Respiratory nitric oxide and pulmonary artery pressure in children of aymara and European ancestry at high altitude.

Invasive studies suggest that healthy children living at high altitude display pulmonary hypertension, but the data to support this assumption are sparse. Nitric oxide (NO) synthesized by the respiratory epithelium regulates pulmonary artery pressure, and its synthesis was reported to be increased in Aymara high-altitude dwellers. We hypothesized that pulmonary artery pressure will be lower in Aymara children than in children of European ancestry at high altitude, and that this will be related to increased respiratory NO. We therefore compared pulmonary artery pressure and exhaled NO (a marker of respiratory epithelial NO synthesis) between large groups of healthy children of Aymara (n = 200; mean +/- SD age, 9.5 +/- 3.6 years) and European ancestry (n = 77) living at high altitude (3,600 to 4,000 m). We also studied a group of European children (n = 29) living at low altitude. The systolic right ventricular to right atrial pressure gradient in the Aymara children was normal, even though significantly higher than the gradient measured in European children at low altitude (22.5 +/- 6.1 mm Hg vs 17.7 +/- 3.1 mm Hg, p < 0.001). In children of European ancestry studied at high altitude, the pressure gradient was 33% higher than in the Aymara children (30.0 +/- 5.3 mm Hg vs 22.5 +/- 6.1 mm Hg, p < 0.0001). In contrast to what was expected, exhaled NO tended to be lower in Aymara children than in European children living at the same altitude (12.4 +/- 8.8 parts per billion [ppb] vs 16.1 +/- 11.1 ppb, p = 0.06) and was not related to pulmonary artery pressure in either group. Aymara children are protected from hypoxic pulmonary hypertension at high altitude. This protection does not appear to be related to increased respiratory NO synthesis.

The daily energy expenditure in stable chronic obstructive pulmonary disease.

Resting energy expenditure is frequently increased in chronic obstructive pulmonary disease (COPD), but it is unknown if this hypermetabolism holds true over 24 h. The aim of this study was to measure the actual 24-h energy expenditure (24-h EE) in patients with stable COPD. Energy expenditure was measured by indirect calorimetry, using a metabolic chamber for 24-h EE and a canopy for basal metabolic rate (BMR). Physical activity was detected in the chamber by a radar system, and its duration was quantified. Two groups matched for age and height were studied: 16 male ambulatory patients with stable COPD and 12 male normal subjects. Body weight was 92 +/- 12% of ideal body weight in the group with COPD and 108 +/- 11% in the control group (p = 0.01). BMR was 120 +/- 7% of predicted in the group with COPD and 108 +/- 12% in the control group (p < 0.01). However, 24-h EE was similar in the two groups, amounting to 1,935 +/- 259 kcal in patients with COPD and 2,046 +/- 253 kcal in the control group (NS). This corresponded to 145% and 137% of predicted BMR, and to 121% and 126% of measured BMR in patients with COPD and the control group, respectively (NS). Patients were allowed to pursue their usual treatment within the chamber, and a positive correlation existed between 24-h EE and the daily dose of inhaled beta 2-agonists (p < 0.03). During daytime, physical activity was lower in patients with COPD. This study shows that patients with stable COPD are characterized by a normal daily energy expenditure in controlled conditions in spite of an increased basal metabolic rate. They appear to save energy by reducing their spontaneous level of physical activity.

The cost of breathing in stable chronic obstructive pulmonary disease.

1. The hypermetabolism frequently observed at rest in patients with chronic obstructive pulmonary disease has been attributed to a high cost of breathing. However, measurement of the cost of breathing by the usual hyperventilation procedure is fraught with methodological problems. The purpose of this study was to measure more directly the cost of breathing in a group of ambulatory patients with stable chronic obstructive pulmonary disease. 2. The cost of breathing was calculated as the difference in oxygen consumption measured by indirect calorimetry between spontaneous breathing and noninvasive mechanical ventilation. Inspiratory muscle rest was achieved by negative or positive pressure ventilation and assessed by the recording of surface electromyograms of the diaphragm and parasternal intercostal muscles. 3. Seven tests were performed in six ambulatory patients with stable chronic obstructive pulmonary disease, four tests using positive pressure ventilation and three with negative pressure ventilation. During mechanical ventilation, the electromyographic activity of the diaphragm decreased by 70 +/- 22%, while that of the parasternals was suppressed in four tests, and remained unchanged in three. However, oxygen consumption was only 1.6 +/- 6.2% lower during mechanical ventilation. 4. The cost of breathing measured in this study was therefore much lower than previously published values. Stress was not likely to influence the results, as both the heart rate and plasma catecholamines did not change between spontaneous breathing and mechanical ventilation. These results suggest that the cost of breathing in ambulatory patients with stable chronic obstructive pulmonary disease may be lower than previously estimated.

