A Survey of Pancreatic Lesions in Nonhuman Primates

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1 Vet. Pathol. IY(Supp. 7): , 1982 A Survey of Pancreatic Lesions in Nonhuman Primates H. M. MCCLURE and F. W. CHANDLER Yerkes Regional Primate Research Center, Emory University, Atlanta, Ga. and The Centers for Disease Control, Public Health Service, US. Department of Health and Human Services, Atlanta, Ga. Abstract. Approximately 3,000 microslides of hematoxylin and eosin (HE)-stained sections of pancreas from 1,000 nonhuman primates were reviewed. Sections were from 557 females and 443 males; 658 were adults of unknown age and 342 were laboratory-born animals of known age. The latter included 94 animals less than one year old, 92 from one to five years old, and 156 from five to more than 20 years old. There were 326 squirrel monkeys, 3 19 rhesus monkeys, 100 great apes, 123 other macaques, 61 other Old World monkeys, 39 other New World monkeys, and 32 prosimians. Pancreatic lesions of varied severity found in 187 (18.7%) of these nonhuman primates included focal parenchymal or periductal accumulations of mononuclear inflammatory cells with varied degrees of periductal fibrosis in 77; hyalinized islets (amyloidosis) in 29; acute or chronic diffuse pancreatitis in 18; chronic focal pancreatitis with or without ductal hyperplasia in ten; neoplasms in 11; hemorrhage of the parenchyma or islets in eight; parasites in seven; lymphoid or ectopic splenic nodules of the parenchyma in six; acinar ectasia in six; focal parenchymal fat in six; ectopic pancreas in four; parenchymal cysts without fibrosis in three; acinar cell atrophy in one; and cystic fibrosis-like changes in one. Little information is available on the normal anatomy or microstructure of the nonhuman primate pancreas or on clinical disease or lesions of the pancreas or pancreatic function tests in nonhuman primate species. Individual reports are available on the light and electron microscopic features of the squirrel monkey pancreas [49], innervation of the pancreas of the Formosan macaque [50], the pancreaticoduodenal junction in chimpanzees [2], anatomical features of the accessory pancreatic duct in rhesus monkeys [46], and organ weights for the pancreas of macaques, mangabeys, and chimpanzees [26]. Tests for exocrine pancreatic function have been made recently in the patas monkey [12-141, and studies related to the metabolic turnover and renal excretion of salivary and pancreatic amylase have been done in the baboon [ 1 I]. The most frequently reported pancreatic disease in nonhuman primates has been diabetes mellitus caused by amyloidosis of the islets of Langerhans [8, 15-17, 19-24, 27, 28, 39, 45, 471. Diabetes mellitus has been induced in nonhuman primates by treatment with streptozotocin [25]. Treatment with glucocorticoids has been shown 193

2 194 McClure and Chandler to produce hyperglycemia and elevation of serum immunoreactive insulin in macaques [33]. Pancreatitis has been induced experimentally in rhesus monkeys by obstruction of the pancreatic duct or interference with the blood supply to the pancreas [5]. Spontaneous pancreatitis has been documented infrequently in nonhuman primates [lo, 421, and at least two of these cases were caused by adenovirus infection [4, 341. Lesions associated with parasite infections have been found in the pancreas of marmosets and capuchin monkeys [3,6]. In one report, nematodes were found in the pancreatic ducts of 28 of 107 marmosets. Lesions in the infected marmosets included chronic fibrosing pancreatitis and inflammation of the pancreatic ducts [6]. Chronic, multifocal or diffuse pancreatitis with a periductal distribution was seen in capuchin monkeys infected with Molineus torulosus, a nematode that localizes in the proximal small intestine [3]. Pancreatic changes characterized as dilatation of ducts, flattened ductal epithelium, and slight periductal fibrosis with accumulations of lymphocytes and eosinophils have been described in New World monkeys infected with Trichospirura [37]. Pancreatic lesions associated with cryptosporidiosis have been seen in a rhesus monkey [29]. The pancreas from this monkey contained areas of lobular atrophy with increased connective tissue that was infiltrated by lymphocytes and plasma cells. A few ducts were lined by hyperplastic epithelium, and cryptosporidia were seen on the luminal surface of some of the ductal epithelial cells [29]. Although ectopic pancreas occurs with some frequency in man, usually in the submucosa of the duodenum, stomach, or jejunum [30], this condition has not been reported in nonhuman primates. There is one report of ectopic splenic nodules in the pancreas of a capuchin monkey [32]. Pancreatic changes have been found in rhesus monkeys maintained on a proteindeficient diet. These changes included loss of cytoplasmic zymogen granules, which progressed to shrinkage and partial disruption of acini [7]. A similarity between changes in the pancreas, liver, and lungs of vitamin E-deficient monkeys and those in people with cystic fibrosis was noted in one report [38]. In other reports on lesions in vitamin E-deficient monkeys, however, no pancreatic lesions were noted [ 1, 9, 181. Pancreatic neoplasms also have been reported infrequently in nonhuman primates. Five pancreatic tumors listed in recent reviews [31, 35, 361 included an insulinoma and a malignant papillary adenoma [31], two adenocarcinomas [40, 411, and a fibroadenoma [48]. Two other pancreatic islet cell tumors [44] and an adenocarcinoma [43] have been recorded. To determine the incidence and types of pancreatic lesions in nonhuman primates, we reviewed sections of pancreas taken from 1,000 nonhuman primates at necropsy. In this report, we document the findings of this retrospective histologic survey. Materials and Methods For this survey, approximately 3,000 microslides of hematoxylin and eosin (HE)-stained sections of pancreas from 1,000 nonhuman primates were retrieved from the files of the Yerkes

