4
Protein

Protein and the element nitrogen (N) have been known as essential dietary components since before the 20th century. In all animals, protein and many of its constituent amino acids are required for maintenance of body tissues, for growth, and as a source of nonprotein N-containing bioactive compounds. Dietary requirements are increased during pregnancy and lactation, stress, and illness and are also influenced by the quality and digestibility of the protein consumed.

PROTEIN SOURCES

Protein can be obtained from a wide variety of foodstuffs. In highly controlled research studies, protein is often provided by purified or semipurified ingredients, such as lactalbumin, casein, and isolated soy protein. In diets composed of natural ingredients, protein is commonly supplied by grains, grain byproducts, legume meals, leafy vegetables, seeds, and seed processing byproducts. Animal products— such as meat meal, fish meal, milk and milk-processing byproducts, and processed eggs—are sometimes used in dry or canned complete diets, and insects can be provided separately as protein sources or as “treats.” There are excellent data demonstrating that the nitrogen in the protein in most animal and cereal protein sources varies between 14% and 18% (Jones, 1931), with a mean of 16%. Conversion from nitrogen to protein values is conventionally accomplished by multiplying by 6.25. Based upon amino acid analyses, it has been proposed that the appropriate factor for converting nitrogen concentrations (by Kjeldahl analysis) to protein in the pulp of the tropical fruits Cecropia peltata, Chlorophora tinctoria, Ficus ovalis, and Piper amalogo may be 4.13, 3.28, 3.67, and 3.12, respectively (Herbst, 1986). Alternatively, nitrogen bound to acid-detergent residue has been subtracted from nitrogen in the whole plant before multiplication by 6.25 to estimate available crude protein concentration (Van Soest, 1994). Conklin-Brittain and colleagues (1999) showed that in some wild tropical vegetation, substantial nitrogen is bound to lignin, making nitrogen bound to acid-detergent residue correction particularly important. For the purposes of the present review, the protein data in Table 4-1 were estimated by using 6.25 to multiply measured nitrogen concentrations in the plant or animal protein sources commonly used in diets for nonhuman primates.

ASSESSMENT OF PROTEIN REQUIREMENTS

Methods

The earliest information on protein requirements of nonhuman primates was derived empirically; that is, concentrations of protein in the diet that appeared to maintain nonhuman primates satisfactorily in active colonies in zoos and research laboratories were considered “adequate.” Needs of nonhuman primates also were extrapolated from well-defined requirements for other laboratory, domestic, and wild animals and for humans. Later, several researchers conducted studies of protein requirements, using dose-response experiments in which graded concentrations of dietary protein were evaluated with respect to selected dependent variables, including weight change or growth, urinary and fecal nitrogen, nitrogen balance, and serum albumin. In studies in which multiple dietary protein concentrations were chosen strategically from below to slightly above the expected requirement, a regression analysis could be used to predict the requirement necessary to support the tested outcome variables. In any experiment, the estimate of the dietary protein requirement would, by definition, be the average amount needed to produce a given result. In setting dietary protein requirements for humans, this “average” amount is commonly increased by factors to account for variability in digestibility, protein



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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 4 Protein Protein and the element nitrogen (N) have been known as essential dietary components since before the 20th century. In all animals, protein and many of its constituent amino acids are required for maintenance of body tissues, for growth, and as a source of nonprotein N-containing bioactive compounds. Dietary requirements are increased during pregnancy and lactation, stress, and illness and are also influenced by the quality and digestibility of the protein consumed. PROTEIN SOURCES Protein can be obtained from a wide variety of foodstuffs. In highly controlled research studies, protein is often provided by purified or semipurified ingredients, such as lactalbumin, casein, and isolated soy protein. In diets composed of natural ingredients, protein is commonly supplied by grains, grain byproducts, legume meals, leafy vegetables, seeds, and seed processing byproducts. Animal products— such as meat meal, fish meal, milk and milk-processing byproducts, and processed eggs—are sometimes used in dry or canned complete diets, and insects can be provided separately as protein sources or as “treats.” There are excellent data demonstrating that the nitrogen in the protein in most animal and cereal protein sources varies between 14% and 18% (Jones, 1931), with a mean of 16%. Conversion from nitrogen to protein values is conventionally accomplished by multiplying by 6.25. Based upon amino acid analyses, it has been proposed that the appropriate factor for converting nitrogen concentrations (by Kjeldahl analysis) to protein in the pulp of the tropical fruits Cecropia peltata, Chlorophora tinctoria, Ficus ovalis, and Piper amalogo may be 4.13, 3.28, 3.67, and 3.12, respectively (Herbst, 1986). Alternatively, nitrogen bound to acid-detergent residue has been subtracted from nitrogen in the whole plant before multiplication by 6.25 to estimate available crude protein concentration (Van Soest, 1994). Conklin-Brittain and colleagues (1999) showed that in some wild tropical vegetation, substantial nitrogen is bound to lignin, making nitrogen bound to acid-detergent residue correction particularly important. For the purposes of the present review, the protein data in Table 4-1 were estimated by using 6.25 to multiply measured nitrogen concentrations in the plant or animal protein sources commonly used in diets for nonhuman primates. ASSESSMENT OF PROTEIN REQUIREMENTS Methods The earliest information on protein requirements of nonhuman primates was derived empirically; that is, concentrations of protein in the diet that appeared to maintain nonhuman primates satisfactorily in active colonies in zoos and research laboratories were considered “adequate.” Needs of nonhuman primates also were extrapolated from well-defined requirements for other laboratory, domestic, and wild animals and for humans. Later, several researchers conducted studies of protein requirements, using dose-response experiments in which graded concentrations of dietary protein were evaluated with respect to selected dependent variables, including weight change or growth, urinary and fecal nitrogen, nitrogen balance, and serum albumin. In studies in which multiple dietary protein concentrations were chosen strategically from below to slightly above the expected requirement, a regression analysis could be used to predict the requirement necessary to support the tested outcome variables. In any experiment, the estimate of the dietary protein requirement would, by definition, be the average amount needed to produce a given result. In setting dietary protein requirements for humans, this “average” amount is commonly increased by factors to account for variability in digestibility, protein

