Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study of the Penetration of a Monoclonal Antibody Combination (ASN100) Targeting Staphylococcus aureus Cytotoxins in the Lung Epithelial Lining Fluid of Healthy Volunteers.

ASN100 is a novel antibody combination of two fully human IgG1(κ) monoclonal antibodies (MAbs), ASN-1 and ASN-2, which neutralize six Staphylococcus aureus cytotoxins, alpha-hemolysin (Hla) and five bicomponent leukocidins. We assessed the safety, tolerability, and serum and lung pharmacokinetics of ASN100 in a randomized, double-blind, placebo-controlled single-dose-escalation first-in-human study. Fifty-two healthy volunteers were enrolled and randomized to receive either ASN-1, ASN-2, a combination of both MAbs (ASN100), or a corresponding placebo. Thirty-two subjects in the double-blind dose escalation portion of the study received ASN-1 or ASN-2 at a 200-, 600-, 1,800-, or 4,000-mg dose, or placebo. Eight subjects received both MAbs simultaneously in a 1:1 ratio (ASN100) at 3,600 or 8,000 mg, or they received placebos. Twelve additional subjects received open-label ASN100 at 3,600 or 8,000 mg to assess the pharmacokinetics of ASN-1 and ASN-2 in epithelial lining fluid (ELF) by bronchoalveolar lavage fluid sampling. Subjects were monitored for 98 days (double-blind cohorts) or 30 days (open-label cohorts) for safety assessment. No dose-limiting toxicities were observed, and all adverse events were mild and transient, with only two adverse events considered possibly related to the investigational product. ASN100 exhibited linear serum pharmacokinetics with a half-life of approximately 3 weeks and showed detectable penetration into the ELF. No treatment-emergent anti-drug antibody responses were detected. The toxin neutralizing potency of ASN100 in human serum was confirmed up to 58 days postdosing. The favorable safety profile, ELF penetration, and maintained functional activity in serum supported the further clinical development of ASN100.

Dissociation between systemic and pulmonary anti-inflammatory effects of dexamethasone in humans.

AIMS: The local pulmonary inflammatory response has a different temporal and qualitative profile compared with the systemic inflammatory response. Although glucocorticoids substantially downregulate the systemic release of acute-phase mediators, it is not clear whether they have comparable inhibitory effects in the human lung compartment. Therefore, we compared the anti-inflammatory effects of a pure glucocorticoid agonist, dexamethasone, on bronchoalveolar lavage and blood cytokine concentrations in response to bronchially instilled endotoxin. METHODS: In this randomized, double-blind and placebo-controlled trial, 24 volunteers received dexamethasone or placebo and had endotoxin instilled into a lung segment and saline instilled into a contralateral segment, followed by bronchoalveolar lavage. RESULTS: Bronchially instilled endotoxin induced a local and systemic inflammatory response. Dexamethasone strongly blunted the systemic interleukin (IL) 6 and C-reactive protein release. In sharp contrast, dexamethasone left the local release of acute-phase mediators in the lungs virtually unchanged: bronchoalveolar lavage levels of IL-6 were only 18% lower and levels of IL-8 were even higher with dexamethasone compared with placebo, although the differences between treatments were not statistically significant (P = 0.07 and P = 0.08, respectively). However, dexamethasone had inhibitory effects on pulmonary protein extravasation and neutrophil migration. CONCLUSIONS: The present study demonstrated a remarkable dissociation between the systemic anti-inflammatory effects of glucocorticoids and its protective effects on capillary leak on the one hand and surprisingly low anti-inflammatory effects in the lungs on the other.

Portable recording for detecting sleep disorder breathing in patients under the care of a heart failure clinic.

