Laszlo T. Vaszar

Simvastatin Rescues Rats From Fatal Pulmonary Hypertension by Inducing Apoptosis of Neointimal Smooth Muscle Cells

Background—Pulmonary vascular injury by toxins can induce neointimal formation, pulmonary arterial hypertension (PAH), right ventricular failure, and death. We showed previously that simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in pneumonectomized rats injected with the alkaloid toxin monocrotaline. The present study was undertaken to investigate the efficacy of simvastatin and its mechanism of reversing established neointimal vascular occlusion and pulmonary hypertension. Methods and Results—Pneumonectomized rats injected with monocrotaline at 4 weeks demonstrated severe PAH at 11 weeks (mean pulmonary artery pressure [mPAP]=42 versus 17 mm Hg in normal rats) and death by 15 weeks. When rats with severe PAH received simvastatin (2 mg · kg−1 · d−1 by gavage) from week 11, there was 100% survival and reversal of PAH after 2 weeks (mPAP=36 mm Hg) and 6 weeks (mPAP=24 mm Hg) of therapy. Simvastatin treatment reduced right ventricular hypertrophy and reduced proliferation and increased apoptosis of pathological smooth muscle cells in the neointima and medial walls of pulmonary arteries. Longitudinal transcriptional profiling revealed that simvastatin downregulated the inflammatory genes fos, jun, and tumor necrosis factor-&agr; and upregulated the cell cycle inhibitor p27Kip1, endothelial nitric oxide synthase, and bone morphogenetic protein receptor type 1a. Conclusions—Simvastatin reverses pulmonary arterial neointimal formation and PAH after toxic injury.

Causes of pulmonary granulomas: a retrospective study of 500 cases from seven countries

Background The frequencies of various causes of pulmonary granulomas in pathological material are unknown, as is the influence of geographical location on aetiology. The aim of this study was to identify the causes of pulmonary granulomas in pathological specimens, to define their frequencies, and to determine whether these causes vary by geographical location. Methods 500 lung biopsies and resections containing granulomas were reviewed retrospectively by expert pulmonary pathologists from 10 institutions in seven countries. Fifty consecutive cases from each location were assigned a diagnosis based on histological features and available clinical/microbiological data. Results A specific cause was identified in 58% of cases (290/500), most commonly sarcoidosis (136, 27%) and mycobacterial or fungal infections (125, 25%). Mycobacteria were identified in 19% of cases outside the USA versus 8% within the USA. In contrast, fungi accounted for 19% cases in the USA versus 4% in other locations. Fungi were mostly detected by histology, whereas most mycobacteria were identified in cultures. In 42% of cases (210/500) an aetiology could not be determined. Conclusions Across several geographical settings, sarcoidosis and infections are the most common causes of pulmonary granulomas diagnosed in pathological specimens. Fungi are more commonly identified than mycobacteria in the USA, whereas the reverse is true in other countries. A definite aetiology cannot be demonstrated in more than a third of all cases of pulmonary granulomas, even after histological examination. These findings highlight the need to submit material for histology as well as cultures in all cases in which granulomatous disease enters the differential diagnosis.

A quantitative assessment of a methodology for collaborative specification and evaluation of clinical guidelines

We introduce a three-phase, nine-step methodology for specification of clinical guidelines (GLs) by expert physicians, clinical editors, and knowledge engineers and for quantitative evaluation of the specifications quality. We applied this methodology to a particular framework for incremental GL structuring (mark-up) and to GLs in three clinical domains. A gold-standard mark-up was created, including 196 plans and subplans, and 326 instances of ontological knowledge roles (KRs). A completeness measure of the acquired knowledge revealed that 97% of the plans and 91% of the KR instances of the GLs were recreated by the clinical editors. A correctness measure often revealed high variability within clinical editor pairs structuring each GL, but for all GLs and clinical editors the specification quality was significantly higher than random (p<0.01). Procedural KRs were more difficult to mark-up than declarative KRs. We conclude that given an ontology-specific consensus, clinical editors with mark-up training can structure GL knowledge with high completeness, whereas the main demand for correct structuring is training in the ontologys semantics.