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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 TABLE 4-1 Estimated Protein Requirements for Primates Using High-Quality Reference Proteins   Protein Intake   Species Age BW Kg Protein % of DMa g·BWkg-1 ·day-1 % of MEb Protein Source Dependent Variable Reference Saguinus fuscicollis Adult 0.452 7.3 2.80 6.2 Casein Weight change Flurer and Zucker, 1985 Callithrix jacchus Adult 0.408 6.6 2.50 6.0 Soy concentrate Nitrogen balance Flurer et al., 1988 Saimiri sciureus 2-3 wk, infant 0.150 20.8 17.70 14.8 Casein Weight change Ausman et al., 1979 2-3 m, infant 0.300 10.0 7.30 7.1 Casein Weight change Ausman et al., 1979 9 m, juvenile 0.500 8.1 4.30 5.8 Casein Weight change Ausman et al., 1979 Cebus albifrons 5 wk 0.400 9.8 5.30 7.0 Lactalbumin Weight change Samonds and Hegsted, 1973 3 m 0.600 8.9 4.20 6.4 Lactalbumin Weight change Samonds and Hegsted, 1973 5 m 0.800 8.1 3.60 5.8 Lactalbumin Weight change Samonds and Hegsted, 1973 7 m 1.000 7.2 3.30 5.2 Lactalbumin Weight change Samonds and Hegsted, 1973 Adult 2.000 7.1 1.80 7.5 Lactalbumin Weight change Ausman and Hegsted, 1980 Macaca mulatta 1-7 m, infant 0.500 7.3 4.00 1.7 Milk protein Weight change Kerr et al., 1970 Adult 5.000 7.6-15.1c 2-4c 6.7-13.4c Casein Weight change Riopelle et al., 1974 Adult 4-12 <16.4d <2.60d <18.9d Mixed Nitrogen balance Robbins and Gavan, 1966 Macaca fascicularis Infant 0.5 9.3 3.8 6.6 Lactalbumin Weight change Ausman et al, 1979 Young 1.000 6.4 2.50 4.6 Lactalbumin Weight change Ausman et al., 1979 Pan troglodytes Young 10-24 <14.2d <4d <14.4d Mixed Weight change Hodson et al., 1967 Homo sapiens 3-5.9 m 6.000 — 1.38 5.1 Egg or milk protein Factorial NRC, 1989 6-11.9 m 9.000 — 1.21 4.9 Egg or milk protein Factorial NRC, 1989 1 yr 9-13 — 0.97 3.8 Egg or milk protein Factorial NRC, 1989 9 yr 28.000 — 0.80 4.6 Egg or milk protein Factorial NRC, 1989 Adult female 58.000 — 0.59 6.3 Egg protein Nitrogen balance NRC, 1989 Adult male 70.000 — 0.59 5.8 Egg protein Nitrogen balance NRC, 1989 aDM=dry matter. Calculations assume 10% moisture content in ingredients in typical diet. All calculations based on crude protein (6.25 × N) or, if not possible, reported protein value in citation. bME= metabolizable energy. cInsufficient data between 7.6% and 15.1% protein diet to determine actual requirement. dAbove requirement. Lower dietary protein concentrations were not tested. quality, and need within the population. Usually, an extra 30% is added to meet average needs of the population ± 2 standard deviations. Digestibility Digestibility of a protein is easily measured over a period of a few days. To determine apparent digestibility, one subtracts fecal nitrogen from ingested nitrogen, divides the result by ingested nitrogen, and multiplies by 100 to express digestibility in percent. Note that estimates of apparent digestibility do not take into account obligatory fecal nitrogen losses that would have occurred (from sloughed mucosal cells, bacterial cells, and enzymes) even if the diets contained no nitrogen. Estimates of true digestibility are always higher and are corrected for this bias by subtracting obligatory fecal nitrogen losses from measured fecal nitrogen before calculating nitrogen disappearance (presumably

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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 absorbed). Differences between estimates of true and apparent digestibility are larger when dietary protein concentrations are low, because obligatory fecal losses make up a larger proportion of total fecal nitrogen loss. Very few data on protein digestibility (apparent or true) are available for protein sources fed to nonhuman primates. Robbins and Gavin (1966) fed a commercial monkey diet containing ground wheat and corn, soybean meal, alfalfa meal, and lactalbumin as protein sources to rhesus monkeys and found that the apparent digestibility of total dietary protein was 83.8%. Hodson et al. (1967), using chimpanzees, estimated the apparent digestibility of protein in diets containing ground wheat, dehydrated alfalfa meal, ground corn, dried skim milk, and soybean meal, and providing 12-18% protein. Apparent digestibility was 63-66%. Liquid diets (1.5-8.5% protein) formulated primarily with purified casein and fed to infant capuchin monkeys had an apparent protein digestibility of about 88.3% (Gallina and Ausman, 1986). Protein in diets fed to Saguinus fuscicollis had an apparent digestibility varying from 72.9% to 87.1% as dietary protein concentration increased. When fed in increasing percentages to Callithrix jacchus, apparent digestibility of dietary proteins increased from 76.6 to 86.8% (Flurer and Zucker, 1985). Thus, the apparent digestibilities of dietary proteins (purified or natural sources) fed to five species of monkeys were found to be 63-88%. Requirements Protein requirements of primates do not appear markedly different from those predicted from studies of other mammals. Table 4-1 summarizes the estimated protein requirements of several species of primates, including humans. Requirements for juvenile to adult primates, expressed as grams of protein per kilogram of body weight (BW) per day, range from 0.59 g·BWkg-1·day-1 for adult humans to 4.3 g·BWkg-1·day-1 for juvenile squirrel monkeys; most adult primates (when there were sufficient data) required less than 3 g·BWkg-1·day-1. When the daily energy intakes of the species were considered, protein concentrations needed to support requirements were 4.6-7.5% of ME calories or 6.4-8% of dietary dry matter. There were insufficient data on adult rhesus macaques and chimpanzees to fix requirements exactly. Five primate species have been studied from infancy through adulthood: a squirrel monkey, a cebus monkey, two species of macaques, and humans. In each species, protein requirements, expressed as above, decreased as growth rates declined and animals matured. PROTEIN QUALITY The nutritional quality of a protein is heavily influenced by its amino acid composition. Mitchell and Block (1946) suggested that the quality of a protein is inversely proportional to its percent deficit in essential amino acids; that is, “limiting” amino acids determine the quality amino acid score of the protein. Given the chemically determined pattern of amino acids in a reference protein, such as that of whole egg, and in a test protein, the amino acid score of the test protein can be calculated without using live animals. Later, other measures of protein quality such as biologic value (BV), net protein utilization (NPU), and protein efficiency ratio (PER) were popularized in studies with humans or rodents (Pellett and Young, 1980; Rand et al., 1981). The most accurate measure, relative nutritive value (RNV), relies on feeding both a reference protein (or standard) and a test protein at several different growth-limiting concentrations in the same experimental paradigm and comparing animal responses to the test protein and the standard (Hegsted and Worcester, 1966; Rand et al, 1981). The result is expressed as potency (test-protein response as a percentage of reference-protein response). Tests of the RNV of proteins have been conducted with squirrel and cebus monkeys and with humans (Table 4-2). The degree to which an essential amino acid becomes limiting is thought to depend, in part, on the growth rate of the test subject; rapidly growing animals require more amino acids for new tissue growth than do adults. Proteins Limiting in Sulfur Amino Acids Data from studies of infant and young squirrel monkeys (Ausman et al, 1979) and cebus monkeys (Samonds and Hegsted, 1973; Ausman et al., 1986) indicate that soy protein, limiting in the essential amino acid methionine, has a lower potency than a standard of casein or lactalbumin. It is noteworthy that the addition of methionine in appropriate amounts provided a dietary protein mixture that was not different from the reference protein as judged by nitrogen balance (Ausman et al., 1986). In a final set of experiments, growth and nitrogen-balance assays with growing cebus monkeys indicated that the potency of casein with respect to lactalbumin was 60-70%, reflecting its relative paucity of cysteine. The results were consistent with the lower potency of the same lots of soy protein and casein when assayed with growing rats (Ausman et al., 1986). In comparison, nitrogen-balance experiments with adult humans fed soy protein yielded potencies less than 100% but often not significantly different from the reference protein (Rand et al., 1981). Experiments in which protein quantity and quality are limiting cannot ethically be conducted with infants or children.

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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 TABLE 4-2 Potency of Common Proteins Measured by Bioassay in Primates   Potencya   Species Age Growth/Weight Maintenance Nitrogen Balance Protein Source Reference Saimiri sciureus Infant 100.0 N.D. Casein Ausman et al., 1979 Infant 86.7 ± 13.4b N.D. Lactalbumin Infant 69.4 ± 13.3c N.D. Soy protein isolate Cebus albifrons Infant 100.0 N.D. Lactalbumin Samonds and Hegsted, 1973 Infant 46.1 ± 5.6c N.D. Soy Infant 15.3 ± 2.5c N.D. Gluten Infant 48.2 ± 5.1c N.D. Gluten + lysine Cebus albifrons Adult 100.0 N.D. Lactalbumin Ausman and Hegsted, 1980 Adult 46.3 N.D. Bread + gluten + lysine Cebus albifrons Infant 100.0 100.0 Lactalbumin Ausman et al, 1986 Infant 40.6 ± 8.1c 46.8 ± 9.4e Soy isolate Infant 72.1 ± 12.7c 62.2 ± 12.9c Casein Infant 52.5 ± 8.8c 69.0 ± 11.6c Soy concentrate Infant 72.2 ± 13.0c 90.7 ± 16.7 Soy isolate + methionine Homo sapiens Adult males N.A. 100.0 Egg or beef protein Rand et al, 1981   N.A. 78.8 Soy isolate N.A. 54.0c Wheat protein aND = not done; NA = not applicable. bMean ± SD. cSignificantly different from reference values (P < 0.05). Proteins Limiting in Lysine The potency of gluten, the major protein in wheat, for infant cebus monkeys was extremely poor—about 15% (Samonds and Hegsted, 1973). It was improved by adding lysine to the diet in an amount equal to that in the reference protein, but performance was still substantially lower than that of the standard. The same situation was found in studies with adult cebus monkeys fed diets containing bread protein and gluten with various amounts of added lysine. Doubling the lysine concentration in the diet was necessary to allow the monkeys to attain their pre-experimental body weights. Additions of threonine and methionine also were helpful in promoting body-weight gain (Ausman and Hegsted, 1980). Experiments with adult humans commonly indicate that the potency of wheat protein, unsupplemented with lysine, is less than 50% of the standard (see the experiment cited in Table 4-2). Humans rarely consume a diet containing only a single protein source. The exception might be infants that are fed diets containing only milk or soy proteins for the first few weeks of life. Ordinarily, the amino acid composition of the proteins in the diet complement each other. Indeed, the latest edition of Recommended Dietary Allowances (National Research Council, 1989) suggests that no correction for protein quality need be made in protein-requirement values for humans in the United States in as much as the biologic value of a typical mixed-protein diet is not distinguishable from that of reference protein. Given that both young and adult monkeys are sensitive to protein quality, it is extremely important that semipurified and natural-product diets contain nutritionally balanced amino acid mixtures. Combining grain and legume proteins (limiting in lysine and methionine, respectively) or animal and plant proteins generally accomplishes this. Of course, to be satisfactory, commercial monkey biscuits should be formulated to contain adequate concentrations and appropriate proportions of essential amino acids. AMINO ACID REQUIREMENTS The essential amino acid requirements of monkeys appear to be similar to those of humans. Although data are insufficient to fix the amino acid requirements absolutely, results of experiments in which essential amino acids were limiting produced results as predicted from studies with humans and with growing and adult mammals of other species. In primate species with significant foregut fermentation, dietary amino acid requirements may vary. The extent of amino acid degradation and microbial protein synthesis in foregut fermenting species are unknown. Research, similar to the extensive studies that have been conducted in ruminants, is needed to elucidate the effect of foregut fermentation on amino acid bioavailability and requirements. Lysine and Methionine The preceding sections have established that lysine and methionine are essential amino acids needed in appropriate

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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 amounts for normal growth and development of primates. A report by Stegink and colleagues (1980) conclusively showed that D-methionine is poorly used by monkeys. That is in agreement with data from humans but in contrast with data from rats, chickens, pigs, and rabbits, in which D-methionine may be converted to L-methionine by an oxidase. Although no studies have used a pure amino acid mixture to titrate the exact lysine or methionine requirement, the addition of lysine to gluten or bread diets and of methionine to soy-isolate diets markedly improved protein potency (Table 4-2). In the case of methionine-supplemented soy protein, potency was not distinguishable from the reference. That addition of lysine alone to wheat protein did not make its potency equivalent to the reference suggests that a secondary and perhaps tertiary amino acid was limiting (Samonds and Hegsted, 1973; Ausman and Hegsted, 1980). Phenylalanine Human infants with phenylketonuria have a deficiency of the hepatic enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Treatment for this condition is life-long restriction of dietary phenylalanine. Kerr et al. (1969a) fed a commercial formula low in phenylalanine to infant rhesus monkeys. Those maintained on the formula up to the age of 70 days developed lethargy, anemia, anorexia, diarrhea, hair depigmentation, dermatitis, and edema. Supplementation of the formula with phenylalanine ameliorated all the signs except dermatitis. The experiments suggest how difficult it might be to restrict phenylalanine in the diet of a phenylketonuric without producing evidence of protein deficiency. Tryptophan Experimental studies with the vervet monkey (Cercopithecus aethiops) focused on the role of tryptophan and its neurotransmitter, 5-hydroxytryptamine, in aggression (Chamberlain et al., 1987). Monkeys were given amino acid mixtures that contained no tryptophan (T−), were nutritionally balanced (B), or had tryptophan in excess (T+). During competition for food, the T− solution increased aggression in male vervet monkeys whereas the T+ solution decreased aggression in both males and females. In a second study with these monkeys, Young et al. (1989) were able to show that the change in behavior (aggression) was inversely correlated with the amount of tryptophan and 5-hydroxyindoleacetic acid in the cerebrospinal fluid, adding further support to the idea that altered behavior in humans could be due to a decrease in 5-hydroxytryptamine. Of the common proteins fed, maize has the lowest ratio of tryptophan to total protein. Taurine Taurine was first isolated in 1827 from ox bile (Hayes, 1985). Taurine ( γ-aminoethanesulfonic acid) is synthesized in liver and brain of all animals studied, but the synthetic system might be poorly developed in young or preterm infants of any species (Hayes, 1985), thereby necessitating an exogenous supply. Taurine is found in most cells, and it is suggested that it performs a wide variety of functions (Gaull, 1989). Initial observations centered on stabilization of the membranes of the central retinal tapetum (Hayes, 1985). It is also thought to play a role in the developing nervous system, conjugation of bile acids, brain osmoregulation, and platelet and muscle function. Infant monkeys fed soy-based human-infant formulas (lacking supplemental taurine) showed a depression in growth and an alteration in the ratio of glycine to taurine in conjugated bile acids (Hayes et al., 1980; Stephan et al., 1981). Indeed, in this latter study, infant cynomolgus monkeys showed no change in bile acid pool size during taurine depletion whereas bile acid pool size dropped from 89.0 to 73.0 μmol·BWkg−1 in the infant capuchin monkey under the same conditions. It is noteworthy that cynomolgus monkeys normally conjugated 84% of their bile acids with taurine, and taurine depletion decreased this value to 64%. In contrast, capuchin monkeys obligatorially conjugated 97% of their bile acids with taurine, independent of taurine status. Infant rhesus macaques fed a taurine-free diet exhibited a loss of visual acuity and retinal degeneration (Sturman et al., 1984; Neuringer and Sturman, 1987; Imaki et al., 1987). In a further study, Sturman et al. (1988) compared monkeys fed a liquid soy diet with those fed one supplemented with taurine at 70 μmol·dl−1, the amount in rhesus monkey milk. Taurine concentrations in 28 of 31 tissues measured were significantly increased (by 50-75%) over nonsupplemented concentrations. Further studies showed that by 12 months of age, infant rhesus monkeys were no longer dependent on an exogenous source of dietary taurine (Sturman et al., 1991; Neuringer et al., 1992). Collectively, those results suggest that it is important to provide an exogenous source of taurine for primates for the first year of life. EFFICIENCY OF PROTEIN USE Given a high-quality “reference” protein, the efficiency of protein use in the growing rat is greater than 90%. That is to say, given 1 g of dietary protein, a growing rat will deposit more than 0.9 g in its carcass (Rand et al., 1981). Humans are not nearly as efficient; their efficiency of protein use is 50-70% (Rand et al., 1981). Cynomolgus monkeys (Macaca fascicularis) fed lactalbumin protein have an efficiency of 65% (Ausman et al., 1979). In one study, infant cebus monkeys fed lactalbumin were reported to

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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 have an efficiency of 65% (Samonds and Hegsted, 1973) measured by weight gain. In a second study, lactalbuminfed monkeys showed efficiencies of 43% measured by weight gain or 47% measured by nitrogen balance (Ausman et al., 1986). Finally, when infant squirrel monkeys were fed lactalbumin or casein, their efficiencies of protein use were 28.8 and 37.4%, respectively; this suggests that the animals were extremely inefficient users of the protein provided (Ausman et al., 1979). In all species, efficiency drops as protein quality is decreased. PROTEIN DEFICIENCY Beginning in the 1960s, several laboratories worldwide were engaged in studies of protein and calorie malnutrition, using the monkey as a model in which to produce the human diseases of kwashiorkor and marasmus (Oftedal, 1991). Protein deficiency and its sequelae are easily produced in several primate models. The studies have been reviewed by Knapka et al. (1995). Biochemical and clinical signs of protein deficiency include decreased total serum protein and albumin concentrations, decreased plasma amino acid concentrations, decreased serum transferrin concentrations, alopecia, anemia, edema, altered hormone and enzyme concentrations, abnormal neural cytochemistry, and pathologic alterations in several organs. In some of the studies, the investigators studied pure protein deficiency, pure caloric deficiency, or a combination of the two. Samonds and Hegsted (1978) found that a 33% caloric restriction in the face of an otherwise adequate diet with added proteins, minerals, and vitamins produced a small but otherwise apparently “healthy” monkey. When the caloric restriction was combined with a protein-deficient diet, the resulting animals appeared no worse than either group alone; that suggests that in the face of an energy deficit protein was not “burned” for calories, as implied by several short-term studies in humans (Calloway, 1981; Garza et al., 1976; Calloway and Margen, 1971). The same experimental paradigm was repeated in infant squirrel monkeys fed protein-deficient, calorie-deficient, and protein and calorie-deficient diets (Gallina et al., 1987; Ausman et al., 1989). Again, the double-deficient animals appeared no worse than the others. The observations made on these squirrel and cebus monkeys appeared to be restricted to serum biochemical measurements, food intake, body weight, and appearance. The authors could make no judgments about body composition; rates of protein synthesis, turnover, or degradation; or any other index of protein and calorie metabolism. See Chapter 9 for further discussion of caloric restriction and health. Alopecia and weight loss in a colony of western lowland gorillas over a 3-year period was ascribed to a dietary protein deficiency, based on findings of hypoalbuminemia, low serum amino acid and protein concentrations, and the positive response to dietary protein supplementation (Mundy et al., 1998). PROTEIN FOR PREGNANCY AND LACTATION Protein requirements for pregnancy and lactation have not been systematically studied. The protein requirement for infant monkeys is presumed to be the amount provided in the mother’s milk. The protein concentration in mature nonhuman-primate milk is 7-22% of GE (Oftedal, 1984, 1991). Studies of infant squirrel monkeys show that mean protein requirements for maximal growth approximate 18% of ME calories (Ausman et al., 1985b), which is similar to what is found in squirrel monkey milk (Buss and Cooper, 1972). It is clear that protein deficiency in the pregnant nonhuman primate can have untoward effects on the offspring. When pregnant rhesus monkeys were fed diets containing 3.4% ME calories as protein, neonatal mortality was 40-50% (Riopelle et al., 1975a, 1976; Kohrs, 1976). If the diet provided protein at 0.4-0.5 g·BWkg-1·day-1, infants had reduced birth weights (Kohrs 1976; Novy, 1981) and decreased head circumferences for several months after birth (Kohrs et al., 1980). Maternal protein intakes of at least 1 g·BWkg-1·day-1 were associated with normal prenatal linear growth; normal birth weight; normal skeletal maturity and measurements; and normal post-natal food intake (Riopelle et al., 1975b, 1976; Cheek et al., 1976; Riopelle and Favret, 1977). PROTEIN-CALORIE MALNUTRITION IN YOUNG PRIMATES Nutritional requirements per unit body weight are highest for the young of any species, and growing children or growing animals exhibit the most serious clinical and biochemical evidence of malnutrition when fed diets deficient in essential nutrients. Studies of malnutrition conducted with young rats and pigs have not proved relevant to the pathogenesis of the malnourished human child, primarily because the animals grow more rapidly and have shorter periods between weaning and puberty (Coward and Whitehead, 1972). A closer relationship between higher primates and humans in growth patterns suggests that nonhuman primates would be more realistic experimental models. Nonhuman-primate models of protein-calorie malnutrition (PCM) could provide a means to study biochemical and physiologic responses to a primary deficiency of either protein or energy and could replicate the related clinical

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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 syndromes, kwashiorkor and marasmus (Whitehead, 1980). In kwashiorkor, characterized by edema, there is a deficiency in the quantity and quality of dietary protein, whereas energy intake can be adequate; other clinical signs include hypoalbuminemia and consequent fatty liver, growth retardation, loss of weight and muscle mass, and dermal and hair changes (Wilgram et al., 1958; Whitehead, 1980; Coward and Lunn, 1981; Ausman et al., 1989; Murray et al., 1996). Marasmus is most commonly associated with energy-deficient diets, but there can be generalized wasting due to severe and prolonged restriction of both energy and protein and characterized by severe muscle and body-fat loss. To serve as valid models, the pathologic effects manifested in those two disorders should be produced under dietary and environmental circumstances (often including infection) as similar as possible to those of the human population that typically develops these syndromes (Whitehead, 1980). Furthermore, persons conducting animal studies designed to reproduce clinical signs of kwashiokor and marasmus in children should recognize that there are likely to be other essential-nutrient deficits coincidental with the protein and energy deficiencies. Nonhuman primates (Macaca mulatta) have served as models of undernutrition in the study of prepubertal and pubertal reproductive events as related to nutrition and the neuroendocrine system (Steiner, 1987). Young rhesus macaques (M. mulatta) with a body mass of 1.5-2.0 kg exhibited PCMafter only 45 days when energy (undefined) and protein intake were restricted to an intake of 55 kcal·BWkg-1·day-1 and 2.42 g·BWkg-1·day-1, respectively (Mehta et al., 1980). Ad libitum intakes were 90 kcal·BWkg-1·day-1 and 3.0 g·BWkg-1·day-1, respectively. The degree of restriction proved severe, and 70% of the monkeys died during acclimatization or during different phases of the study, whereas the monkeys fed ad libitum thrived. PCMwas induced in male rhesus macaques 1-12 months old, when 50% of the allotted control diet was fed per day for 10-12 weeks. That restriction provided undefined energy at 55 kcal·BWkg-1·day-1 and protein at 2.32 g·BWkg-1·day-1 and resulted in a 36% loss in BW, decreased serum albumin concentrations, hair loss, easily peeled skin, muscular wasting, and decreased physical activity (Chopra et al., 1987). During a study spanning several years, young rhesus macaques (M. mulatta) were subjected to various degrees of protein or calorie malnutrition to evaluate effects on physical growth (Kerr et al., 1970), organ size and skeletal growth (Kerr et al., 1973), cerebral lipids (Kerr and Helmuth, 1973), growth failure and “catch-up” growth (Kerr et al., 1975), and biochemical and cytochemical composition of major organs (Kerr et al., 1976). Nutritional rehabilitation of surviving monkeys produced responses comparable with those seen in rehabilitated undernourished children; 2 years later, the external dimensions of the monkeys were within the range of normal controls (Kerr et al., 1973). The study design included feeding the young monkeys (from 1 to 7 months of age) various combinations of five diets: a commercial human-infant milk preparation (ME at about 0.67 kcal·ml-1, protein at 0.0182 g· ml-1 [Kerr et al., 1969b]); a 1:1 milk:water dilution of the commercial milk; a 1:3 milk:water dilution of the commercial milk; and the commercial milk with 50% or 25% of normal protein concentration made isocaloric by lactose additions. Mortality of 44-54% was reported in monkeys fed the diet made isocaloric with lactose and containing only 25% of the normal protein level (Kerr et al., 1970; Kerr et al., 1973). Monkeys fed this adequate-energy, low-protein diet exhibited evidence of malnutrition: gastrointestinal distention, diarrhea, enteric infections, lymphoid hypoplasia, anemia, muscular wasting, reduced organ mass, and extensive fatty metamorphosis of the liver. It was noted that, whereas total intake by monkeys fed the low-protein diet was reduced below that appropriate for age, total intake per kilogram of body mass was comparable with that of the controls, owing primarily to weight loss in the protein-restricted monkeys (Kerr et al., 1970). However, during 5 months of rehabilitation, energy and protein deficits (expressed as intake of diet volume in liters, kilocalories of energy, and grams of protein) continued to increase in these animals compared with normal-weight controls (Kerr et al., 1975). A mortality of 17% was reported for monkeys fed the 1:3 diet, in which all nutrients were diluted (Kerr et al., 1970). These monkeys also exhibited marked growth failure despite satisfactory intake (they consumed 3-4 times the usual volume) of all nutrients except for an excess of water. Monkeys that did not consume enough of the dilute diet to provide a normal intake of nutrients had a nutrient deficit of about 20-30% in terms of kilograms of body mass (Kerr et al., 1973). By the age of 7 months, the monkeys fed the 1:3 dilute diet were consuming 217% of the volume of control animals, providing only 54% of the normal energy and protein intake (Kerr et al., 1975). Monkeys fed the dilute diet accumulated nutrient deficits that were not restored during nutritional rehabilitation, but the deficits did not continue to increase. Young (10-28 months old), pigtail macaques (M. nemestrina) were fed 400 g of synthetic diet per day, containing either 20% or 2% casein and ME at 3.96 or 3.24 kcal·g-1, respectively, for about 3 months to determine biochemical and morphologic alterations in response to PCM(Enwonwu et al., 1973). In a preliminary study, the protein content of the diet was gradually reduced over a period of 9 months from 8% through 6% to 2%. Monkeys fed the 8% or 6% casein diets ad libitum gained BW and showed no clinical or biochemical signs suggestive of PCM. After 3 months of the 2% casein diet, however, serum albumin concentration was reduced by 25%, plasma corticosteroid had increased by 132%, and impairment of liver-protein biosynthesis resulted in extensive fatty liver metamorphosis.

