Increased BAEP latency and reduced brain cytochrome c oxidase activity observed in the Suzuki model of Alzheimer's disease [abstract]

Cytochrome c oxidase (COX), the terminal respiratory enzyme, is reported to be deficient and to exhibit reduced activity in a number of neurodegenerative disorders. The Alzheimer's rabbit model is based on the intracerebral injection of Holt's adjuvant, an aluminum salt solution. This model was used to compare the brain activity and the activity of brain COX in treated and controlled rabbits. Of a total of 26 New Zealand white rabbits, thirteen were injected intracerebrally with Holt's adjuvant solution, five with physiologically saline solution and the remainder were kept as controls. The auditory responses (BAEP) of the rabbits were monitored for 14 days before injections and 14 days thereafter. The animals were then sacrificed and brain mitochondrial extracts were used for SDS-PAGE analysis, difference spectra spectrophotometry and polarographic assays. The results of SDS-PAGE showed that there were no differences in the protein composition of the brain mitochondria of the three groups. Similarly, difference spectra (reduced minus oxidized, 400-630 nm) from both treated groups were identical to that of the control with characteristic maxima centered around 434, 550 and 604 nm. Polarographic assays, however, showed that while the enzyme from both treated groups displayed the characteristic biphasic kinetics, there was reduced activity in the enzymes from the brain of rabbits receiving the adjuvant but not the saline solution. This result is significant in light of the fact that several researchers have reported reduced activity of COX from Alzheimer's disease (AD) patients. Of particular significance, BAEP results reveal an increase in the interpeak latency between peaks III and V of the Holt's injected but not the saline injected or control rabbits. This latter result suggests that monitoring the BAEP might provide a simple non-invasive method for confirming AD. (AU)

Determination of nerve conduction velocity distribution from sampled compound action potential signals.

The sampled compound action potential (CAP) data sequence was expressed as the circular convolution of the delay sequence and the sampled single fiber action potential (SFAP) data sequence. An algorithm, based on Hirose's method [1], was then developed to separate the delay sequence from the sampled CAP data sequence, and the nerve conduction velocity distribution (NCVD) was consequently calculated from the delay sequence. The NCVD was found to be the product of the amplitude of the SFAP and the number of fibers. Simulations show that the estimated results were in good agreement with the calculated results. Experiments were performed on ten sciatic nerves from five bullfrogs (Rana pipens) using two independent variables: interelectrode distance and stimulus current strength. The results estimated from CAP's recorded under each condition reflect the corresponding feature of NCVD of the condition. The advantage of the technique is to provide detailed information about both slow and fast conducting fibers. This technique also offers the possibility to directly calculate the nerve fiber diameter distribution from the sampled CAP data sequences.

Clinical signs of ivermectin toxicity and the efficacy of antigabaergic convulsants as antidotes for ivermectin poisoning in epileptic chickens.

The clinical signs of ivermectin toxicity were determined in 6 groups of 10 epileptic and 8 non-epileptic chickens for 72 h after dosing with sc injections of 5.0, 7.5, 10.0, 12.5 or 15.0 mg ivermectin/kg bw. At the 5.0 mg/kg dose, mild diarrhea developed 4 h post-dosing and lasted until the end of the 72-h monitoring period. With higher doses of ivermectin body weight, egg production and feed and water consumption were markedly reduced. Severe diarrhea, mydriasis, bradypnea, ataxia, sedation, coma and death occurred with the highest dose of ivermectin. No differences in the signs of ivermectin toxicity were observed between epileptic and non-epileptic chickens. To assess the efficacy of the antiGABAergic convulsants, methyl-beta carboline-carboxylate (beta-CCM), picrotoxin and pentylenetetrazol (PTZ), as antidotes for ivermectin toxicity, 8 epileptic and 6 non-epileptic chickens/treatment group were given dosages of each convulsant which previously induced convulsions in 50% (ED50) and again in 100% (ED100) of treated chickens. These convulsants were given 6 h after dosing with 15.0 mg ivermectin/kg. The ED100 dosages of picrotoxin and PTZ alleviated mydriasis and sedation, but did not reduce the diarrhea. The ED50 dose convulsants were not effective in reducing or alleviating ivermectin toxicity, nor was alleviation of any sign of ivermectin toxicity obtained with any dosage of beta-CCM. Although the dosages of these antiGABAergic convulsants used normally produced convulsions in epileptic and non-epileptic chickens, no convulsions were observed in chickens with ivermectin toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Inheritance of myotonic discharges in American quarter horses and the relationship to hyperkalemic periodic paralysis.

