Abstract
Case Description—A 5-year-old sexually intact male cockatiel was examined because of progressive dyspnea of 1 week's duration.
Clinical Findings—On auscultation of the lungs and air sacs, crackles were detected; the abdomen was distended and fluctuant on palpation. Eleven milliliters of clear yellow fluid was collected via abdominocentesis. Radiography (with and without contrast medium) and ultrasonography revealed a soft tissue mass in the caudoventral portion of the coelom.
Treatment and Outcome—Exploratory surgery of the coelomic cavity was performed and the neoplasm was excised. Histologic examination of the neoplasm was consistent with a high-grade pancreatic exocrine adenocarcinoma. Celecoxib, a cyclooxygenase (COX)-2 inhibitor, was administered for pain management and for potential antineoplastic activity. For 4.5 months after surgery, the bird had no recurrence of clinical signs; however, dyspnea recurred and during evaluation, the bird died. Necropsy findings indicated that the pancreatic adenocarcinoma had metastasized to surrounding tissues and vessels, which was not unexpected given the high grade assigned to the neoplasm during histologic analysis.
Clinical Relevance—Pancreatic neoplasms are associated with a poor prognosis, regardless of treatment modality. Celecoxib can be administered as palliative treatment to affected birds, but as with any nonsteroidal anti-inflammatory drug, COX-2 inhibitors should be used cautiously because they can adversely affect renal function by decreasing renal prostaglandin synthesis.
A 5-year-old male cockatiel was referred for evaluation and treatment of progressive dyspnea of 1 week's duration. Two weeks earlier, the cockatiel had flown into a window and was taken to the referring veterinarian for treatment; the bird recovered from the incident but became dyspneic later that week. On physical examination, the cockatiel was bright, alert, responsive, and well hydrated. Abnormal findings included a slightly thin body and a severely distended and fluctuant abdomen; mild dyspnea was evident at rest, and crackles were detected via auscultation of the lungs and air sacs. Abdominocentesis was performed to alleviate the bird's dyspnea. Eleven milliliters of clear yellow fluid was aspirated via abdominocentesis, and a sample was submitted for fluid analysis and cytologic examination. On microscopic examination of concentrated preparations of coelomic fluid, findings were consistent with either a pure or modified transudate. No bacterial organisms or evidence of neoplasia was observed in the fluid.
A blood sample was collected for clinicopathologic analyses. Mild hemoconcentration (PCV, 58%; reference range, 42% to 55%) was detected, and the plasma biochemical analyses revealed mild lipemia, hyperphosphatemia (6.1 mg/dL; reference range, 3.0 to 5.5 mg/dL), high creatine kinase activity (2,101 U/L; reference range, 50 to 400 U/L), hypoproteinemia (0.2 g/dL; reference range, 3.0 to 5.5 g/dL), and low bile acids concentration (9.6 μmol/L; reference range, 20 to 100 μmol/L). Radiography revealed a soft tissue mass in the caudoventral portion of the coelom (Figure 1). To further characterize the coelomic mass effect, barium (2.5 mL) was administered by gavage and radiographs were obtained 1 hour later. Contrast radiography of the abdomen revealed centripetal displacement of the small intestine and caudal displacement of the cloaca, which suggested the presence of a centrally located coelomic mass (Figure 2). Additional tests, such as ultrasonography and endoscopy, were discussed with the owner. However, at the owner's request, further diagnostic testing was not undertaken at that time. Because dyspnea had resolved after abdominocentesis and the bird had no other clinical signs, it was taken home by the owner.
Right lateral radiographic view of the thoracic and abdominal regions of a cockatiel with abdominal distention and a 1-week history of progressively worsening dyspnea. Eleven milliliters of clear straw-colored fluid was collected via abdominocentesis before obtaining this image. A soft tissue mass effect (arrows) is seen in the caudoventral portion of the coelom.
Citation: Journal of the American Veterinary Medical Association 228, 1; 10.2460/javma.228.1.69
Right lateral radiographic view of the cockatiel in Figure 1 obtained 1 hour after administration of contrast agent via gavage. Centripetal displacement of the small intestine, cranial displacement of the ventriculus, and caudal displacement of the cloaca suggest the presence of a centrally located coelomic mass (arrows).
