Gene Therapy in a Humanized Mouse Model of Familial Hypercholesterolemia Leads to Marked Regression of Atherosclerosis

Familial hypercholesterolemia (FH) is an autosomal codominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Homozygous FH patients (hoFH) have severe hypercholesterolemia leading to life threatening atherosclerosis in childhood and adolescence. Mice with germ line interruptions in the Ldlr and Apobec1 genes (Ldlr(-/-)Apobec1(-/-)) simulate metabolic and clinical aspects of hoFH, including atherogenesis on a chow diet.In this study, vectors based on adeno-associated virus 8 (AAV8) were used to deliver the gene for mouse Ldlr (mLDLR) to the livers of Ldlr(-/-)Apobec1(-/-) mice. A single intravenous injection of AAV8.mLDLR was found to significantly reduce plasma cholesterol and non-HDL cholesterol levels in chow-fed animals at doses as low as 3×10(9) genome copies/mouse. Whereas Ldlr(-/-)Apobec1(-/-) mice fed a western-type diet and injected with a control AAV8.null vector experienced a further 65% progression in atherosclerosis over 2 months compared with baseline mice, Ldlr(-/-)Apobec1(-/-) mice treated with AAV8.mLDLR realized an 87% regression of atherosclerotic lesions after 3 months compared to baseline mice. Immunohistochemical analyses revealed a substantial remodeling of atherosclerotic lesions.Collectively, the results presented herein suggest that AAV8-based gene therapy for FH may be feasible and support further development of this approach. The pre-clinical data from these studies will enable for the effective translation of gene therapy into the clinic for treatment of FH

The convergence analysis and error estimation for unique solution of a p-Laplacian fractional differential equation with singular decreasing nonlinearity

© 2018, The Author(s). In this paper, we focus on the convergence analysis and error estimation for the unique solution of a p-Laplacian fractional differential equation with singular decreasing nonlinearity. By introducing a double iterative technique, in the case of the nonlinearity with singularity at time and space variables, the unique positive solution to the problem is established. Then, from the developed iterative technique, the sequences converging uniformly to the unique solution are formulated, and the estimates of the error and the convergence rate are derived

Impact of group housing of pregnant sows on health

Group housing of sows during gestation is mandatory in the EU since 2013. Compared to housing in individual crates, group housing allows the animals to express normal activity and behavior. The present paper discusses the impact of group housing on health, with emphasis on lameness, aggression and possible spread of infectious diseases. The prevalence of lameness is generally higher in sows housed in group than in sows housed individually. Floor space per sow, group size, pen design and flooring are the main factors of group housing involved in lameness development. Especially floor characteristics are important, and particular attention should be paid to the type, building material and quality of the floor, hygiene and the use of bedding such as straw or rubber mats. Aggression between sows is another critical issue in group housing systems. It occurs predominantly because of competition for access to a limited resource, or to establish a social hierarchy. Key factors to prevent aggression in group housing include gradual familiarization of unfamiliar animals, sufficient space and pen structure during initial mixing, minimizing opportunities for dominant sows to steal food from subordinates, provision of a good quality floor, environmental enrichment and use of straw bedding. Very scarce evidence-based information is available on the relationship between group housing and infectious disease. Compared to individual housing, sows in group housing have more nose-to-nose contact, and they have more oral contact with feces and urine. These factors could contribute to a higher or faster transmission of pathogens, but so far, there is no evidence showing more disease problems in group housing systems. In conclusion, in group housing systems, particular attention should be paid to prevention of lameness and aggression. Management is crucial but also feeding strategies, floor and bedding, and design of housing are very important as relatively minor adjustments may exert major effects on the animals.Peer reviewe