Amine oxidase activity of ß-amyloid precursor protein modulates systemic and local catecholamine levels.

The catecholamines dopamine (DA), norepinephrine (NE) and epinephrine (E) are neurotransmitters and hormones that mediate stress responses in tissues and plasma. The expression of ß-amyloid precursor protein (APP) is responsive to stress and is high in tissues rich in catecholamines. We recently reported that APP is a ferroxidase, subsuming, in neurons and other cells, the iron-export activity that ceruloplasmin mediates in glia. Here we report that, like ceruloplasmin, APP also oxidizes synthetic amines and catecholamines catalytically (K(m) NE=0.27 mM), through a site encompassing its ferroxidase motif and selectively inhibited by zinc. Accordingly, APP knockout mice have significantly higher levels of DA, NE and E in brain, plasma and select tissues. Consistent with this, these animals have increased resting heart rate and systolic blood pressure as well as suppressed prolactin and lymphocyte levels. These findings support a role for APP in extracellular catecholaminergic clearance.

Suppressor of cytokine signaling-1 attenuates the duration of interferon gamma signal transduction in vitro and in vivo.

Suppressor of cytokine signaling-1 (SOCS-1) is a cytokine-inducible intracellular protein that functions to negatively regulate cytokine signal transduction pathways. Studies in vitro have shown that constitutive overexpression of SOCS-1 inhibits signaling in response to a range of cytokines, including interferons (IFN). Mice lacking SOCS-1 die from a complex disease characterized by liver degeneration and massive inflammation. Whereas there is clear evidence of increased IFNgamma signaling in SOCS-1(-/-) mice, it is unclear to what extent this is due to increased IFNgamma levels or to increased IFNgamma sensitivity. Here we have used SOCS-1(-/-) IFNgamma(-/-) mice, which remain healthy and produce no endogenous IFNgamma, to demonstrate that in vitro and in vivo hepatocytes lacking SOCS-1 exhibit a prolonged response to IFNgamma and that this correlates with a dramatically increased sensitivity to the toxic effects of IFNgamma in vivo. Thus, SOCS-1 is required for the timely attenuation of IFNgamma signaling in vivo.

SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine.

Mice lacking suppressor of cytokine signaling-1 (SOCS1) develop a complex fatal neonatal disease. In this study, SOCS1-/- mice were shown to exhibit excessive responses typical of those induced by interferon gamma (IFNgamma), were hyperresponsive to viral infection, and yielded macrophages with an enhanced IFNgamma-dependent capacity to kill L. major parasites. The complex disease in SOCS1-/- mice was prevented by administration of anti-IFNgamma antibodies and did not occur in SOCS1-/- mice also lacking the IFNgamma gene. Although IFNgamma is essential for resistance to a variety of infections, the potential toxic action of IFNgamma, particularly in neonatal mice, appears to require regulation. Our data indicate that SOCS1 is a key modulator of IFNgamma action, allowing the protective effects of this cytokine to occur without the risk of associated pathological responses.

Dietary fiber for dogs: III. Effects of beet pulp and oat fiber additions to dog diets on nutrient intake, digestibility, metabolizable energy, and digesta mean retention time.

The objective of this experiment was to determine whether alkaline hydrogen peroxide-treated oat hulls (termed oat fiber; OF) are nutritionally efficacious as a source of dietary fiber in meat-based dog foods. Thirty female English Pointers were assigned in a completely randomized design to isonitrogenous diets. Treatments were 1) control diet, 2) 7.5% added beet pulp (BP), and 3) 2.5, 4) 5.0, and 5) 7.5% added OF. Inclusion of 7.5% BP increased (P less than .05) DM intake and decreased (P less than .05) digestibility of DM and OM compared with the control. Dry matter intake increased (P less than .05) with increasing level of OF and digestibility of DM, OM, and total dietary fiber (TDF) decreased (P less than .05). Digestibility of DM, OM, and TDF were higher for dogs fed the 7.5% BP than for those fed the 7.5% OF treatment. Digestible energy, expressed as a percentage of GE, was greater for the control treatment than for the 7.5% BP treatment. A linear decrease in DE (percentage of GE) was noted as the concentration of OF increased, and the DE value (percentage of GE) for the 7.5% BP treatment was greater (P less than .05) than that for the 7.5% OF treatment. A linear decrease (P less than .05) was noted in ME, expressed as a percentage of GE, as the level of OF increased. Frequency of defecation and mean retention time were unaffected (P greater than .05) by treatment. Oat fiber was an effective substitute for BP in dog diets.

Dietary fiber for dogs: I. Effects of graded levels of dietary beet pulp on nutrient intake, digestibility, metabolizable energy and digesta mean retention time.

The optimal level of beet pulp (BP) inclusion in a meat-based dog diet and the effects of graded levels of dietary BP on fecal excretion responses and mean retention time of marked fiber in the gastrointestinal tract of the dog were evaluated using 30 female English Pointers assigned to isonitrogenous diets containing 0, 2.5, 5.0, 7.5, 10.0 or 12.5% BP (DM basis). Beet pulp replaced portions of dietary cornstarch. Digestibilities of DM and OM decreased by an average of 6% when comparing diets containing BP to the control diet, and quadratic and cubic responses were noted in digestibilities of fiber constituents (lower values at the 7.5 and 10.0% levels, higher values at the 2.5, 5.0 and 12.5% levels). Digestible energy (DE) and ME intakes (kcal/d) were not affected by treatment, but when expressed as a percentage of GE, values decreased (4.8% for DE; 6.2% for ME) linearly with increasing BP levels. Wet weight of feces increased (from 117 to 374 g/d) linearly as percentage of dietary BP increased. Frequency of defecation was higher (P less than .05) for dogs fed the diet containing 12.5% BP than for dogs fed the other diets (5.2 vs mean value of 2.8/24 h). Mean retention time of marked fiber decreased linearly (high value of 23.4 h for the 2.5% BP treatment, low value of 13.0 h for the 10.0% BP treatment) with increased level of BP. Beet pulp levels up to 7.5% of diet DM appear acceptable as a dietary fiber source in a meat-based canine diet.

Dietary fiber for dogs: II. Iso-total dietary fiber (TDF) additions of divergent fiber sources to dog diets and their effects on nutrient intake, digestibility, metabolizable energy and digesta mean retention time.

The objectives of this study were to examine widely divergent fiber sources for their efficacy as ingredients in a meat-based dog diet and to determine the effects of these fibers on fecal excretion responses and mean retention time of marked fiber in the gastrointestinal tract of the dog. Fiber sources tested included beet pulp (BP), tomato pomace (TP), peanut hulls (PH), wheat bran (WB) and alkaline hydrogen peroxide-treated wheat straw (AHPWS). Diets were isonitrogenous (5.3% N) and iso-total dietary fiber (TDF; 12.5%). Thirty female English Pointers (five/treatment) were used in the experiment. Intakes of DM and OM were similar among treatments. The highest intakes of ether extract (EE) occurred on the TP, PH and WB treatments. Dogs fed PH ingested the most crude fiber (23.6 g/d), NDF (53.5 g/d), ADF (34.3 g/d) and TDF (59.7 g/d). Digestibilities of DM and OM for all fiber treatments were lower than the control (87.6 vs 81.8% for DM; 90.2 vs 85.4% for OM), but values were similar among fiber sources. The highest EE and N digestibilities occurred on the control and AHPWS treatments. No differences were noted among exogenous fiber-containing treatments in fiber component digestibility. Digestible energy and ME values generally were similar among treatments. Among fiber sources, BP resulted in the greatest amount of wet feces excreted (270 g/d) and the lowest fecal DM (30.3%). No differences among fiber sources were noted in frequency of defecation or mean retention time. Iso-TDF diets (containing, on average, 12.5% TDF) appear to be utilized similarly, regardless of the diversity in sources of fiber tested.

Intravenous administration of lenperone and glycopyrrolate followed by continuous infusion of sufentanil in dogs: cardiovascular effects.

Cardiopulmonary effects of IV administration of lenperone (0.44 mg/kg) and glycopyrrolate (0.11 mg/kg) were determined in 6 healthy adult (2 to 5 years) Pointers during controlled ventilation with oxygen. Sufentanil was then administered as a loading dose (5 micrograms/kg, IV) and continually infused (0.1 microgram/kg/min) for 120 minutes. Lenperone-glycopyrrolate did not significantly affect heart rate, but induced a significant decrease in systemic vascular resistance, rate-pressure product, and mean arterial pressure, and significantly increased cardiac index. Administration of sufentanil did not significantly affect mean arterial pressure. Heart rate and rate-pressure product were significantly decreased during sufentanil infusion. Systemic vascular resistance gradually increased during the 2-hour sufentanil infusion and was not significantly different from base-line values at end of study. Cardiac index was not significantly different from baseline values during sufentanil infusion, except at 90 and 120 minutes, when it was significantly less. As administered in the present study, lenperone, glycopyrrolate, and sufentanil are safe and efficacious in adult dogs.

Extracutaneous histologic changes accompanying zinc deficiency in pups.

The extracutaneous tissues in pups fed a Zn-deficient diet were examined. Four pups were fed a Zn-deficient diet and 3 littermates were fed a Zn-adequate diet. After 5 weeks, the pups were euthanatized. Lesions found only in pups fed a Zn-deficient diet were located in the buccal mucosa, lymph nodes, spleen, and thymus. In the buccal mucosa, lesions consisted of irregular epithelial hyperplasia and disruption of epithelial cell layers. There was a marked absence of lymphocytes in the thymus and in T-cell areas of the lymph nodes and spleen.

Species susceptibility to the pulmonary toxicity of 3-furyl isoamyl ketone (perilla ketone): in vivo support for involvement of the lung monooxygenase system.

To explore a possible relationship between metabolism and lethality, the acute toxicity of naturally occurring perilla ketone (PK), 1-(3-furyl)-4-methyl-pentan-1-one, was examined in the uninduced mouse, hamster, rabbit, dog and pig. The LD50 (+/- SE), determined using intraperitoneal (ip) injection, for the mouse and hamster were low at 5.0 +/- .3 and 13.7 +/- .9 mg/kg, respectively. The rabbit died from an ip dosage of near 14 mg/kg and estimated ip LD50 dosages were quite high for the dog and pig, being 106 +/- 25 mg/kg and over 158 mg/kg, respectively. Dogs and the pig that died from ip injections of PK displayed varying degrees of midzonal and centrilobular liver damage and dogs also had elevated serum alkaline phosphatase and glutamic-pyruvic transaminase activities. In contrast, rodents and rabbits display only pulmonary toxicity from this agent. Cytochromes P-450 and b5 concentrations and NADPH-cytochrome c reductase activity were determined for the lung, liver and kidney of mice, hamsters, rabbits, dogs, swine, sheep and cattle. High correlation between lethality and enzyme concentration further supports the hypothesis that enzymatic bioactivation of PK is required for toxicity in all species.

Halothane-sparing effect of xylazine in dogs and subsequent reversal with tolazoline.

Halothane MAC (the minimum alveolar concentration of halothane to produce anaesthesia in 50% of the animals tested) was determined to be 0.92 +/- 0.16 volumes % in eight English Pointer dogs. Alterations in halothane MAC induced by an intravenous bolus of xylazine (1.1 mg/kg) and then tolazoline (5 mg/kg) was determined in each dog following control (halothane MAC) measurement. Following xylazine administration, MAC significantly decreased to 0.57 +/- 0.023%. Immediately following determination of the xylazine-halothane MAC value in each dog, tolazoline was administered and the halothane requirement (MAC) was again assessed. Halothane MAC significantly increased to 1.24 +/- 0.036%. Tolazoline administration induced immediate arousal in the xylazine-halothane anaesthetized dogs requiring a rapid increase in halothane concentration to maintain anaesthesia. Thus, the administration of tolazoline, an alpha adrenergic antagonist, following xylazine administration significantly increased the anaesthetic requirement (MAC) of halothane. Xylazine, an alpha 2 adrenergic agonist, decreased halothane anaesthetic requirement (MAC) in the eight dogs studied. These results are consistent with the hypotheses that stimulation of central alpha 2 receptors is the mechanism by which xylazine produces sedation and that inhibition of CNS excitatory neurotransmitter release decreases halothane anaesthetic requirement.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue changes in dogs fed a zinc-deficient ration.

Six-week-old puppies fed a corn-soy based zinc-deficient diet developed lesions of parakeratosis, mild hyperkeratosis, alterations in germinal epithelium, erosions, ulcerations, vesiculation, alopecia, and inflammation of the skin. These changes were prominent in the skin of dependent regions, in areas of stretch and friction, and external contact. The epithelial lesions were reversible by adding zinc to the diet, with complete remission of external lesions by 6 weeks.

Estimating body fat in mature beagle bitches.

Body composition was determined in 24 female Beagle dogs ranging in age from 2 to 4 years (live weight 11.1 +/- 3.3 kg). Subcutaneous fat measurements were made using an ultrasonic probe device on the live animal and direct measurements after death. Measurements were made near the shoulder, mid-rib, last rib, mid-lumbar, and last lumbar areas. The actual fat measurement giving the highest correlation with body fat was the one made directly over the longissimus muscle near the last rib (r2 x 100 = 93.6). Multiple linear regression, using live weight and the last rib fat thickness measurement, estimated body fat with a standard error of 0.27 kg (r2 x 100 = 98.4). Body fat = 2.2 + (0.13 x fat thickness + (0.36 x live weight) where body fat and live weight were measured in kg and fat thickness in mm.

Arginine: an indispensable amino acid for mature dogs.

