Yehuda Schwarz

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. Eligible subjects were adults with idiopathic pulmonary fibrosis of <3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo. Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n=119) or placebo (n=59). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients. In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. Long-term exposure to macitentan was well tolerated in IPF in a trial that did not meet its primary end-point http://ow.ly/p0RDL

Electromagnetic Navigation during Flexible Bronchoscopy

Background: Flexible bronchoscopy is routinely utilized in the diagnosis and treatment of various lung diseases. Nondiagnostic bronchoscopy leads to more invasive interventions, such as transthoracic needle aspiration, mediastinoscopy or even thoracotomy. Electromagnetic navigation is a novel technology that facilitates approaching peripheral lung lesions, which are difficult to sample by conventional means. The navigation system involves creating an electromagnetic field around the chest and localizing an endoscopic tool using a microsensor overlaid upon previously acquired CT images. Objectives: To determine the practicality, accuracy and safety of real-time electromagnetic navigation, coupled with previously acquired 3D CT images, in locating artificially created peripheral lung lesions in a swine model. Methods: Peripheral lung lesions were created in four swine models by insertion of a metal tube (1 × 10 mm) via a transthoracic approach. An electromagnetic field was created by placing the animal on an electromagnetic location board. A position sensor incorporated into the distal tip of a dedicated tool was used to navigate to the various target lesions. Information gathered in real time during bronchoscopy was presented on a monitor simultaneously by displaying previously acquired CT images. Upon reaching the target lesion, biopsies were performed and the functionality and safety of the superDimension/Bronchus System was observed and documented. Results: The registration accuracy expressed by the fiducial target registration error, expressing both the registration quality and the stability of fiducial (registration) points, was 4.5 mm on average. No adverse effects, such as pneumothorax or internal bleeding, were encountered in any of the animals in this study. Conclusions: Real-time electromagnetic positioning technology coupled with previously acquired CT images is an accurate technology added to standard bronchoscopy to assist in reaching peripheral lung lesions and performing biopsies.

Effect of endothelin-1 on α-smooth muscle actin expression and on alveolar fibroblasts proliferation in interstitial lung diseases

Abstract Endothelin-1 (ET-1) is a potent constrictor and mitogen peptide which is expressed in several pulmonary diseases. To elucidate the involvement of ET-1 in lung interstitial pathologic events, we assessed ET-1 secretion by alveolar macrophages (AM) and fibroblasts recovered from the bronchoalveolar lavage (BAL) of patients with idiopathic pulmonary fibrosis (IPF), sarcoidosis (SA) and from control subjects. We characterized in vitro alveolar fibroblasts of all subjects using monoclonal antibody specific to α-smooth muscle actin (α-SM actin) and human fibroblast marker. We also examined the effect of ET-1 on the fibroblasts’ mitogenesis and on their cytoskeletal phenotype. The AM recovered from IPF patients showed increased spontaneous secretion of ET-1 compared with cells from SA and control subjects. The expression of α-SM actin in the fibroblasts from IPF patients was significantly higher than in SA fibroblasts and normal lung fibroblasts. Assessing alveolar fibroblasts purity revealed a negative staining for α-SM actin in all SA and control fibroblasts, while alveolar fibroblasts recovered from IPF were 100% positive for α-SM actin, a reliable differentiation marker of myofibroblastic cells. Exposure of SA alveolar fibroblasts to ET-1 resulted in an increased expression of α-SM actin. Addition of exogenous ET-1 to alveolar fibroblasts culture stimulated DNA synthesis and proliferation in all groups. Moreover, neutralization of ET-1 by monoclonal antibody was shown to decrease 3 H-thymidine incorporation in fibroblasts cultured with AM supernatants. These results suggest possible interactions between AM, myofibroblasts and fibroblasts in interstitial lung diseases (ILD). By modulating α-SM actin expression and exertion of the mitogenic effect on alveolar fibroblasts, ET-1 might play an important role in the fibrogenesis of ILD.