Surfactant protein A, exposure to endotoxin, and asthma in garbage collectors and in wastewater workers.

Endotoxin causes an inflammation at the bronchial and alveolar level. The inflammation-induced increase in permeability of the bronchoalveolar epithelial barrier is supposed to cause a leakage of pneumoproteins. Therefore, their concentrations are expected to increase in the bloodstream.This study aimed at examining the association between occupational exposure to endotoxin and a serum pneumoprotein, surfactant protein A, to look for nonoccupational factors capable of confounding this association, and examine the relation between surfactant protein A and spirometry. There were 369 control subjects, 325 wastewater workers, and 84 garbage collectors in the study. Exposure to endotoxin was assessed through personal sampling and the Limulus amebocytes lysate assay. Surfactant protein A was determined by an in house sandwich enzyme-linked immunosorbent assay (ELISA) in 697 subjects. Clinical and smoking history were ascertained and spirometry carried out according to American Thoracic Society criteria. Multiple linear regression was used for statistical analysis. Exposure was fairly high during some tasks in wastewater workers but did not influence surfactant protein A. Surfactant protein A was lower in asthmatics. Interindividual variability was large. No correlation with spirometry was found. Endotoxin has no effect on surfactant protein A at these endotoxin levels and serum surfactant protein A does not correlate with spirometry. The decreased surfactant protein A secretion in asthmatics requires further study.

Combinations of prognostic tools for identification of high-risk normotensive patients with acute symptomatic pulmonary embolism.

Background: In haemodynamically stable patients with acute symptomatic pulmonary embolism (PE), studies have not evaluated the usefulness of combining the measurement of cardiac troponin, transthoracic echocardiogram (TTE), and lower extremity complete compression ultrasound (CCUS) testing for predicting the risk of PE-related death. Methods: The study assessed the ability of three diagnostic tests (cardiac troponin I (cTnI), echocardiogram, and CCUS) to prognosticate the primary outcome of PE-related mortality during 30 days of follow-up after a diagnosis of PE by objective testing. Results: Of 591 normotensive patients diagnosed with PE, the primary outcome occurred in 37 patients (6.3%; 95% CI 4.3% to 8.2%). Patients with right ventricular dysfunction (RVD) by TTE and concomitant deep vein thrombosis (DVT) by CCUS had a PE-related mortality of 19.6%, compared with 17.1% of patients with elevated cTnI and concomitant DVT and 15.2% of patients with elevated cTnI and RVD. The use of any two-test strategy had a higher specificity and positive predictive value compared with the use of any test by itself. A combined three-test strategy did not further improve prognostication. For a subgroup analysis of high-risk patients, according to the pulmonary embolism severity index (classes IV and V), positive predictive values of the two-test strategies for PE-related mortality were 25.0%, 24.4% and 20.7%, respectively. Conclusions: In haemodynamically stable patients with acute symptomatic PE, a combination of echocardiography (or troponin testing) and CCUS improved prognostication compared with the use of any test by itself for the identification of those at high risk of PE-related death.

Effects of polymer-coated multi-wall carbon nanotubes on mouse RAW 264.7 macrophages

Surface characteristics (area, chemical reactivity) play an important role in cell response to nanomaterials. The aim of this study was to evaluate the oxidative and inflammatory effects of multi−wall carbon nanotubes (MWCNT) uncoated (P0) or coated with carboxylic polyacid or polystyrene polybutadiene polymetacrylate of methyl polymers (P1 and P2 respectively) on murine macrophages (RAW 264.7 cell line). Carbon black nanoparticles (CB, diameter 95 nm) and crocidolite fibers (diameter: 80 nm, length: < 10 μm) were used as controls. Surface functional groups present on MWCNTs were analyzed by Knudsen flow reactor. The amount of acidic sites was P1> P0> P2, for basic sites was P0> P1>> P2 and for oxidizable sites was P0> P2> P1. In contact with cells, P2 formed smaller aggregates than P0 and P1, which were of similar size. Optical microscopy showed the formation of vacuoles after exposure only to P0, P1 and crocidolite. Incubation of cells with P0, P1 and crocidolite fibers induced a significant and similar decrease in metabolic activity, whereas P2 and CB had no effect. Cell number and membrane permeability were unmodified by incubation with the different particles. Incubation of macrophages with P0, P1 and crocidolite induced a dose− and time−dependent increase in mRNA expression of oxidative stress marker (HO−1, GPX1) and inflammatory mediators (TNF−a, MIP−2). No such responses were observed with P2 and CB. In conclusion, MWCNT coated with a carboxylic polyacid polymer exerted similar oxidative and inflammatory effects to uncoated MWCNT. By contrast, no such effects were observed with MWCNT coated with a polystyrene−based polymer. This kind of coating could be useful to decrease MWCNT toxicity.

Diagnosis and management of chronic obstructive pulmonary disease: the swiss guidelines: official guidelines of the Swiss Respiratory Society.

The new Swiss Chronic Obstructive Pulmonary Disease (COPD) Guidelines are based on a previous version, which was published 10 years ago. The Swiss Respiratory Society felt the need to update the previous document due to new knowledge and novel therapeutic developments about this prevalent and important disease. The recommendations and statements are based on the available literature, on other national guidelines and, in particular, on the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report. Our aim is to advise pulmonary physicians, general practitioners and other health care workers on the early detection and diagnosis, prevention, best symptomatic control, and avoidance of COPD as well as its complications and deterioration.

The Macklin effect: a frequent etiology for pneumomediastinum in severe blunt chest trauma.

STUDY OBJECTIVES: To review the etiology and pathophysiology of pneumomediastinum in severe blunt trauma, with a special interest in one of its possible origins, the Macklin effect. The Macklin effect relates to a three-step pathophysiologic process: blunt traumatic alveolar ruptures, air dissection along bronchovascular sheaths, and spreading of this blunt pulmonary interstitial emphysema into the mediastinum. The clinical relevance of the Macklin effect was also evaluated. SETTING: A university hospital serving as a reference trauma center. PATIENTS: A selection of 51 patients with severe blunt trauma between 1995 and 2000. Inclusion criteria: Severe trauma or high-speed deceleration justifying chest CT; if chest CT demonstrated a pneumomediastinum, bronchoscopy and esophagoscopy were performed to rule out tracheobronchial or esophageal injury. DESIGN: Retrospective analysis of patients' clinical files, chest CT, and bronchoscopy and esophagoscopy reports. The Macklin effect was diagnosed when an air collection adjacent to a bronchus and a pulmonary vessel could be clearly identified on the chest CT. Clinical relevance of the Macklin effect was statistically evaluated regarding its repercussions on the pulmonary gas exchange function, the respective durations of intensive care and total hospital stay, and the associated injuries. RESULTS: Twenty (39%) Macklin effects and 5 tracheobronchial injuries (10%) were identified. One tracheobronchial injury occurred simultaneously with the Macklin effect. The presence of the Macklin effect affected neither the clinical profile nor the result of pulmonary gas analysis on hospital admission, but was associated with a significant (p < 0.001) lengthening of the intensive care stay. CONCLUSIONS: The Macklin effect is present in 39% of severe blunt traumatic pneumomediastinum detected by CT. Its identification does not rule out a tracheobronchial injury. The Macklin effect reflects severe trauma, since it is associated with significantly prolonged intensive care stay.

Video-assisted thoracoscopic resection of a small pulmonary nodule after computed tomography-guided localization with a hook-wire system. Experience in 45 consecutive patients.

BACKGROUND: This study is a single-institution validation of video-assisted thoracoscopic (VATS) resection of a small solitary pulmonary nodule (SPN) previously localized by a CT-guided hook-wire system in a consecutive series of 45 patients. METHODS: The records of all patients undergoing VATS resection for SPN preoperatively localized by CT-guided a hook-wire system from January 2002 to December 2004 were assessed with respect to failure to localize the lesion by the hook-wire system, conversion thoracotomy rate, duration of operation, postoperative complications, and histology of SPN. RESULTS: Forty-five patients underwent 49 VATS resections, with simultaneous bilateral SPN resection performed in 4. Preoperative CT-guided hook-wire localization failed in two patients (4%). Conversion thoracotomy was necessary in two patients (4%) because it was not possible to resect the lesion by a VATS approach. The average operative time was 50 min. Postoperative complications occurred in 3 patients (6%), one hemothorax and two pneumonia. The mean hospital stay was 5 days (range: 2-18 days). Histological assessment revealed inflammatory disease in 17 patients (38%), metastasis in 17 (38%), non-small-cell lung cancer (NSCLC) in 4 (9%), lymphoma in 3 (6%), interstitial fibrosis in 2 (4%), histiocytoma in one (2%), and hamartoma in one (2%). CONCLUSIONS: Histological analysis of resected SPN revealed unexpected malignant disease in more than 50% of the patients indicating that histological clarification of SPN seems warranted. Video-assisted thoracoscopic resection of SPN previously localized by a CT-guided hook-wire system is related to a low conversion thoracotomy rate, a short operation time, and few postoperative complications, and it is well suited for the clarification of SPN.

