Author: Gottfried Heinz

Authors: Stephanie D. Davis; Felix Ratjen

Authors: Y. C. Gary Lee; Sylwia Wilkosz

Authors: Kathryn DeRiemer; Bouke C. de Jong

Authors: Nicole Livermore; Jane E. Butler; Louise Sharpe; Rachel A. McBain; Simon C. Gandevia; David K. McKenzie

Rationale: Panic attacks are common in chronic obstructive pulmonary disease (COPD), and the prevalence of panic disorder is at least 10 times higher than in the general population. In the current study, we examined resistive load perception in patients with COPD with and without panic attacks.

Objectives: We tested competing hypotheses, based on conflicting results of earlier studies, that those patients with COPD with panic attacks or panic disorder would show either heightened or blunted perception of dyspnea as the magnitude of inspiratory resistive loads increased.

Methods: We compared 20 patients with COPD with panic attacks or panic disorder, 20 patients without panic, and 20 healthy, age-matched subjects using an inspiratory resistive load–testing protocol.

Measurements and Main Results: We administered a diagnostic interview for panic attacks and panic disorder. We measured perceived dyspnea in response to increasing inspiratory resistive loads (modified Borg scale) and several respiratory variables. Dyspnea ratings increased linearly for all groups as the size of resistive loads increased. No significant differences were found between groups on the respiratory variables. Patients with COPD with panic attacks or panic disorder rated their level of dyspnea significantly higher than did other subjects.

Conclusions: Patients with COPD with panic attacks showed heightened sensitivity to inspiratory loads. The result reinforces the influence of psychological factors on symptom perception in this disease.

Authors: Mateusz Siedlinski; Dirkje S. Postma; Cleo C. van Diemen; Anneke Blokstra; Henriette A. Smit; H. Marike Boezen

Rationale: Smoking-induced oxidative stress contributes to chronic obstructive pulmonary disease, a lung disease characterized by low lung function and increasing mortality worldwide. The counterbalance for this effect may be provided by, for example, increased intake of the antioxidant vitamin C or endogenously acting antioxidant enzymes like glutamate-cysteine ligase (GCL), which is responsible for glutathione biosynthesis.

Objectives: To investigate associations of functional polymorphisms in GCL subunits (GCLM and GCLC) with lung function level and its longitudinal course, with vitamin C and smoking habits as potential interactive factors.

Methods: Two independent general population samples (Doetinchem, n = 1,152, and Vlagtwedde-Vlaardingen, n = 1,390) with multiple lung function (FEV1, VC) measurements were genotyped for three polymorphisms (C[−129]T, C[−588]T, and a trinucleotide GAG repeat [TNR]) in the subunits of GCL. Genetic effects on lung function level and decline were estimated using linear regression and linear mixed effect models adjusted for confounders. Findings were further investigated for interactions with vitamin C intake in the Doetinchem cohort.

Measurements and Main Results: GCLC polymorphisms were significantly associated with lower lung function levels in interaction with pack-years smoked in both cohorts. TNR variants in GCLC were associated with accelerated FEV1 decline in both cohorts in interaction with pack-years. All significant effects were specifically present in subjects within the lowest tertile of vitamin C intake.

Conclusions: GCLC is a novel susceptibility gene for low level of lung function in two independent populations. We provide suggestive evidence that this occurs due to an interaction between GCLC polymorphisms, smoking, and low vitamin C intake, which all contribute to the oxidative burden.

Authors: Djillali Annane; Véronique Sébille; Denis Duboc; Jean-Yves Le Heuzey; Nicolas Sadoul; Erik Bouvier; Eric Bellissant

Rationale: Sustained arrhythmias are common in postoperative and cardiac intensive care units (ICUs), but their incidence and prognosis in general ICUs have never been reported.

Objectives: To estimate the incidence and prognosis of sustained arrhythmias in a general ICU population.

Methods: Prospective, multicenter, 1-month inception cohort study.

