Anatomical Differences Determine Distribution of Adenovirus after Convection-Enhanced Delivery to the Rat Brain

Background: Convection-enhanced delivery (CED) of adenoviruses offers the potential of widespread virus distribution in the brain. In CED, the volume of distribution (Vd) should be related to the volume of infusion (Vi) and not to dose, but when using adenoviruses contrasting results have been reported. As the characteristics of the infused tissue can affect convective delivery, this study was performed to determine the effects of the gray and white matter on CED of adenoviruses and similar sized super paramagnetic iron oxide nanoparticles (SPIO). Methodology/Principal Findings: We convected AdGFP, an adenovirus vector expressing Green Fluorescent Protein, a virus sized SPIO or trypan blue in the gray and white matter of the striatum and external capsule of Wistar rats and towards orthotopic infiltrative brain tumors. The resulting Vds were compared to Vi and transgene expression to SPIO distribution. Results show that in the striatum Vd is not determined by the Vi but by the infused virus dose, suggesting diffusion, active transport or receptor saturation rather than convection. Distribution of virus and SPIO in the white matter is partly volume dependent, which is probably caused by preferential fluid pathways from the external capsule to the surrounding gray matter, as demonstrated by co-infusing trypan blue. Distant tumors were reached using the white matter tracts but tumor penetration was limited. Conclusions/Significance: CED of adenoviruses in the rat brain and towards infiltrative tumors is feasible when regional anatomical differences are taken into account while SPIO infusion could be considered to validate proper catheter positioning and predict adenoviral distribution

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

Changes in susceptibility to life-threatening infections after treatment for complicated severe malnutrition in Kenya

Background Goals of treating childhood Severe Acute Malnutrition (SAM), besides anthropometric recovery and preventing short-term mortality, include reducing risks of subsequent serious infections. How quickly and how much the risk of serious illness changes during rehabilitation is unknown, but could inform improving design and scope of interventions. Objective To investigate changes in the risk of life-threatening events (LTEs) in relation to anthropometric recovery from SAM. Design Secondary analysis of a clinical trial including 1,778 HIV-uninfected Kenyan children aged 2-59 months with complicated SAM, enrolled following the inpatient stabilization phase of treatment, and followed for 12 months. The main outcome was LTEs, defined as infections requiring re-hospitalization or causing death. We examined anthropometry measured at months one, three and six after enrolment in relation to LTEs occurring during the 6 months following each of these time points. Results During 12 months, there were 823 LTEs (257 fatal), predominantly severe pneumonia and diarrhea. At months one, three and six, 557(34%), 764(49%) and 842(56%) children had WHZ≥-2 respectively which, compared to WHZ Conclusion Anthropometric response was associated with rapid and substantial reduction risk of LTEs. However, reduction in susceptibility lagged behind anthropometric improvement. Disease events, alongside anthropometric assessment may provide a clearer picture of the effectiveness of interventions. Robust protocols for detecting and treating poor anthropometric recovery, and addressing broader vulnerabilities that complicated SAM indicates may save lives.</p

Determinants of Sustainability Disclosure in the Global Forest Industry

This study aims to investigate the current patterns and determinants of sustainability disclosure in the global forest industry. Under the extensive quantifiable measures and occurrences of the Global Reporting Initiative (GRI) framework, a content analysis is performed on the voluntary disclosure of 66 largest forest companies worldwide to evaluate their economic, environmental and social performance. By taking industry and firm characteristics into account, the study also seeks to shed more light on the key determinants influencing the quality and level of disclosure. Significant emphasis was found to be placed on environmental and economic issues in contrast to areas such as human rights, labour practices, social and product responsibilities in the forest industry. The results of regression analysis suggest that company size and business diversity are significantly associated with disclosure, whereas profitability and regional differences are not decisive factors in formulating sustainability reporting strategies in the forest industry