Pleural effusion as a presenting symptom of ovarian hyperstimulation syndrome

Pharmacological ovarian stimulation is an accepted technique for amplifying the normal process of follicular development and maturation. It has been in use for the past decade, especially in cases of infertility. Pleural effusion associated with ovarian hyperstimulation syndrome (OHSS), a complication of this therapy, may be more prevalent than is commonly accepted. Four young women presented to our department with dyspnoea caused by pleural effusion as a result of ovarian hyperstimulation syndrome (OHSS). The diagnosis of OHSS was based on a history of pharmacological ovarian stimulation, clinical and laboratory evidence of ovarian enlargement and exclusion of other potential causes of pleural effusion in young women, such as infections, malignancy, pulmonary embolism and collagen vascular diseases. The fluid characteristics in all cases were exudative, with low to normal LDH. All of these patients required fluid evacuation for symptomatic relief. Resolution was achieved with supportive measures and rest. Ovarian hyperstimulation syndrome may be common enough to warrant routine consideration in the differential diagnosis of pleural effusion in young women.

Percutaneous core needle biopsy in the diagnosis of mediastinal tumors

OBJECTIVE to determine the contribution of percutaneous core cutting needle biopsy (PCNB) in the diagnosis of mediastinal tumors. DESIGN retrospective review of 70 patients with mediastinal lesions who underwent CT-guided PCNB between 1988 and 1996. RESULTS PCNB provided adequate material in 62/70 cases, giving a total sample rate of 88.6%. Of these 62 patients, 57 were diagnosed correctly by PCNB whereas 5/62 were misdiagnosed as nonspecific inflammation, providing an overall sensitivity of 91.9%. PCNB established a specific histologic diagnosis in 90.3% of the patients, mainly in cases of lymphoma, bronchogenic carcinoma, and thymoma. Pneumothorax was the most commonly encountered complication (11%). Hemoptysis (30-50 ml) occurred in only one (1.6%) of the patients. CONCLUSION CT guided PCNB is an easy and safe procedure which can provide a precise diagnosis in the majority of mediastinal tumors and can obviate the need for exploratory thoracic surgery in cases which are medically treatable or non-resectable.

The association of perennial rhinitis with Trichophyton infection

Trichophyton was recently reported to be the cause of respiratory allergy in patients with severe bronchial asthma. We describe eight patients with perennial rhinitis in combination with skin or toe‐nail infection, in whom Type I hypersensitivity reaction to Trichophyton was confirmed by skin test, RAST and nasal provocation. When treated with oral fungicidal therapy, there was significant improvement in both their skin and nasal symptoms. Local therapy produced only a mild, transient improvement. We emphasize the need for thorough evaluations in patients with respiratory allergies and negative routine skin tests.

Evaluation of Workers Exposed to Dust Containing Hard Metals and Aluminum Oxide

BACKGROUND Fourteen worker exposed to hard metals and aluminum oxide were evaluated. METHODS Six heavily exposed workers underwent bronchoscopy and bronchoalveolar lavage, and five workers underwent transbronchial biopsy. RESULTS Microchemical analysis of transbronchial biopsies showed a high lung burden of exogenous particles, especially metal related to their hard metals exposure. Lung tissue and cellular changes, which were associated with exposure to hard metal and aluminum oxide, corresponded well with the microanalytic test results. CONCLUSIONS Three workers had at biopsy diffuse interstitial inflammatory changes: two of them were asymptomatic with normal chest X-ray films, and one had clinically evident disease with severe giant cell inflammation. Two other workers showed focal inflammation. The worker showing clinical disease and one asymptomatic worker with interstitial inflammatory changes had evaluated bronchoalveolar lavage fluid-eosinophilia counts. These two were father (with clinical disease) and son (asymptomatic).