Citation: Journal of the American Veterinary Medical Association 228, 1; 10.2460/javma.228.1.69
The bird was reexamined 4 days later by a local veterinarian because of recurrence of dyspnea and ascites. Abdominocentesis was repeated, and an unknown volume of abdominal fluid was removed; the cockatiel was again referred for evaluation. On repeat physical examination, the cockatiel was quiet and had signs of depression but it was responsive. Its mucous membranes were moist and pink. Feathers over the abdomen were matted, but the abdomen was not distended. Although the cockatiel was breathing comfortably during the examination, crackles were detected via auscultation of the air sacs. Other findings of the physical examination were unremarkable. Abdominal ultrasonography revealed a moderate amount of fluid around a discrete, large hyperechoic mass containing multiple hypoechoic nodules; displaced, gas-filled intestinal loops also were detected. Both the radiographic and the ultrasonographic examination findings confirmed the presence of an intracoelomic mass that was displacing intestinal loops centripetally, suggesting that the mass originated from the mesentery, spleen, or pancreas. Because the cockatiel was male (on the basis of species sexual dimorphism), ovarian and uterine masses were not included as differential diagnoses.
An exploratory celiotomy was performed to obtain a biopsy specimen of the mass and, if possible, resect the mass. The bird was routinely anesthetized with 3% isoflurane in oxygen administered via a face mask attached to a nonrebreathing Bain circuit. The cockatiel was then intubated with a noncuffed 1.5-mm endotracheal tube and maintained on 2% isoflurane. Because administration of fluids or drugs might be necessary perioperatively, a 25-gauge needle was placed in the distal portion of the ulna for use as an intraosseous catheter. The cockatiel was placed in dorsal recumbency on a forced-air warmer, and a Doppler monitor was placed over the brachial vein to monitor the heart rate. By use of electrocauterya with a bendable 3/32-inch electrode needle,b a skin incision was made from the left inguinal region to the midline, just caudal to the keel, and was extended distally along the midline to 1 cm anterior to the vent. Abdominal muscle bellies also were incised via electrocautery, and care was taken not to damage underlying portions of the gastrointestinal tract and other organs. On entry into the coelomic cavity, free fluid was observed; the fluid was suctioned out to prevent aspiration through the caudal thoracic and abdominal air sacs. Numerous adhesions, which were likely a result of chronic ascites, were bluntly dissected with sterile cotton-tipped applicators and hemostats. A large, firm, white multinodular pedunculated mass (2.5 cm in diameter) that originated between the distal portion of the pancreas and ascending loop of the duodenum was identified. Another smaller 1-cm-diameter mass of similar appearance was found free in the abdomen (not attached to any structures) and was removed. Hemoclips were placed on the base of the attached pedunculated mass, and the entire mass was excised. No other masses were found on inspection of the coelomic cavity. Additionally, a biopsy specimen of the distal tip of the pancreas that was adjacent to the mass was collected by use of hemoclips to isolate the tissue and a No. 15 scalpel blade to excise the sample. Muscle and skin were closed separately with 4-0 polydioxanone suture in simple continuous and Fordinterlocking patterns, respectively. The cockatiel recovered from anesthesia without complication. After recovery, the bird was treated with warmed lactated Ringer's solution (30 mL/kg [13.6 mL/lb], SC, q 12 h), buprenorphine hydrochloridec (0.03 mg/kg [0.014 mg/lb], IM, q 12 h]), carprofend (2 mg/kg [0.9 mg/lb], PO, q 12 h), and trimethoprim sulfamethoxazole (30 mg/kg, PO, q 12 h). The next day, the cockatiel was quiet but responsive and was discharged from the hospital; the owner was instructed to administer carprofen and trimethoprim sulfamethoxazole for the next 5 and 7 days, respectively.
Histologic examination of sections of the mass revealed an invasive and poorly circumscribed neoplasm composed of an acinar arrangement of cells in a fine, vascularized stroma (Figure 3). Neoplastic cells were polyhedral and contained moderate amounts of eosinophilic to basophilic cytoplasm. Nuclei were oval and varied markedly in size; each had a coarse chromatin pattern with prominent nucleoli. Mitotic activity was high (6 to 10 mitotic nuclei/hpf), and large, abnormally shaped nuclei were present. These features were consistent with a high-grade pancreatic exocrine adenocarcinoma. Neoplastic cells were detected at the surgical margins of the mass. On histologic examination, the biopsy specimen of the pancreatic tissue adjacent to the mass had a normal appearance and did not contain any neoplastic features.