Electromyography (EMG) was used to detect myotonic discharges in Quarter Horse breeding stock and to follow the results of mating horses with hyperkalemic periodic paralysis (HPP). The studies were performed on two brood mare farms. A total of six breeding stock showed myotonic discharges and 15 were nonmyotonic. Myotonic discharges were seen in five of six horses belonging to the blood line previously implicated as being predisposed to HPP. Two of these horses had shown clinical signs of HPP. Only one of 15 breeding horses unrelated to the HPP predisposed blood line showed myotonic discharges. When both parents were non-myotonic on EMG than the F1 generation (n = 6) were also nonmyotonic. When a stallion with HPP and myotonic discharges was mated to eight nonmyotonic mares over a six year period half the animals of the F1 generation (n = 25) showed myotonic discharges. When both parents showed myotonic discharges four F1 offspring were myotonic and two were nonmyotonic on EMG testing. There was no evidence of sex linkage. The results are consistent with an autosomal dominant mode of inheritance. Hyperkalemic periodic paralysis and myotonic discharges on EMG may be different manifestations of the same underlying defect.

Pharmacological relaxation of the urethra in male cats: a study of the effects of phenoxybenzamine, diazepam, nifedipine and xylazine.

Urethral pressure profiles (UPPs) were recorded in ten adult healthy male cats before and after administration of either phenoxybenzamine, diazepam, nifedipine or xylazine. A significant decrease (p less than 0.05) in urethral pressure at the level of the prostate was observed following treatment with all drugs. Xylazine produced a significant decrease in urethral pressure 4 to 7 cm from the tip of the penis in healthy male cats. None of the drugs used decreased urethral pressure in the zones of pure striated muscle or pure smooth muscle in these cats, making current recommendations for pharmacological management of urethral spasm suspect. Further studies are necessary to evaluate clinical cases of urethral spasm and to study the effects of these drugs on the urethral pressure of cats suffering from this spasm.

Use of electromyography for the diagnosis of equine hyperkalemic periodic paresis.

The use of electromyography (EMG) as a diagnostic aid for equine hyperkalemic periodic paresis (EHPP) was investigated in seven affected and seven control horses. Affected horses were confirmed positive for EHPP either by elevated serum potassium concentration with clinical signs of myotonia, or by inducing hyperkalemia and clinical signs using oral potassium chloride challenge. All horses were asymptomatic at the time EMG was performed, using bipolar fine wire needle electrodes. The myopotentials were recorded on magnetic tape and displayed on paper charts for analysis. Insertional and resting activity were recorded from the right supraspinatus, triceps, extensor carpi radialis and gluteal muscles in standing horses. Myotonic discharges were seen in six of seven affected horses but not in any of the controls. All seven affected horses and two control horses had prolonged insertional activity. Five out of seven affected horses and one control horse displayed spontaneous motor unit discharges unrelated to recording electrode movement. Myoelectrical potentials containing closely timed muscle potentials, i.e. doublets, were found in all affected horses, with four of seven affected horses also showing triplets. These potentials were not observed in any of the controls. No obvious difference in activity was observed among the four muscle sites tested. It is concluded that EMG is a safe and useful tool for diagnosing EHPP in horses not currently displaying clinical signs. Myotonic discharges and doublets appear to be the most diagnostically significant electromyographic abnormalities in EHPP affected horses.

The effects of thiamin on the neurophysiological alterations induced by lead.

The neurophysiological and histopathological alterations were evaluated in Sprague-Dawley rats exposed to 1,000 ppm lead in drinking water and treated with thiamin (25 mg/kg or 50 mg/kg bw), calcium ethylenediamine tetraacetic acid (CaEDTA) (50 mg/kg bw) or their combination for 8 weeks. Alterations in the brain-stem auditory evoked responses (BAERs) were observed during the treatment period. Latency periods associated with the BAERs were increased after 4 weeks of lead exposure. The neurophysiological alterations induced by lead exposure were prevented by thiamin or CaEDTA treatment. The latency periods in the lead exposed rats treated with thiamin, CaEDTA or the combined treatment did not increase in a similar fashion, but resembled more closely the latency periods observed in the rats which were not exposed to lead. The higher dose of thiamin (50 mg/kg) was more effective than the lower dose (25 mg/kg) in the comparable treatment groups. Histopathological examination of the animals did not reveal any pathological changes in the brain, although lesions often associated with lead toxicity were observed in the kidney. The severity of the lesions was not influenced by thiamin or CaEDta treatment. The absence of morphological damage in the CNS in the presence of neurophysiological alterations, indicates that functional deficits may be observed prior to histological evidence of pathological damage.