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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 Four infant crab-eating macaques (M. fasicularis), 5-7 months old, also were fed a 2% casein diet over 14 weeks (Worthington et al., 1979) and exhibited significant decreases in plasma essential amino acids (especially the branched-chain group), whereas plasma nonessential amino acids tended to rise (especially glycine and alanine). The peak response was noted within 3-4 weeks of protein restriction. Nine 6- to 9-month-old male crab-eating macaques (M. nemestrina) from the study of Enwonwu et al. (1977) were later further diet-restricted and fed the 20% and 2% casein diets at 200 g·day-1 for 20 weeks to examine hepatic alterations associated with PCM. Mean initial BW of both groups was 1.4 ± 0.13 kg. Control monkeys fed the 20% casein diet showed a 40% net gain of BW during the 20-week study. Monkeys receiving the 2% casein diet showed a 4% net gain of BW, which was consistent with marked accumulation of extracellular fluid. Severe disturbances of the structure and function of the liver were noted. Female rhesus macaques (M. mulatta), 12-24 months old and weighing 2.1 to 3.0 kg, were fed either 2% or 0% protein diets (isocaloric to 20% casein diet) to provide undefined energy at 100 kcal·BWkg-1·day-1. Structural changes were observed in the liver, myocardium, and striated muscle. There also was extensive cytoplasmic necrosis of the pancreas, the organ most severely affected; and cellular injury was evident in pancreatic secretions that were enzyme-deficient (Racela et al., 1966). In kwashiorkor, pancreatic enzymes have been described as deficient at a very early stage of the disease before fatty change of the liver is evident. During a 6-week interval, six 4-kg rhesus macaques (M. mulatta) were fed a diet deficient in protein but providing undefined energy at 100 kcal·BWkg-1·day-1. They developed carbohydrate intolerance attributed to diminished insulin production, hepatic dysfunction, and decreased glucose disposal as a consequence of protein deprivation (Khardori et al., 1980). Young squirrel monkeys (Saimiri sciureus, Leticia) have been used as pediatric models in malnutrition studies because they share several physiologic characteristics with human infants. They were fed diets restricted in protein, in energy, or in both (Gallina et al., 1987; Ausman et al., 1989) from the age of 2 to 8 weeks, or were only protein-restricted from the age of 4 to 24 weeks (Gallina et al., 1987) to support maintenance of BW without significant weight gain. The earlier study was designed to investigate the effects of particular nutritional deficiencies on plasma concentrations of albumin and transferrin, proteins used as biochemical indexes of nutritional status. Imposition of severe energy restriction (less than 250 kcal ME·BWkg-1· day-1) with adequate protein intake (23% of calories) did not lower serum albumin concentrations in four animals— a finding similar to that observed in another ceboidea species (Cebus albifrons) fed similarly (Samonds and Hegsted, 1978). Plasma albumin levels were decreased only when dietary protein (6.82% or 3.41% of calories), but not energy, was low (Gallina et al., 1987). Plasma transferrin in the control animals was significantly higher than in animals that were diet-restricted in protein, energy, or both. Sixteen monkeys exhibited an adaptive response to dietary manipulation in which energy restriction (288 ± 30 kcal ME·BWkg-1·day-1 vs control 449 ± 71 kcal ME·BWkg-1· day-1) coupled with protein restriction (4.9 ± 0.3 g·BWkg-1 ·day-1 vs control 14.6 ± 2.3 g·BWkg-1·day-1) provided no evidence of a more severe protein deficiency than protein restriction alone (Ausman et al., 1989). The effects of PCMon early growth of 8- to 28-week-old, 520-g cebus monkeys (Cebus albifrons) were studied when they were fed a synthetic liquid control diet (13% of calories as lactalbumin protein and undefined energy at 135 kcal·day-1), a low-protein diet (2.8% of calories), or a low-calorie diet (90 kcal·day-1) (Fleagle et al., 1975). By week 4 of the 20-week study, significant body-size differences were apparent. By 20 weeks, both protein- and calorie-restricted animals had developed a thin, emaciated appearance associated with marasmus, not from continuous loss of tissue but from redistribution of tissue over a slowly expanding skeleton that differed in proportion and shape from that of control monkeys. Fatty liver also was associated with a low protein concentration or dietary amino acid imbalance in cebus and rhesus (M. mulatta) monkeys (Wilgram et al., 1958). Sucrose, when provided as the primary carbohydrate— 20% of the total energy in a low-protein diet—potentiated the development of fatty liver, a rapid fall in serum albumin concentration to 1 g·dl-1, edema, and other signs of kwashiorkor among young baboons (Papio spp.). These baboons were diet-manipulated (low-protein, high-carbohydrate staples: banana, cassava, and matooke) and periodically stressed with acute energy restriction to produce models of PCM(Coward and Whitehead, 1972). Average protein and undefined energy intakes of control baboons were 6.1 g·BWkg-1· day-1 and 290 kcal·BWkg-1·day-1, respectively. Average serum albumin concentrations in the controls were maintained at 4.05 g·dl-1. When starch was the primary carbohydrate, there was a notable absence of fatty liver infiltration among similar baboons (Coward and Whitehead, 1972; Whitehead, 1980). Suppressed immune response in three baboons with signs of kwashiorkor also has been reported (Qazzaz et al., 1981). Marmosets and tamarins, members of the family Callitrichidae, also have served as nonhuman-primate models of human disease. In research laboratories, they have suffered reproductive inefficiencies and high mortality due to the occurrence of “wasting marmoset syndrome” (WMS), a protein-calorie deficiency that is characterized by weight loss, alopecia, chronic diarrhea, muscle atrophy, chronic

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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 colitis, and often anemia (Barnard et al., 1988). Seventeen male and 22 female adult Saguinus mystax were offered a commercial canned (60.3% moisture) marmoset diet at 120 g·day-1. The diet contained 23.4% crude protein (CP, dry basis) and 4.74 kcal gross energy (GE) per g of dry matter (DM), and was supplemented 3 days per week (20 ml per supplemented day) with a preparation (78.7% moisture) containing 14.2% CP (dry basis) and GE at 4.11 kcal·DMg-1. Ingredients in the commercial diet included water, ground wheat, whole egg, soy grits, sucrose, brewer’s rice, dried skimmed milk, vegetable oil, dehydrated alfalfa meal, dicalcium phosphate, iodized salt, and brewer’s dried yeast. The supplement contained water, wheat germ, honey, grape juice, and Biozyme®. On those days when only the commercial canned product was offered, average consumption was 172 g·BWkg-1·day-1, providing 12.0 g of protein and 290 kcal GE·BWkg-1·day-1. When the supplement was available, consumption of the commercial diet decreased to 110 g·BWkg-1·day-1, providing 10.2 g of protein and 185 kcal GE·BWkg-1·day-1. The tamarins preferred the supplement and, when offered, consumed it prior to consumption of the canned diet. The tamarins lost weight and exhibited alopecia and chronic diarrhea. During 3 months of feeding a pelleted diet (10.3% moisture), formulated to contain 26.2% protein (dry basis) and 4.78 kcal GE·DMg-1, mean food intake was 82 g·BWkg-1· day-1, providing protein at 19.3 g and GE at 335 kcal·BWkg-1 ·day-1, and the marmosets gained an average of 56 g. The pelleted diet contained rice gel, glucose, soybean meal, dried apple pomace, high fat milk solids, casein, beet pulp, soy oil, soy lecithin, and mineral and vitamin premixes. Evidence of WMS abated, and hematologic and serum-biochemistry profiles were no longer consistent with those of protein-calorie deficiency. The authors concluded that the tamarins appeared physically unable to consume sufficient amounts of the high-moisture canned diet and supplement to meet apparent protein and energy requirements for prevention of WMS. Because some of the pathophysiologic signs exhibited during consumption of the commercial diet and supplement resemble those of gluten intolerance, and these signs disappeared when the pelleted diet containing no gluten source was fed, it may be appropriate to consider the possibility of a multifactorial nutritional disease. The issue of callitrichid nutrition and food sensitivity has been explored further by Gore et al. (2001). PROTEIN EXCESS Although pathologic protein excess is more rare in monkeys than in other species, such as the rat, monkeys can develop pathologic changes in the kidney, which sometimes lead to terminal renal failure (Burek et al., 1988). It is common practice in all species, including humans, to limit protein intake to prolong the preterminal period in renal disease (Bourgoignie, 1992). It has not been shown in humans that a high-protein diet will compromise an otherwise healthy kidney. Bourgoignie et al. (1994) monitored renal function in 14 baboons that had been subjected to right nephrectomy and 20-30% infarction in the left kidney and that had been fed either 8% or 25% protein diets. Hemodynamic and metabolic characteristics were measured every 4 months for 5 years. Modest proteinuria developed after the kidney infarction, and hypertension after the nephrectomy. There was no difference in these measures between the monkeys fed 8% and 25% protein diets and no progression of the proteinuria or hypertension during the 60 months. Inulin clearance and glomerular filtration rate were significantly greater in baboons fed the 25% than the 8% protein diet throughout the study. The results suggest that within the 5-year experimental period excess protein was not detrimental to kidney function in the absence of other disease. In humans, it has been clearly shown that excess dietary protein increases urinary calcium loss (see Chapter 6) and thus calcium requirements. There are no data on calcium requirements of nonhuman primates relative to different dietary protein intakes. Therefore, the conservative approach is to keep dietary protein within reasonable bounds. NON-AMINO-ACID EFFECTS OF PROTEIN SOURCES Soy protein can have biologic effects other than those that depend strictly on protein quality. Fitch et al. (1964) reported reduced iron absorption and later anemia in rhesus monkeys fed a diet of soy isolate. Ausman et al. (1977) also reported anemia when infant squirrel monkeys were fed a protein-limiting diet based on soy isolate but not when they were fed lactalbumin. It was unclear which aspect of the soy protein was responsible for the anemia, although phytic acid in soybean meal has been shown to chelate iron and reduce its availability. A slightly lower digestibility of soy-protein was observed when diets containing soy-protein concentrate, casein, or lactalbumin were fed to Callithrix jacchus and Saguinus fuscicollis (Flurer et al., 1985). Protein sources are often carriers of potentially harmful or beneficial non-amino-acid components in the primate diet. Examples are saturated fat and cholesterol in red meat and fiber in grains. Raw soybeans have harmful concentrations of trypsin inhibitor, which, when incorporated into the diet, interfere with protein digestion in all species and are associated with pancreatic hypertrophy and cancer in rodents (McGuinness et al., 1980, 1982). Heat treatment of soybean meal or isolating soy protein decreases trypsin