Measurements and Main Results: A total of 1,341 patients were included: 12% (163/1,341) had sustained arrhythmias, including 8% (113/1,341) and 2% (30/1,341) with supraventricular and ventricular arrhythmias, respectively, and 2% (30/1,341) with conduction abnormalities. In-hospital death rates were 17% (205/1,178) in patients without arrhythmia and 29% (33/113) in patients with supraventricular arrhythmias (odds ratio [OR], 1.95; 95% confidence interval [CI], 1.27–3.01), 73% (22/30) in patients with ventricular arrhythmias (OR, 13.20; 95% CI, 5.79–30.10), and 60% (18/30) in patients with conduction abnormalities (OR, 7.46; 95% CI, 3.52–15.82). Neurological sequel rates were 6% (55/973) in arrhythmia-free survivors and 15% (12/80) in survivors with supraventricular arrhythmias (OR, 2.92; 95% CI, 1.45–5.89), 38% (3/8) in survivors with ventricular arrhythmias (OR, 7.53; 95% CI, 1.60–35.50), and 17% (2/12) in survivors with conduction abnormalities (OR, 8.77; 95% CI, 1.65–46.57). After adjusting for prognosis factors and propensity scores, ventricular arrhythmias still increased mortality (OR, 3.53; 95% CI, 1.19–10.42) but supraventricular arrhythmias and conduction abnormalities did not.

Conclusions: Sustained arrhythmias are observed in 12% of patients admitted to general ICUs. Ventricular arrhythmias increase the risk of death.

Authors: Scot T. Bateman; Jacques Lacroix; Katia Boven; Peter Forbes; Roger Barton; Neal J. Thomas; Brian Jacobs; Barry Markovitz; Brahm Goldstein; James H. Hanson; H. Agnes Li; Adrienne G. Randolph

Rationale: Minimizing exposure of children to blood products is desirable.

Objectives: We aimed to understand anemia development, blood loss, and red blood cell (RBC) transfusions in the pediatric intensive care unit (PICU).

Methods: Prospective, multicenter, 6-month observational study in 30 PICUs. Data were collected on consecutive children (<18 yr old) in the PICU for 48 hours or more.

Measurements and Main Results: Anemia development, blood loss, and RBC transfusions were measured. A total of 977 children were enrolled. Most (74%) children were anemic in the PICU (33% on admission, 41% developed anemia). Blood draws accounted for 73% of daily blood loss; median loss was 5.0 ml/day. Forty-nine percent of children received transfusions; 74% of first transfusions were on Days 1–2. After adjusting for age and illness severity, compared with nontransfused children, children who underwent transfusion had significantly longer days of mechanical ventilation (2.1 d, P < 0.001) and PICU stay (1.8 d, P = 0.03), and had increased mortality (odds ratio [OR], 11.6; 95% confidence interval [CI], 1.43–90.9; P = 0.02), nosocomial infections (OR, 1.9; 95% CI, 1.2–3.0; P = 0.004), and cardiorespiratory dysfunction (OR, 2.1; 95% CI, 1.5–3.0; P < 0.001). High blood loss per kilogram body weight from blood draws (OR, 1.11; 95% CI, 1.03–1.2; P = 0.01) was associated with RBC transfusion more than 48 hours after admission. The most common indication for transfusion was low hemoglobin (42%). Pretransfusion hemoglobin values varied greatly (mean, 9.7 ± 2.7 g/dl).

Conclusions: Critically ill children are at significant risk for developing anemia and receiving blood transfusions. Transfusion in the PICU was associated with worse outcomes. It is imperative to minimize blood loss from blood draws and to set clear transfusion thresholds.

Authors: Jacobien J. Hoogerwerf; Alex F. de Vos; Paul Bresser; Jaring S. van der Zee; Jennie M. Pater; Anita de Boer; Michael Tanck; Daniel L. Lundell; Chung Her-Jenh; Christian Draing; Sonja von Aulock; Tom van der Poll

Rationale: Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is considered to be important for an appropriate immune response against pathogens that enter the lower airways.

Objectives: We studied the effects of two different TLR agonists relevant for respiratory infections in the human lung: lipoteichoic acid (LTA; TLR2 agonist, component of gram-positive bacteria) and lipopolysaccharide (LPS; TLR4-agonist, component of gram-negative bacteria).

Methods: Fifteen healthy subjects were given LPS or LTA: by bronchoscope, sterile saline was instilled into a lung segment followed by instillation of LTA or LPS into the contralateral lung. After 6 hours, a bronchoalveolar lavage was performed and inflammatory parameters were determined. Isolated RNA from purified alveolar macrophages was analyzed by multiplex ligation–dependent probe amplification. In addition, spontaneous cytokine release by alveolar macrophages was measured.