3 Pancreatic Lesions 195 Regional Primate Research Center. Nonhuman primates from which these sections were taken had died from various causes between 1966 and Sections were from 557 females and 443 males of 33 nonhuman primate species; 658 were adults of unknown age and 342 were laboratory-born animals of known age, including 94 less than one year old, 92 from one to five years old, and 156 from five to more than 20 years old. The numbers of animals in each species were 326 squirrel monkeys, 319 rhesus monkeys, 100 great apes, 123 other macaques, 6 1 other Old World monkeys, 39 other New World monkeys, and 32 prosimians. Each author examined all sections independently. Results Pancreatic lesions of varied severity were found in 187 (18.7%) of these nonhuman primates. They included the following: focal parenchymal or periductal accumulations of mononuclear inflammatory cells with varied degrees of periductal fibrosis in 77; hyalinized islets (amyloidosis) in 29; acute or chronic diffuse pancreatitis in 18; chronic focal pancreatitis with or without ductal hyperplasia in ten; neoplasms in 11; hemorrhage of the parenchyma or islets in eight; parasites in seven; lymphoid or ectopic splenic nodules in the pancreatic parenchyma in six; acinar ectasia in six; focal parenchymal fat in six; ectopic pancreas in four; parenchymal cysts without fibrosis in three; acinar cell atrophy in one; and cystic fibrosis-like changes in one. Many of these changes could be classified only as incidental findings and probably had little, if any, relation to death of the animal or antemortem clinical abnormalities. Cysticfibrosis-like lesions: The monkey with cystic fibrosis-like pancreatic lesions was a six-month-old male rhesus that was removed from a gang cage unit for examination because he was pale and inactive. He was severely anemic and weighed approximately 50% less than rhesus infants of comparable age. He later showed signs of respiratory distress, failed to respond to treatment, and died two weeks after illness first was noted. At necropsy, the infant was pale and undernourished, and had a thin haircoat. The lungs were edematous and did not collapse when the thorax was opened. The pancreas was small and firm, and had a slightly nodular, irregular surface; when sectioned, it showed an accentuated lobular pattern. Histologically, the normal architecture of the pancreas was almost completely effaced. The acinar epithelium was flat, and the lumina of many acini were dilated and contained eosinophilic debris. Individual acini were separated by narrow bands of fibrous tissue, and perilobular fibrosis was prominent. Most of the pancreatic ductules and many of the larger ducts also were dilated and filled with eosinophilic debris (fig. 1, 2). Islets of Langerhans were essentially normal in number and morphology. Findings in other organs were nonspecific and included mild focal periportal fibrosis of the liver, focal pulmonary edema and atelectasis, and focal pneumonia. Hyalinized islets of Langerhans: Various degrees of amyloidosis of the islet tissue was found in 29 nonhuman primates (fig. 3). In most, hyalinization of islets was severe and indicated that the affected monkeys were probably diabetic, although a clinical history of diabetes had been noted in only five of 29 animals. Two were killed for experimental purposes without having shown any clinical signs of disease; all others died as the result of fight wounds or clinical disease problems. Two cases

4 196 McClure and Chandler Fig. 1: Cystic fibrosis-like changes in pancreas of young rhesus monkey. Acini and ductules dilated and filled with eosinophilic debris. Perilobular and periacinar fibrosis (F); morphologically normal islet (I). Fig. 2 Cystic fibrosis-like changes in pancreas of young rhesus monkey. Dilated acini and ductules; prominent perilobular and periacinar fibrosis (F).