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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 inhibitor several fold, decreasing risk of an adverse effect. Cebus monkeys fed diets based on soy isolate or soy concentrate for 4 years showed no differences from controls in tests strategically chosen to examine pancreatic function and disease (Harwood et al., 1986; Ausman et al., 1985a). Chacma baboons showed no untoward pancreatic effects of raw soy protein (Robbins et al., 1988). Consumption of diets based on soy protein has been associated with a reduction in plasma LDL-cholesterol concentrations in humans and nonhuman primates (Anderson et al., 1995; Anthony et al., 1996). Although early research suggested that the amino acid pattern of soy protein was responsible for the hypocholesterolemic effect, the latest evidence suggests that the isoflavonoid phytoestrogens genistein and diadzein may be the active compounds (Anthony et al., 1997). REFERENCES Anderson, J.W., B.M. Johnstone, and M.E. Cook-Newell. 1995. Meta-analysis of the effects of soy protein intake on serum lipids. N. Engl. J. Med. 333:276-282. Anthony, M.S., T.B. Clarkson, C.L. Hughes, T.M. Morgan, and G.L. Burke. 1996. Soybean isoflavones improve cardiovascular risk factors without affecting the reproductive system of peripubertal rhesus monkeys. J. Nutr. 126:43-50. Anthony, M.S., T.B. Clarkson, B.C. Bullock, and J.D. Wagner. 1997. Soy protein versus soy phytoestrogens in the prevention of diet-induced coronary artery atherosclerosis of male cynomolgus monkeys. Arterio. Thromb. Vasc. Biol. 17:2524-2531. Ausman, L.M., and D.M. Hegsted. 1980. Protein requirements of adult cebus monkeys (Cebus albifrons). Am. J. Clin. Nutr. 33:2551-2558. Ausman L.M., D.L. Gallina, B.M. Camitta, L.C. Flath, D.M. Hegsted. 1977. Acute erythroid hypoplasia in malnourished infant squirrel monkeys fed isolated soy protein. Am. J. Clin. Nutr. 30:1713-1720. Ausman, L.M., D.L. Gallina, K.W. Samonds, and D.M. Hegsted. 1979. Assessment of the efficiency of protein utilization in young squirrel and macaque monkeys. Am. J. Clin. Nutr. 32:1813-1823. Ausman, L.M., J.P. Harwood, N.W. King, P.K. Sehgal, R.J. Nicolosi, D.M. Hegsted, I.E. Liener, D. Donatucci, and J. Tarcza. 1985a. The effects of long term soy protein and milk protein feeding on the pancreas of Cebus albifrons monkeys. J. Nutr. 115:1691-1701. Ausman, L.M., D.L. Gallina, and R.J. Nicolosi. 1985b. Nutrition and metabolism of the squirrel monkey. Pp. 349-378 in Handbook of Squirrel Monkey Research, L.A. Rosenblum and C.L. Coe, Eds. New York: Plenum Press. Ausman, L.M., D.L. Gallina, K.C. Hayes, and D.M. Hegsted. 1986. Comparative assessment of soy and milk protein quality in infant cebus monkeys. Am. J. Clin. Nutr. 43:112-127. Ausman, L.M., D.L. Gallina, and D.M. Hegsted. 1989. Protein-calorie malnutrition in squirrel monkeys: adaptive response to calorie deficiency. Am. J. Clin. Nutr. 50:19-29. Barnard, D., J. Knapka, and D. Renquist. 1988. The apparent reversal of a wasting syndrome by nutritional intervention in Saguinus mystax. Lab. Anim. Sci. 38:282-288. Bourgoignie, J.J. 1992. Progression of renal disease: current concepts and therapeutic approaches. Kidney Int. 36(Supplement):S61-65. Bourgoignie, J.J., G. Gavellas, S.G. Sabnis, and T.T. Antonovych. 1994. Effect of protein diets on the renal function of baboons (Papio hamadryas) with remnant kidneys: a 5-year follow-up. Am. J. Kidney Dis. 23:199-204. Burek, J.D., P. Duprat, R. Owen, C.P. Peter, and M.J. Van Zwieten. 1988. Spontaneous renal disease in laboratory animals. Int. Rev. Exp. Path. 30:231-319. Buss, D.H., R.W. Cooper. 1972. Composition of squirrel monkey milk. Folia Primatol. 17:285-291. Calloway, D.H., and S. Margen. 1971. Variation in endogenous nitrogen excretion and dietary nitrogen utilization as determinants of human protein requirement. J. Nutr 101:205-212. Calloway, D.N. 1981. Energy-protein relationships. Pp. 148-165 in Protein Quality in Humans: Assessment and In Vitro Estimation, C.E. Bodwell, J.S. Adkins, and D.T. Hopkins, Eds. Westport: AVI Publishing. Chamberlain, B, F.R. Ervin, R.O. Pihl, and S.N. Young. 1987. The effect of raising or lowering tryptophan levels on aggression in vervet monkeys. Pharmacol. Biochem. Behav. 28:503-510. Cheek, D.B., A.B. Holt, W.T. London, J.H. Ellenberg, D.E. Hill, and J.L. Sever. 1976. Nutritional studies in the pregnant rhesus monkey— the effect of protein-calorie or protein deprivation on growth of the fetal brain. Am. J. Clin. Nutr. 29:1149-1157. Chopra, J.S., J. Mehta, S.V. Rana, U.K. Dhand, and S. Mehta. 1987. Muscle involvement during postnatal protein calorie malnutrition and recovery in rhesus monkeys. Acta Neurol. Scand. 75:234-243. Conklin-Brittain, N.L., E.S. Dierenfeld, R.W. Wrangham, M. Norconk, and S.C. Silver. 1999. Chemical protein analysis: a comparison of Kjeldahl crude protein and total ninhydrin protein using wild, tropical plant parts. J. Chem. Ecol. 25:2601-2622. Coward, D.G., and R.G. Whitehead. 1972. Experimental protein-energy malnutrition in baby baboons. Brit. J. Nutr. 28:223-237. Coward, W.A., and P.G. Lunn. 1981. The biochemistry and physiology of kwashiorkor and marasmus. Brit. Med. Bull. 37:19-24. Enwonwu, C.O., B.S. Worthington, and K.L. Jacobson. 1977. Protein-energy malnutrition in infant non-human primates (Macaca nemestrina). I. Correlation of biochemical changes with fine structural alterations in the liver. Brit. J. Exp. Path 58:78-94. Enwonwu, C.O., R.V. Stambaugh, and K.L. Jacobson. 1973. Protein-energy deficiency in nonhuman primates: biochemical and morphological alterations. Am. J. Clin. Nutr. 26:1287-1302. Fitch, C.D., W.E. Harville, J.S. Dinning, and F.S. Porter. 1964. Iron deficiency in monkeys fed diets containing soybean protein. Proc. Soc. Exp. Biol. Med. 116:130-133. Fleagle, J.G., K.W. Samonds, and D.M. Hegsted. 