There studies examined the effect of dietary arginine deficiency in the mature dog. Deletion of arginine from the diet resulted in a slight but significant loss of body weight. Severe episodes of emesis were observed in all experiments. Muscle tremors and frothing around the mouth were also observed in the experiments where the arginine-free diet was force fed. Increasing the amount of diet force-fed to mature dogs accentuated the symptoms of emesis, muscle tremors and frothing. Elevated plasma ammonia and orotate were detected in dogs fed an arginine-deficient diet. Urinary citric and orotic acid was also increased in mature dogs fed a diet devoid of arginine. Nitrogen balance was not significantly altered by deletion of arginine from the diet. Based on the occurrence of emesis, loss of body weight and alterations in intermediary metabolism, we concluded that the mature dog does require a dietary source of arginine. Dietary inclusions of 0.28% arginine prevented the symptoms of arginine deficiency.

Effects of sodium acetate, bicarbonate and lactate on acid-base status in anaesthetized dogs.

Equal doses of sodium acetate, bicarbonate and lactate (6.6 mEq/L) infused intravenously over 30 min into three groups of halothane-anaesthetized dogs caused changes in acid-base status. Arterial carbon dioxide tension (PaCO2), pHa, base excess (BE) and standard bicarbonate (SB) increased. Sodium bicarbonate caused the most rapid and greatest changes. The bicarbonate group was significantly different (P less than 0.05) from the other groups at 15 and 30 min after the start of infusion for pHa, BE and SB. The greater effects of bicarbonate are due to its production of alkalinization without a requirement for metabolism; acetate and lactate require oxidation to be effective. The acetate and bicarbonate groups were not statistically different at 45 min after the onset of drug infusion, but both had significantly higher SB and BE mean values than the lactate group. All measurements made after 45 min revealed no significant differences among groups. Thus, after the earlier differences noted above, the three alkalinizers caused similar effects on acid-base status. PaCO2 was elevated in all groups, but there were no differences among groups. Cardiovascular effects caused by infusion of the three drugs were minimal.

Nitrogen requirement of the kitten.

Three experiments were conducted to determine the nitrogen (N) requirement of the young kitten. The feline basal diet contained minimal requirement levels of each indispensable amino acid (IAA) to comprise a total dietary N concentration of 2.52% and an IAA N to dispensable amino acid (DAA) N ratio (I/D) of 0.70. In experiments 1 and 2, both the dietary N concentration and I/D ratio were varied through changes in either the DAA level (experiment 1) or IAA level (experiment 2). The results revealed that a reduction in either dietary N or in I/D ratio from basal levels (ie, 2.52% N and I/D ratio of 0.70) depressed (P less than 0.05) kitten weight gain, feed efficiency, and N retention, whereas simultaneous increases in each resulted in no further improvement in these responses. Comparison of this feline basal diet with a commercial ration (experiment 3) revealed no differences (P less than 0.10) in gain, gain/feed, or N retention, although the purified diet showed superiority (P less than 0.01) when gain/N intake was determined (13.3 vs 5.7). Therefore, the feline dietary N requirement has been estimated to be 2.52% (15.75% protein equivalent) or 16% of the calories as protein. In the process of these experiments, creatinine and orotic acid excretion from kittens fed the purified diet were constant, averaging (+/- SEM) 24.7 +/- 0.7 mg/kg of body weight and 9.95 +/- 2.3 micrograms/mg of creatinine, respectively. Urea-N and ammonia-N comprised approximately 83.0% and 3.8% of the total urinary nitrogen.

Histidine, phenylalanine-tyrosine and tryptophan requirements for growth of the young kitten.

Growth assays were conducted to estimate the minimal dietary requirement levels of histidine, tryptophan, phenylalanine and tyrosine for the young kitten. Dietary concentrations of histidine and tryptophan of .30 and .15%, respectively, were found to support optimal kitten performance. A preliminary study of the total aromatic amino acid (TAAA) requirement indicated that no more than 1.20% TAAA (.60% phenylalanine + .60% tyrosine) is required by the kitten. Subsequent experiments revealed no decrease in growth rate when TAAA were reduced to 1.00% of the diet. At this level of TAAA, tyrosine could supply 50% of the requirement for TAAA.

Lysine and arginine requirements of the domestic cat.

Domestic kittens were used in four experiments to establish quantitative requirements for lysine and arginine. A purified L-amino acid diet (by calculation, 4,700 kcal metabolizable energy/kg diet) was employed throughout. Weight gain, gain:feed and nitrogen retention data of cats fed dietary lysine levels ranging from 0.48 to 1.92% suggested a requirement not exceeding 0.80%. The dietary arginine requirement for maximal gain was assayed at this level of lysine and found to be not greater than 0.83%. A dietary arginine level of 0.33% resulted in vomiting and extreme lethargy within 4 hours of ingestion.