A randomised trial of lung sealant versus medical therapy for advanced emphysema

Uncontrolled pilot studies demonstrated promising results of endoscopic lung volume reduction using emphysematous lung sealant (ELS) in patients with advanced, upper lobe predominant emphysema. We aimed to evaluate the safety and efficacy of ELS in a randomised controlled setting. Patients were randomised to ELS plus medical treatment or medical treatment alone. Despite early termination for business reasons and inability to assess the primary 12-month end-point, 95 out of 300 patients were successfully randomised, providing sufficient data for 3- and 6-month analysis. 57 patients (34 treatment and 23 control) had efficacy results at 3 months; 34 (21 treatment and 13 control) at 6 months. In the treatment group, 3-month lung function, dyspnoea, and quality of life improved significantly from baseline when compared to control. Improvements persisted at 6 months with >50% of treated patients experiencing clinically important improvements, including some whose lung function improved by >100%. 44% of treated patients experienced adverse events requiring hospitalisation (2.5-fold more than control, p=0.01), with two deaths in the treated cohort. Treatment responders tended to be those experiencing respiratory adverse events. Despite early termination, results show that minimally invasive ELS may be efficacious, yet significant risks (probably inflammatory) limit its current utility

Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary edema

BACKGROUND: Non-invasive positive pressure ventilation (NPPV) has been widely used to alleviate signs and symptoms of respiratory distress due to cardiogenic pulmonary edema. NPPV prevents alveolar collapse and helps redistribute intra-alveolar fluid, improving pulmonary compliance and reducing the pressure of breathing. OBJECTIVES: To determine the effectiveness and safety of NPPV in the treatment of adult patients with cardiogenic pulmonary edema. SEARCH STRATEGY: We undertook a comprehensive search of the following databases in April 2005: CENTRAL, MEDLINE, EMBASE, CINAHL, DARE and LILACS. We also reviewed reference lists of included studies and contacted experts, equipment manufacturers, and the Cochrane Heart Group. We did not apply language restrictions. SELECTION CRITERIA: We selected blinded or unblinded randomized or quasi-randomized clinical trials, reporting on adult patients with acute or acute-on-chronic cardiogenic pulmonary edema and where NPPV (continuous positive airway pressure (CPAP)) and/or bilevel NPPV plus standard medical care was compared with standard medical care alone. DATA COLLECTION AND ANALYSIS: Two authors independently selected articles and abstracted data using a standardized data collection form. We evaluated study quality with emphasis on allocation concealment, adherence to the intention-to-treat principle and losses to follow-up. MAIN RESULTS: We included 21 studies involving 1,071 participants. Compared to standard medical care, NPPV significantly reduced hospital mortality (RR 0.6, 95% CI 0.45 to 0.84) and endotracheal intubation (RR 0.53, 95% CI 0.34 to 0.83) with numbers needed to treat of 13 and 8, respectively. We found no difference in hospital length of stay with NPPV, however, intensive care unit stay was reduced by 1 day (WMD -1.07 days, 95% CI -1.60 to -0.53). Compared to standard medical care, we did not observe significant increases in the incidence of acute myocardial infarction with NPPV during (RR 1.24, 95% CI 0.79 to 1.95) or after (RR 0.82, 95% CI 0.09 to 7.54) its application. AUTHORS' CONCLUSIONS: NPPV, especially CPAP, in addition to standard medical care is an effective and safe intervention for the treatment of adult patients with acute cardiogenic pulmonary edema

KAP1 controls endogenous retroviruses in embryonic stem cells

More than forty per cent of the mammalian genome is derived from retroelements, of which about one-quarter are endogenous retroviruses (ERVs). Some are still active, notably in mice the highly polymorphic early transposon (ETn)/MusD and intracisternal A-type particles (IAP). ERVs are transcriptionally silenced during early embryogenesis by histone and DNA methylation (and reviewed in ref. 7), although the initiators of this process, which is essential to protect genome integrity, remain largely unknown. KAP1 (KRAB-associated protein 1, also known as tripartite motif-containing protein 28, TRIM28) represses genes by recruiting the histone methyltransferase SETDB1, heterochromatin protein 1 (HP1) and the NuRD histone deacetylase complex, but few of its physiological targets are known. Two lines of evidence suggest that KAP1-mediated repression could contribute to the control of ERVs: first, KAP1 can trigger permanent gene silencing during early embryogenesis, and second, a KAP1 complex silences the retrovirus murine leukaemia virus in embryonic cells. Consistent with this hypothesis, here we show that KAP1 deletion leads to a marked upregulation of a range of ERVs, in particular IAP elements, in mouse embryonic stem (ES) cells and in early embryos. We further demonstrate that KAP1 acts synergistically with DNA methylation to silence IAP elements, and that it is enriched at the 5' untranslated region (5'UTR) of IAP genomes, where KAP1 deletion leads to the loss of histone 3 lysine 9 trimethylation (H3K9me3), a hallmark of KAP1-mediated repression. Correspondingly, IAP 5'UTR sequences can impose in cis KAP1-dependent repression on a heterologous promoter in ES cells. Our results establish that KAP1 controls endogenous retroelements during early embryonic development