Relationships between faecal dry matter, worm burdens and inflammatory mediators and cells in parasite-resistant Merino rams.

Immune-mediated scouring due to ingested parasite larvae is a major concern for sheep producers in Mediterranean climates. We investigated immune-mediated scouring in parasite-resistant Merino sheep in Australia. Forty-adult, parasite-resistant Merino rams were judged to be either susceptible or non-susceptible to immune-mediated scouring on the basis of dag scores taken under field conditions. We hypothesised that the susceptible rams would have lower faecal dry matter during larval challenge than non-susceptible rams and that, at post-mortem examination, inflammatory mediators and granulocytes would be negatively correlated with both faecal dry matter and worm numbers. In pens, the rams received a dose of 500 Teladorsagia circumcincta L(3) and 500 Trichostrongylus colubriformis L(3) each day for 6 weeks before euthanasia. Ten rams acted as unchallenged controls. Challenging sheep with larvae reduced faecal dry matter at 2, 3 and 4 weeks after challenge began and the greatest reductions were with the sheep susceptible to scouring. The sheep showed good resistance to the parasite challenge as evidenced by low faecal worm egg counts and low total worm counts at post-mortem, with the numbers of T. colubriformis particularly low. Sheep with low faecal dry matter had significantly higher numbers of eosinophils in small intestine tissue. Sheep with low total worm counts had significantly higher levels of bradykinin in abomasum mucus. Sheep with more granulocytes in tissue and inflammatory mediators in mucus tended to have fewer numbers of T. circumcincta but there was little relationship with numbers of T. colubriformis. Our results show that dag scores are correlated to a reduction in faecal dry matter, which can be attributed to the challenge with infective parasite larvae. Inflammation during worm infection is associated with rejection of the worm challenge and may result in more fluid faeces and consequently diarrhoea. Therefore, sheep breeders should focus on breeding for both low worm egg counts and also low dag scores.

Faecal dry matter, inflammatory cells and antibodies in parasite-resistant sheep challenged with either Trichostrongylus colubriformis or Teladorsagia circumcincta.

Sheep that are highly resistant to parasitic nematodes can suffer bad diarrhoea due to the inflammation associated with rejection of ingested larvae from pasture. We hypothesised that challenging parasite-resistant sheep indoors with nematode larvae would result in reduced faecal dry matter, and that faecal dry matter would be lowest in sheep challenged with a mixture of Trichostrongylus colubriformis and Teladorsagia circumcincta compared to those challenged with either species alone. We also hypothesised that inflammatory cells and serum antibodies and interleukin-5 would be highest in those sheep that received the mixed larval challenge. We found that faecal dry matter was reduced (P<0.05) in challenged sheep compared to unchallenged sheep, with the fastest reduction being in those sheep challenged with only Tric. colubriformis. At 14 and 23 days after challenge began, there were no differences in faecal dry matter between the three challenged groups. Within the abomasum, there were no differences in inflammatory cell numbers between unchallenged sheep and those challenged only with Tric. colubriformis. Cell numbers in sheep challenged with Tela. circumcincta were higher (P<0.05) than those in unchallenged sheep, but there were no differences between sheep challenged only with Tela. circumcincta or as a mixed challenge. In the small intestine, inflammatory cell numbers were higher (P<0.05) in sheep that received the mixed challenge compared to controls. Cell numbers in sheep challenged with either Tela. circumcincta or Tric. colubriformis were also slightly higher than those in controls. Larval challenge increased (P<0.05) levels of IgA and IgE in serum, but there were no differences between the three challenged groups. Larval challenge also increased (P<0.05) levels of IL-5, with the greatest increase being in those sheep challenged with both species. We concluded that both Tela. circumcincta and Tric. colubriformis can cause immune-mediated diarrhoea in sheep, and that a mixed challenge will not necessarily lead to worse diarrhoea or higher concentrations of antibodies in serum. We also concluded that challenge with Tric. colubriformis leads to no inflammation in the abomasum, but challenge with Tela. circumcincta may lead to some inflammation in the small intestine.

Gas exchange patterns of bumble bee foragers before and after exposing to lowered temperature.