Measurements and Main Results: Marked differences were detected between LTA- and LPS-induced lung inflammation. Whereas both elicited neutrophil recruitment, only LPS instillation was associated with activation of neutrophils (CD11b surface expression, degranulation product levels) and consistent rises of chemo-/cytokine levels. Moreover, LPS but not LTA activated alveolar macrophages, as reflected by enhanced expression of 10 different mRNAs encoding proinflammatory mediators and increased spontaneous cytokine release upon incubation ex vivo. Remarkably, only LTA induced C5a release.

Conclusions: This is the first study to report the in vivo effects of LTA in men and to compare inflammation induced by LTA and LPS in the human lung. Our data suggest that stimulation of TLR2 or TLR4 results in differential pulmonary inflammation, which may be of relevance for understanding pathogenic mechanisms at play during gram-positive and gram-negative respiratory tract infection.

Authors: Wanda J. Kozlowska; Andrew Bush; Angela Wade; Paul Aurora; Siobhán B. Carr; Rosie A. Castle; Ah-Fong Hoo; Sooky Lum; John Price; Sarath Ranganathan; Clare Saunders; Sanja Stanojevic; John Stroobant; Colin Wallis; Janet Stocks

Rationale: After recent standardization of forced expiratory maneuvers for both infants and preschool children, longitudinal measurements are now possible from birth.

Objectives: The aim of this study was to investigate the evolution of lung function during the first 6 years of life after a clinical diagnosis of cystic fibrosis (CF) in infancy in children with CF and in healthy control subjects.

Methods: The raised volume technique was used during infancy and incentive spirometry during the preschool years.

Measurements and Main Results: Forty-eight children with CF and 33 healthy control subjects had up to seven (median, 3) measurements. Over these early years, the diagnosis of CF itself accounted for a significant mean reduction of 7.5% (95% confidence interval, 0.9 – 13.6%) in FEV0.75 and 15.1% (95% confidence interval, 3.6 – 25.3%) in FEF25–75. Wheeze on auscultation, recent cough, and Pseudomonas aeruginosa (PsA) infection (even if apparently effectively treated) were all independently associated with further reductions in lung function. Premorbid lung function did not predict infection with PsA.

Conclusions: This is the first study to describe physiologic measurements from infancy through the preschool years in subjects with CF and healthy control subjects, the understanding of which is critical for future intervention trials. Airflow obstruction in uncomplicated CF persists through the preschool years despite treatment, with PsA acquisition being associated with further deterioration in lung function, even when apparently eradicated. This suggests that new therapies are needed to treat the airflow obstruction of uncomplicated CF, and rigorous strategies to prevent PsA acquisition.

Authors: Georgios T. Stathopoulos; Charalampos Moschos; Heleni Loutrari; Androniki Kollintza; Ioannis Psallidas; Sophia Karabela; Sophia Magkouta; Zongmin Zhou; Spyros A. Papiris; Charis Roussos; Ioannis Kalomenidis

Rationale: Aminobiphosphonates, such as zoledronic acid (ZA), exert potent indirect antitumor effects and are currently being tested against human solid tumors. The antitumor actions of aminobiphosphonates, including angiostasis, are relevant to the pathogenesis of malignant pleural effusion (MPE), but no study has addressed the efficacy of these compounds against malignant pleural disease.

Objectives: Here we hypothesized that treatment of immunocompetent mice with ZA would halt tumor progression in a mouse model of adenocarcinoma-induced MPE.

Methods: To induce MPE in mice, Lewis lung carcinoma cells were delivered directly into the pleural space. Subsequently, animals were treated with ZA in both a prevention and a regression protocol.

Measurements and Main Results: ZA treatment resulted in significant reductions in pleural fluid accumulation and tumor dissemination, while it significantly prolonged survival. These effects of ZA were linked to enhanced apoptosis of pleural tumor cells, decreased formation of new vessels in pleural tumors, and reduced pleural vascular permeability. In addition, ZA was able to inhibit the recruitment of mononuclear cells to pleural tumors, with concomitant reductions in matrix metalloproteinase-9 release into the pleural space. Finally, ZA limited the expression of proinflammatory and angiogenic mediators, as well as the activity of small GTP proteins Ras and RhoA, in tumor cells in vivo and in vitro.

Conclusions: ZA is effective against experimental MPE, suggesting that this intervention should be considered for testing in clinical trials.

Authors: Cheng-Xiong Xu; Dhananjay Jere; Hua Jin; Seung-Hee Chang; Youn-Sun Chung; Ji-Young Shin; Ji-Eun Kim; Sung-Jin Park; Yong-Hoon Lee; Chan-Hee Chae; Kee-Ho Lee; George R. Beck; Chong-Su Cho; Myung-Haing Cho

Rationale: The low efficiency of conventional therapies in achieving long-term survival of patients with lung cancer calls for the development of novel therapeutic options. Recent advances in aerosol-mediated gene delivery have provided the possibility of an alternative for the safe and effective treatment of lung cancer.

