Pharmacoresponsiveness of spontaneous recurrent seizures and the comorbid sleep disorder of epileptic Kcna1-null mice.

Drug resistant epilepsy affects ∼30% of people with epilepsy and is associated with epilepsy syndromes with frequent and multiple types of seizures, lesions or cytoarchitectural abnormalities, increased risk of mortality and comorbidities such as cognitive impairment and sleep disorders. A limitation of current preclinical models is that spontaneous seizures with comorbidities take time to induce and test, thus making them low-throughput. Kcna1-null mice exhibit all the characteristics of drug resistant epilepsy with spontaneous seizures and comorbidities occurring naturally; thus, we aimed to determine whether they also demonstrate pharmacoresistanct seizures and the impact of medications on their sleep disorder comorbidity. In this exploratory study, Kcna1-null mice were treated with one of four conventional antiseizure medications, carbamazepine, levetiracetam, phenytoin, and phenobarbital using a moderate throughput protocol (vehicle for 2 days followed by 2 days of treatment with high therapeutic doses selected based on published data in the 6 Hz model of pharmacoresistant seizures). Spontaneous recurrent seizures and vigilance states were recorded with video-EEG/EMG. Carbamazepine, levetiracetam and phenytoin had partial efficacy (67%, 75% and 33% were seizure free, respectively), whereas phenobarbital was fully efficacious and conferred seizure freedom to all mice. Thus, seizures of Kcna1-null mice appear to be resistant to three of the drugs tested. Levetiracetam failed to affect sleep architecture, carbamazepine and phenytoin had moderate effects, and phenobarbital, as predicted, restored sleep architecture. Data suggest Kcna1-null mice may be a moderate throughput model of drug resistant epilepsy useful in determining mechanisms of pharmacoresistance and testing novel therapeutic strategies.

Simulation of fretting wear at orthopaedic implant interfaces.

Osteolysis due to wear debris is a primary cause of failure of total joint replacements. Although debris produced by the joint articulating surfaces has been studied and simulated extensively, fretting wear debris, produced at nonarticulating surfaces, has not received adequate attention. We developed a three-station fretting wear simulator to reproduce in vivo motion and stresses at the interfaces of total joint replacements. The simulator is based on the beam bending theory and is capable of producing cyclic displacement from 3 to 1000 microns, under varying magnitudes of contact stresses. The simulator offers three potential advantages over previous studies: The ability to control the displacement by load, the ability to produce very small displacements, and dynamic normal loads as opposed to static. A pilot study was designed to test the functionality of the simulator, and verify that calculated displacements and loads produced the predicted differences between two commonly used porous ingrowth titanium alloy surfaces fretting against cortical bone. After 1.5 million cycles, the simulator functioned as designed, producing greater wear of bone against the rougher plasma-sprayed surface compared to the fiber-mesh surface, as predicted. A novel pin-on-disk apparatus for simulating fretting wear at orthopaedic implant interfaces due to micromotion is introduced. The test parameters measured with the fretting wear simulator were as predicted by design calculations, and were sufficient to measure differences in the height and weight of cortical bone pins rubbing against two porous ingrowth surfaces, plasma-sprayed titanium and titanium fiber mesh.