The anti-malarial drug chloroquine (CHL) has been reported to cause the accumulation of beta-amyloid peptide containing fragments (fA beta) of the amyloid precursor protein within lysosomes in vitro. However, the significance of this finding with regards to the development of Alzheimer's disease (AD) pathology in vivo is not known. Hence, we investigated the effects of chronic CHL administration in the mouse. Systemically administered CHL caused an astrocytic response and an increase in intracellular A beta immunoreactivity throughout the brain, but no plaque-like pathology. Pharmacological challenge with the excitotoxin kainic acid (KA) revealed a mild proconvulsant effect of CHL pretreatment (P < 0.06). Interestingly, CHL protected the blood-brain barrier from characteristic KA-induced dysfunction. Given the hypothesized involvement of both excitotoxic processes and the vascular system in AD, the observed interactions may assist in elucidating the pathogenesis of AD.

Correct geometric relationships between the annulus and sinotubular junction during stentless valve implantation are critical to minimize the development of insufficiency. Some patients with aortic valve disease have dilatation of the sinotubular junction and are unable to have a stentless valve placed by standard techniques. We recently encountered such a patient and reconstructed the sinotubular junction by aortic crenation. Multiple interrupted plicating sutures were used to reduce the aorta from a diameter of 42 mm to 28 mm. This method allows tailoring of the aorta to appropriate size by varying the number of crenating sutures.

Short-term electrical kindling, a widely used experimental model of epilepsy, appears to have little effect on behavior. The effects of extended kindling are largely unknown. Rats implanted with kindling electrodes in amygdala (AM) or perforant path (PP) received 300 kindling trials over approximately 7 months, and were tested in the Morris watermaze after a 7–10 day recovery period. Kindled animals were impaired during the initial training on hidden-platform acquisition, but not in retention of platform location. No deficits were found in acquiring a new hidden-platform location, latency to reach a visible-platform, or in swim speed. Open-field activity showed a sustained increase when tested during kindling, but only a transient increase when tested following suspension of kindling. Similar results were obtained for both AM and PP kindled animals. Hence, long-term kindling of both of these sites produced behavioral changes that were transient in nature. Further, these results also indicate that propagation of seizure activity from remote sites can alter hippocampally-mediated or related behavior.

Male and female Fischer 344 rats (N = 55) aged approximately 18, 21, and 24 months were tested for spatial learning in the water maze with intertrial intervals of 1-4 min (Massed) or 23-33 min (Spaced). Animals tested in the Massed condition showed an age-related impairment on trials to criterion; rats aged 24 months performed more poorly than younger subjects. Spaced animals did not differ at any age nor did they differ from 18- or 21-month-old Massed subjects. The youngest rats in both groups were comparable to animals aged 7-8 months tested under Massed conditions. Tests on swim distance, swim speed, and escape latency produced similar results. Our data suggest that acquisition deficits in 24-month-old rats tested with long intertrial intervals are due at least in part to increased susceptibility to fatigue and/or thermal stress. Caution should be used, therefore, when interpreting age-related impairments in water maze performance.

BACKGROUND:Regression of left ventricular hypertrophy is an important and well-recognized salutary effect of aortic valve replacement. The earliest evidence of left ventricular mass regression after aortic valve replacement and the influence of prosthesis type are not well known, and were the focus of this study.METHODS:Transthoracic echocardiography was used to measure left ventricular mass index preoperatively and before discharge in 57 consecutive patients undergoing isolated aortic valve replacement (with or without coronary artery bypass grafting).RESULTS:Three patients were excluded from the study because of inability to obtain accurate M-mode echocardiographic images for left ventricular mass measurement preoperatively (1) or postoperatively (2). Of the remaining 54 patients, mechanical bileaflet valves were used in 19, stented tissue bioprostheses were implanted in 15, and a stentless porcine bioprosthesis was chosen for 20. Postoperative echocardiograms were obtained 4.9 +/- 2.3 days after aortic valve replacement (range, 2 to 9 days). A two-way repeated-measures analysis of variance demonstrated a significant reduction of left ventricular mass index before discharge (preoperative 141.4 +/- 45.2 g/m2, postoperative 127.5 +/- 32.8 g/m2; p = 0.0005) but no differences between prostheses.CONCLUSIONS:Left ventricular mass regression begins early after aortic valve replacement, probably because of reduction of transvalvular gradients and left ventricular wall stress. At least in the very early postoperative period, the type of prosthesis does not influence the extent of mass regression.