5 Pancreatic Lesions 197 Fig.3 Accumulation of amyloid (A) in pancreatic islet of 23-year-old female rhesus monkey. of islet amyloidosis occurred in conjunction with disseminated amyloidosis. Eight nonhuman primate species were affected, and there was an equal sex distribution (1 5 males, 14 females). Ten cases involved adult animals of unknown age; the ages of the remaining animals ranged from nine months to 48 years. Most of the cases of hyalinized islet tissue were in animals more than 15 years old; the mean age of affected animals was 20 years. Insular amyloidosis is discussed in greater detail in the preceding paper (see Palotay and Howard). Pancreatitis: Diffuse, acute, or chronic pancreatitis was found in 18 nonhuman primates; 12 cases showed predominantly acute inflammatory changes, five cases were chronic, and one case was characterized by an intense infiltrate of eosinophils (fig. 4-6). Focal chronic pancreatitis was found in ten other nonhuman primates. One case of acute necrotizing pancreatitis was caused by adenovirus infection; another was associated with a perforated duodenal ulcer; another occurred seven days after abdominal surgery (splenectomy); and three more cases were associated with an acute, generalized peritonitis. Specific causes were not identified in the other six cases of acute pancreatitis. One monkey with chronic pancreatitis also had a duodenal ulcer and one had had previous gastric surgery. Specific causes were not identified in the other cases. The one monkey with eosinophilic pancreatitis had been used in experimental studies that involved implantation of brain electrodes. This

6 198 McClure and Chandler Fig. 4 Interlobular fibrin and polymorphonuclear leukocytes in acute pancreatitis in tenyear-old male chimpanzee. Fig. 5: Parenchymal degeneration, necrosis, and acute inflammatory cell infiltrate in pancreas of adult female cynomolgus monkey with acute pancreatitis.

7 Pancreatic Lesions 199 Fig. 6 Periductal and parenchymal fibrosis with mononuclear inflammatory cell infiltrate in pancreas of adult male rhesus monkey with chronic pancreatitis. monkey died while it was anesthetized. It had no history of clinical illness, and there was no apparent cause for the pancreatitis. The 18 cases of diffuse, acute, or chronic pancreatitis occurred in nine nonhuman primate species which included six rhesus monkeys, five squirrel monkeys, and one each of cynomolgus, bonnet macaque, chimpanzee, owl monkey, mangabey, stumptailed macaque, and cebus monkey. There was an equal sex distribution (ten females, eight males), and most cases occurred in adults of unknown age. The age was known for seven animals; it ranged from nine months to 18 years. Gross lesions of acute pancreatitis included various degrees of congestion, petechial to diffuse hemorrhage, necrosis, and focal fat necrosis. Gross changes of chronic pancreatitis usually were minimal, and, when present, consisted of increased firmness, slight accentuation of lobular pattern, and, in one monkey, atrophy and a prominent decrease in the amount of remaining pancreatic parenchyma. Histologic changes in the acute cases usually were characterized by necrosis of the pancreatic parenchyma, with various amounts of hemorrhage and polymorphonuclear leukocyte infiltrate. Chronic cases showed prominent perilobular fibrosis with various degrees of periacinar fibrosis, atrophy of remaining parenchyma, and infiltrates of mononuclear cells and occasional polymorphonuclear leukocytes. The one case of eosinophilic

8 200 McClure and Chandler Fig. 7: Islet cell adenoma in pancreas of adult female pigtailed macaque. Fig. 8: Islet cell adenomatosis in pancreas of 47-year-old female chimpanzee. pancreatitis also had a prominent fibrous tissue component that was diffusely infiltrated with eosinophils and fewer mononuclear cells. Neoplasms: Twelve neoplasms were found in pancreata from 11 nonhuman primates. These included five islet cell adenomas, two neoplasms classified as islet