1975. Physical growth of cebus monkeys, Cebus albifrons, during protein or calorie deficiency. Am. J. Clin. Nutr. 28:246-253. Flurer, C., and H. Zucker. 1985. Long-term experiments with low dietary protein levels in Callithricidae. Primates 26:479-490. Flurer, C.I., G. Krommer, and H. Zucker. 1988. Endogenous N-excretion and minimal protein requirement for maintenance of the common marmoset (Callithrix jacchus). Lab. Anim. Sci.38:183-186. Gallina, D.L., and L.M. Ausman. 1986. Assessment of the efficiency of nitrogen utilization in the infant cebus monkey (Cebus albifrons)by nitrogen balance. J. Med. Primatol. 15:199-213. Gallina, D.L., L.M. Ausman, K. Kriauciunas, and D.M. Hegsted. 1987. Dissociated response of plasma albumin and transferrin to protein-calorie restriction in squirrel monkeys (Saimiri sciureus). Am. J. Clin. Nutr. 46:941-948. Garza, C., N.S. Scrimshaw, and V.R. Young. 1976. 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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 Harwood, J.P., L.M. Ausman, N.W. King, P.K. Sehgal, R.J. Nicolosi, I.E. Liener, D. Donatucci, and J. Tarcza. 1986. Effect of long-term feeding of soy-based diets on the pancreas of cebus monkeys. Adv. Exp. Biol. Med. 199:223-237. Hayes, K.C. 1985. Taurine requirement in primates. Nutr. Rev. 43:65-70. Hayes, K.C., Z.F. Stephan, and J.A. Sturman. 1980. Growth depression in taurine-depleted infant monkeys. J. Nutr. 110:119-125. Hegsted, D.M., and J. Worcester. 1966. Assessment of protein quality with young rats. Problems of World Nutrition in Proceedings of the Seventh International Congress of Nutrition (Volume 1-5), Hamburg 1966, Verlag Friedr. Vieweg and Sohn GmbH, Braunschweig, West Germany. Herbst, L.H. 1986. The role of nitrogen from fruit pulp in the nutrition of the frugivorous bat Carollia perspicillata. Biotropica 18:39-44. Hodson, H.H., V.L. Mesa, and D.C. Van Riper. 1967. Protein requirement of the young, growing chimpanzee. Lab. An. Care 17:551-562. Imaki, H., R. Moretz, H.M. Wisniewski, M. Neuringer, and J. Sturman. 1987. Retinal degeneration in 3-month-old rhesus monkey infants fed a taurine-free human infant formula. J. Neurosci. Res. 18:602-614. Jones, D.B. 1931. Factors for converting percentages of nitrogen in foods and feeds into percentages of proteins. Pp. 1-21 in Circular No. 183, USDA, Washington, DC. Kerr, G.R., A.S. Chamove, H.F. Harlow, and H.A. Waisman. 1969a. The development of infant monkeys fed low phenylalanine diets. Pediat. Res. 3:305-312. Kerr, G.R., G. Scheffler, and H.A. Waisman. 1969b. Growth and development of infant M. mulatta fed a standardized diet. Growth 33:185-199. Kerr, G.R., J.R. Allen, G.Scheffler, and H.A. Waisman. 1970. Malnutrition studies in the rhesus monkey. I. Effect on physical growth. Am. J. Clin. Nutr. 23:739-748. Kerr, G.R., H.A. Waisman, J.R. Allen, J. Wallace, and G.Scheffler. 1973. Malnutrition studies in Macaca mulatta. II. The effect on organ size and skeletal growth. Am. J. Clin. Nutr. 26:620-630. Kerr, G.R., and A.C. Helmuth. 1973. Malnutrition studies in Macaca mulatta. III. Effect on cerebral lipids. Am. J. Clin. Nutr. 26:1053-1059. Kerr, G.R., M. el Lozy, and G. Scheffler. 1975. Malnutrition studies in Macaca mulatta. IV. Energy and protein consumption during growth failure and “catch-up” growth. Am. J. Clin. Nutr. 28:1364-1376. Kerr, G.R., A. Helmuth, J.A. Campbell, and M. el Lozy. 1976. Malnutrition studies in Macaca mulatta. V. Effect on biochemical and cytochemical composition of major organs. Am. J. Clin. Nutr. 29:868-879. Khardori, R., J.S. Bajaj, M.B. Deo, and D.D. Bansal. 1980. Insulin secretion and carbohydrate metabolism in experimental protein malnutrition. J. Endocrinol. Invest. 3:273-278. Knapka, J.J., D.E. Barnard, K.A.L. Bayne, S.M. Lewis, B. Marriott, and O.T. Oftedal. 1995. Nonhuman Primates in Biomedical Research: Biology and Management, B.T. Bennett, C.R. Abee, and R. Henrickson, Eds. New York: Academic Press. Kohrs, M.B., A.E. Harper, and G.R. Kerr. 1976. Effects of a low-protein diet during pregnancy of the rhesus monkey. I. Reproductive efficiency. Am. J. Clin. Nutr. 29:136-145. Kohrs, M.B., M.D. Kerr, and A.E. Harper. 1980. Effects of a low protein diet during pregnancy of the rhesus monkey. III. Growth of infants. Am. J. Clin. Nutr. 33:625-630. McGuinness, E.E., R.G.H. Morgan, D.A. Levison, D.L. Frape, D. Hopwood, and K.G. Wormsley. 1980. The effects of long-term feeding of soya flour on the rat pancreas. Scand. J. Gastroenterol. 15:497-502. McGuinness, E.E., D. Hopwood, and K.G. Wormsley. 1982. Further studies of the effects of raw soya flour on the rat pancreas. Scand. J. Gastroenterol. 17:272-277. Mehta, S., C.K. Nain, N.K. Relan, and H.K. Kalsi. 1980. Energy metabolism of the brain in malnutrition, an experimental study in young rhesus monkeys. J. Med. Primatol. 9:335-342. Mitchell, H.H., and R.J. Block. 1946. Some relationships between the amino acid contents of proteins and their nutrition values for the rat. J. Biol. Chem. 163:599-620. Mundy, N.I., M. Ancrenaz, E.J. Wickings, and P.G. Lunn. 1998. Protein deficiency in a colony of western lowland gorillas (Gorilla g. gorilla). J. Zoo Wildl. Med. 29:261-268. Murray, R.K., D.K. Granner, P.A. Mayes, and V.W. Rodwell. 1996. Biochemical case histories. Pp. 816-817 in Harper’s Biochemistry, 24th ed. Stamford, CT: Appleton and Lange. National Research Council. 1989. Recommended Dietary Allowances, 10th ed. Washington, DC: National Academy Press. Neuringer, M.D., and J. Sturman. 1987. Visual acuity loss in rhesus monkey infants fed a taurine-free human infant formula. J. Neurosci. Res. 18:597-601. Neuringer, M., J. A. Sturman, H. Imaki, and T. Palackal. 1992. 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