Pressure Load: The Main Factor for Altered Gene Expression in Right Ventricular Hypertrophy in Chronic Hypoxic Rats

BACKGROUND: The present study investigated whether changes in gene expression in the right ventricle following pulmonary hypertension can be attributed to hypoxia or pressure loading. METHODOLOGY/PRINCIPAL FINDINGS: To distinguish hypoxia from pressure-induced alterations, a group of rats underwent banding of the pulmonary trunk (PTB), sham operation, or the rats were exposed to normoxia or chronic, hypobaric hypoxia. Pressure measurements were performed and the right ventricle was analyzed by Affymetrix GeneChip, and selected genes were confirmed by quantitative PCR and immunoblotting. Right ventricular systolic blood pressure and right ventricle to body weight ratio were elevated in the PTB and the hypoxic rats. Expression of the same 172 genes was altered in the chronic hypoxic and PTB rats. Thus, gene expression of enzymes participating in fatty acid oxidation and the glycerol channel were downregulated. mRNA expression of aquaporin 7 was downregulated, but this was not the case for the protein expression. In contrast, monoamine oxidase A and tissue transglutaminase were upregulated both at gene and protein levels. 11 genes (e.g. insulin-like growth factor binding protein) were upregulated in the PTB experiment and downregulated in the hypoxic experiment, and 3 genes (e.g. c-kit tyrosine kinase) were downregulated in the PTB and upregulated in the hypoxic experiment. CONCLUSION/SIGNIFICANCE: Pressure load of the right ventricle induces a marked shift in the gene expression, which in case of the metabolic genes appears compensated at the protein level, while both expression of genes and proteins of importance for myocardial function and remodelling are altered by the increased pressure load of the right ventricle. These findings imply that treatment of pulmonary hypertension should also aim at reducing right ventricular pressure

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics

Early mobilisation in mechanically ventilated patients:A systematic integrative review of definitions and activities

From PubMed via Jisc Publications RouterHistory: received 2018-10-23, accepted 2018-12-11Publication status: epublishMechanically ventilated patients often develop muscle weakness post-intensive care admission. Current evidence suggests that early mobilisation of these patients can be an effective intervention in improving their outcomes. However, what constitutes early mobilisation in mechanically ventilated patients (EM-MV) remains unclear. We aimed to systematically explore the definitions and activity types of EM-MV in the literature. Whittemore and Knafl's framework guided this review. CINAHL, MEDLINE, EMBASE, PsycINFO, ASSIA, and Cochrane Library were searched to capture studies from 2000 to 2018, combined with hand search of grey literature and reference lists of included studies. The Critical Appraisal Skills Programme tools were used to assess the methodological quality of included studies. Data extraction and quality assessment of studies were performed independently by each reviewer before coming together in sub-groups for discussion and agreement. An inductive and data-driven thematic analysis was undertaken on verbatim extracts of EM-MV definitions and activities in included studies. Seventy-six studies were included from which four major themes were inferred: (1) , (2) , (3) and (4) . The first theme indicates that EM-MV is either not fully defined in studies or when a definition is provided this is not standardised across studies. The remaining themes reflect the diversity of EM-MV activities which depends on patients' characteristics and ICU settings; the negotiated decision-making process between patients and staff; and their interdependent relationship during the implementation. This review highlights the absence of an agreed definition and on what constitutes early mobilisation in mechanically ventilated patients. To advance research and practice an agreed and shared definition is a pre-requisite