Secreted exosomes are bioactive particles that elicit profound responses in target cells. Using targeted metabolomics and global microarray analysis, we identified a role of exosomes in promoting mitochondrial function in the context of pulmonary arterial hypertension (PAH). Whereas chronic hypoxia results in a glycolytic shift in pulmonary artery smooth muscle cells (PASMCs), exosomes restore energy balance and improve O2 consumption. These results were confirmed in a hypoxia-induced mouse model and a semaxanib/hypoxia rat model of PAH wherein exosomes improved the mitochondrial dysfunction associated with disease. Importantly, exosome exposure increased PASMC expression of pyruvate dehydrogenase (PDH) and glutamate dehydrogenase 1 (GLUD1), linking exosome treatment to the TCA cycle. Furthermore, we show that although prolonged hypoxia induced sirtuin 4 expression, an upstream inhibitor of both GLUD1 and PDH, exosomes reduced its expression. These data provide direct evidence of an exosome-mediated improvement in mitochondrial function and contribute new insights into the therapeutic potential of exosomes in PAH.

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Objective. To evaluate the nondiagnostic rate of computed tomography pulmonary angiography (CTPA) in pregnant and postpartum patients with suspected pulmonary embolism (PE) to determine whether CTPA or ventilation-perfusion (VQ) scan should be considered first line imaging in this patient population considering their equivalent accuracy and the greater radiation exposure to proliferating breast tissue of CTPA. Methods. All pregnant/postpartum female patients between 18 and 50 years of age who had CTPA within the Eastern Health Authority between November 2012 and November 2016 were included. Each scan was evaluated for nondiagnosis based on two criteria: contrast density in the main pulmonary artery, and respiratory motion artefact. If either of these criteria were not met, the scan was labelled as nondiagnostic. Results. The nondiagnostic rate overall was 43% (n=83). This is similar to current literature values for rates of CTPA nondiagnosis, and comparable to the reported diagnostic quality of the reporting radiologist. This is much greater compared to rates of ventilation/perfusion nondiagnosis in comparable populations. Even in patients with normal chest radiographs, which represents the main patient group where VQ may be considered as an alternative, the nondiagnostic rate of CT is much higher. Conclusion. This is the first study to attempt to identify an objective method of determining nondiagnosis in pregnant and postpartum patients undergoing a CTPA. Our results strengthen the argument that alternative imaging should be considered when investigating for PE in this population in order to protect the proliferating breast tissue, and VQ scan should be considered especially in patients with normal chest X-rays.

Background: Post-haemorrhagic ventricular dilatation (PHVD) after intraventricular haemorrhage (IVH) remains a significant problem in preterm infants. Due to serious disadvantages of ventriculoperitoneal shunt dependence, there is an urgent need for non-surgical interventions. Considerable experimental and clinical evidence implicates transforming growth factor β (TGFβ) in the pathogenesis of PHVD. Colchicine and decorin are both compounds with anti-TGFβ properties. The former downregulates TGFβ production and is in clinical use for another fibrotic disease, and the latter inactivates TGFβ. Objectives: We hypothesized that administration of decorin or colchicine, which both have anti-TGFβ properties, would reduce ventricular dilatation in a model of PHVD. Methods: 142 rat pups underwent intraventricular blood injection on postnatal days (PN) 7 and 8. Sixty-nine pups were randomized to colchicine 20 and 50 µg/kg/day or water by gavage for 13 days. Seventy were randomized to decorin 4 mg/kg or saline by intraventricular injection on PN8 and PN13. At PN21, the ventricular area was measured on coronal brain sections. Negative geotaxis was tested at PN14 in controls and in the decorin study group. Results: Ventricular size was not different between animals receiving either drug or water/saline. Intraventricular blood impaired neuromotor performance, but decorin had no effect. Conclusion: Two drugs that block TGFβ by different mechanisms do not reduce ventricular dilatation in this model. Together with our previous work on losartan and pirfenidone, we conclude that blocking TGFβ alone does not prevent the development of PHVD.