Photomicrograph of a section of a pancreatic mass surgically resected from the cockatiel in Figure 1. In portions of the section, histologically normal exocrine pancreatic acini (asterisks) and an endocrine pancreatic islet (arrowhead) are replaced by a nonencapsulated, invasive malignant neoplasm composed of haphazardly arranged acinar structures. Notice the numerous mitotic figures (arrows) within the neoplastic cell population. H&E stain; bar = 100 μm.
Citation: Journal of the American Veterinary Medical Association 228, 1; 10.2460/javma.228.1.69
At the recheck appointment 14 days after surgery, the bird was eating well and had almost returned to its normal activity level. The owner reported that no signs of dyspnea had been observed at home. On physical examination, the cockatiel was bright, alert, and responsive; the incision site had healed; and new feather growth was present over the abdomen. Sutures were removed. Results of the histologic evaluation of the mass were discussed with the owner, and a poor longterm prognosis was given. Chemotherapeutic options were also discussed with the owner, but the owner declined further treatment because of the lack of knowledge about the use of such drugs in birds and the bird's poor prognosis despite ancillary treatments.
Six weeks after surgery, the cockatiel was brought to the hospital to have its wings trimmed. The owner reported that the cockatiel was doing well with the exception of tiring easily after flying. Options for further treatment of pancreatic adenocarcinoma were again discussed, including the use of COX-2 inhibitors that have potential antineoplastic effects in humans.1,2 The COX-2 inhibitor celecoxibe (10 mg/kg [4.5 mg/lb], PO, q 24 h) was administered to the bird as a palliative treatment; at monthly updates, the owner reported that the cockatiel was doing well and had returned to a normal routine. Celecoxib was administered daily to the cockatiel for 3 months.
One hundred forty-two days (4.5 months) after surgery, the cockatiel was evaluated at the hospital because of a 2-day history of recurrent dyspnea. On physical examination, the cockatiel was mildly dyspneic with a slightly distended abdomen; crackles were auscultated over the air sacs. Approximately 8 mL of blood-tinged fluid was aspirated via abdominocentesis. The bird was anesthetized with 3% isoflurane in oxygen (administered via a face mask) for radiographic evaluation. However, the cockatiel went into respiratory arrest before recovery from anesthesia, and attempts at cardiopulmonary resuscitation were unsuccessful. Radiographs revealed increased soft tissue and fluid opacity diffusely throughout the coelomic cavity and hemoclips at the previous surgical site. Cytologic examination of the coelomic fluid revealed a modified transudate with no evidence of bacterial organisms or neoplastic cells.
At necropsy, multiple coelomic masses that invaded the liver and lungs bilaterally were detected. Additionally, serosanguineous fluid was present throughout the coelomic cavity. Via histologic examination of various tissues, it was determined that the pancreatic adenocarcinoma had metastasized to lungs, air sacs, liver, proventriculus, kidneys, and intestinal serosae and walls. A small area of histologically normal pancreas was identified on necropsy; however, the vessels surrounding this area of histologically normal pancreas contained neoplastic cells. Metastatic lesions were generally associated with the serosal surfaces (carcinomatosis). Diffuse acute renal tubular necrosis was also detected (Figure 4).
Photomicrograph of a section of kidney from the cockatiel in Figure 1 obtained after treatment with a COX-2 inhibitor (celecoxib) for pancreatic adenocarcinoma. There is acute degeneration and necrosis of proximal convoluted tubular epithelial cells, which are dissociated from each other and contain hypereosinophilic cytoplasm with pyknotic and karyolytic nuclei. Basement membrane zones surrounding renal tubules appear intact. Notice few glomeruli of normal histologic appearance (arrowheads) and rare, viable, distal, convoluted renal tubules (arrows). H&E stain; bar = 100 μm.