9 Monkey number 1* * 6* 7 8* 9 10* 11 Species M. mulatta M. nemestrina M. mulatta P. troglodytes M. mulatta M. mulatta M. mulatta M. mulatta P. troglodytes M. mulatta M. sphinx * History of irradiation. Pancreatic Lesions 20 1 Table I. Pancreatic neoplasms in nonhuman primates Sex F F F F M M F F M M M Age (years) - 17 Adult Adult Adult Pancreatic tumor Islet cell adenoma Islet cell adenoma Ductal adenoma Islet cell adenoma- tosis Adenocarcinoma Islet cell adenoma Islet cell adenoma Islet cell adenoma Islet cell adenoma Islet cell adenomatosis Acinar cell adenoma Acinar cell adenoma Cause of death Endometriosis Pneumonia Esophagostomiasis Bacterial endocarditis Acute peritonitis; pheochromocytoma, adrenal; hyperglycemia (420 mg/dl) Cortical adenoma, adrenal; hyperglycemia (280 mg/dl) Shigellosis; mucoid carcinoma, colon; amyloidosis Colon carcinoma Experiment related Duodenal carcinoma Hemorrhagic pancreatitis cell adenomatosis, two acinar cell adenomas, one ductal adenoma and in one monkey, a well-differentiated adenocarcinoma and an islet cell adenoma (fig ). Species with tumors included seven Macaca mulatta, two Pan troglodytes, one M. nemestrina, and one Mandrillus sphinx. There was an equal sex distribution (six females, five males), and a definite association between tumor occurrence and age. Nonhuman primates with pancreatic tumors ranged from 13 to 47 years of age; three tumors were in adults of unknown age (table I). Gross lesions associated with pancreatic tumors were not found in eight of the 11 animals. Lesions in one chimpanzee with islet cell adenomatosis were focal yellowwhite spots throughout the parenchyma; one acinar cell adenoma was seen grossly as a 1-cm, circular white nodule in the tail of the pancreas; and the pancreatic carcinoma was evident grossly as an irregular, 1-cm nodule in the head of the pancreas. None of the animals had shown clinical signs that could be related to the pancreatic neoplasms. Two monkeys were hyperglycemic (280 and 420 mg/dl), but they also had an adrenal neoplasm (one pheochromocytoma and one fibrotic, mineralized mass that was thought to be a cortical adenoma). Five monkeys with pancreatic tumors had a history of irradiation; there was no record of exposure to carcinogenic agents in any of the other animals. Five of the monkeys with pancreatic tumors also had other neoplastic disease (two adrenal tumors and three carcinomas of the

10 202 McClure and Chandler Fig. 9 Ductal adenoma in pancreas of adult female rhesus monkey. intestinal tract). Four of these five monkeys with multiple primary tumors were in the irradiated group. Parasites: Parasites were found in the pancreatic parenchyma of seven nonhuman primates, including one each of the following: Hylobates lar, Pongo pygmaeus, Pan paniscus, Saguinus nigricollis, Saimiri sciureus, Cercocebus atys, and Cebus apella. Parasites were found in one colony-born monkey, three animals that had been in the colony for more than one year, and three animals that had been in the colony for less than one year. Parasites included flukes in the pancreatic ducts of four animals, unidentified nematodes in the pancreatic parenchyma of two, and Strongyloides larvae in the parenchyma of one. In one pygmy chimpanzee, flukes were detected in the pancreatic ducts at necropsy; in all of the other monkeys, parasites were detected only at histologic examination. The one orangutan with Strongyloides larvae in the pancreatic parenchyma was known to have a disseminated Strongyloides infection, and larvae were found in a number of other tissues. Tissue response to the parasites varied from essentially none to an intense periductal or parenchymal accumulation of eosinophils and mononuclear cells. A slight periductal fibrosis also was evident in some animals (fig. 12, 13). Miscellaneous lesions: A variety of miscellaneous lesions, most of which had little effect on the monkeys clinical conditions, were found during this survey and are summarized in the following paragraphs. Ectopic pancreatic tissue was found in four monkeys (two M. mulatta, one M.

11 Pancreatic Lesions 203 Fig. 10 Well-differentiated pancreatic adenocarcinoma in 20-year-old male rhesus monkey. Fig. 11: Higher magnification of pancreatic adenocarcinoma in fig. 10: neoplastic cells form irregular clusters and acini.