BACKGROUND: Sleep disordered breathing (SDB) has important clinical implications in patients with congestive heart failure (CHF). We performed portable recording in unselected CHF patients on contemporary therapy. Data on the interactions of SDB in patients supervised at heart failure clinics are rare and we illustrate diversities of obstructive sleep apnoea (OSA) and central sleep apnoea (CSA). METHODS: We studied 176 consecutive subjects on contemporary medical therapy with a median left ventricular ejection fraction of 25.0 % (range 7-35%) and median NT-pro BNP levels of 3,413.0 pg/ml (range 305.1-35,000.0 pg/ml). Participants underwent prospective overnight portable recording. RESULTS: 50% presented with an at least moderate form of nocturnal breathing disorder [apnoea-hypopnoea index (AHI) ≥15/h]. Only 15 patients (17.1%) with AHI ≥15/h reported excessive daytime sleepiness. Irrespective of left ventricular ejection fraction, patients with CSA had higher levels of NT-pro BNP compared to patients with OSA (differences in medians = 2,639.0 pg/ml, p = 0.016), and compared to patients with an AHI <15/h (differences in medians = 2,710.0 pg/ml, p < 0.001). OSA affected 26 patients (14.8%). CONCLUSIONS: Patients with severe stable CHF on contemporary therapy have a prevalence of 50.0% of moderate to severe SDB. The natural cascade of the failing heart is initially characterised by absent SDB or OSA, whereas end-stage CHF is associated with CSA.

Maxillomandibular advancement for treatment of obstructive sleep apnea syndrome: a systematic review.

PURPOSE: To perform a systematic review of the published data concerning maxillomandibular advancement for the treatment of obstructive sleep apnea syndrome. MATERIALS AND METHODS: A systematic literature search was performed in the PubMed database. Original articles in the English language were reviewed to obtain information about patient data, success rates, and outcome measures. RESULTS: The systematic literature search yielded 1,113 citations, of which 101 articles met our inclusion criteria. After a review of the full text, 39 studies were included in the analysis. Most articles were classified as evidence level 4, and 5 met the inclusion criteria for level 2b. The only prospective randomized controlled study had been published in January 2010 and was assigned level 1b. CONCLUSIONS: A recommendation grade of A to B was achieved with regard to the levels of evidence-based medicine. Our results have shown that maxillomandibular advancement is the most successful surgical therapy, and the postoperative polysomnography results are comparable to those under ventilation therapy.

Comparison of plethysmographic and helium dilution lung volumes: which is best for COPD?

BACKGROUND: Theoretical considerations and limited scientific evidence suggest that whole-body plethysmography overestimates lung volume in patients with severe airflow obstruction. We sought to compare plethysmography (Pleth)-, helium dilution (He)- and CT scan-derived lung volume measurements in a sample containing many patients with severe airflow obstruction. METHODS: We measured total lung capacity (TLC) in 132 patients at three hospitals, with monitored application of recommended techniques for Pleth and He measurements of lung volume and by thoracic CT scans obtained during breath hold at full inspiration. RESULTS: Average TLC among 132 subjects was 6.18 L (+/- 1.69 L) by Pleth-derived TLC, 5.55 L (+/- 1.39 L) by He-derived TLC, and 5.31 L (+/- 1.47) by CT scan-derived TLC. Pleth-derived TLC was significantly greater than either He-derived TLC or CT scan-derived TLC (P < or = .001), whereas there was no significant difference between He-derived and CT scan-derived values. When examined separately, there were significant within-subject differences in TLC by measurement technique among subjects with airflow obstruction, but not among those without airflow obstruction. Plethysmographic overestimation of TLC was greatest among subjects with FEV(1) < 30% of predicted. CONCLUSIONS: In the setting of airflow obstruction, Pleth systematically overestimates lung volume relative to He or thoracic imaging despite adherence to current recommendations for proper measurement technique.

T1 mapping of the entire lung parenchyma: Influence of respiratory phase and correlation to lung function test results in patients with diffuse lung disease.

