Mode of parainfluenza virus transmission determines the dynamics of primary infection and protection from reinfection.

Little is known about how the mode of respiratory virus transmission determines the dynamics of primary infection and protection from reinfection. Using non-invasive imaging of murine parainfluenza virus 1 (Sendai virus) in living mice, we determined the frequency, timing, dynamics, and virulence of primary infection after contact and airborne transmission, as well as the tropism and magnitude of reinfection after subsequent challenge. Contact transmission of Sendai virus was 100% efficient, phenotypically uniform, initiated and grew to robust levels in the upper respiratory tract (URT), later spread to the lungs, grew to a lower level in the lungs than the URT, and protected from reinfection completely in the URT yet only partially in the lungs. Airborne transmission through 7.6-cm and 15.2-cm separations between donor and recipient mice was 86%-100% efficient. The dynamics of primary infection after airborne transmission varied between individual mice and included the following categories: (a) non-productive transmission, (b) tracheal dominant, (c) tracheal initiated yet respiratory disseminated, and (d) nasopharyngeal initiated yet respiratory disseminated. Any previous exposure to Sendai virus infection protected from mortality and severe morbidity after lethal challenge. Furthermore, a higher level of primary infection in a given respiratory tissue (nasopharynx, trachea, or lungs) was inversely correlated with the level of reinfection in that same tissue. Overall, the mode of transmission determined the dynamics and tropism of primary infection, which in turn governed the level of seroconversion and protection from reinfection. These data are the first description of the dynamics of respiratory virus infection and protection from reinfection throughout the respiratory tracts of living animals after airborne transmission. This work provides a basis for understanding parainfluenza virus transmission and protective immunity and for developing novel vaccines and non-pharmaceutical interventions.

Immunophenotype of Spontaneous Hematolymphoid Tumors Occurring in Young and Aging Female CD-1 Mice. [Corrected].

A few reports indicated the incidence of hematolymphoid neoplasms in old CD-1 mice, but the cellular lineage of CD-1 mouse neoplasms has not been published. In this study, immunohistochemistry (IHC) was used to characterize the cellular lineage of spontaneous hematolymphoid neoplasms arising in 24 young female CD-1 mice used as health-monitoring sentinels and 32 aging female CD-1 mice used as controls in 80-week carcinogenesis studies. Lymphoblastic lymphomas of T-cell and B-cell lineage were common in mice aged 12 months or less, whereas a wide range of non-lymphoblastic B-cell lymphomas and lymphoblastic B-cell lymphomas were common in mice >12-mo-old. Renal hyaline droplets positive for lysozyme were observed in aged mice with a histiocytic-associated large B-cell lymphoma (HA-BCL) and a myeloid leukemia. Endogenous ecotropic mouse leukemia virus (MuLV) genes have been recovered from CD-1 mice, but MuLV protein expression has not been previously demonstrated. We reported for the first time the expression of a MuLV protein p30 by IHC in lymphomas and some normal tissues of both young and aging CD-1 mice. This report should help to differentiate spontaneous lymphomas and leukemias in CD-1 mice from those induced by chemicals and other methods.

Observational Evaluations of Mice during Cerebral Microdialysis for Pediatric Brain Tumor Research.

In vivo animal experiments are critical in the process of finding and developing new treatments for children with CNS tumors. Cerebral microdialysis, which enables researchers to measure drug concentrations in the brain or tumor tissue of unanesthetized mice, is a highly specialized procedure that provides valuable information that cannot be gained by using an in vitro system. When designing any in vivo animal study, 3 Rs principles (replacement, reduction, and refinement) must be considered to ensure that the highest standards of care are followed. As part of the refinement process, the objectives of this study were to collect behavioral monitoring data from mice undergoing cerebral microdialysis, to identify any behaviors predictive of significant pain or distress that could affect the animal's welfare, and to use these data to refine the existing monitoring checklist and schedule for its use by others performing this procedure. We developed a monitoring checklist for assessing wellbeing and distress of mice during cerebral microdialysis experiments. Comparison of 79 mice that underwent cerebral microdialysis experiments with a control group of 20 mice revealed that cerebral microdialysis and tethering of mice are well tolerated for as long as 24 h with only minor evidence of stress.

A mouse model for glucocorticoid-induced osteonecrosis: effect of a steroid holiday.

Glucocorticoid-induced osteonecrosis is a common and dose-limiting adverse event. The goal of this study was to establish a mouse model of glucocorticoid-induced osteonecrosis suitable for testing the effects of different treatment strategies on its frequency. Fourteen murine strains were screened using various glucocorticoids, routes of administration, and diets. Four-week-old male BALB/cJ mice were treated with oral dexamethasone for up to 12 weeks either by continuous dosing or by discontinuous dosing, with or without asparaginase. Histopathological features of the distal femurs were examined by light microscopy. Osteonecrotic lesions were characterized by empty lacunae and osteocyte ghosts in trabecular bone surrounded by necrotic marrow and edema. The incidence of dexamethasone induced osteonecrosis in BALB/cJ mice was 40-45% (4/10 or 5/11) at 12 weeks. The frequency of osteonecrosis trended lower after discontinuous compared to continuous dosing for 12 weeks (8 vs. 45%) (p = 0.06) despite comparable cumulative plasma exposure. Asparaginase hastened the occurrence of osteonecrosis, which was observed as early as 4 weeks and the incidence was 50% after 6 weeks. A mouse model of glucocorticoid-induced osteonecrosis was established. Discontinuous was less osteonecrotic than continuous dexamethasone treatment, consistent with the possible benefits of a "steroid holiday" seen in clinical settings. Moreover, asparaginase hastened osteonecrosis, indicating that drugs may interact with glucocorticoids to affect osteonecrosis risk.