The gas exchange patterns are known to vary between insect species, individuals and even intra-individually. Using volumetric-manometric and flow-through respirometry combined with IR-actography we studied how periods of low temperature affect the respiratory patterns of bumble bee Bombus terrestris foragers. We have shown, in this study, that there is a change in the respiratory patterns of individual B. terrestris foragers after exposing to low temperatures. The bumble bees seemed to become more inactive. The different respiratory patterns appeared in succession and the transition from one pattern to another was associated with the change from an active to a resting state. Typical patterns after exposition to low temperature were discontinuous gas exchange cycles (DGCs).

Dietary exposure of pregnant ewes to salt dictates how their offspring respond to salt.

We investigated changes in salt preference, food and water intake, renin activity and salt excretion in adult offspring from ewes that were fed a high-salt diet (14% NaCl, high-salt offsrping) or grazed saltbush (saltbush offspring) from day 60 of pregnancy until day 21 of lactation. High-salt offspring were compared to offspring born to ewes consuming a control diet (2% NaCl) and saltbush offspring were compared to offspring from ewes which grazed a control diet of dry pasture. All offspring were weaned at 3 months of age and grazed the same clover-based pasture until testing started at 8 months of age. The preference for a low-salt diet (0.5% NaCl) when offered with an alternative (7% NaCl) did not differ between the offspring groups. High-salt offspring and saltbush offspring had a lower food intake (14% and 27% respectively) and lower water intake (35% and 20% respectively) than their control offspring. Both high-salt offspring and saltbush offspring had lower basal renin activity than their respective controls. After consuming salt, the renin activity of the saltbush offspring continued to be lower than controls whereas the renin activity of the high-salt offspring became similar to controls. In general, the saltbush offspring excreted an oral salt load more rapidly, though this depended on the extent of the salt load. This important adaptation of offspring born to ewes that consumed saltbush during pregnancy may improve their ability to cope with high-salt diets such as saltbush when they consume it themselves. However, the high-salt offspring did not possess such beneficial adaptations.

Feeding pregnant ewes a high-salt diet or saltbush suppresses their offspring's postnatal renin activity.

If ewes consumed a high-salt diet or saltbush during the last 3 months of pregnancy and for 3 weeks after birth, we expected the renin activity of their lamb to be suppressed at birth and at 3 weeks of age. We also expected an increase in the concentration of cations other than sodium in the ewe's milk and an increase in the plasma Na concentration of the lamb at birth. To test these hypotheses, Merino ewes were fed a high-salt diet (14% NaCl) in an animal house and compared to control ewes eating a control diet (2% NaCl). In addition, we compared ewes grazing saltbush (about 13% salt in diet) to ewes grazing pasture from day 60 of pregnancy to 3 weeks after birth. Lambs born to ewes consuming saltbush had 85% lower (P < 0.001) renin activity than offspring from ewes consuming pasture at 3 weeks of age. Similarly, lambs born to ewes consuming a high-salt diet had 20% lower renin activity at birth and 3 weeks (P = 0.07). Feeding ewes a high-salt diet or saltbush altered the mineral composition of the milk; the largest change was a 10% increase in K levels (P 0.05). Consuming a high-salt diet or saltbush lowered the plasma Na of ewes at 130 days of gestation (by 3-5 mmol/l; P < 0.001), but only lambs from ewes fed the high-salt diet had a lower plasma Na at birth (P < 0.05). Suppression of the renin activity of lambs could lead to permanent physiological changes in salt balance in later life.

The separation of two hymenopteran parasitoids, Tersilochus obscurator and Tersilochus microgaster (Ichneumonidae), of stem-mining pests of winter oilseed rape using DNA, morphometric and ecological data.

Tersilochus obscurator Aubert and Tersilochus microgaster (Szépligeti) are larval endoparasitoids of economically-important stem-mining pests of winter oilseed rape (Brassica napus L.) in Europe. They are difficult to separate morphologically. Their hosts are Ceutorhynchus pallidactylus (Marsham) and Psylliodes chrysocephala Linnaeus, respectively. The parasitoids' taxonomic status, identification, host range and phenology were studied using genetic, morphometric and ecological data. The study used 527 female parasitoids from the UK and Germany, either field-collected in emergence traps or reared from field-collected host larvae. Two morphometric characters, the ovipositor sheath to first metasomal tergite ratio and the percentage of the mesopleuron spanned by the sternaulus, were measured. A 440 bp section of mitochondrial DNA cytochrome oxidase subunit I (COI) gene was sequenced from 35 parasitoids reared from C. pallidactylus, 20 reared from P. chrysocephala and individuals from two outgroups, Tersilochus heterocerus Thomson and Phradis interstitialis Thomson. Distinct and invariable COI sequences corresponded exclusively to each parasitoid group, confirming that T. obscurator and T. microgaster are discrete species. Measurements of host-reared and COI-sequenced specimens indicated that the ranges of both morphometric characters overlapped between species. Using these ranges as criteria, all but 3.6% of UK specimens and 2% of German specimens were identifiable to species without reference to host or phenology. There were differences in emergence phenology in the UK, adult T. microgaster emerging from winter diapause by 29 March 2000, T. obscurator emerging between 12 April and 24 May 2000. The value of molecular techniques in the identification of closely-related parasitoid species is discussed.

