Objective. To identify changes in gene expression in mice with osteoarthritis (OA) in order to explore the mechanisms of the disease.Methods. Gene expression profiling was performed in cartilage from mice with surgically induced OA. We used wild-type (WT) mice and Adamts5⌬cat mice, in which ADAMTS-5 activity is lacking and aggrecan loss and cartilage erosion are inhibited, to distinguish gene expression changes that are independent of ADAMTS-5 activity and cartilage breakdown. Mechanical instability was introduced into the knee joints of 10-week-old male mice via surgical destabilization of the medial meniscus (DMM). Cartilage from the developing lesion in the destabilized medial meniscus and corresponding regions in sham-operated joints was harvested by microdissection at 1, 2, and 6 weeks postsurgery, and RNA was extracted, amplified, and hybridized to wholegenome microarrays.Results. Several previously identified OA-related genes, including Ptgs2, Crlf1, and Inhba, and novel genes, such as Phdla2 and Il11, were up-regulated in both WT mice and Adamts5⌬cat mice, indicating that they are independent of ADAMTS-5 activity. The altered expression of other genes, including Col10a1, the sentinel marker of cartilage hypertrophy, and Wnt/␤-catenin pathway genes, required ADAMTS-5 activity. Cell death pathway genes were dysregulated, and Tp53, Foxo4, and Xbp1 endoplasmic reticulum-stress transcriptional networks were activated. Analysis of degradome genes identified up-regulation of many proteases, including Mmp3, Capn2, and the novel cartilage proteases Prss46 and Klk8. Comparison with other studies identified 16 genes also dysregulated in rat and human OA as priorities for study.Conclusion. We have identified, for the first time, several genes that have an ADAMTS-5-independent role in OA, identifying them as possible OA initiation candidates. This work provides new insights into the sequence of gene dysregulation and the molecular basis of cartilage destruction in OA.

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Since 2002 we have been investigating the use of an electronic classroom communication system in large first year lecture classes. Handheld keypads were distributed to teams of students during a lecture class. Students used the keypads to answer two step multiple choice problems after a discussion within their group. The questions were generated using students' answers from previous exams. We have evaluated our use of the classroom communication system using a survey about how comfortable students are with this type of interaction. In addition, we have tried to determine if the use of the classroom communication system can be linked to student performance on exams. Our results show that students are comfortable with this technology and feel that, on the whole, interactive lectures are useful. At a first glance, there is an improvement in students' exam performance, but there are too many competing factors to clearly say that this improvement is solely due to the use of the classroom communication system. Even though this paper is based in physics and a physics example is used to illustrate points, the technique can be applied to other discipline areas.

Changes in typical whole-animal dependent variables following drug administration represent an integral of the drug’s pharmacological effect, the individual’s autonomic and behavioral responses to the resulting disturbance, and many other influences. An archetypical example is core temperature (Tc), long used for quantifying initial drug sensitivity and tolerance acquisition over repeated drug administrations. Our previous work suggested that rats differing in initial sensitivity to nitrous oxide (N2O)-induced hypothermia would exhibit different patterns of tolerance development across N2O administrations. Specifically, we hypothesized that rats with an initially insensitive phenotype would subsequently develop regulatory overcompensation that would mediate an allostatic hyperthermic state, whereas rats with an initially sensitive phenotype would subsequently compensate to a homeostatic normothermic state. To preclude confounding due to handling and invasive procedures, a valid test of this prediction required non-invasive thermal measurements via implanted telemetric temperature sensors, combined direct and indirect calorimetry, and automated drug delivery to enable repeatable steady-state dosing. We screened 237 adult rats for initial sensitivity to 70% N2O-induced hypothermia. Thirty highly sensitive rats that exhibited marked hypothermia when screened and 30 highly insensitive rats that initially exhibited minimal hypothermia were randomized to three groups (n=10 each/group) that received: 1) twelve 90-min exposures to 70% N2O using a classical conditioning procedure, 2) twelve 90-min exposures to 70% N2O using a random control procedure for conditioning, or 3) a no-drug control group that received custom-made air. Metabolic heat production (via indirect calorimetry), body heat loss (via direct calorimetry) and Tc (via telemetry) were simultaneously quantified during N2O and control gas administrations. Initially insensitive rats rapidly acquired (3rd administration) a significant allostatic hyperthermic phenotype during N2O administration whereas initially sensitive rats exhibited classical tolerance (normothermia) during N2O inhalation in the 4th and 5th sessions. However, the sensitive rats subsequently acquired the hyperthermic phenotype and became indistinguishable from initially insensitive rats during the 11th and 12th N2O administrations. The major mechanism for hyperthermia was a brisk increase in metabolic heat production. However, we obtained no evidence for classical conditioning of thermal responses. We conclude that the degree of initial sensitivity to N2O-induced hypothermia predicts the temporal pattern of thermal adaptation over repeated N2O administrations, but that initially insensitive and sensitive animals eventually converge to similar (and substantial) magnitudes of within-administration hyperthermia mediated by hyper-compensatory heat production.

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