Objectives: To demonstrate the feasibility and emphasize the importance of noninvasive aerosol delivery of Akt1 small interfering RNA (siRNA) as an effective and selective option for lung cancer treatment.

Methods: Nanosized poly(ester amine) polymer was synthesized and used as a gene carrier. An aerosol of poly(ester amine)/Akt1 siRNA complex was delivered into K-ras^LA1 and urethane-induced lung cancer models through a nose-only inhalation system. The effects of Akt1 siRNA on lung cancer progression and Akt-related signals were evaluated.

Measurements and Main Results: The aerosol-delivered Akt1 siRNA suppressed lung tumor progression significantly through inhibiting Akt-related signals and cell cycle.

Conclusions: The use of poly(ester amine) serves as an effective carrier, and aerosol delivery of Akt1 siRNA may be a promising approach for lung cancer treatment and prevention.

Authors: Indra Narang; Mark Rosenthal; David Cremonesini; Mike Silverman; Andrew Bush

Rationale: There are limited longitudinal data about respiratory morbidity and lung function after preterm birth into adulthood.

Objectives: To determine the evolution of respiratory symptoms, spirometry, and airway hyperresponsiveness of ex-preterm subjects from childhood into adulthood.

Methods: Ex-preterm subjects (median birth weight, 1,440 g; median gestation, 31.5 wk), recruited at birth (not treated with surfactant), had excess respiratory symptoms, airway obstruction, and increased airway hyperresponsiveness in mid-childhood. At a median age of 21.7 years, 60 of these subjects (the index study group) and 50 healthy term control subjects were recruited to determine respiratory morbidity and spirometry.

Measurements and Main Results: Respiratory symptom questionnaire, spirometry, and methacholine challenge test. The index study group had significantly more respiratory symptoms (16 of 60) than did control subjects (4 of 50) (odds ratio, 4.2; 95% confidence interval, 1.3 to 13.5; P = 0.01), but no significant difference in measured spirometry. Specifically, in the index study group and control subjects, the mean z scores (95% confidence interval of the group difference) for the FEV1 were –0.60 and –0.58 (–0.44 to 0.49), respectively (P = 0.92); for the forced mid-expiratory flow they were –1.02 and –0.86 (–0.33 to 0.64), respectively (P = 0.52); and for the FVC they were –0.29 and –0.33 (–0.46 to 0.38), respectively (P = 0.85). Ex-preterm adults did not show evidence of increased airway hyperresponsiveness compared with control subjects, 23 and 19%, respectively (P = 0.89).

Conclusions: There are still excess respiratory symptoms 21 years after preterm birth. Reassuringly, this longitudinal study did not show evidence of persistent airway obstruction or airway hyperresponsiveness in ex-preterm adults.

Authors: Frédéric Perros; David Montani; Peter Dorfmüller; Ingrid Durand-Gasselin; Colas Tcherakian; Jérôme Le Pavec; Michel Mazmanian; Elie Fadel; Sacha Mussot; Olaf Mercier; Philippe Hervé; Dominique Emilie; Saadia Eddahibi; Gérald Simonneau; Rogério Souza; Marc Humbert

Rationale: Platelet-derived growth factor (PDGF) promotes the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), and may play a role in the progression of pulmonary arterial hypertension (PAH), a condition characterized by proliferation of PASMCs resulting in the obstruction of small pulmonary arteries.

Objectives: To analyze the expression and pathogenic role of PDGF in idiopathic PAH.

Methods: PDGF and PDGF receptor mRNA expression was studied by real-time reverse transcription–polymerase chain reaction performed on laser capture microdissected pulmonary arteries from patients undergoing lung transplantation for idiopathic PAH. Immunohistochemistry was used to localize PDGF, PDGF receptors, and phosphorylated PDGFR-β. The effects of imatinib on PDGF-B–induced proliferation and chemotaxis were tested on human PASMCs.