Identification of the gland secreting oviposition-deterring pheromone in the cabbage seed weevil, Ceutorhynchus assimilis, and the mechanism of pheromone deposition.

After laying an egg into a pod of Brassica napus, the female cabbage seed weevil, Ceutorhynchus assimilis, brushes the caudal setae of the eighth abdominal tergite (VIII UT) on the host pod as she walks along it, depositing oviposition-deterring pheromone (ODP). The VIII UT is periodically extended and withdrawn, thus repeatedly rubbing against the posterior fold of the seventh urotergite (VII UT) which bears the individual outlets of glandular epidermal cells. In post-diapause, sexually mature, gravid (i.e. oviferous) females (virgin or mated) the cells of this VII UT gland were hypertrophic, showing intense secretory activity. Extracts of VII UT from these individuals elicited strong electrophysiological responses from antennal club gustatory sensilla and deterred oviposition. In pre-diapause (sexually immature) females, the cells of the VII UT gland were neither hypertrophic nor active and an extract of their VII UT elicited no significant electrophysiological or behavioural response. Extract of female rectum was a less potent oviposition deterrent than VII UT extract and elicited an electrophysiological response similar to male rectum extract. An extract of ovarian calyces and ovaries elicited no behavioural response. We conclude that ODP is secreted by the epidermal cells of the VII UT posterior fold.

Body composition at farrowing and nutrition during lactation affect the performance of primiparous sows: I. Voluntary feed intake, weight loss, and plasma metabolites.

We used 35 primiparous sows to investigate the link between body fatness at farrowing and voluntary feed intake (VFI) during lactation. Two groups of sows were fed differently throughout gestation (either 2.3 kg/d of a diet containing 5.8% CP and 14.6 MJ DE/kg as fed or 1.7 kg/d of a diet containing 15.6% CP and 14.5 MJ DE/kg as fed) so that they commenced lactation at a similar body weight (158 to 152 kg) but with different body compositions: either 340 (fat) or 280 (lean) g of body fat/kg BW (P < .001). During lactation, sows were offered either a low-protein diet (7.9% CP and 15.5 MJ DE/kg as fed) or a high-protein diet (19.0% CP and 15.6 MJ DE/kg as fed) on an ad libitum basis. During lactation, VFI was measured daily, and sow body weight and backfat were measured weekly. Blood samples were collected from sows on d 110 of gestation and d 14 and 28 of lactation, and plasma was analyzed for NEFA, glycerol, insulin, glucose, and beta-hydroxybutyrate. Fat sows ate 30% less than their lean counterparts during lactation (P < .001), which corresponded to a 70% higher concentration of NEFA in plasma (P = .01) and a 30% higher concentration of glycerol (P = .15). The VFI during the first 2 wk of lactation was affected only by body fatness and not by the protein content of the lactation diet. The dietary supply of protein influenced VFI during wk 3 and 4 of lactation, possibly by affecting milk production and hence the drive to consume feed. Weight loss, particularly lean tissue loss, was minimized by feeding the high-protein diet during lactation (P < .002).

Body composition at farrowing and nutrition during lactation affect the performance of primiparous sows: II. Milk composition, milk yield, and pig growth.