Surgery for Pulmonary Coccidioidomycosis: A 10-Year Experience

BACKGROUND Coccidioidomycosis results from infection with Coccidioides species endemic to the southwestern United States. The mobile US population has resulted in incremental cases being found throughout the world. The fungal infection can result in pulmonary sequelae, including nodules, cavities, and complications requiring treatment by the thoracic surgeon. METHODS A retrospective chart review was conducted of 1,496 patients with coccidioidomycosis treated at our institution (January 1998 to December 2008) to identify those requiring surgery. RESULTS Of the 1,496 patients, 86 (6%; mean age, 58 years [range, 18 to 81], 48 women) underwent operations. Radiographs revealed 59 nodules, 18 cavities, 2 infiltrates, and 7 complications of disease (e.g., effusion, pneumothorax, and empyema). Of the 86 patients, 40% underwent resection for persistent symptoms or disease progression despite adequate antifungal therapy. One third of the operations were performed by video-assisted thoracoscopic surgery. Morbidity, 21% (18 patients), and in-hospital mortality, 2% (2 patients), were greater after resection for cavitary lesions with resultant complications versus for nodular disease: 41% versus 12% (p < or = 0.002) and 8% versus 0% (p < 0.005). Prolonged air leaks or bronchopleural fistulas were the most common complications (13 patients). Postoperative antifungal therapy was administered to 42% of patients (89% of cavitary and complicated). There were no cases of recurrence at follow-up (mean, 24 months). CONCLUSIONS Surgical intervention was indicated for only a few patients, most commonly for diagnostic dilemmas involving nodular disease, symptomatic nonresponsive cavitary disease, or complications. Prolonged air leaks were the main cause of morbidity. Resection should result in symptom resolution and long-term freedom from recurrence.

Pleuropulmonary infection by paragonimus westermani in the united states: A rare cause of eosinophilic pneumonia after ingestion of live crabs

Infections caused by the parasite Paragonimus westermani are endemic to Southeast Asia. Most infections reported in the United States are among immigrants who acquired the disease abroad. Due to the nonspecific nature of its presentation and rarity in the United States, the diagnosis may first be suggested by the pathologist on biopsy review. Definitive diagnosis may need serologic testing for confirmation. We report 4 cases of pleuropulmonary disease caused by United States-acquired P. westermani, which were identified in the consultation files of the authors. Patients (3 men and 1 woman; aged, 20 to 66 y) presented with pulmonary complaints and chest imaging abnormalities including cavitary infiltrates (2), lung mass (1), pleural effusion (1), and pneumothorax (1). Biopsies showed chronic eosinophilic pneumonia and organizing pneumonia in all cases. Other pathologic findings included granulomatous inflammation with geographic necrosis (3), vasculitis (3), and pleuritis (3). Paragonimus organisms and/or eggs were identified in 2 cases. Serologic studies were positive for P. westermani in 3 cases (2 enzyme-linked immunosorbent assay and 1 immunoblot). Three patients ate live crabs at sushi bars (including crabs in martinis, a previously unreported mechanism for infection). In 1 patient, the source of infection was uncertain. Paragonimiasis should be considered in the differential diagnosis of patients with eosinophilic pleuropulmonary disease in the United States. Although eosinophilic pneumonia was a consistent finding, the biopsies may be nonspecific as the organisms and/or eggs are not always visualized. Unusual features include marked pleuritis, foci of geographic necrosis and granulomatous vasculitis. A history of ingestion and targeted serologies are the keys to diagnosis.

Pneumonia and Osteomyelitis Due to Legionella longbeachae in a Woman with Systemic Lupus Erythematosus

A patient with risk factors of systemic lupus erythematosus, corticosteroid use, and malignancy received a diagnosis of concomitant pneumonia and osteomyelitis caused by Legionella longbeachae. In this report, the first description of Legionella osteomyelitis, previous cases of extrapulmonary Legionella infection are detailed.

Characteristics of Patients with Mild to Moderate Primary Pulmonary Coccidioidomycosis

Convalescence is prolonged, regardless of whether the patient receives treatment.