Dogs were administered capsules containing L-deprenyl daily over 3 weeks at dose levels of 0, 0.1, 0.5, and 1.0 mg/kg. Spontaneous behavior was measured using a canine open field test, and was not significantly affected by L-deprenyl. Plasma levels of amphetamine showed a clear dose-dependent elevation 2 h and was not significantly affected by L-deprenyl. Plasma levels of amphetamine showed a clear dose-dependent elevation 2 h following treatment, but were markedly lower after 24 h, and were undetectable 5 days following the last treatment. Plasma levels of phenylethylamine were increased, but were highly variable. Animals sacrificed 1 day following the last treatment showed a dose-dependent inhibition of monoamine oxidase B in the brain, liver, and kidney, whereas monoamine oxidase A was unaffected in these tissues. L-Deprenyl also caused an increase in phenylethylamine in the striatum and hypothalamus, but not in the neocortex. Brain levels of DA, DOPAC, 3-MT, HVA, 5-HT, and 5-HIAA were unaffected. The pharmacological profile for the dog is distinct from that of other species in that long-term treatment did not produce any significant inhibition of MAO-A activity. The absence of an effect on biogenic amines or metabolites suggests that the metabolism of dopamine is mediated at least in part through pathways other than MAO-B in the normal adult dog.

A total of 107 Fischer 344 rats (male and female, 2 to 29 months old) were tested on three tasks designed to measure sensorimotor function. In the first task, a new test of sensorimotor function, animals were required to maintain their balance on a stationary inclined Plexiglas plane for 5 s. Performance was evaluated with a series of increasing angles ranging from 25 degrees to 50 degrees in 1 degree increments (four trials/angle). The animals were also evaluated on two common tests of sensorimotor function: suspension from a wire by the forepaws and traversing a narrow, horizontal bar (three trials each). Age effects were significant (p < .043 to p < .0001) for each of the 11 dependent measures (first fall angle, threshold angle, and total falls for the inclined plane, and first, best, mean, and median latencies to fall for the remaining two tests). No relationship was observed between performance, sex, and body weight. Coefficients of variation differed between tests, with the inclined plane being the least variable and the horizontal bar the most. Importantly, the inclined plane was least likely to violate the ANOVA assumption of homogeneity of variance, a problem often encountered when measuring age-related variables. Since the inclined plane test has a relatively low degree of variability, and since the between-group variation is homogeneous, it should serve as both a useful and robust test for sensorimotor function in the aged rat.

The effect of an extended program of perforant path or amygdala kindling on paired-pulse suppression in the dentate gyrus was studied in male hooded rats. Repeated kindling stimulations were delivered twice or three times daily until either 300 stimuli had been delivered or generalized convulsions had been observed to occur spontaneously. Paired-pulse suppression was monitored prior to and over the course of kindling using a standard variable interval paradigm. We also used a variable intensity paradigm in which the intensity of the conditioning pulse was varied while the test pulse intensity was fixed at 600 μA and the interpulse interval was fixed at 30 ms. Both procedures revealed progressive increases in paired-pulse suppression which persisted over the course of kindling. This increased inhibition also persisted in animals which developed spontaneous seizures. The variable intensity paired-pulse procedure also allowed us to monitor facilitation effects which were relatively uncontaminated by recurrent inhibition (when the conditioning pulse intensity was low). Kindling was found to increase paired-pulse facilitation. With the standard variable interval paradigm, these increases in facilitation masked the increases in suppression.

The monoamine oxidase B (MAO-B) inhibitor L-deprenyl, widely used to treat Parkinson's disease, has frequently been studied in animal models. We have examined the effects of several variables on activity levels of MAO-A and B in rat brain and liver following chronic (3 wks) treatment with L-deprenyl. Significant effects were observed for sex (females showed lower overall MAO-B activity in the liver), dose (MAO-A and B inhibition increased with dose, with females exhibiting greater sensitivity), route of administration (subcutaneous injection was more efficient than oral dosing), and dosing interval (MAO-B was significantly inhibited when dosing interval was increased to as long as 168 hours). Our results thus indicate that the effectiveness of L-deprenyl in vivo is dependent on several factors and that these must be taken into account in studies involving the benefits or risks of this drug.

Behavioral and pharmacological effects of oral administration ofl-deprenyl in the dog are described. Spontaneous behavior is unaffected at doses below 3 mg/kg while at higher doses there was stereotypical responding. There was evidence of improved cognitive function in animals chronically treated with a 1 mg/kg dose but the effectiveness varied considerably between subjects. Chronic administration produced a dose dependent inhibition in brain, kidney and liver monoamine oxidase B, and had no effect on monoamine oxidase A. There were also dose dependent increases in brain phenylethylamine and in plasma levels of amphetamine. Dog platelets did not have significant levels of MAO-B. Brain dopamine and serotonin metabolism were unaffected byl-deprenyl at doses up to 1 mg/kg. It appears that for the dog, deamination of catecholamines is controlled by MAO-A. Nevertheless, it is suggested thatl-deprenyl serves as a dopaminergic agonist, and there is also evidence that it affects adrenergic transmission. These catecholaminergic actions may account for the effects ofl-deprenyl on behavior and cognitive function.