Effects of high dietary sulfur on brain functions using evoked potentials technique.

Brain stem auditory-evoked response (BAER) is a noninvasive technique used for detecting neurophysiological abnormalities of the brain stem along the auditory pathway. Brain stem auditory-evoked response recordings were obtained from subcutaneous skin electrodes from two control sheep and 22 other sheep fed high sulfur (S) diets with low or high concentration of thiamine (B1), copper (Cu), and molybdenum (Mo). At least four peaks (I,II,III,IV) of varied amplitude were observed in all animals. Neurophysiological abnormalities due to decreased conductivity and/or excitability of nerve fibers along the auditory pathway were found on the BAER recordings of sheep fed high S diet. Abnormalities of peaks and interpeak latencies within BAER recordings were related to histopathological observations of brain stem lesions. Lesions in the areas of the cochlear nuclei and lateral lemniscus were seen in conjunction with altered BAER components. However, abnormalities in BAER recordings and lesions in the brain stem also occurred in the absence of overt clinical signs. Analysis of interpeak latencies between peaks I and IV revealed significant differences among dietary groups. Sheep given diets low in Cu, Mo, and B1 were affected most. Factorial analysis indicated B1 and interactions among Cu, Mo, and B1 as significant factors influencing interpeak latencies.

Loss of forestomach motility in sheep experiencing ruminal lactic acidosis is not dependent on duodenal acidification by lactic acid.

Reticuloruminal motility, duodenal myoelectrical activity, and the pH and lactic acid concentrations of ruminal and duodenal contents were monitored in rumen fistulated sheep that were intraruminally loaded with finely ground wheat (50 g/kg). Following ruminal loading, reticuloruminal motility was enhanced. However, within 6 hours of loading, forestomach motility was impaired and within 9 hours ruminal stasis occurred. During loss of forestomach motility, lactic acid concentrations in ruminal contents increased and may, in part, have contributed to the decrease in pH of ruminal fluids. The levels of lactic acid within duodenal contents also rose, however, the pH of duodenal contents remained unchanged. During the loss of reticuloruminal motility, premature regular spiking activity (RSA) and/or abnormal patterns of migrating myoelectric complexes (MMC) were not observed on the duodenum. These findings indicate that loss of forestomach motility in ruminal lactic acidosis may not be a consequence of acidification of the proximal duodenum by lactic acid produced in the forestomach.

Involvement of serotonergic mechanisms in the disruption of ovine duodenal migrating myoelectric complex cycles by duodenal acidification.

Infusions of 1 and 4 mmol of HCl (pH 2.0) into the duodenal bulb of conscious sheep, within 30% of the period of the migrating myoelectric complex (MMC) cycle, induced aborally propagated premature phases of regular spiking activity (RSA) on the proximal duodenum. A transient inhibition of reticular contractions and a shortening of the period of subsequent duodenal MMC cycles were obtained with infusions of 4 mmol of HCl but not with infusions of 1 mmol. When the animals were pretreated with the 5-hydrotryptamine (5-HT) antagonists, ritanserin (0.2 mg/kg) and metergoline (0.5 mg/kg), 15 min before duodenal infusions of 4 mmol of HCl, premature RSAs and inhibition of reticular contractions were still elicited, but shortening of the subsequent duodenal MMC cycles did not occur. It is concluded that the shortening of duodenal MMC cycles induced by duodenal infusions of 4 mmol of HCl involved a serotonergic mechanism incorporating 5-HT2 receptors. The premature duodenal RSA and inhibition of reticular motility also elicited by these infusions appeared to be independent of this serotonergic system.

Ruminal lactic acidosis: forestomach epithelial receptor activation by undissociated volatile fatty acids and rumen fluids collected during loss of reticuloruminal motility.

