Reduction of Purkinje Cell Pathology in SCA1 Transgenic Mice by p53 Deletion

The expansion of a polyglutamine tract in the ataxin-1 protein beyond a critical threshold causes spinocerebellar ataxia type 1 (SCA1). To investigate the mechanism of neuronal degeneration in SCA1, we analyzed the phenotype of an SCA1 transgenic mouse model in the absence of p53, an important regulator of cell death. p53 deficiency did not affect the early features of SCA1 mice such as impaired motor coordination and ataxin-1 nuclear inclusion formation but caused a notable reduction in later pathological features, including Purkinje cell heterotopia, dendritic thinning, and molecular layer shrinkage. To determine if this protective effect was mediated by an anti-apoptotic property of p53 deficiency, we looked for apoptosis in SCA1 mice but failed to detect any evidence of it even in the presence of p53. We propose that p53 acts after the initial pathogenic events in SCA1 to promote the progression of neuronal degeneration in SCA1 mice, but this activity may be unrelated to apoptosis.     

Diet and Ethanol Modulate Immune Responses in Young C57BL/6 Mice

Chronic ethanol (ETOH) ingestion adversely affects the immunocompetence of alcohol abusers. ETOH directly impairs host defense mechanisms and indirectly modulates immunocompetence by interfering with the nutritional status of the alcoholic. It is not clear from the current literature, however, to what extent ETOH, nutritional status, or the combination of the two factors modulates immune mechanisms in chronic alcoholics. To date, most animal studies investigating the immunotoxicity of ETOH have neglected the dietary factors, which may have masked additional immunotoxic effects of ETOH. To examine these dietary factors, we fed mice three liquid ETOH diets with different dietary sufficiencies for 7 weeks and investigated various immune responses. Spleen cell number and secretions of immunoreactive interleukin-2 and tumor necrosis factor were totally independent of the diet, being affected only by ETOH. Body, spleen, and thymus weights, interferon-γ secretion, and natural killer cell and phagocytic activities were modulated by ETOH as well as by diet. Natural killer cell and phagocytic activities were also directly affected by the nutritional quality of the diet. These results suggest that animal diets used in experimental studies of ETOH-induced immunomodulation must be planned and controlled carefully in order to single out the direct effects that ETOH has on the host defense system.     

Vancomycin-Rifampin Combination Therapy Has Enhanced Efficacy against an Experimental Staphylococcus aureus Prosthetic Joint Infection

Treatment of prosthetic joint infections often involves a two-stage exchange, with implant removal and antibiotic spacer placement followed by systemic antibiotic therapy and delayed reimplantation. However, if antibiotic therapy can be improved, one-stage exchange or implant retention may be more feasible, thereby decreasing morbidity and preserving function. In this study, a mouse model of prosthetic joint infection was used in which Staphylococcus aureus was inoculated into a knee joint containing a surgically placed metallic implant extending from the femur. This model was used to evaluate whether combination therapy of vancomycin plus rifampin has increased efficacy compared with vancomycin alone against these infections. On postoperative day 7, vancomycin with or without rifampin was administered for 6 weeks with implant retention. In vivo bioluminescence imaging, ex vivo CFU enumeration, X-ray imaging, and histologic analysis were carried out. We found that there was a marked therapeutic benefit when vancomycin was combined with rifampin compared with vancomycin alone. Taken together, our results suggest that the mouse model used could serve as a valuable in vivo preclinical model system to evaluate and compare efficacies of antibiotics and combinatory therapy for prosthetic joint infections before more extensive studies are carried out in human subjects.