Sows that were either fat or lean at farrowing (340 or 280 g of body fat/kg BW, respectively) were offered either a low-protein (LP; 7.9% CP and 15.5 MJ DE/kg as fed) or a high-protein (HP; 19.0% CP and 15.6 MJ DE/kg as fed) diet on an ad libitum basis throughout a 4-wk lactation to test the hypothesis that the amount of milk and its composition are responsive to the supply of endogenous (body reserves) and exogenous (diet) substrates. Pigs were weighed at birth and weekly during lactation, milk yield was estimated using deuterium oxide in early (d 4 to 8) and late lactation (d 24 to 28), and milk samples were collected to determine composition in early (d 4 to 6) and late lactation (d 25 to 27). Throughout lactation, milk yield and composition were mainly associated with differences in litter size. Milk yield was about 15% higher in lean than in fat sows and in sows fed HP rather than LP, but large CV (17 to 32%) prevented these differences from attaining significance (P > .273). The responses in milk yield were reflected in pig growth. Differences in milk composition between treatment groups were not significant; however, during early lactation there was a tendency for fat sows to produce milk with a fat content 21% higher, and a protein content 12% lower, than that of lean sows. Changes in the protein:energy ratio of milk during the course of lactation and small changes in milk yield composition collectively suggested that in early lactation, sow body composition affected milk production but, as lactation progressed, the dietary supply of precursors for milk synthesis became more important.

Feeding lactating primiparous sows to establish three divergent metabolic states: I. Associated endocrine changes and postweaning reproductive performance.

We investigated effects of different metabolic states on reproductive performance in lactating, primiparous sows. Sows were fed ad libitum (AL; n = 12), alimentated via a gastric cannula to 125% of AL feed intake (SA; n = 8), or restricted (R; n = 9) to 50% of AL from d 1 to 28 of lactation. At weaning, all sows were fed 2.5x maintenance energy requirements until standing heat and then fed twice maintenance energy requirement until slaughter. Sow weight, backfat, and litter weights were recorded weekly. After weaning, sows were tested twice daily for the onset of estrus and inseminated twice using pooled semen. At d 28 of gestation, sows were slaughtered, and the reproductive tracts were recovered to determine ovulation rate and embryo survival. Intensive blood sampling was performed before and after weaning for 12-h periods to characterize changes in plasma LH, insulin, and IGF-I. After weaning, additional samples were taken to monitor changes in LH and progesterone. Insulin and IGF-I were determined at standing heat. During lactation, AL and R sows lost, whereas SA sows gained, body weight and backfat (P < .001). Litter growth rates did not differ among treatments. Although plasma insulin was not different among treatments, plasma IGF-I concentration was lower (P < .001) in R sows. Mean LH and pulse frequency before (P < .03 and P < .06, respectively) and after (P < .001; for both) weaning were lower in R than in AL or SA sows. After weaning, SA sows lost more weight (P < .01) and backfat (P < .01) and ate less feed (P < .001) than AL or R sows. At standing heat, no differences in plasma IGF-I or insulin were observed, although energy balance for SA sows was lower (P < .01) than for AL or R sows. Weaning-to-estrus interval was extended (P < .02) in R sows. We observed no treatment difference in ovulation rate or embryo survival. Our results demonstrate that making sows anabolic during lactation did not ameliorate the negative impact of the suckling stimulus or improve fertility after weaning.

Feeding lactating primiparous sows to establish three divergent metabolic states: III. Milk production and pig growth.

First-litter sows fitted with stomach cannulas were used to test the hypothesis that making gilts anabolic during lactation by providing them with extra nutrition would increase milk production and pig growth. Gilts were allocated to one of three dietary treatments after farrowing: 1) restricted, sows were fed 50% of their estimated ad libitum intake; 2) ad libitum, sows were encouraged to eat as much feed as possible; and 3) superalimented, sows were infused seven times daily through their cannula to achieve a 25 to 30% increase in energy intake in excess of that achieved by sows fed on an ad libitum basis. Milk production was estimated in mid- (d 10 to 15) and late (d 21 to 25) lactation by a modification of the isotope dilution technique. Milk production was similar between treatments in mid- and late lactation (P > .05), and this was reflected in a similarity in weaning litter weight (P = .238). Milk composition was similar also (P > .05) between dietary treatments. Superalimentation provided gilts with 38% more energy (P < .001) than gilts fed on an ad libitum basis, and they accrued live weight (5.1 kg) and backfat (1.8 mm) during lactation (P < .001). These data provide evidence that, unlike multiparous sows that show an increase in milk yield when made anabolic during lactation, primiparous sows seem to partition extra energy into body growth rather than into milk production.