Dextromethorphan Premedication Reduces Midazolam Requirement: Objective and Subjective Parameters in Peribronchoscopy

Background:Coughing is increased during bronchoscopy and may last for several hours after the procedure. Also prior to the procedure patients show high levels of anxiety due to fear of the pain and breathing difficulties that they might experience during the procedure. Objectives: To evaluate the antitussive, anxiolytic and sedative effect of dextromethorphan (DM) premedication on the amount of intravenous midazolam during bronchoscopic procedures. Methods: Sixty consecutive patients undergoing scheduled bronchoscopy were randomly allocated in a double-blind, placebo-controlled study. Half received 90 mg DM and half placebo. Local anesthesia with 2 ml of repeated intratracheal instillation of 1% lidocaine as needed during bronchoscopy was applied. Midazolam 1 mg (maximum of 5 mg) was administered intravenously until a satisfactory sedation was achieved. Results: Heart rate, systolic and diastolic pressure and SpO2 were assessed before and during bronchoscopy. A visual analog score (VAS) for pain, cough, communication, cooperation, emotional state, complaints, expectoration, level of information about the procedure, feeling of unpleasantness and stress level assessed before and after the examination by the patient and the physician was used. There were no significant differences in the reported degrees of difficulty in undergoing bronchoscopic procedures. DM patients needed significantly fewer lidocaine instillations and lower midazolam dosage, achieved better analgesia, had lower emotion and complaint scores, significantly less coughing, significantly less stress, were significantly more cooperative, found that the procedure was much less unpleasant than they had expected, and produced less sputum at end of the procedure. Conclusions: DM is an effective bronchoscopic premedication in combination with midazolam and improves the overall well-being of the patients.

Biological Exposure Metrics of Beryllium-Exposed Dental Technicians

ABSTRACT Beryllium is commonly used in the dental industry. This study investigates the association between particle size and shape in induced sputum (IS) with beryllium exposure and oxidative stress in 83 dental technicians. Particle size and shape were defined by laser and video, whereas beryllium exposure data came from self-reports and beryllium lymphocyte proliferation test (BeLPT) results. Heme oxygenase-1 (HO1) gene expression in IS was evaluated by quantitative polymerase chain reaction. A high content of particles (92%) in IS >5 μ in size is correlated to a positive BeLPT risk (odds ratio [OR] = 3.4, 95% confidence interval [CI]: 0.9–13). Use of masks, hoods, and type of exposure yielded differences in the transparency of IS particles (gray level) and modulate HO1 levels. These results indicate that parameters of size and shape of particles in IS are sensitive to workplace hygiene, affect the level of oxidative stress, and may be potential markers for monitoring hazardous dust exposures.

Changes in sensitivity to methacholine after inhalation with distilled water: the role of the bronchoconstrictive response

The inhalation of distilled water can induce bronchoconstriction and a transient increase in sensitivity to methacholine in asthmatics. The purpose of this study was to determine the role of the induced bronchoconstriction in the increased sensitivity to methacholine which follows the challenge with distilled water. Eighteen asthmatic children (age 9-17 yrs) were challenged by inhalation of distilled water. Bronchial responsiveness, the provocative concentration of methacholine producing a 20% decrease in forced expiratory volume in one second (PC20), was determined before inhalation of distilled water, and 1.5 and 24 h thereafter. Following inhalation of distilled water, eight patients (Group I) had a greater than 15% decrease in FEV1 (mean 23%); whereas, in the remaining 10 (Group II) the decrease was less than 7% (mean 1%). PC20 to methacholine, geometric mean and 95% confidence interval (CI), decreased transiently only at 1.5 h following inhalation of distilled water. The decrease was from 0.78 mg.ml-1 (95% CI 0.11-5.54 mg.ml-1) at baseline to 0.25 mg.ml-1 (95% CI 0.03-2.14 mg.ml-1) after challenge in Group I; and from 2.67 mg.ml-1 (95% CI 0.35-20.34 mg.ml-1) at baseline to 0.72 mg.ml-1 (95% CI 0.18-14.87 mg.ml-1) after challenge in Group II. The transient increase in sensitivity to methacholine observed following inhalation of distilled water occurred independently of the bronchoconstrictive response. This finding may have important clinical implications when hypo-osmolar solutions are used for delivery of drugs.