis are commonly alarmed by the fear of constriction. We studied their long-term outcome and the possible presence of systemic diseases. Sixty-one Italian patients (36 men) were followed for an average of 8.3 years according to a predefined protocol, including testing for autoimmune diseases and familial Mediterranean fever. Symptomatic pericarditis lasted from 1 to 43 years (mean 5.4 years). Fifty-two patients had been referred to us after failure of previous therapies, including steroids. We observed 378 attacks with a mean of 1.6 per patient per year and 156 hospital admissions. Thirteen patients had a post-cardiac injury syndrome. In 43 (70.5%), the pericarditis remained idiopathic, whereas we made a new diagnosis of rheumatoid arthritis in 1 and of Sjogren's syndrome in 4 patients, but in these patients pericarditis represented the dominant clinical manifestation. Cardiac tamponade occurred during the initial attacks in 4 patients (6.5%) but never recurred. Pleural effusions were present during the first attack in 22 patients (36.0%) and liver involvement in 5 (8%). No patients developed constrictive pericarditis. Echocardiographic examination produced no evidence of chronic myocardial disease. Response to therapy was good. Thirty-one patients (50.8%) are in sustained remission, without any therapy; their total observation period has averaged 10.3 years. In idiopathic patients, antinuclear antibodies were present in 56.2% and anti-Ro/SSA in 8.3%. Mutations linked to familial Mediterranean fever were absent. In conclusion, in this large series of difficult patients with recurrent acute pericarditis and a very long follow-up, the long-term prognosis is good.

Amiodarone may induce lung damage by direct toxicity or indirectly through inflammation. To clarify the mechanism of direct toxicity, we briefly exposed rabbit alveolar macrophages to amiodarone and analyzed their morphology, synthesis, and degradation of dipalmitoylphosphatidylcholine (DPPC); distribution of lysosomal enzymes; and uptake of diphtheria toxin and surfactant protein (SP) A used as tracers of the endocytic pathway. Furthermore, in newborn rabbits, we studied the clearance of DPPC and SP-A instilled into the trachea together with increasing amounts of amiodarone. We found that in vitro amiodarone decreases the surface density of mitochondria and lysosomes while increasing the surface density of inclusion bodies, increases the incorporation of choline into DPPC, modifies the distribution of lysosomal enzymes, and does not affect the uptake and processing of diphtheria toxin but inhibits the degradation of SP-A. In vivo amiodarone inhibits the degradation of SP-A but not of DPPC. We conclude that the acute exposure to amiodarone perturbs the endocytic pathway acting after the early endosomes, alters the traffic of lysosomal enzymes, and interferes with the turnover of SP-A.

PURPOSE: To identify the rate of occurrence and type of incorrect echocardiographic diagnoses in patients with mechanical valve prostheses. PATIENTS AND METHODS: We studied 170 consecutive patients (73 women and 97 men) with a total of 208 prostheses who underwent surgery for mitral (n = 136) or aortic (n = 72) valve dysfunction between January 1991 and December 1997. Preoperative echocardiographic data were compared with surgical findings. Any major discrepancy between the echocardiographic reports and surgery was judged to be unconfirmed when the preoperative echocardiographic diagnosis was not confirmed at surgery, but the prosthesis was found to be dysfunctioning; and was judged to be erroneous when the preoperative echocardiographic diagnosis was not confirmed, and surgical inspection failed to reveal any other prosthetic abnormality. RESULTS: There were 25 (12%) diagnostic errors. Of the 136 mitral prostheses, there were 9 unconfirmed diagnoses of paravalvular regurgitation (6 had a fibrous tissue overgrowth, 1 had a thrombus with fibrous tissue overgrowth, 1 had endocarditis vegetations, and 1 had a ball variance) and 5 erroneous diagnoses. Eleven diagnostic errors were made in the 72 aortic prostheses: there were 9 unconfirmed diagnoses (paravalvular regurgitation was diagnosed as transvalvular in 7, and transvalvular regurgitation as paravalvular in 2 cases), and 2 erroneous diagnoses. CONCLUSIONS: Although echocardiography has gained great credibility among clinicians, special care should be taken when assessing patients in whom prosthetic valve dysfunction is suspected.