Feeding lactating primiparous sows to establish three divergent metabolic states: II. Effect on nitrogen partitioning and skeletal muscle composition.

We established an experimental model to study nitrogen (N) partitioning in lactating primiparous sows alimented to three levels of nutrient intake. Thirty-six sows fitted with a gastric cannula and fed a 15.4 MJ DE/kg and 18.6% CP diet were allocated to one of three treatments after farrowing: 1) ad libitum-fed; 2) restricted-fed to 55% of the ad libitum feed intake; and 3) superalimented to at least 125% of the ad libitum feed intake. These feed intakes were successfully achieved throughout lactation. Nitrogen balance was studied for three 5-d periods starting on d 2, 11, and 19 of lactation, and a triceps muscle biopsy was taken on d 26. For all treatments, N intake increased, milk N production increased, urinary N losses decreased, but fecal N losses increased as the 28-d lactation progressed. Restricted-fed sows had the lowest fecal N and urinary losses and mobilized the most maternal protein (-23.0 vs -7.4 +/- 6.5 g N/d for ad libitum-fed sows) during lactation. As a consequence of these economies, and extensive protein mobilization, restricted-fed sows were able to maintain milk N production similar to that of sows on the other treatments. Superalimented sows did not mobilize protein, had the poorest protein digestibility, directed the least digestible N toward milk (40.1 vs 78.3% in restricted-fed sows), and produced amounts of milk N similar to those produced by sows on the other treatments. The treatment differences in N retention measured by N balance were reflected in differences in skeletal muscle variables and urinary creatinine. Skeletal muscle cell size (protein:DNA ratio) and protein synthetic capacity (RNA:DNA ratio) increased in response to feed intake. The protein:DNA ratio increased (P < .01) linearly and the RNA:DNA ratio increased (P < .05) in a curvilinear manner. These data suggest that primiparous sows partition additional retained N toward their maternal reserves rather than milk N. They also suggest that sows fed inadequate N intakes maintain milk production by mobilizing maternal protein reserves. Such sows also conserve maternal N during lactation, possibly by reducing muscle protein synthesis.

Maintenance of villus height and crypt depth, and enhancement of disaccharide digestion and monosaccharide absorption, in piglets fed on cows' whole milk after weaning.

The aims of the present study were (a) to maintain the structure and function of the small intestine of the piglet after weaning, and (b) to compare the capacity in vivo of sucking and weaned piglets to digest oral boluses of lactose and sucrose and absorb their monosaccharide products. Piglets were fed on cows' whole milk ad libitum every 2 h for 5 d after weaning. Physiological doses of lactose plus fructose (treatment LAC+FRU) and sucrose plus galactose (treatment SUC+GAL) were administered on day 27 of lactation and on the fifth day after weaning, after which time piglets were killed. Villus height and crypt depth were maintained (P > 0.05) by feeding cows' milk after weaning. The areas under the curves (AUC) for galactose and glucose, adjusted for live weight and plasma volume, increased (P < 0.05) after weaning. Despite the enhancement of gut function after weaning, the galactose index (GalI:AUC for galactose ingested as lactose divided by the AUC for the same dose of galactose ingested as the monosaccharide) and fructose index (FruI: AUC for fructose ingested as sucrose divided by the AUC for the same dose of fructose ingested as the monosaccharide), which are indices of digestive and absorptive efficiency, both decreased after weaning. This apparent anomaly may be reconciled by increased growth, and hence surface area, of the small intestine between weaning and slaughter such that 'total' digestion and absorption most probably increased despite apparent decreases in GalI and FruI. Positive correlations (P < 0.05) between villus height and GalI are consistent with the maximum activity of lactase occurring more apically along the villus. Significant linear relationships (P < 0.05) were recorded between villus height at the proximal jejunum and adjusted AUC for galactose and glucose following treatment LAC+FRU, and between villus height at the proximal jejunum and adjusted glucose AUC following treatment SUC+GAL. These relationships suggest that maximum digestion and absorption occurs at increasing distances along the crypt:villus axis in the weaned pig.

Increased tolerance to annual ryegrass toxicity in sheep given a supplement of cobalt.