12 204 McClure and Chandler Fig. 12: Unidentified trematodes in major pancreatic duct of adult male gibbon. Fig. 13: Strongyloides larva (arrow) in pancreatic parenchyma of nine-month-old female orangutan. No inflammatory cell response. nemestrina, one M. fascicularis). The aberrant locations of pancreatic tissue included the submucosa of the stomach in one, duodenal submucosa in one, and the wall of major pancreatic ducts in two monkeys. Ectopic pancreas was found in only one of the four monkeys at necropsy. Grossly, the ectopic pancreas in this monkey was a submucosal nodule in the midportion of the greater curvature of the stomach. The

13 Pancreatic Lesions 205 Fig. 14 Acinar ectasia of pancreas of adult female squirrel monkey. nodule measured approximately 7 mm in diameter and protruded approximately 2 mm above the level of the gastric mucosa. In all cases, the ectopic pancreatic tissue was histologically normal; in some, this tissue included islets of Langerhans. Ectopic splenic tissue was found in the pancreata of two monkeys, and four other monkeys had lymphoid follicles with prominent germinal centers within the pancreatic parenchyma. The splenic tissue was evident grossly as small, circular areas of reddish-brown tissue. Acinar ectasia was the only histologic finding in six monkeys; this lesion, however, also was seen frequently in conjunction with other pancreatic diseases. The ectatic changes were characterized by various degrees of dilatation of the acini and small ducts, both of which contained small amounts of inspissated, eosinophilic debris (fig. 14). Multiple cysts of various sizes, with minimal fibrosis, were present throughout the pancreatic parenchyma in three monkeys (two M. mulatta, one M. nemestrina). The cysts were lined by flat to low cuboidal epithelium, and usually were empty. Occasionally, cysts were surrounded by a slightly increased amount of fibrous connective tissue; in most instances, however, the cysts were immediately contiguous to the surrounding normal pancreatic parenchyma. There was no associated inflammatory cell infiltrate (fig. 15). All three monkeys with pancreatic cysts also had grossly detectable cysts in the liver or kidneys. Atrophy of pancreatic acinar cells was found in one monkey with a clinical history

14 206 McClure and Chandler Fig. 15: Multiple cysts in pancreas of 12-year-old female pigtailed macaque. No parenchymal fibrosis or inflammatory cells. of hypoglycemia (blood glucose of 32 mg/dl or less). Focal fatty infiltrate in the pancreatic parenchyma was found in six monkeys, and focal hemorrhages of the pancreatic parenchyma or islet tissue in eight. Focal parenchymal or periductal accumulations of mononuclear cells with various degrees of periductal fibrosis were found in the pancreas of 77 nonhuman primates. Discussion The gross and microscopic lesions of the pancreas in 1,000 nonhuman primates have been reviewed. This retrospective survey showed a striking similarity between the types of pancreatic lesions reported for man and those that occur in nonhuman primates. Alterations in islet tissue with subsequent diabetes mellitus have been well documented in nonhuman primates, especially in Mucaca nigra [19-221, and have been confirmed in this survey. Other pancreatic diseases that constitute significant clinical problems in man, although reported infrequently in nonhuman primates, were found to occur with considerable frequency in this survey. Such diseases include acute pancreatitis, chronic pancreatitis, neoplasms, and developmental anomalies. Two conditions documented in this survey have not been reported previously in