The T(1) values of lung parenchyma of 25 patients with fibrosis and emphysema were measured in the entire lung, and the effect of inspiration and expiration was investigated. T(1) map acquisition was based on a snapshot-fast low-angle shot (FLASH) sequence. Lung function and blood gas tests were measured. The study documents reverse respiratory phase dependence of T(1) measurements of the entire lung parenchyma in patients with emphysema and fibrosis. Furthermore, expiratory measurements showed higher and reverse differences between patient groups compared to inspiratory measurements. For the emphysema group, the average T(1) value in inspiration was 1033 +/- 74 ms. The average of the mean T(1) values in expiration was 982 +/- 56 ms. For the patients with fibrosis, the average T(1) value in inspiration was 996 +/- 103 ms. Compared to that, the average T(1) value in expiration was 1282 +/- 170 ms. Linear regression of T(1) vs. lung function parameters showed the highest regression coefficients for total lung capacity (TLC) and residual volume (RV) in expiration, the values were inversely proportionally dependent on the pooled expiratory T(1) values. These findings underline the strong but nonuniform influence of the inspirational status during T(1) measurements of the lung. T(1) maps in both emphysema and fibrosis should preferably be acquired at expiration if reliable data are to be obtained.

Abnormal pulmonary arterial pressure limits exercise capacity in patients with COPD.

OBJECTIVE: Pulmonary hypertension (PH) is common in patients with chronic obstructive pulmonary disease (COPD). Mean pulmonary artery pressure (mPAP) is often only slightly elevated at rest but is increased by exercise. The purpose of this study was to determine whether abnormal pulmonary artery pressure impairs exercise capacity in patients with COPD. PATIENTS AND METHODS: 42 patients with moderate-to-very-severe COPD (28 men, 14 women) underwent symptom-limited incremental cardiopulmonary exercise testing and also right-heart catheterization at rest. Abnormal pulmonary artery pressure was defined as mPAP>20 mmHg at rest. RESULTS: Resting mPAP was elevated in 32 patients (PH, mPAP=26.8+/-5.9 mmHg) and normal in 10 non-hypertensive (NPH) patients (NPH, mPAP=16.8+/-2 mmHg). There were no significant differences in lung function between the PH and NPH groups. Maximum oxygen uptake during exercise (VO2max) was significantly lower in PH (785+/-244 ml/min) than in NPH (1052+/-207 ml/min, P=0.004). Dead-space ventilation (Vd/Vt) was greater in PH (P=0.05) with higher VE/VCO2 (ratio of minute ventilation to carbon dioxide output=47.3+/-10 vs 38.6+/-3.5, P=0.025) and significantly higher arterial-end-tidal pCO2 difference [p(a-ET)CO2]. Pulmonary vascular resistance measured at rest correlated significantly with VO2max, VE/VCO2 and p(a-ET)CO2. CONCLUSIONS: In patients with COPD, abnormal pulmonary artery pressure impairs gas exchange, decreases maximum oxygen uptake during exercise and impairs exercise capacity.

Quantitative and o(2) enhanced MRI of the pathologic lung: findings in emphysema, fibrosis, and cystic fibrosis.

PURPOSE: beyond the pure morphological visual representation, MR imaging offers the possibility to quantify parameters in the healthy, as well as, in pathologic lung parenchyma. Gas exchange is the primary function of the lung and the transport of oxygen plays a key role in pulmonary physiology and pathophysiology. The purpose of this review is to present a short overview of the relaxation mechanisms of the lung and the current technical concepts of T1 mapping and methods of oxygen enhanced MR imaging. MATERIAL AND METHODS: molecular oxygen has weak paramagnetic properties so that an increase in oxygen concentration results in shortening of the T1 relaxation time and thus to an increase of the signal intensity in T1 weighted images. A possible way to gain deeper insights into the relaxation mechanisms of the lung is the calculation of parameter Maps. T1 Maps based on a snapshot FLASH sequence obtained during the inhalation of various oxygen concentrations provide data for the creation of the so-called oxygen transfer function (OTF), assigning a measurement for local oxygen transfer. T1 weighted single shot TSE sequences also permit expression of the signal changing effects associated with the inhalation of pure oxygen. RESULTS: the average of the mean T1 values over the entire lung in inspiration amounts to 1199 +/- 117 milliseconds, the average of the mean T1 values in expiration was 1333 +/- 167 milliseconds. T1 Maps of patients with emphysema and lung fibrosis show fundamentally different behavior patterns. Oxygen enhanced MRT is able to demonstrate reduced diffusion capacity and diminished oxygen transport in patients with emphysema and cystic fibrosis. DISCUSSION: results published in literature indicate that T1 mapping and oxygen enhanced MR imaging are promising new methods in functional imaging of the lung and when evaluated in conjunction with the pure morphological images can provide additional valuable information.