To determine whether oral cobalt supplements could modify the clinical onset of annual ryegrass toxicity, groups (n = 5) of sheep were dosed orally with 0, 4 or 16 mg cobalt/day. After 3 weeks on this treatment, toxic ryegrass seed was added to their feed to provide 0, 0.15 and 0.30 mg corynetoxins/kg body weight, daily. Sheep receiving cobalt ingested 30% more toxin than did unsupplemented sheep before clinical signs developed (P = 0.03). There was no significant difference between groups receiving 4 and 16 mg cobalt. The results showed that cobalt delayed, but did not prevent, the onset of clinical signs of annual ryegrass toxicity.

Nutrition for optimizing breeding herd performance.

Modern sows are younger and leaner at time of mating and probably have poorer appetites than sows of 10 to 15 years ago. Therefore, feeding strategies should aim to minimize weight loss and maintain a sow's body condition throughout her reproductive life. The efficiency with which gilts are introduced into the breeding herd is as important in economic terms as is the efficiency with which the sow returns to estrus after weaning. Gilts should be selected at 50 to 60 kg, and fed a 16% protein diet ad libitum until mated at their second estrus, when they weigh 115 to 120 kg and have 17 to 20 mm backfat. Flushing gilts before the onset of second or third estrus increases ovulation rate of restricted gilts to the levels achieved by gilts fed ad libitum. During gestation, maintenance represents 75 to 85% of total energy requirements. The aim should be to achieve 20 to 25 mm backfat at farrowing. Increased feed intake from day 2 to 3 after mating will not increase embryo mortality. Feeding an extra 1 kg feed/sow/day for the last 10 days of gestation increases piglet birth weight slightly and prevents a loss of 1.5 to 2.0 mm of sow backfat. Wherever possible, sows should be fed ad libitum from the day after farrowing until weaning. Reduced feed intake by lactating sows, for whatever reason, results in excessive weight and condition loss. Excessive weight loss in lactation causes extended remating intervals, a lower percentage of sows returning to estrus within 10 days of weaning, reduced pregnancy rate, and reduced embryo survival. Ovulation rate is not affected by level of feed intake in lactation. It has been suggested that sows will have minimum weaning-to-service intervals when they weigh 150 kg or more at weaning. It is likely that the sow must be anabolic for about 10 days before she will exhibit postweaning estrus. The decision when to rebreed is made some time prior to weaning and is mediated by a host of substrates, hormones, and neurotransmitters. Sows with a delayed return to estrus also have a lower pregnancy rate and smaller subsequent litters. If sows lose considerable weight or condition during lactation, a high level of feeding in the postweaning period will improve embryo survival.

Nicotinamide ethers: novel inhibitors of calcium-independent phosphodiesterase and [3H]rolipram binding.

The synthesis and biological properties of a series of nicotinamide ethers are described. These compounds, structurally novel calcium-independent phosphodiesterase inhibitors, also inhibit the binding of [3H]rolipram to rat brain membranes and reverse reserpine-induced hypothermia in the mouse. Several compounds exhibited potent in vivo activity comparable to the standard agent, rolipram.

Correlation of brain levels of 9-amino-1,2,3,4-tetrahydroacridine (THA) with neurochemical and behavioral changes.

9-Amino-1,2,3,4-tetrahydroacridine (THA) has been reported to cause improvement in patients with senile dementia of the Alzheimer's type. We have examined some effects of THA in vitro and in vivo to define its mechanism of action. In vitro, THA inhibits acetylcholinesterase (AChE) (IC50 = 223 nM) and blocks [3H]AFDX-116 (M2) and [3H]telenzepine (M1) binding (IC50 s of 1.5 and 9.1 microM respectively). In vivo levels of THA were 10-fold higher in brain than plasma following 3.2 mg/kg i.p., a dose which was found to be active in reversing amnesia induced by scopolamine assessed in T-maze tests in rats and passive avoidance tests in mice. Additionally, these brain concentrations were above the IC50 of THA for AChE inhibition. THA (5.6-17.8 mg/kg i.p.) also elevated acetylcholine levels in the rat CNS. THA-induced side effects were blocked by the central muscarinic antagonist, scopolamine, but not by the peripheral antagonists methscopolamine and glycopyrrolate, nor by nicotinic antagonists. We conclude that brain AChE inhibition by THA is sufficient to explain its purported therapeutic activity in Alzheimer's disease and that its favorable brain/plasma distribution in vivo may account for its central cholinergic action without inducing the severe peripheral cholinergic effects typically seen with other AChE inhibitors.