Pharmacogenomics and the challenge to privacy

Pharmacogenomics is an emerging discipline that defines patterns of genetic polymorphism, which account for the variations in human response to drugs. These responses cover the gamut from ‘no effect’ to ‘normal’ response to ‘tolerable’ side effects to severe, even fatal adverse reactions. The ultimate goal of pharmacogenomics is to tailor pharmacologic treatments to the genetic makeup of the individual, thus allowing personalized care with maximal therapeutic drug response and minimal adverse reactions. This process is predicted to streamline drug design (through better quality targets, lower attrition rates, smaller clinical trials and faster approval), and profoundly alter prescription practices (through inclusion of genetic tests in the selection of medications and dosing).

Lymphoid Hyperplasia and Eosinophilic Pneumonia as Histologic Manifestations of Amiodarone-induced Lung Toxicity

Amiodarone use is often limited by pulmonary toxicity. Amiodarone lung disease (ALD) classically manifests as organizing pneumonia with intra-alveolar foamy macrophages, but other patterns may also occur. Here we report 2 previously unreported patterns of ALD: lymphoid hyperplasia (LH) and eosinophilic pneumonia (EP). We identified patients with LH or EP as a prominent feature among 75 cases of probable ALD from the authors’ teaching files collected from 1997 to 2010. Clinical history and lung wedge biopsies were reviewed. Twelve patients (7 men) met inclusion criteria (median age, 71 y). The exact amiodarone dose was known in all cases (median, 200 mg/d). Treatment duration was known in 10 cases and ranged from 1 to 12 years. Thoracic imaging showed diffuse infiltrates causing concern for a diagnosis of ALD. Histologic review revealed intra-alveolar foamy macrophages in all cases. Eight cases prominently displayed patterns of LH, including diffuse LH (7), follicular bronchiolitis (5), lymphoid interstitial pneumonia (2), and lymphocytic perivascular cuffing (2). Two showed features of acute EP, including diffuse alveolar damage with abundant eosinophils. Two showed features of chronic EP, including interstitial pneumonia with abundant eosinophils, patchy organization, and fibrinous exudates with macrophages and eosinophils. One chronic EP case also showed focal LH. Additional features included intra-alveolar giant cells (6), pleuritis (3), small poorly formed granulomas (3), and thrombi (2). LH and EP are previously unrecognized histopathologic manifestations of ALD, and amiodarone exposure should be included in their differential diagnosis.

Ability of expert physicians to structure clinical guidelines: reality versus perception

RATIONALE, AIMS AND OBJECTIVES Structuring Textual Clinical Guidelines (GLs) into a formal representation is a necessary prerequisite for supporting their automated application. We had developed a collaborative guideline-structuring methodology that involves expert physicians, clinical editors and knowledge engineers, to produce a machine-comprehensible representation for automated support of evidence-based, guideline-based care. Our goals in the current study were: (1) to investigate the perceptions of the expert physicians and clinical editors as to the relative importance, for the structuring process, of different aspects of the methodology; (2) to assess, for the clinical editors, the inter-correlations among (i) the reported level of understanding of the guideline structuring ontologys (knowledge schemes) features, (ii) the reported ease of structuring each feature and (iii) the actual objective quality of structuring. METHODS A clinical consensus regarding the contents of three guidelines was prepared by an expert in the domain of each guideline. For each guideline, two clinical editors independently structured the guideline into a semi-formal representation, using the Asbru guideline ontologys features. The quality of the resulting structuring was assessed quantitatively. Each expert physician was asked which aspects were most useful for formation of the consensus. Each clinical editor filled questionnaires relating to: (1) the level of understanding of the ontologys features (before the structuring process); (2) the usefulness of various aspects in the structuring process (after the structuring process); (3) the ease of structuring each ontological feature (after the structuring process). Subjective reports were compared with objective quantitative measures of structuring correctness. RESULTS Expert physicians considered having medical expertise and understanding the ontological features as the aspects most useful for creation of a consensus. Clinical editors considered understanding the ontological features and the use of the structuring tools as the aspects most useful for structuring guidelines. There was a positive correlation (R = 0.87, P < 0.001) between the reported ease of understanding ontological features and the reported ease of structuring those features. However, there was no significant correlation between the reported level of understanding the features - or the reported ease of structuring by using those features - and the objective quality of the structuring of these features in actual guidelines. CONCLUSIONS Aspects considered important for formation of a clinical consensus differ from those for structuring of guidelines. Understanding the features of a structuring ontology is positively correlated with the reported ease of using these features, but neither of these subjective reports correlated with the actual objective quality of the structuring using these features.