What every radiologist should know about idiopathic interstitial pneumonias.

The American Thoracic Society-European Respiratory Society classification of idiopathic interstitial pneumonias (IIPs), published in 2002, defines the morphologic patterns on which clinical-radiologic-pathologic diagnosis of IIPs is based. IIPs include seven entities: idiopathic pulmonary fibrosis, which is characterized by the morphologic pattern of usual interstitial pneumonia (UIP); nonspecific interstitial pneumonia (NSIP); cryptogenic organizing pneumonia (COP); respiratory bronchiolitis-associated interstitial lung disease (RB-ILD); desquamative interstitial pneumonia (DIP); lymphoid interstitial pneumonia (LIP); and acute interstitial pneumonia (AIP). The characteristic computed tomographic findings in UIP are predominantly basal and peripheral reticular opacities with honeycombing and traction bronchiectasis. In NSIP, basal ground-glass opacities tend to predominate over reticular opacities, with traction bronchiectasis only in advanced disease. COP is characterized by patchy peripheral or peribronchovascular consolidation. RB-ILD and DIP are smoking-related diseases characterized by centrilobular nodules and ground-glass opacities. LIP is characterized by ground-glass opacities, often in combination with cystic lesions. AIP manifests as diffuse lung consolidation with ground-glass opacities, which usually progress to fibrosis in patients who survive the acute phase of the disease. Correct diagnosis of IIPs can be achieved only by means of interdisciplinary consensus and stringent correlation of clinical, imaging, and pathologic findings. (c) RSNA, 2007.

Bovine distal pulmonary arterial media is composed of a uniform population of well-differentiated smooth muscle cells with low proliferative capabilities.

The media of the normal bovine main pulmonary artery (MPA) is composed of phenotypically heterogeneous smooth muscle cells (SMC) with markedly different proliferative capabilities in response to serum, mitogens, and hypoxia. Little, however, is known of the SMC phenotype in distal pulmonary arteries (PA), particularly in arterioles, which regulate the pulmonary circulation. With a panel of muscle-specific antibodies against alpha-smooth muscle (SM)-actin, SM-myosin heavy chains (SM-MHC), SM-MHC-B isoform, desmin, and meta-vinculin, we demonstrate a progressive increase in phenotypic uniformity and level of differentiation of SMC along the proximal-to-distal axis of normal adult bovine pulmonary circulation so that the media of distal PA (1,500- to 100-microm diameter) is composed of a phenotypically uniform population of "well-differentiated" SMC. Similarly, when isolated and assessed in vitro, distal PA-SMC is composed of a single, uniform population of differentiated SMC that exhibited minimal growth responses to a variety of mitogens while their cell size increased substantially in response to serum. Their growth was inhibited by hypoxic exposure under all conditions tested. Distal PA-SMC also differed from MPA-SMC by exhibiting a distinct pattern of DNA synthesis in response to serum and mitogens. Thus, in contrast to the MPA, distal PA media is composed of an apparently uniform population of well-differentiated SMC that are proliferation resistant and have a substantial capacity to hypertrophy in response to growth-promoting stimuli. We thus speculate that distinct SMC phenotypes present in distal vs. proximal PA may confer different response mechanisms during remodeling in conditions such as hypertension.

Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension.