Citation: Journal of the American Veterinary Medical Association 228, 1; 10.2460/javma.228.1.69
Discussion
Pancreatic adenocarcinomas and adenomas are rarely identified in birds but have been identified in Amazon parrots (Amazona spp), cockatiels (Nymphicus hollandicus), macaws (Ara spp), budgerigars (Melopsittacus undulatus), chickens (Gallus gallus), peaceful doves (Geopelia striata striata), waterfowl (Anseriformes), ratites (Struthioniformes), and a mynah bird (Gracula religiosa).3–8 Although the cause of pancreatic adenocarcinoma in birds is unknown, genetic as well as viral causes have been proposed. Pancreatic carcinomas have been induced experimentally in guinea fowl and chickens via inoculation with avian leukosis virus strains Pts-56 and HPRS-103 in studies9,10 to investigate the etiology and pathology of these tumors.In previous reports,3,5,11 pancreatic adenocarcinomas and adenomas in birds have been associated with bile duct adenocarcinomas and oviductal adenocarcinomas; however, it is unclear whether these masses were neoplasms that had developed independently or metastases or whether all of the aforementioned masses resulted from a common mutagenic process.
Diagnosis of pancreatic neoplasia in birds is made on the basis of clinical signs and results of diagnostic tests that rule out other coelomic masses. Contrast radiography and ultrasonography are used to provide information about the size, location, and organ involvement of a coelomic mass. If present, intracoelomic fluid can be collected via abdominocentesis and evaluated to differentiate between transudates (typically associated with neoplasms and heart disease) and exudates (typically associated with septic or egg-yolk peritonitis). Plasma biochemical analyses, including measurement of activities of aspartate aminotransferase and creatine kinase and concentrations of bile acids and uric acid, are used to evaluate hepatic and renal function. However, in birds, changes in the aforementioned clinicopathologic variables are not pathognomonic for pancreatic neoplasms.
Effacement of pancreatic parenchyma by neoplastic tissue can lead to dysfunctions of the pancreas, though only exocrine pancreatic insufficiency has been reported.4 In birds and dogs, dysfunction of the exocrine pancreas (in which the pancreas fails to secrete digestive enzymes) results in maldigestion; affected individuals excrete voluminous, pale-tan, greasy feces.4,12 In a yellow-naped Amazon (Amazona ochrocephala) parrot with pancreatic adenocarcinoma, diagnostic tests to evaluate exocrine pancreatic function were performed because the neoplasm had resulted in near complete obliteration of pancreatic tissue and clinically evident exocrine pancreatic insufficiency.4 Fecal samples were collected from the affected Amazon parrot for comparison with fecal samples from 2 clinically normal Amazon parrots. In the Amazon parrot with adenocarcinoma, results of fecal analyses were positive for neutral and split fats and negative for trypsin, whereas in the 2 clinically healthy Amazon parrots, results of fecal analyses were negative for neutral and split fats and positive for trypsin. In the same bird, plasma triglyceride concentration was assessed after a triglyceride challenge test was performed.4 Two hours after administration of corn oil to the affected Amazon parrot, plasma triglyceride concentration (73 mg/dL) was not increased, compared with baseline pretreatment values (94 mg/dL). Two days later, the triglyceride challenge test was repeated with pancreatic enzymes added to the corn oil that was administered to the affected bird; 2 hours after that treatment, plasma triglyceride concentration had increased by approximately 70%, compared with baseline values (154 vs 89 mg/dL).4 Serum amylase assays have also been advocated for the diagnosis of pancreatic disease in avian species; however, these tests have not yet been validated in birds.13 Furthermore, in dogs with exocrine pancreatic insufficiency, serum amylase concentration is usually within reference range or slightly low; therefore, results of that assessment are considered unreliable in the diagnosis of exocrine pancreatic insufficiency.12 Diagnostic tests of pancreatic function were not performed in the bird of this report because the cockatiel did not have signs of pancreatic dysfunction; in general, clinical signs do not become apparent in affected individuals as long as sufficient normal pancreatic tissue remains.
For the bird of this report, various additional diagnostic options were discussed with the owner once a coelomic mass had been identified via radiographic and ultrasonographic examinations. Although invasive, endoscopic or exploratory celiotomy not only allows for the assessment of size and location of a mass but also allows for the procurement of a biopsy specimen for histologic examination. In this case, an exploratory surgery was selected as the best option because it would allow for excision of the mass if it was resectable.