Forty-three reticuloruminal epithelial receptors, with excitatory receptive fields within the reticulum, were isolated in 19 anaesthetised sheep. The responsiveness of these receptors to acetic, propionic, butyric and DL-lactic acids were assessed as well as their ability to be activated by rumen fluids obtained from sheep with induced ruminal lactic acidosis. Eighteen (41.9 per cent) receptors were excited by all three volatile fatty acids (VFAs) and 17 (39.5 per cent) responded to two VFAs. Butyric acid was the most potent volatile fatty acid eliciting responses in 41 (95.3 per cent) receptors. Acetic acid activated 33 (76.7 per cent) receptors and propionic acid excited 22 (53.5 per cent) receptors. DL-lactic acid only activated 13 (30.2 per cent) receptors, six of which required concentrations of 200 mM to be activated. Rumen fluids obtained when forestomach motility was impaired, activated 37 (81.1 per cent) of the 43 receptors, whereas rumen fluids obtained when forestomach motility was normal did not activate any receptors. Despite the high levels of lactic acid in rumen fluids which activated epithelial receptors, this acid was not responsible for receptor excitation.

Effects of various high-fat diets on myocardial contractility and morphology in rats.

The effects of various high-fat diets (20% w/w) containing commercially available fats and oils (butter, corn oil, corn oil margarine, canola oil, canola oil margarine, soybean oil, soybean oil margarine, sunflower oil, sunflower oil margarine) on myocardial contractility and morphology and on plasma lipids were investigated in male Sprague-Dawley rats fed the diets for 16 weeks. Diets containing corn oil caused significantly (P less than or equal to .05) higher plasma total cholesterol levels than diets containing butter. Significant differences were also determined in lipoprotein levels. Plasma triglyceride levels were significantly (P less than or equal to .05) higher with butter than with sunflower oil or sunflower margarine. No significant differences among the groups occurred in blood pressure, heart rate, or myocardial contractility. Histological evaluation revealed that animals fed canola oil had the highest incidence and severity of myocarditis and fibrosis and that the degree of cardiac lipidosis was not correlated to the erucic-acid content of the diet. Myocardial damage was significantly (P less than or equal to .05) negatively correlated with stearic and palmitic acids and positively correlated with oleic acid. The results indicate that diets low in saturated fats may have adverse long-term effects on the heart.

Hexamethonium: a probe to assess autonomic nervous system involvement in upper gastrointestinal functions in conscious sheep.

Hexamethonium, which inhibits cholinergic transmission by preventing acetylcholine release, has been considered an ideal reference drug for the blockade of autonomic ganglia, Auerbach plexus and reflex gastrointestinal secretions. The degree of inhibition of ruminant gastrointestinal functions with this reference drug were as follows: cyclical contractions of the reticulo-rumen and abomasal motility greater than gastric acid secretion and duodenal migrating myoelectrical complexes. Although reduced at high dosages, the initiation of migrating myoelectric complexes was enhanced at clinically used dosages. The duration of the inhibition of reticular contractions was dose-related varying from 0.5 to 5 h for 1.25 to 20 mg/kg subcutaneously. Abomasal motility and acid secretion were similarly reduced but exhibited strong and long-lasting rebound effects. Inhibition of the reticulum by the blockade of muscarinic receptors by atropine was also dose-related lasting from 0.5 to 3 h for 0.5 to 2 mg/kg, whereas inhibition of the abomasal motor and secretory functions lasted from 1 to 6 h. These results suggest a higher degree of impingement of the parasympathetic pathways on abomasal acid secretion and motility than on the cyclical activity of the reticulum and only a modulatory role of the extrinsic neural activity on the cyclical motor events of the duodenum.

Anticonvulsant effects of ivermectin in genetically-epileptic chickens.

In genetically-photosensitive epileptic chickens, the anti-parasitic agent ivermectin, at 1.0 and 5.0 mg/kg, decreased or prevented seizures induced by intermittent photic stimulation without any side-effects on the central nervous system. The latency and duration of this anti-convulsant effect was dose-dependent. When combined with diazepam, ivermectin prolonged the anti-convulsant action of diazepam.

Forestomach epithelial receptor activation by rumen fluids from sheep given intraruminal infusions of volatile fatty acids.

