ABSTRACT
Objective: The aim of the study was to investigate how social housing with high locomotion activity affects experimental osteoarthritis (OA) in rats. Design: Rats were housed either conventionally in type IV cages in pairs or in rat colony cages (RCC) on 4 levels interconnected by jump holes or staircase in groups of 48. OA was induced by anterior cruciate ligament transection and resection of the medial meniscus (ACLT + tMx), medial meniscal tear (MMT) or destabilization of the medial meniscus (DMM). Functional changes were characterized by continues tracking of individual activity and catwalk gait analysis. Cartilage volume and bone structure were investigated at week 20 after surgery by histology and micro-CT. Results: In the RCC, healthy rats changed cage levels 82 ± 15 times daily, reduced by 30% after ACLT + tMx (p < 0.0001). In both housing systems, the order of severity of the investigated models was ACLT + tMx > MMT > DMM in all outcome measures. Compared to Type IV, RCC housed rats developed stronger gait disturbance symptoms (ACLT + tMx; 95%CI = -15-2; p < 0.004), the cartilage volume was reduced (ACLT + tMx: 95%CI = -0.1-0.5; p < 0.0001), serum levels of the cartilage remodeling marker AGNx1 were higher (MMT; 95%CI = -53-(-6); p = 0.001), bone was denser with increased volume (ACLT + tMx; 95%CI = 0.8-7.5; p = 0.004) and joints were less flexible (ACLT + tMx; 95%CI = 3.6-14; p < 0.0001). Conclusion: Housing rats in an environment allowing increased locomotion and socialization promotes structural and functional alterations during joint instability-induced OA. This increases the assay window, improves the relevance for the human disease and enables to discriminate the models in structural and behavioral parameters.
ABSTRACT
A self-deleting retrovirus vector carrying a herpes simplex virus (HSV)-thymidine kinase suicide gene has been developed to selectively kill cancer cells expressing a dysfunctional p53 tumor suppressor protein. When cells containing functional p53 are infected with the virus, the integrated provirus and the HSV-thymidine kinase gene are deleted from the genome by site-specific recombination (Cre/loxP). In contrast, cells without p53 or cells expressing a DNA-binding mutant of p53 retain the provirus and become susceptible to killing by ganciclovir. This strategy provides a new concept for the selective killing of cancer cells that can be adapted to any other dysfunctional transcription factor expressed by different tumors.
Subject(s)
Genetic Therapy/methods , Retroviridae/genetics , Tumor Suppressor Protein p53/deficiency , Animals , Female , Ganciclovir/pharmacokinetics , Ganciclovir/pharmacology , Genetic Vectors/genetics , Humans , Mice , Mice, Nude , Proviruses/genetics , Simplexvirus/enzymology , Simplexvirus/genetics , Thymidine Kinase/genetics , Thymidine Kinase/metabolism , Tumor Cells, Cultured , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/physiology , Virus Integration/genetics , Xenograft Model Antitumor AssaysABSTRACT
As reported in the literature, oral endotracheal intubation of rats is considered to be very difficult. Specialised equipment and complicated techniques have been described to perform this procedure. In our experiment we adopted a simple method, which allowed-without any complicated equipment-the insertion of a relatively wide tube into the trachea of rats, allowing drug administration.
