LDLR-Gene therapy for familial hypercholesterolaemia: Problems, progress, and perspectives

Coronary artery diseases (CAD) inflict a heavy economical and social burden on most populations and contribute significantly to their morbidity and mortality rates. Low-density lipoprotein receptor (LDLR) associated familial hypercholesterolemia (FH) is the most frequent Mendelian disorder and is a major risk factor for the development of CAD. To date there is no cure for FH. The primary goal of clinical management is to control hypercholesterolaemia in order to decrease the risk of atherosclerosis and to prevent CAD. Permanent phenotypic correction with single administration of a gene therapeutic vector is a goal still needing to be achieved. The first ex vivo clinical trial of gene therapy in FH was conducted nearly 18 years ago. Patients who had inherited LDLR gene mutations were subjected to an aggressive surgical intervention involving partial hepatectomy to obtain the patient's own hepatocytes for ex vivo gene transfer with a replication deficient LDLR-retroviral vector. After successful re-infusion of transduced cells through a catheter placed in the inferior mesenteric vein at the time of liver resection, only low-level expression of the transferred LDLR gene was observed in the five patients enrolled in the trial. In contrast, full reversal of hypercholesterolaemia was later demonstrated in in vivo preclinical studies using LDLR-adenovirus mediated gene transfer. However, the high efficiency of cell division independent gene transfer by adenovirus vectors is limited by their short-term persistence due to episomal maintenance and the cytotoxicity of these highly immunogenic viruses. Novel long-term persisting vectors derived from adeno-associated viruses and lentiviruses, are now available and investigations are underway to determine their safety and efficiency in preparation for clinical application for a variety of diseases. Several novel non-viral based therapies have also been developed recently to lower LDL-C serum levels in FH patients. This article reviews the progress made in the 18 years since the first clinical trial for gene therapy of FH, with emphasis on the development, design, performance and limitations of viral based gene transfer vectors used in studies to ameliorate the effects of LDLR deficiency

Performance of single skin masonry walls subjected to hydraulic loading

Property owners are facing increasing threats from flooding and in response are likely to turn to products designed to waterproof or ‘seal’ the outside of the building in an effort to prevent the ingress of flood water. However, very limited research has been conducted on the effect of this sealing action and the consequent hydraulic load acting upon the structure of the building. The theoretical safe application of waterproofing products has been suggested to be between 0.6 and 1 m (published guidance suggests 0.9 m), although the experimental evidence supporting these suggestions is either absent or limited in nature. This paper presents the findings of an experimental programme that has examined the effect of out-of-plane hydrostatic loading on masonry walls typical of domestic or commercial buildings. The study, conducted at 1/6th scale using a geotechnical centrifuge considers wall panels constructed from a variety of masonry units (autoclaved aerated concrete block, brick and brick-block) bound together with two different types of mortar. The wall panels were subject to an axial load representative of 1 storey of loading and were simply supported on all 4 sides. The load—out-of-plane deflection response of the panels was captured by a 3D digital image correlation system, and the water level at failure was compared to that predicted from previous research and the established yield line analysis method with encouraging results. When partial material and load factors were taken into consideration the results illustrated that a safe sealing height of 0.9 m, as quoted in the literature, would generally be inappropriate, whilst the safe sealing height of 0.6 m was not suitable for every case investigated. This supports the need for a suitable approach for the calculation of water levels at failure rather than the use of fixed values given in published literature

Error reduction therapy in reducing struggle and grope behaviours in apraxia of speech

We report an intervention study focused on the speech production difficulties present in acquired apraxia of speech (AOS). The intervention was a self-administered computer therapy that targeted whole word production and incorporated error reduction strategies. The effectiveness of the therapy was contrasted to that of a visuospatial sham computer program, and performance across treated words, and two sets of matched words, was assessed. Two groups of participants completed the study which employed a two-phase cross-over treatment design. Participants were randomly assigned to a speech first or sham first condition. Treatments were administered for six weeks, with a four week rest between interventions. Participants were assessed five times in total; twice at baseline, once following each of the intervention phases, and once following a lapse of eight weeks after the end of the second phase of intervention. The occurrence of accurate word production and speech characterised by struggle and groping behaviours was recorded on a repetition task. Participants showed significant gains in speech accuracy and fluency, and reductions in articulatory groping and struggle behaviours following the use of the speech program. These gains were largely maintained once the therapy was withdrawn