15 Pancreatic Lesions 207 nonhuman primates. These are ectopic pancreas and cystic fibrosis-like lesions. The latter finding is of potential significance because currently there is no animal model for use in cystic fibrosis studies. Work is under way in our laboratory to determine whether this cystic fibrosis-like disease in monkeys is associated with genetic factors, as is the disease in man. In the interim, the detection of pancreatic lesions in a nonhuman primate that are essentially identical to those in children with cystic fibrosis should stimulate both retrospective and prospective searches for additional cases. Clinicians and pathologists concerned with nonhuman primates should be aware that pancreatic diseases do occur in these species, and clinicopathologic evaluations of ill animals should include procedures to evaluate both exocrine and endocrine pancreatic functions. Further studies and documentation of pancreatic disease in nonhuman primates may also contribute to the development of models for such human diseases as chronic pancreatitis and cystic fibrosis-two relatively common diseases of man for which no animal models are now available. Acknowledgements This investigation was supported in part by PHS Research Grant No. RR from the National Institutes of Health, Grant No. G330A from the Cystic Fibrosis Foundation, and Contract No. NO 1-CP from the National Cancer Institute. References 1 AUSMAN, L.M.; HAYES, K.C.: Vitamin E deficiency anemia in Old and New World monkeys. Am J Clin Nutr 27: , BOYDEN, E.A.: The choledocho- and pancreaticoduodenal junctions in the chimpanzee. Surgery 37: , BRACK, M.; MYERS, B.J.; KUNTZ, R.E.: Pathogenic properties of Molineus torulosus in capuchin monkeys, Cebus upella. Lab Anim Sci 23: , CHANDLER, F.W.; CALLAWAY, C.S.; ADAMS, S.R.: Pancreatitis associated with an adenovirus in a rhesus monkey. Vet Pathol 11: , CHHUTTANI, P.N.; BALASUBRAHMANYAN, M.; SHARMA, T.D.; SARONWALA, K.C.: Experimental pancreatitis in the rhesus monkey. Ind J Med Res 53: , COSGROVE, G.E.; HUMASON, G.; LUSHBAUGH, C.C.: Trichospiruru leptostoma, a nematode of the pancreatic ducts of marmosets (Suguinus spp.) J Am Vet Med Assoc , DEO, M.G.; SOOD, S.K.; RAMALINGASWAMI, V.: Experimental protein deficiency: Pathological features in the rhesus monkey. Arch Path , DIGIACOMO, R.F.; MYERS, R.E.; BAEZ, L.R.: Diabetes mellitus in a rhesus monkey (Mucaca muluttu): A case report and literature review. Lab Anim Sci 21: , DINNING, J.S.; DAY, P.L.: Vitamin E deficiency in the monkey. I. Muscular dystrophy, hematologic changes, and the excretion of urinary nitrogenous constituents. J Exp Med , DOEPEL, F.M.; ANVER, M.R.; HOFING, G.L.: Pancreatitis in two New World monkeys. Vet Pathol , DUANE, W.C.; FRERICHS, R.; LEVITT, M.D.: Simultaneous study of the metabolic turnover and renal excretion of salivary amylase- Iz5I and pancreatic amylase- 13'1 in the baboon. J Clin Invest 51: , 1972

16 208 McClure and ChandleI 12 GYR, K.; WOLF, R.H.; FELSENFELD, 0.: Exocrine pancreatic function tests in patas monkeys (Erythrocebuspatas). Am J Vet Res , GYR, K.; WOLF, R.H.; IMONDI, A.R.; FELSENFELD, 0.: Experiences with a new test of exocrine pancreatic function in protein deficient patas monkeys. Schweiz Med Wochenschr 104: , GYR, K.; WOLF, R.H.; IMONDI, A.R.; FELSENFELD, 0.: Exocrine pancreatic function in protein-deficient patas monkeys studied by means of a test meal and an indirect pancreatic function test. Gastroenterology W , HAMILTON, C.L.: An observation of long-term experimental obesity and diabetes mellitus in the monkey. J Med Primatol1: , HAMILTON, C.L.; CIACCIA, P.: The course of development of glucose intolerance in the monkey (Macaca mulatta). J Med Primatol7: , HAMILTON, C.L.; LEWIS, D.: Feeding behavior in monkeys with spontaneous diabetes mellitus. J Med Primato , HAYES, K.C.: Pathophysiology of vitamin E deficiency in monkeys. Am J Clin Nutr 27: , HOWARD, C.F., JR.: Spontaneous diabetes in Macaca nigra. Diabetes 21: , HOWARD, C.F., JR.: Correlations of serum triglyceride and prebetalipoprotein levels to the severity of spontaneous diabetes in Macaca nigra. J Clin Endocrinol Metab , HOWARD, C.F., JR.: Diabetes in Macaca nigra: Metabolic and histologic changes. Diabetologia , HOWARD, C.F., JR.: Basement membrane thickness in muscle capillaries of normal and spontaneously diabetic Macaca nigra. Diabetes , HOWARD, C.F., JR.: The relationship of diet and atherosclerosis in diabetic Macaca nigra. Adv Exp Med Biol , HOWARD, C.F., JR.; PALOTAY, J.L.: Spontaneous diabetes mellitus in Macaca cyclopis and Mandrillus leucophaeus: Case reports. Lab Anim Sci , HOWARD, C.F., JR.; PETERSON, L.H.: Cataract development in streptozotocin-diabetic monkeys (Macaca nemestrina). Lab Anim Sci , INAY, M.; RUCH, T.C.; FINAN, S.; FULTON, J.F.: The endocrine weights of primates. Endocrinology , JONES, S.M.: Spontaneous diabetes in monkeys. Lab Anim , ~ R K J.H.;, CASEY, H.W.; HARWELL, J.F., JR.: Diabetes mellitus in two rhesus monkeys. Lab Anim Sci , KOVATCH, R.M.; WHITE, J.D.: Cryptosporidiosis in two juvenile rhesus monkeys. Vet Pathol , LACY, P.E.: Pancreas and Diabetes Mellitus. In: Pathology, ed. Anderson, 5th ed., pp C.V. Mosby Co., St. Louis, LAPIN, B.A.; KRILOVA, R.I.: Spontaneous tumors in monkeys of the Sukhumi colony. In: Verhandlungsbericht des XVIII. Internationalen Symposiums iiber die Erkrankungen der Zootiere, pp Akademie-Verlag, Innsbruck, Berlin, LAU, D.T.L.: Ectopic splenic nodules in the pancreas of a capuchin monkey (Cebus albfrons). J Med Primatol267-70, LIKE, A.A.; CHICK, W.L.: Pancreatic beta cell replication induced by glucocorticoids in subhuman primates. Am J Pathol , MCCLURE, H.M.; CHANDLER, F.W.; HIERHOLZER, J.C.: Necrotizing pancreatitis due to simian adenovirus type 31 in a rhesus monkey. Arch Pathol Lab Med , O CONOR, G.T.: Cancer-A general review. Primates Med 39-22, O GARA, R.W.; ADAMSON, R.H.: Spontaneous and induced neoplasms in nonhuman