Because of the high recurrence rate of pancreatic masses and the inability to perform complete resection in some instances, chemotherapy also may be indicated in the treatment of pancreatic adenocarcinoma. In humans, many chemotherapeutic drugs have been investigated in the treatment of pancreatic cancer; however, there has been no significant increase in the response rate or median survival time in affected humans as a result of administration of any chemotherapeutic agent.1 Although the number of reports14,15 on the use of chemotherapy in avian species is increasing, pharmacodynamic and pharmacokinetic data regarding most chemotherapeutic agents in birds are limited. In anecdotal reports,14–16 cyclic carboplatin administered intraosseously at a dose of 5 mg/kg (2.2 mg/lb) has been associated with some success in the treatment of carcinomas in birds. Corticosteroids have been used in birds as palliative treatments of various neoplasms, although these agents should be used cautiously because they can predispose birds to fungal infections.14 Several studies1,2,14–18 in mammals have revealed increases in COX-2 enzyme expression in association with many cancers. Cyclooxygenase-2 is involved in processes such as apoptosis, angiogenesis, and invasion of tissue; thus, the use of COX-2 inhibitors has been advocated for their potential antineoplastic and anticarcinogenic effects.1,2,14–18 The COX-2 inhibitors, such as celecoxib, inhibit cell growth by arresting the cell cycle and inducing apoptosis in some types of cancers.1,2,18 In other studies,1,2,18 COX-2 inhibitors appear to inhibit tumor growth by hindering angiogenesis. To our knowledge, studies have not been conducted on the use of COX-2 inhibitors in birds for the treatment of neoplasia; however, there are anecdotal reports19–21 of the use of COX-2 inhibitors in the treatment of birds with proventricular dilatation disease. Proventricular dilatation disease is characterized by a lymphoplasmacytic infiltrate in the central and peripheral nervous systems, especially the nerve ganglia of the myenteric plexus of the gastrointestinal tract. It is thought that celecoxib decreases the inflammation associated with the ganglioneuritis, thereby resulting in resolution of clinical signs.20,21 Finally, a COX-2 inhibitor was administered to the cockatiel of this report not only for its potential antineoplastic effects but also for pain management because pancreatic neoplasms are reported to be painful in humans and it is likely that they would also be associated with pain in other species.
As with any NSAID, COX-2 inhibitors should be used cautiously because they can adversely affect renal function by decreasing renal prostaglandin synthesis.22,23 Originally, most of the adverse effects of NSAIDs on renal function were thought to be caused by COX-1 inhibition; however, results of a more recent study23 in mammals indicate that COX-2 inhibition also may result in such adverse effects. On histologic examination of kidney tissue from the bird of this report, acute diffuse renal tubular necrosis was detected, which is a finding generally associated with renal toxicosis or ischemia. No definitive cause for the tubular necrosis was identified, but NSAID-induced renal damage is a possibility. In 1 report,24 NSAID-induced renal damage was described in northern bobwhites following administration of flunixin meglumine. Further studies to assess how selective NSAIDs, such as COX-2 inhibitors, affect the kidneys of birds are warranted. In retrospect, the plasma uric acid concentration in the cockatiel of this report could have been monitored periodically to assess renal function.
Although the bird of this report died as a result of anesthetic complications, underlying organ dysfunction may also have been a contributory factor. Invasion of the pancreatic adenocarcinoma into organs such as the liver and lungs may have resulted in organ failure that caused cardiorespiratory decompensation during anesthesia. Additionally, renal tubular necrosis may have resulted in dysfunction of the kidneys. Metastasis of the adenocarcinoma was expected on the basis of the high neoplastic grade determined from histologic analysis of the initial biopsy specimen. Birds with pancreatic neoplasms have a poor survival rate regardless of type of treatment. In 1 report,6 a cockatiel died 66 days after resection of a pancreatic adenocarcinoma; at necropsy, metastases of the neoplasm were detected throughout the bird's coelom. In other case reports,3–5,7,8 birds with pancreatic masses either were euthanatized or died before treatment. The cockatiel of this report was free from clinical signs for approximately 142 days after resection of the pancreatic adenocarcinoma before effects of the metastases became apparent.
| COX | Cyclooxygenase |
| NSAID | Nonsteroidal anti-inflammatory drug |
Ellman Vetsurg, Ellman International, Oceanside, NY.
Ellman Vari-tip bendable 3/32-inch needle electrode, Ellman International, Oceanside, NY.
Buprenex, Reckitt & Colman Inc, Richmond, Va.