Heavy metal leaching and environmental risk from the use of compost-like output as an energy crop growth substrate

Conversion of productive agricultural land towards growth of energy crops has become increasingly controversial. Closed landfill sites represent significant areas of brownfield land, which have potential for the establishment of energy crops. Increasingly composts are now being produced from the degradable fraction of mixed municipal solid waste (MSW) and are commonly referred to as Compost-Like-Output (CLO). However, leaching of heavy metal and other elements due to the use of CLO as soil amendment has the potential to pose a risk to the wider environment as a diffuse pollution source if not managed correctly. Salix viminalis and Eucalyptus nitens were grown at 5 different CLO application rates (equivalent to 250, 1000, 3000, 6000, 10000 kg N/Ha) with weekly leachate analysis to assess the solubility of heavy metals and the potential release into the environment. The change in plant total dry mass suggested 3000 kg N/Ha as the optimum application rate for both species. Weekly leachate analysis identified excess soluble ions within the first 4 weeks, with heavy metals concentrations exceeding water quality limits at the higher application rates (> 3000 kg N/Ha). Heavy metal uptake and accumulation within each species was also investigated; S. viminalis accumulated greater levels of heavy metals than E. nitens with a general trend of metal accumulation in root > stem > leaf material. Heavy metal leaching from soils amended with CLO has the potential to occur at neutral and slightly alkaline pH levels as a result of the high buffering capacity of CLO. The use of CLO at application rates of greater than 250 kg N/Ha may be limited to sites with leachate collection and containment systems, not solely for the heavy metal leaching but also excess nitrogen leaching. Alternatively lower application rates are required but will also limit biomass production

Electrokinetic-enhanced bioremediation of organic contaminants: A review of processes and environmental applications

There is current interest in finding sustainable remediation technologies for the removal of contaminants from soil and groundwater. This review focuses on the combination of electrokinetics, the use of an electric potential to move organic and inorganic compounds, or charged particles/organisms in the subsurface independent of hydraulic conductivity; and bioremediation, the destruction of organic contaminants or attenuation of inorganic compounds by the activity of microorganisms in situ or ex situ. The objective of the review is to examine the state of knowledge on electrokinetic bioremediation and critically evaluate factors which affect the up-scaling of laboratory and bench-scale research to field-scale application. It discusses the mechanisms of electrokinetic bioremediation in the subsurface environment at different micro and macroscales, the influence of environmental processes on electrokinetic phenomena and the design options available for application to the field scale. The review also presents results from a modelling exercise to illustrate the effectiveness of electrokinetics on the supply electron acceptors to a plume scale scenario where these are limiting. Current research needs include analysis of electrokinetic bioremediation in more representative environmental settings, such as those in physically heterogeneous systems in order to gain a greater understanding of the controlling mechanisms on both electrokinetics and bioremediation in those scenarios

Compositional attribution of non-provenienced Maya polychrome vessels

Procedures and a few of the results of the Maya ceramic project are discussed from the perspective of non-provenienced vessel attribution ranging from site specific through a more inferential level to the rather hypothetical. The examples presented serve to illustrate the manner in which compositional and stylistic covariation are viewed in an investigation of Maya Ceramic art. The large data base from neutron activation analysis including archaeologically recovered pottery as well as the stylistically and iconographically elaborate vessels requires continued refinement in our methods of statistical analysis along with gaining a greater understanding of the sources of ceramic compositional variation in the Maya area. The mutually beneficial collaboration between science, art, and archaeology are emphasized