Involvement of gap junctional intercellular communication in the pathophysiology of inflammation

SUMMARY Inflammation has evolved as a mechanism to defend the body against invading microorganisms and to respond to injury. It requires the coordinated response of a large number of cell types from the whole organism in a time- and space-dependent fashion. This coordination involves several cell-cell communication mechanisms. Exchange of humoral mediators such as cytokines is a major one. Moreover, direct contact between cells happens and plays a primordial role, for example when macrophages present antigens to lymphocytes. Contact between endothelial cells and leucocytes occurs when the latter cross the blood vessel barrier and transmigrate to the inflammatory site. A particular way by which cells communicate with each other in the course of inflammation, which at this time starts to gain attention, is the intercellular communication mediated by gap junctions. Gap junctions are channels providing a direct pathway (i.e. without transit through the extracellular space) for the diffusion of small molecules between adjacent cells. This process is known as gap junctional intercellular communication (GJIC). The general aim of this thesis was to study a possible involvement of GJIC in the pathophysiology of inflammation. A first part of the work was dedicated to study the implication of GJIC in the modification of vascular endothelial function by inflammation. In a second part, we were interested in the possible role of GJIC in the transmigration of neutrophil polymorphonuclear leucocytes through the endothelium. The main positive finding of this work is that acute inflammation preferentially modulates the expression of connexin 40 (Cx40), a gap junction protein specifically expressed in vascular endothelium. The modulation could be towards overexpression (aortic endothelium of septic rats) or towards downregulation (acutely inflamed mouse lung). We put a lot of efforts in search of possible functions of these modulations, in two directions: a potential protective role of Cx40 increased expression against sepsis-induced endothelial dysfunction, and a facilitating role of Cx40 decreased expression in neutrophil transmigration. To pursue both directions, it seemed logical to study the impact of Cx40 deletion using knock-out mice. Concerning the potential protective role of Cx40 overexpression we encountered a roadblock as we observed, in the aorta, a Cx40 downregulation in wild type mouse whereas Cx40 was upregulated in the rat. Regarding the second direction and using an in vivo approach, we observed that pulmonary neutrophil transmigration was not affected by the genetic deletion of Cx40. In spite of their negative nature, these results are the very first ones regarding the potential implication of GJIC concerning leucocyte transmigration in vivo. Because this process involves such tight cell-cell physical contacts, the hypothesis for a role of GJIC remains attractive.

Métastases pulmonaires: quelle place pour la chirurgie [Management pulmonary metastases: when operate?].

Thirty percent of patients suffering from malignant disease will develop pulmonary metastases. Effective chemotherapy is lacking for many of these tumors. Many studies suggest survival benefit in selected patients when pulmonary metastasectomy allows complete resection. Several operative approach may be offered in order to achieve complete resection and maximal lung sparring. Pre-operative workup must assess the control of the primary tumor and the possibility of performing complete resection. Minimally invasive approaches may offer better quality life and equivalent oncologic outcomes than open approach.

Ventilation-induced pulmonary vasodilatation in lambs with congenital diaphragmatic hernia is modulated by nitric oxide.

Endogenous nitric oxide (NO) mediates pulmonary vasodilatation at birth, but inhaled NO fails to reduce pulmonary vascular resistance (PVR) in newborns with congenital diaphragmatic hernia (CDH). This study was designed to investigate the effects of ventilation, and the nature of its endogenous mediator, in fetal lambs with experimental CDH. Investigations at 138 days of gestation showed that ventilation markedly decreased PVR. Inhibition of NO synthesis reduced ventilation-induced pulmonary vasodilatation in vivo and increased in vitro isometric tension of vascular rings. Ventilation therefore reduces PVR at birth in lambs with CDH, and endogenous NO seems to contribute to this reduction.

Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia.

BACKGROUND: Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem. METHODS AND RESULTS: We assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). Pulmonary artery pressure was roughly 30% higher (mean+/-SD, 32.1+/-5.6 versus 25.3+/-4.7 mm Hg; P<0.001) and flow-mediated dilation was 30% smaller (6.3+/-1.2% versus 8.3+/-1.4%; P<0.0001) in offspring of mothers with preeclampsia than in control subjects. A strong inverse relationship existed between flow-mediated dilation and pulmonary artery pressure (r=-0.61, P<0.001). The vascular dysfunction was related to preeclampsia itself because siblings of offspring of mothers with preeclampsia who were born after a normal pregnancy had normal vascular function. Augmented oxidative stress may represent an underlying mechanism because thiobarbituric acid-reactive substances plasma concentration was increased in offspring of mothers with preeclampsia. CONCLUSIONS: Preeclampsia leaves a persistent defect in the systemic and the pulmonary circulation of the offspring. This defect predisposes to exaggerated hypoxic pulmonary hypertension already during childhood and may contribute to premature cardiovascular disease in the systemic circulation later in life.