17 Pancreatic Lesions 209 primates. In: Pathology of Simian Primates, ed. Fiennes, pp S. Karger, Basel, ORIHEL, T.C.; SEIBOLD, H.R.: Trichospirurosis in South American monkeys. J Parasitol 57: , PENTSCHEW, A.: Formal genesis of cystic fibrosis. Am J Path la, RABB, G.B.; GETTY, R.E.; WILLIAMSON, W.M; LOMBARD, L.S.: Spontaneous diabetes mellitus in tree shrews, Urogale everetti. Diabetes 15: , RATCLIFFE, H.L.: Tumors in captive primates with a description of a giant cell tumor in a chacma baboon, Papio porcarius. J Cancer Res , RATCLIFFE, H.L.: Tumors in captive primates: Report of two cases. Am J Pathol 8: , ROSENBERG, D.P.; ANDERSON, J.H.; HENRICKSON, R.V.: Acute pancreatitis in a baboon. J Am Vet Med Assoc , RYDER-DAVIES, P.; HIME, J.M.: Hypertrophic osteoarthropathy in a gibbon (Hylobates lar). J Small Anim Pract , SEIBOLD, H.R.; WOLF, R.H.: Neoplasms and proliferative lesions in 1065 nonhuman primate necropsies. Lab Anim Sci 23: , SHELDON, W.G.; GLEISER, C.A.: Amyloidosis of the islets of Langerhans in a crab-eating monkey (Macacafascicularis). Vet Path , SINGH, I.: The terminal part of the accessory pancreatic duct and its musculature in the rhesus monkey. J Anat 97: , VALERIO, D.A.; MILLER, R.L.; INNES, J.R.M.; COURTNEY, K.D.; PALLOTTA, A.J.; GUTT- MACHER, R.M.: Macaca mulatta: Management of a Laboratory Breeding Colony, pp Academic Press, New York, WADSWORTH, J.R.: Neoplasia of captive zoo species. Vet Med (Praha) , WINBORN, W.B.: Light and electron microscopy of the islets of Langerhans of the Saimiri monkey pancreas. Anat Rec , YAMAMOTO, T.: On the innervation, especially sensory innervation, of the pars pylorica, the duodenum and the pancreas in Formosan macaque. J Comp Neurolll , 1960 Request reprints from Dr. Harold M. McClure, Division of Pathobiology and Immunobiology, Yerkes Regional Primate Research Center, Emory University, Atlanta, GA (USA).