Growth and differentiation factor-15 and microRNA in intensive care unit acquired paresis

Intensive Care Unit Acquired Paresis (ICUAP) is a major health concern facing today’s critical care patients. This syndrome of severe muscle wasting and weakness is associated with significant morbidity and mortality, resulting in a substantial clinical and financial burden. However as yet, other than early mobilisation and rehabilitation, there are no available treatments. The aim of this work was to identify molecular mechanisms in the aetiology of ICUAP with a view to finding novel therapeutic targets. In a prospective study of high-risk elective cardiothoracic patients, prolonged elevation of circulating GDF-15, a stress-induced cytokine and TGF-β family member, was associated with acute muscle wasting. Following on from this work, the hypothesis that GDF-15 might be a driver of muscle wasting in ICUAP was tested in an observational study of 20 ICUAP patients and 7 elective cardiothoracic controls. Both circulating GDF-15 and muscle GDF-15 mRNA expression were elevated in patients compared to controls. In addition microRNAs essential for muscle homeostasis and protection against TGF-β signalling were found to be down-regulated. In vitro experiments demonstrated that GDF-15 could increase expression of muscle atrophy-related genes and supress these microRNAs. Increased sensitivity to TGF-β signalling secondary to down-regulation of muscle microRNAs driven by GDF-15 hypothesised as an aetiological mechanism of muscle wasting in critical illness. Supporting this hypothesis, transfection of miR-181a into C2C12 cells reduced the response to TGF-β1 and increased TGF-β signalling was found in the muscle of ICUAP patients. 9 An interventional study of neuromuscular electrical stimulation (NMES) in ICU demonstrated that although increased mobility in critical care patients can improve outcomes there is a risk that NMES may cause muscle damage. Finally preliminary data, suggested that miR-181a is a potential biomarker for ICUAP. GDF-15 and microRNAs are potential therapeutic targets and this work supports the need for further investigation into these pathways in ICUAP.Open Acces

Optical observation of lipid- and polymer-shelled ultrasound microbubble contrast agents

High-speed optical experiments demonstrate that the behavior of a polymer-shelled microbubble contrast agent in response to an acoustic pulse is qualitatively and quantitatively different from that of a lipid-shelled agent. The lipid-shelled agent expands in response to a two-cycle pulse, and at pressures approaching 1 MPa, both the shell and its contents fragment. The polymer-shelled agent remains largely intact at pressures up to 1.5 MPa and exhibits a different destruction mechanism: the polymer shell does not oscillate significantly in response to ultrasound; instead, a gas bubble is extruded and ejected through a shell defect while the shell appears to remain largely intact. (C) 2004 American Institute of Physics

Programmed death ligand 1 is over-expressed by neutrophils in the blood of patients with active tuberculosis

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the world's largest infectious disease problems. Despite decades of intensive study, the immune response to Mtb is incompletely characterised, reflecting the extremely complex interaction between pathogen and host. Pathways that may alter the balance between host protection and pathogenesis are therefore of great interest. One pathway shown to play a role in the pathogenesis of chronic infections, including TB, is the programmed death-1 (PD-1) pathway. We show here that the expression of the programmed death ligand 1 (PD-L1), which interacts with PD-1, is increased in whole blood from active TB patients compared with whole blood from healthy controls or Mtb-exposed individuals, and that expression by neutrophils is largely responsible for this increase

An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M. tuberculosis), is a major cause of morbidity and mortality worldwide and efforts to control TB are hampered by difficulties with diagnosis, prevention and treatment 1,2. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease, but current tests cannot identify which individuals will develop disease 3. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines 4,5. We identified a whole blood 393 transcript signature for active TB in intermediate and high burden settings, correlating with radiological extent of disease and reverting to that of healthy controls following treatment. A subset of latent TB patients had signatures similar to those in active TB patients. We also identified a specific 86-transcript signature that discriminated active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-γ and Type I IFNαβ signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis, suggest that this TB signature reflects both changes in cellular composition and altered gene expression. Although an IFN signature was also observed in whole blood of patients with Systemic Lupus Erythematosus (SLE), their complete modular signature differed from TB with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto under-appreciated role of Type I IFNαβ signalling in TB pathogenesis, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic