Macrophage-expressed IFN-β contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia

Influenza viruses (IV) cause pneumonia in humans with progression to lung failure and fatal outcome. Dysregulated release of cytokines including type I interferons (IFNs) has been attributed a crucial role in immune-mediated pulmonary injury during severe IV infection. Using ex vivo and in vivo IV infection models, we demonstrate that alveolar macrophage (AM)-expressed IFN-β significantly contributes to IV-induced alveolar epithelial cell (AEC) injury by autocrine induction of the pro-apoptotic factor TNF-related apoptosis- inducing ligand (TRAIL). Of note, TRAIL was highly upregulated in and released from AM of patients with pandemic H1N1 IV-induced acute lung injury. Elucidating the cell-specific underlying signalling pathways revealed that IV infection induced IFN-β release in AM in a protein kinase R- (PKR-) and NF-κB- dependent way. Bone marrow chimeric mice lacking these signalling mediators in resident and lung-recruited AM and mice subjected to alveolar neutralization of IFN-β and TRAIL displayed reduced alveolar epithelial cell apoptosis and attenuated lung injury during severe IV pneumonia. Together, we demonstrate that macrophage-released type I IFNs, apart from their well-known anti-viral properties, contribute to IV-induced AEC damage and lung injury by autocrine induction of the pro-apoptotic factor TRAIL. Our data suggest that therapeutic targeting of the macrophage IFN-β-TRAIL axis might represent a promising strategy to attenuate IV-induced acute lung injury

Awake uniportal VATS for the evacuation of an extensive, superinfected hemothorax

Background: The so-called non-intubated or awake Video-assisted thoracoscopic surgery (NIVATS) is performed on spontaneously breathing patients, which was shown to reduce postoperative complications and shorten hospital stay. Case Description: Awake uniportal VATS was indicated for the evacuation of an extensive, superinfected hemothorax with symptomatic mediastinal shift in a patient with advanced mediastinal SMARCA4-deficient tumor and declined condition, who did not allow a general anaesthetic procedure and was not a candidate for extensive surgery. Conclusion: This short micro-invasive intervention was a prerequisite to stabilize the threatened in his life patient and thus potentially enable for any further tumor specific therapy

Entwicklung einer Entscheidungshilfe für partizipative Vorausplanungen für Menschen mit Demenz und deren Angehörige

Background!#!Patients with a diagnosis of dementia face various important social and health-related decisions. Due to the progression of the disease it seems crucial that patients try to deal with these decisions early in the course of the disease to have the opportunity to make decisions autonomously. Professional support can help to plan in advance according to the wishes and possibilities in an effective and individualized manner.!##!Material and methods!#!The instrument was developed in a multiphase process based on advance care planning and shared decision-making. The prototype was pretested on 8 patient-relative dyads from a special outpatient department for early recognition and adapted as best as possible to their needs. Subsequently, in a pilot study the applicability of the decision aid was tested as an intervention in a further 19 patient-relative dyads with trained conversion attendants (diagnosis of Alzheimer's dementia or mixed form; mini mental state examination, MMSE (Mini-Mental-State-Test-Summenwert) >20 and <27).!##!Results!#!The result was a written decision-making aid for people with early stage dementia and their relatives, which supports the decision-making process (health care proxy, advance directive, living and care, driving ability). The first results showed good acceptance and handling. Patients and relatives dealt with the individual topics to a high degree and found them to be highly relevant.!##!Conclusion!#!Despite positive feedback from the participants with respect to acceptance and applicability, there were major difficulties in recruiting. In the future, the systematic use of decision support as part of routine care could help to support the decision-making process in this patient group

Diagnostic and Therapeutic Challenges of a Large Pleural Inflammatory Myofibroblastic Tumor

We report a 48-year-old woman with a pleural pseudoneoplasm requiring different diagnostic and therapeutic strategies. After initial presentation with increasing dyspnoea, temperature, dry cough, and interscapular pain diagnostic processing showed a large mediastinal mass with marked pleural effusion and high metabolic activity in the 18F-FDG-PET/CT. Extensive CT-guided biopsy of the tumor reaching from the visceral pleura into the right upper lobe revealed no malignancy, but a marked inflammatory tissue reaction containing foam cells. Initial empiric antibiotic therapy was temporarily successful. However, in the further course the mass relapsed and was resistant to antibiotics and a corticosteroid trial. With the working hypothesis of an inflammatory myofibroblastic tumor the patient underwent surgical tumor resection, finally confirming the suspected diagnosis. Due to residual disease intravenous immunoglobulins were administered leading to sustained response. This case with a pleural localisation of a large inflammatory pseudotumor with responsiveness to immunomodulation after incomplete resection extends the reported spectrum of thoracopulmonary manifestations of this rare entity

Alveolar epithelial cells orchestrate DC function in murine viral pneumonia

Influenza viruses (IVs) cause pneumonia in humans with progression to lung failure. Pulmonary DCs are key players in the antiviral immune response, which is crucial to restore alveolar barrier function. The mechanisms of expansion and activation of pulmonary DC populations in lung infection remain widely elusive. Using mouse BM chimeric and cell-specific depletion approaches, we demonstrated that alveolar epithelial cell (AEC) GM-CSF mediates recovery from IV-induced injury by affecting lung DC function. Epithelial GM-CSF induced the recruitment of CD11b+ and monocyte-derived DCs. GM-CSF was also required for the presence of CD103+ DCs in the lung parenchyma at baseline and for their sufficient activation and migration to the draining mediastinal lymph nodes (MLNs) during IV infection. These activated CD103+ DCs were indispensable for sufficient clearance of IVs by CD8+ T cells and for recovery from IV-induced lung injury. Moreover, GM-CSF applied intratracheally activated CD103+ DCs, inducing increased migration to MLNs, enhanced viral clearance, and attenuated lung injury. Together, our data reveal that GM-CSF-dependent cross-talk between IV-infected AECs and CD103+ DCs is crucial for effective viral clearance and recovery from injury, which has potential implications for GM-CSF treatment in severe IV pneumonia

Correction: Macrophage-expressed IFN-β Contributes to Apoptotic Alveolar Epithelial Cell Injury in Severe Influenza Virus Pneumonia.

[This corrects the article DOI: 10.1371/journal.ppat.1003188.]

Lipoic Acid Synthetase Deficiency Causes Neonatal-Onset Epilepsy, Defective Mitochondrial Energy Metabolism, and Glycine Elevation

Lipoic acid is an essential prosthetic group of four mitochondrial enzymes involved in the oxidative decarboxylation of pyruvate, α-ketoglutarate, and branched chain amino acids and in the glycine cleavage. Lipoic acid is synthesized stepwise within mitochondria through a process that includes lipoic acid synthetase. We identified the homozygous mutation c.746G>A (p.Arg249His) in LIAS in an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine. Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate and decreased pyruvate dehydrogenase complex activity. A pronounced reduction of the prosthetic group lipoamide was found in lipoylated proteins