Aims of this study were to assess (1) whether videodensitometric analysis of myocardial gray-level variation can distinguish normal from rejecting transplanted hearts in a clinical setting and (2) whether this sign, used in combination with the other conventional two-dimensional and Doppler echocardiographic findings, might improve the accuracy of ultrasound techniques. Thirty heart transplant recipients (23 men; mean age 40 years; range 20 to 54 years) were studied in 87 different situations by endomyocardial biopsy and echocardiographic evaluation. Of the 87 situations, 37 ("rejectors") showed histologic evidence of rejection of mild (n = 17) or moderate (n = 10) severity and 50 ("nonrejectors") did not show rejection processes. Cyclic variation was decreased significantly in rejectors compared with nonrejectors in both the septum (15% +/- 10% versus 25% +/- 11%; p < 0.0001) and the posterior wall (19% +/- 10% versus 25% +/- 12%; p < 0.01). When a cutoff of 20% or greater of cyclic variation in the septal wall was taken as a positivity criterion, it yielded a 70% sensitivity and 70% specificity for identifying rejection. Sensitivity of conventional two-dimensional and Doppler echocardiographic signs was 51% and increased to 89%, increased by the videodensitometric criteria (p < 0.001). Specificity was 92% and decreased to 62% with videodensitometric criteria (p < 0.001). Overall diagnostic accuracy was 75% for conventional two-dimensional echocardiographic Doppler criteria alone and remained unchanged by the addition of videodensitometric criteria. In conclusion, blunting of cyclic gray-level variation induced by rejection is detectable with videodensitometric analysis. The clinical impact of this sign appears to be limited, because the resulting increase in sensitivity is counter-balanced by a reduced specificity compared with the currently available conventional ultrasound techniques.

To assess the diagnostic impact of transesophageal echocardiography in the evaluation of mediastinal masses, 30 patients with mediastinal abnormalities detected by routine chest roentgenogram underwent transthoracic and transesophageal echocardiography. Subsequently, 29 of the patients underwent computed tomography and 16 underwent magnetic resonance imaging. The location and structure of the masses as well as their relationship to the surrounding structures were assessed. Anatomic confirmation and histopathologic diagnosis of the mediastinal masses by surgical resection and biopsy was available for all patients. Transesophageal echocardiography was more accurate than transthoracic echocardiography in detecting mediastinal masses (90% versus 73%), in identifying their structure (100% versus 90%), and in evaluating their relationship to contiguous organs (89% versus 81%). No complication was observed during the examinations. Computed tomography correctly diagnosed the location, structure, and relationships in all patients but one; magnetic resonance imaging correctly evaluated the mediastinal masses in all 16 patients. Our study suggests that transesophageal echocardiography is a valuable and safe complementary method of evaluating mediastinal masses. Moreover, this technique allows the obstruction of vessels and heart cavities, valve regurgitation, and right and left ventricular function to be easily assessed.

This paper examines the removal from the airways of Curosurf, a commercial surfactant derived from porcine lungs, administered at pharmacological concentrations to newborn or adult animals. Curosurf was labelled by the addition of radioactive dipalmitoyl phosphatidylcholine (DPPC) and administered intratracheally to newborn and adult rabbits at a dose of 200 mg x kg(-1) body weight. The disappearance of DPPC from the airways and its appearance in alveolar macrophages, lung parenchyma, lamellar bodies, serum, liver, kidneys and brain was then studied for 24-48 h. The in vitro degradation of Curosurf DPPC by alveolar macrophages was also studied. During the first 3 h after instillation, large amounts of Curosurf left the airways and became associated with tissue, indicating that it mixed rapidly with the endogenous pools of surfactant. A fraction of administered DPPC became associated with the lamellar bodies, suggesting that Curosurf can be recycled. Curosurf administration did not stop the secretion of endogenous surfactant. Very little intact radioactive DPPC could be recovered at any time in alveolar macrophages, however, macrophages have the ability, in vitro, to degrade Curosurf. Newborn rabbits lose Curosurf from the lungs at a slower rate than adult rabbits. One and two days after instillation, organic extracts from the liver, kidney, brain and serum contained small but measurable amounts of radioactivity. These results indicate that Curosurf rapidly enters the pathways of surfactant metabolism and that alveolar macrophages may play an important role in the catabolism of Curosurf.

Serum lipoproteins may enter the airways and appear in sputum (chyloptysis) when the lymphatic circulation is impaired by inflammation, neoplasia, or an abnormal proliferation of smooth muscle cells. While analyzing the bronchoalveolar lavage fluid of a patient with chyloptysis, we noticed that surfactant could not be separated from contaminating serum lipoproteins and speculated that lipoproteins might interact with surfactant components. To clarify this point we immobilized surfactant protein (SP) A on microtiter wells and incubated it with125I-labeled very low density lipoproteins (VLDLs), low-density lipoproteins, and high-density lipoproteins. We found that SP-A binds lipoproteins. Studying in greater detail the interaction of SP-A with VLDLs, we found that the binding is time and concentration dependent; is inhibited by unlabeled lipoproteins, phospholipids, and antibodies to SP-A; is increased by Ca2+; and is unaffected by methyl α-d-mannopyranoside. Whole surfactant is a potent inhibitor of binding. Furthermore, we found that SP-A increases the degradation of VLDLs by alveolar macrophages and favors the association of VLDLs with alveolar surfactant. We conclude that SP-A influences the disposal of serum lipoproteins entering the airways and speculate that binding to alveolar surfactant might represent an important step in the interaction between exogenous substances and the lung.