Measurements and Main Results: PDGF-A, PDGF-B, PDGFR-α, and PDGFR-β mRNA expression was increased in small pulmonary arteries from patients displaying idiopathic PAH, as compared with control subjects. Western blot analysis revealed a significant increase in protein expression of PDGFR-β in PAH lungs, as compared with control lungs. In small remodeled pulmonary arteries, PDGF-A and PDGF-B mainly localized to PASMCs and endothelial cells (perivascular inflammatory infiltrates, when present, showed intensive staining), PDGFR-α and PDGFR-β mainly stained PASMCs and to a lesser extent endothelial cells. Proliferating pulmonary vascular lesions stained phosphorylated PDGFR-β. PDGF-BB–induced proliferation and migration of PASMCs were inhibited by imatinib. This effect was not due to PASMC apoptosis.

Conclusions: PDGF may play an important role in human PAH. Novel therapeutic strategies targeting the PDGF pathway should be tested in clinical trials.

Authors: Leanne C. McKay; Jack L. Feldman

Rationale: In adult rats, bilateral ablation of pre-Bötzinger complex (preBötC) neurokinin 1–expressing (NK1R) neurons leads to a progressive and irreversible disruption in breathing pattern, initially during sleep, eventually resulting in an ataxic breathing pattern during wakefulness.

Objectives: Here we determine whether ablation of fewer preBötC NK1R neurons leads to a persistent pattern of disordered breathing during sleep but not during wakefulness.

Methods: Adult male Sprague-Dawley rats (n = 12) were instrumented to record diaphragmatic, abdominal, and neck EMG, and EEG. Fourteen days later, a second surgery was performed to stereotaxically microinject into the preBötC on one side the toxin saporin conjugated to substance P (SP-SAP), which selectively ablates NK1R neurons.

Measurements and Main Results: Postinjection, rats were monitored within a plethysmograph until they were killed (Days 21–51). At Days 6–9 post–unilateral SP-SAP injection, respiratory pattern during sleep, particularly REM sleep, became increasingly disordered, characterized by an increase in frequency of central sleep apnea and hypopneas (36.8 ± 7.4 episodes/h of REM vs. 6 ± 2.0 episodes/h in preinjection controls; P < 0.05), whereas breathing during resting wakefulness remained stable. Unlike bilateral SP-SAP–injected rats, an ataxic breathing pattern did not develop during wakefulness. Rats that were monitored up to 51 days post–SP-SAP injection continued to have sleep-disordered breathing; breathing during wakefulness remained relatively stable. Histologic analysis of the ventrolateral medulla confirmed that NK1R neurons within the preBötC on the injected but not on the contralateral side of the medulla were ablated.

Conclusions: Gradual loss of preBötC NK1R neurons may be an underlying factor of sleep-disordered breathing, in particular of central sleep apnea.

Authors: Sandra V. Kik; Suzanne Verver; Dick van Soolingen; Petra E. W. de Haas; Frank G. Cobelens; Kristin Kremer; Henk van Deutekom; Martien W. Borgdorff

Rationale: Some clusters of patients who have Mycobacterium tuberculosis isolates with identical DNA fingerprint patterns grow faster than others. It is unclear what predictors determine cluster growth.

Objectives: To assess whether the development of a tuberculosis (TB) outbreak can be predicted by the characteristics of its first two patients.

Methods: Demographic and clinical data of all culture-confirmed patients with TB in the Netherlands from 1993 through 2004 were combined with DNA fingerprint data. Clusters were restricted to cluster episodes of 2 years to only detect newly arising clusters. Characteristics of the first two patients were compared between small (2–4 cases) and large (5 or more cases) cluster episodes.

Measurements and Main Results: Of 5,454 clustered cases, 1,756 (32%) were part of a cluster episode of 2 years. Of 622 cluster episodes, 54 (9%) were large and 568 (91%) were small episodes. Independent predictors for large cluster episodes were as follows: less than 3 months' time between the diagnosis of the first two patients, one or both patients were young (<35 yr), both patients lived in an urban area, and both patients came from sub-Saharan Africa.

Conclusions: In the Netherlands, patients in new cluster episodes should be screened for these risk factors. When the risk pattern applies, targeted interventions (e.g., intensified contact investigation) should be considered to prevent further cluster expansion.

Author: Adrian Gillissen

Author: Eric Marchand

Author: Peter G. Middleton

Authors: Jadwiga A. Wedzicha; Peter M. A. Calverley; Terence A. Seemungal; Gerry Hagan; Zainab Ansari; Robert A. Stockley

Authors: Véronique Nève; Régis Matran; Jean-Louis Edmé

Authors: Stephanie Davis; Paul Aurora; Howard Eigen; Nicole Beydon; Enrico Lombardi