Primary pulmonary hypertension is a fatal disease causing progressive right heart failure within 3 years after diagnosis. We describe a new concept for treatment of the disease using vasoactive intestinal peptide, a neuropeptide primarily functioning as a neurotransmitter that acts as a potent systemic and pulmonary vasodilator. Our rationale is based on the finding of a deficiency of the peptide in serum and lung tissue of patients with primary pulmonary hypertension, as evidenced by radioimmunoassay and immunohistochemistry. The relevance of this finding is underlined by an upregulation of corresponding receptor sites as shown by Northern blot analysis, Western blot analysis, and immunological techniques. Consequently, the substitution with the hormone results in substantial improvement of hemodynamic and prognostic parameters of the disease without side effects. It decreased the mean pulmonary artery pressure in our eight study patients, increased cardiac output, and mixed venous oxygen saturation. Our data provide enough proof for further investigation of vasoactive intestinal peptide and its role in primary pulmonary hypertension.

Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension.

OBJECTIVES: To evaluate the effect of long-term oral therapy with sildenafil in patients with pulmonary arterial hypertension receiving long-term IV epoprostenol. DESIGN: Open, uncontrolled trial. SETTING: University hospital. PATIENTS: Two patients with primary pulmonary hypertension and one patient with pulmonary arterial hypertension after surgical closure of an atrial septal defect. All patients were receiving continuous epoprostenol for 1.7 to 7.1 years; two patients also received inhaled iloprost for 1.8 years and 3.8 years, respectively. INTERVENTIONS: Addition of oral sildenafil, up to 200 mg/d, divided in four to six single doses, and hemodynamic measurements and the 6-min walking distance (6MWD) before and after 5 months of treatment with sildenafil. RESULTS: One patient was treated with sildenafil, 200 mg/d; two patients received 75 mg/d due to nausea and headache. Long-term treatment with sildenafil in the three patients reduced mean pulmonary artery pressure by 14%, 41%, and 22%, respectively; in two patients, pulmonary vascular resistance was decreased by 52% and 55%. The 6MWD increased by 34%, 6%, and 29%, respectively. No significant systemic hypotension or decrease of arterial oxygen saturation was seen. CONCLUSION: Sildenafil therapy may be of benefit in patients with pulmonary arterial hypertension receiving long-term infusion of epoprostenol.

[Manual compression versus mechanical compression device (FemoStop) after diagnostic coronary angiography with/without intervention]. / Manuelle Kompression versus mechanischer Kompressionshilfe (FemoStop) nach diagnostischer Koronarangiographie mit/ohne Intervention.

BACKGROUND: The aim of our study was to evaluate the practicability and the complication rates of two different forms of the post-angiographic closure of the femoral artery. METHODS: We randomized 239 patients over a time period of 4 months to either a mechanical compression system (FemoStop, 111 patients) or to conventional manual compression (128 patients). A Doppler-sonographic examination was performed if the patient reported pain of the puncture site, or if auscultation or palpation suspected a complication on the day after compression. RESULTS: After manual compression, Doppler-sonography had to be performed in 21 patients (16.4%). In the FemoStop-group only 14 patients (12.6%, p = ns) had to be referred for ultrasound examination. A complication was detected in 13 patients (10.1%) after manual compression and in 5 patients (4.5%, p = ns) after closure with the mechanical device. The incidence of a pseudo-aneurysma or of an arterio-venous fistula did not show any difference between the two groups. In 6 patients of the manual compression group a hematoma was found (p < 0.05), whereas no hematoma occurred in the FemoStop-group. None of the hematomas required the infusion of blood concentrates or surgical correction. In one patient with extreme overweight the mechanical compression device could not be applied. The mechanical compression device was used successfully in patients who had received heparin, acetyl-salicyl-acid or a glycoprotein IIb/IIIa receptor antagonist and in whom a significantly longer compression time and higher complication rate could have been expected. In addition, post-angiographic closure with the was less time consuming for the staff involved. In contrast, the higher cost of the mechanical compression device presents a disadvantage. CONCLUSION: A mechanical compression device (FemoStop) can be used successfully in routine post-angiographic management and shows a trend to lower complication rates than manual compression and increased acceptance by patients and physicians. However, the overall costs are higher for the mechanical compression device.