Rimadyl, Pfizer Animal Health, Exton, Pa.
Celebrex, Searle, New York, NY.
References
- 1↑
Pino SM, Xiong HQ, McConkey D, et al. Novel therapies for pancreatic adenocarcinoma. Curr Oncol Rep 2004;6:199–206.
- 2
Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst 2002;94:252–266.
- 3
Latimer KS. Oncology. In: Ritchie BR, Harrison GJ, Harrison LR, eds. Avian medicine: principles and application. Lake Worth, Fla: Wingers Publishing, 1994;658–659.
- 4↑
Ritchey JW, Degernes LA, Brown TT Jr. Exocrine pancreatic insufficiency in a Yellow-naped Amazon (Amazona ochrocephala) with pancreatic adenocarcinoma. Vet Pathol 1997;34:55–57.
- 5
Larsen RS, Carpenter JW, Goggin F, et al. What is your diagnosis? J Avian Med Surg 2001;15:226–231.
- 7
Rosskopf WJ, Woerpel RW, Howard EB, et al. Pancreatic adenocarcinoma in a mynah bird. Mod Vet Pract 1982;63:573–574.
- 8
Abdul-Aziz TA. Poorly differentiated pancreatic adenocarcinoma in a chicken. Vet Rec 1995;137:408.
- 9
Toshkov I, Kirev T, Bannasch P. Virus-induced pancreatic cancer in guinea fowl. An electron-microscopical study. Int J Pancreatol 1991;10:51–64.
- 10
Payne LN, Gillespie AM, Howes K. Myeloid leukaemogenicity and transmission of the HPRS-103 strain of avian leukosis virus. Leukemia 1992;6:1167–1176.
- 11
Hillyer EV, Moroff S, Hoefer H, et al. Bile duct carcinoma in two out of ten Amazon parrots with cloacal papillomas. J Am Vet Med Assoc 1991;5:91–95.
- 12↑
Westermarck E, Wiberg M. Exocrine pancreatic insufficiency in dogs. Vet Clin North Am Small Anim Pract 2003;33:1165–1179.
- 13↑
Speer BL. A clinical look at the avian pancreas in health and disease, in Proceedings. Annu Conf Assoc Avian Vet 1998;98–111.
- 14↑
Filippich LJ, Charles BG. Current research in avian chemotherapy. Vet Clin North Am Exot Anim 2004;7:821–831.
- 15
Filippich LJ. Tumor control in birds. Semin Avian Exotic Pet Med 2004;13:25–43.
- 16
Speer BL, Eckermann-Ross C. Diagnosis and clinical management of pancreatic duct adenocarcinoma in a Green-winged macaw (Ara chloroptera), in Proceedings. Eur Conf Avian Med Surg 2001;20–21.
- 17
Tucker ON, Dannenberg AJ, Yang EK, et al. Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res 1999;59:987–990.
- 18
Alshafie GA, Abou-Issa HM, Seibert K, et al. Chemotherapeutic evaluation of Celecoxib, a cyclooxygenase-2 inhibitor, in a rat mammary tumor model. Oncol Rep 2000;7:1377–1381.
- 19
Hawkins MG, Machin KL. Avian pain management and analgesia, in Proceedings. Annu Conf Assoc Avian Vet 2004;165–173.
- 20
Dahlhausen R, Aldred S, Calaizzi E. Resolution of clinical proventricular dilation disease by cyclooxygenase 2 inhibition, in Proceedings. Annu Conf Assoc Avian Vet 2002;9–12.
- 21
Boutette JB, Taylor M. Proventricular dilation disease: a review of research, literature, species differences, diagnostics, prognosis, and treatment, in Proceedings. Annu Conf Assoc Avian Vet 2004;175–181.
- 22
Brater DC. Renal effects of cyclooxygenase-2-selective inhibitors. J Pain Symptom Manage 2002;23 (suppl 4):S15–S20.
- 23↑
Klein PN, Charmatz K, Langenberg J. The effect of flunixin meglumine (Banamine) on the renal function in northern bobwhite (Colinus virginianus): an avian model, in Proceedings. 14th Annu Meet Am Assoc Zoo Vet 1994;128–131.
- 24↑
Harris RC. Interactions between COX-2 and the reninangiotensin system in the kidney. Acta Physiol Scand 2003;177:423–427.
