Analysis of gait in rats with olivocerebellar lesions and ability of the nicotinic acetylcholine receptor agonist varenicline to attenuate impairments.

Studies have demonstrated that administration of the neuronal nicotinic receptor agonist varenicline to rats with olivocerebellar lesions attenuates balance deficits on a rotorod and balance beam, but the effects of this drug on gait deficits have not been investigated. To accomplish this, male Sprague-Dawley rats were trained to walk on a motorized treadmill at 25 and 35 cm/s and baseline performance determined; both temporal and spatial gait parameters were analyzed. A principal component analysis (PCA) was used to identify the key components of gait, and the cumulative gait index (CGI) was calculated, representing deviations from prototypical gait patterns. Subsequently, animals either remained as non-lesioned controls or received injections of 3-acetylpyridine (3-AP)/nicotinamide to destroy the climbing fibers innervating Purkinje cells. The gait of the non-lesioned group was assessed weekly to monitor changes in the normal population, while the gait of the lesioned group was assessed 1 week following 3-AP administration, and weekly following the daily administration of saline or varenicline (0.3, 1.0, or 3.0mg free base/kg) for 2 weeks. Non-lesioned animals exhibited a 60-70% increased CGI over time due to increases in temporal gait measures, whereas lesioned animals exhibited a nearly 3-fold increased CGI as a consequence of increases in spatial measures. Following 2 weeks of treatment with the highest dose of varenicline (3.0mg free base/kg), the swing duration of lesioned animals normalized, and stride duration, stride length and step angle in this population did not differ from the non-lesioned population. Thus, varenicline enabled animals to compensate for their impairments and rectify the timing of the gait cycle.

Gait analysis and the cumulative gait index (CGI): Translational tools to assess impairments exhibited by rats with olivocerebellar ataxia.

Deviations from 'normal' locomotion exhibited by humans and laboratory animals may be determined using automated systems that capture both temporal and spatial gait parameters. Although many measures generated by these systems are unrelated and independent, some may be related and dependent, representing redundant assessments of function. To investigate this possibility, a treadmill-based system was used to capture gait parameters from normal and ataxic rats, and a multivariate analysis was conducted to determine deviations from normal. Rats were trained on the treadmill at two speeds, and gait parameters were generated prior to and following lesions of the olivocerebellar pathway. Control (non-lesioned) animals exhibited stable hindlimb gait parameters across assessments at each speed. Lesioned animals exhibited alterations in multiple hindlimb gait parameters, characterized by significant increases in stride frequency, braking duration, stance width, step angle, and paw angle and decreases in stride, stance, swing and propulsion durations, stride length and paw area. A principal component analysis of initial hindlimb measures indicated three uncorrelated factors mediating performance, termed Rhythmicity, Thrust and Contact. Deviation in the performance of each animal from the group mean was determined for each factor and values summed to yield the cumulative gait index (CGI), a single value reflecting variation within the group. The CGI for lesioned animals increased 2.3-fold relative to unlesioned animals. This study characterizes gait alterations in laboratory rats rendered ataxic by destruction of the climbing fiber pathway innervating Purkinje cells and demonstrates that a single index can be used to describe overall gait impairments.

Neuronal nicotinic receptor agonists improve gait and balance in olivocerebellar ataxia.

Clinical studies have reported that the nicotinic receptor agonist varenicline improves balance and coordination in patients with several types of ataxia, but confirmation in an animal model has not been demonstrated. This study investigated whether varenicline and nicotine could attenuate the ataxia induced in rats following destruction of the olivocerebellar pathway by the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP (70 mg/kg followed by 300 mg niacinamide/kg; i.p.) led to an 85% loss of inferior olivary neurons within one week without evidence of recovery, and was accompanied by a 72% decrease in rotorod activity, a 3-fold increase in the time to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) for one week improved rotorod performance by 50% and normalized the increased hindpaw stride width, effects that were prevented by the daily preadministration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg). Varenicline (1 and 3 mg free base/kg daily) also improved rotorod performance by approximately 50% following one week of administration, and although it did not alter the time to traverse the beam, it did improve the ability to maintain balance on the beam. Neither varenicline nor nicotine, at doses that improved balance, affected impaired locomotor activity in the open field. Results provide evidence that nicotinic agonists are of benefit for alleviating some of the behavioral deficits in olivocerebellar ataxia and warrant further studies to elucidate the specific mechanism(s) involved.

Traditional criteria for observation of splenic trauma should be challenged.

Age less than 55 years, normal Glasgow Coma Score (GCS), and absence of hypotension are traditional criteria for the selection of adult patients with blunt splenic trauma for observation. The objective of this study is to challenge these criteria. Two hundred twelve patients who presented with blunt splenic injury between 1992 and 1997 were identified from the Trauma Registry at our Level I trauma center. The patients were divided into three groups: 100 patients (47%) were observed, 108 (51%) underwent immediate splenorrhaphy or splenectomy, and 4 (2%) failed observation. The three groups were compared by participants' ages, GCSs, and histories of hypotension. No statistical differences were noted between the successfully observed patients and those requiring immediate surgery with respect to these criteria. Of the 4 patients who failed observation, all were younger than 55 years, all had a GCS >12, and all were normotensive. Our findings suggest that traditional criteria used to select patients for splenic trauma observation are not absolute indicators and should be liberalized: patients can be successfully observed despite having criteria that, in the past, would have led to immediate operative intervention.