Forty-four reticuloruminal epithelial receptors were tested with rumen fluids obtained from 12 sheep before they were intraruminally infused with 4.0M acetic acid (8 sheep) or 4.0M butyric acid (4 sheep; preinfusion rumen fluid) and with rumen fluids obtained at the onset of ruminal stasis (abolition rumen fluid). The preinfusion rumen fluids from the 8 acetic acid-infused sheep (mean pH, 6.55) contained 1.7 mM nondissociated volatile fatty acids (VFA)/L and excited none of the 25 receptors tested. Preinfusion rumen fluids from the 4 butyric acid-infused sheep (mean pH, 6.98) contained 0.3 mM nondissociated VFA/L and also did not evoke responses in any of the 19 receptors tested. Abolition rumen fluids from sheep treated with acetic acid excited 17 of the 25 receptors tested and contained 89.4 mM nondissociated VFA/L, of which nondissociated acetic acid comprised 85.0 mM/L. Abolition rumen fluids from sheep treated with butyric acid activated 14 of the 19 receptors tested and contained 61.1 mM nondissociated VFA/L, of which 38.7 mM/L was nondissociated butyric acid. Preinfusion rumen fluids whose pH values were adjusted to that of abolition rumen fluids with HCl contained nondissociated VFA levels ranging from 16.3 mM/L (acetic acid-treated sheep) to 20.6 mM/L (butyric acid-treated sheep) and elicited responses in 4 of 30 receptors tested. Preinfusion rumen fluids whose pH values were adjusted to the pH value of abolition rumen fluid with acetic acid contained 29.5 mM nondissociated VFA/L and excited 7 of 13 tested receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Ruminal lactic acidosis: relationship of forestomach motility to nondissociated volatile fatty acids levels.

Ruminal lactic acidosis was produced in 9 overnight fasted rumen-fistulated sheep by placing ground wheat (40 g/kg of body weight) into the rumen. Ruminal stasis occurred within 8 hours of grain engorgement in 6 sheep (early stasis group) and between 10 and 12 hours in the remaining 3 sheep (late stasis group). The initial impairment to forestomach motility was a decrease in the mean frequency of reticulo-ruminal contractions which occurred within 4 hours of the intraruminal placement of wheat in the early stasis group and within 6 hours in the late stasis group. Since blood pH, carbon dioxide pressure, and serum bicarbonate were all normal, systemic acidosis was not a contributing factor to this decrease in contraction frequency. The concentrations of total nondissociated volatile fatty acids (VFA; acetic, propionic, and butyric acid) in ruminal fluid, however, were significantly increased, being 13.60 mM/L (mean, pH 4.92) in the early stasis group and 15.77 mM/L (pH 4.80) in the late stasis group. Free DL-lactic acid in ruminal fluids was 6.37 +/- 6.1 mM/L (mean +/- SD) in the early stasis group and 9.72 +/- 4.2 mM/L in the late stasis group. A reduction in contraction amplitude was observed within 6 hours of grain engorgement in the early stasis group and within 8 hours in the late stasis group. At these times, the concentrations of nondissociated VFA were 10.19 mM/L (pH 4.46) in the early stasis group and 10.52 mM/L (pH 4.62) in the late stasis group. The ruminal values of free DL-lactic acid were 13.93 mM/L in the early stasis group and 16.14 mM/L in the late stasis group.(ABSTRACT TRUNCATED AT 250 WORDS)

Modification of nocturnal spontaneous and adrenergic-induced feeding in the rat following either A5 or A7 lesions.

The ingestive profiles of intact, A5 and A7 damaged animals were examined during the 2-hr nocturnal period following onset of the dark cycle. A5, A7 and intact rats consumed comparable amounts of food following initial access to food nocturnally. Sebsequent feeding declined in A5 animals below control values and failed to return to baseline at the end of the nocturnal period examined. A7 damaged rats appeared more resistant to the appetite suppressing effects of initial meal taking and consumed more food than control animals. Only A5 damaged rats were noted to be hyperdipsic during the immediate 10 postoperative days. Intracranial injection of 1-norepinephrine bitartrate (10 ug/ul) into the paraventricular nucleus (PVN) of the hypothalmus produced a reliable facilitation of feeding in A5, A7 and intact rats during the first hour of the dark cycle. A5 rats exhibited the largest increase in feeding elicited by NE administration into the PVN. This feeding response was observed in rats with A5 lesions regardless of whether testing was carried out during the initial hours of the dark cycle or during a predetermined "satiation" test. A5 lesions also effected a marked hyperglycemia while A7 lesions were ineffective in this respect. Taken together these data suggest the A5 and A7 cell groupings regulate spontaneous feeding within a rostrally coursing feeding circuitry and appear to interact with the PVN in the elicitation of noradrenergic feeding.

Dust levels in a riding stable.

Over a period of 4 months, in winter, the mean concentration of airborne particles in the ambient air of a riding stable was 0.41 mg/m3. This value was significantly higher than that found outdoors (0.04 mg/m3). During the day, levels of airborne particles were highest when stalls were cleaned and soiled bedding from the previous night replenished, and lowest when all stable activities had ceased. Fine particles, capable of entering the pulmonary alveoli, constituted 30 to 40 per cent of the total mass concentration of airborne particles.