Surfactant subtypes have been identified by gradient centrifugation and characterized by differences in protein composition, vesicle size, and surface activity. The presence of surfactant proteins in each subtype is thought to be critical to the formation of aggregates and their function (Baritussio, Am J Physiol 1994;266:L436). To evaluate whether synthetic surfactant peptides interact with lipids in a manner comparable to native surfactant proteins, we prepared surfactant vesicles containing synthetic 125I-SP-B1-78 and phospholipids (DPPC:PG:Palmitic acid, 7:2:1) [PL], with and without palmitoylated synthetic SP-C1-34. We separated the aggregates by continuous sucrose gradient (0.1-0.8 M; 100,000 g for 48 h), collecting 50 fractions, and analyzed the PL and peptide profile. The PL peak appeared in fraction 17 and > 80% of PL was recovered in fractions 15-17, at a density of 1.07 g/mL, irrespective of the presence of SP-C. In the SP-B/PL aggregates, SP-B peaked at 51% in fraction 15 and > 95% of SP-B appeared in fractions 11-17. In the SP-B&SP-C/PL aggregates, 17% of the SP-B was detected at the bottom of the gradient with

Alveolar macrophages degrade surfactant protein (SP) A and saturated phosphatidycholine [dipalmitoylphosphatidylcholine (DPPC)]. To clarify this process, using rabbit alveolar macrophages, we analyzed the effect of drugs known to affect phagocytosis, pinocytosis, clathrin-mediated uptake, caveolae, the cytoskeleton, lysosomal pH, protein kinase C, and phosphatidylinositol 3-kinase (PI3K) on the degradation of SP-A and DPPC. We found the following: 1) SP-A binds to the plasma membrane, is rapidly internalized, and then moves toward degradative compartments. Uptake could be clathrin mediated, whereas phagocytosis, pinocytosis, or the use of caveolae are less likely. An intact cytoskeleton and an acidic milieu are necessary for the degradation of SP-A. 2) Stimulation of protein kinase C increases the degradation of SP-A. 3) PI3K influences the degradation of SP-A by regulating both the speed of internalization and subsequent intracellular steps, but its inhibition does not prevent SP-A from reaching the lysosomal compartment. 4) The degradation of DPPC is unaffected by most of the treatments able to influence the degradation of SP-A. Thus it appears that DPPC is degraded by alveolar macrophages through mechanisms very different from those utilized for the degradation of SP-A.

Transformations of surfactant after secretion are incompletely understood. To clarify them, we lavaged lungs in fetuses and in newborn rabbits, fractionated the lavage fluid by differential and density gradient centrifugation, and analyzed the distribution of surfactant protein (SP) phospholipids, SP-A, SP-B, and SP-C. Furthermore, we administered into trachea of newborn rabbits labeled surfactant and compared the alveolar clearance of SP-A, SP-B, SP-C and saturated phosphatidylcholine. We found that, in the fetus, secreted lamellar bodies contain all components of surfactant, except a small amount of SP-A. As breathing starts and new surfactant subtypes are generated, the proteins are mostly associated with dense subtypes, but SP-B and SP-C are especially concentrated in dense materials that contain minor amounts of phospholipids and SP-A. Furthermore, we found that, during breathing, alveolar surfactant is degraded into more than one type of remnant, that the lavage fluid contains a pool of SP-A not associated with membranes, and that SP-A, SP-B, and SP-C are all turned over at a faster rate than saturated phosphatidylcholine.

To clarify the life cycle of surfactant protein C (SP-C), we obtained alveolar surfactant from 3-day-old rabbits killed 15 h after the tracheal administration of 32P and L-[35S]methionine. Small amounts of this surfactant were administered into the tracheas of 3-day-old rabbits, which were killed after 1 min and 2 and 4 h. We then analyzed the radioactivity associated with SP-C and with saturated phosphatidylcholine (DPPC) in lung lavage fluid and in a lamellar body-rich fraction isolated from the lung homogenate. We found that SP-C and DPPC are both taken up from the alveolar spaces and incorporated into lamellar bodies, but the time courses of reuptake are different. Our results indicate that in the alveoli SP-C is turned over faster than DPPC.

In patients with idiopathic alveolar proteinosis, the alveoli are filled with materials rich in surfactant components, especially surfactant protein A (SP-A). The anomaly could be caused by either increased secretion, decreased clearance, or both. To clarify this point, we studied five patients who underwent therapeutic lavage and then were ventilated mechanically for 24 h. During the first 8 h of mechanical ventilation, a surfactant-depleted lung was lavaged at selected intervals, and the bronchoalveolar lavage fluid was analyzed. We observed that, after lavage, various surfactant components accumulated in the airways with different time courses. We also observed that SP-A increased until the second hour and then dropped rapidly, suggesting the existence of an efficient mechanism of removal. These findings suggest that idiopathic alveolar proteinosis might be caused by a primary defect in a slow mechanism of removal or by the presence of factor(s) that interfere with the clearance of surfactant and that can be removed by lavage. It seems clear, however, that an increased secretion rate is unlikely to be the major cause of idiopathic alveolar proteinosis.