AFIP Wednesday Slide Conference - No. 25
March 31, 1999

Conference Moderator:
Dr. Wallace B. Baze, Diplomate, ACVP
The University of Texas MD Anderson Cancer Center
Science Park, Department of Veterinary Sciences
Bastrop, Texas 78602.
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Case I - 96-309 (AFIP 2638284)

Signalment: Two-month-old, white-faced, female lamb.
History: Six lambs from a flock of 100 were affected with neurologic signs that were non-responsive to thiamine treatment. This lamb presented with propulsive circling to the left, proprioceptive deficits in all four limbs, unilateral blindness OS, ventral-medial displacement OS, dorsal strabismus, and seizure-like twitching of the head. The lamb was euthanized and necropsied.
Gross Pathology: Gross lesions were confined to the brain. The left cerebrum was diffusely enlarged with transfalcine herniation. The left gyri were enlarged and lacked definition.
Laboratory Results: Liver copper was 1.77 ppm wet weight (normal range is 25-100 ppm wet weight).
Contributor's Diagnoses and Comments:
1. Unilateral acute cerebral cortical necrosis and cerebral edema.
2. Multifocal necrosis and calcification of cerebral vessels.

Etiology: Copper deficiency.
Histologic changes were confined to the left cerebrum and thalamus. Widespread vacuolation was present throughout the cerebral cortex with prominent clear spaces around capillaries and neurons (cytotoxic edema). Numerous neurons had shrunken eosinophilic cytoplasm with nuclear pyknosis and karyolysis (ischemic nerve cell change). Capillaries were prominent, with swollen endothelium and increased numbers of both straight and branched capillaries. Necrosis, mineralization and the accumulation of neutrophils and pyknotic nuclear debris were present in the media of several medium-sized vessels.
Copper is a co-factor in many important enzymes including superoxide dismutase, cytochrome oxidase (c and aa3), lysyl oxidase, and ascorbic acid oxidase. Copper deficiency in sheep is associated with a myriad of clinical signs including anemia, decreased immune responsiveness, decreased growth rate, achromotrichia, inadequate keratinization of wool with loss of crimp, increased parasitism, lameness, spontaneous fractures, diarrhea, and reduced fertility. One of these syndromes usually predominates in a given flock.
Neurologic diseases associated with copper deficiency in lambs include swayback (congenital copper deficiency), enzootic ataxia (delayed-onset ataxia), and cerebral edema. 2 Fetal copper deficiency results in bilaterally symmetric lesions in the cerebral white matter (centrum semiovale and corona radiata) that range from small focal changes to extensive lesions that can result in cavitation (porencephaly or hydranencephaly). Half of affected lambs have grossly visible lesions while the remaining ones have only microscopic changes. Lesions develop prior to significant myelinization, so evidence of myelin degradation is sparse. Laminar neuronal necrosis can be found in the cerebral cortex overlying areas of affected white matter.
Lambs that develop enzootic ataxia are normal at birth but develop a swaying hind limb ataxia by 6 months of age. CNS lesions are microscopic and affect neuronal populations in the brain stem and spinal cord. The most consistently affected neurons are in the red and vestibular nuclei, reticular system of the medulla, ventral motor neurons in the spinal cord and the thoracic nucleus (nucleus dorsalis or Clarke's column). Affected neurons, which are those normally rich in cytochrome oxidase, undergo chromatolysis. Accompanying the neuronal changes is bilateral symmetrical degeneration of white matter mainly affecting the dorsal spinocerebellar tracts and their extension into the caudal cerebellar peduncles and the spinal cord tracts adjacent to the ventral median fissure. Electron microscopy indicates the lesions are a primary axonal degeneration and secondary myelin degeneration.
A unique form of copper deficiency is recognized in England as severe cerebral edema with herniation.3 Similar to the lamb presented here, cerebral edema may be unilateral, but there are no differences in cerebral copper levels between the affected and unaffected sides of the brain. Examination of brains of affected lambs under ultraviolet light reveals autofluorescence, similar to cerebral cortical necrosis due to thiamine deficiency. The neurologic symptoms are thought to reflect a rapid increase in intracranial pressure due to cerebral edema while the ischemic nerve cell change is regarded as secondary to pressure induced anoxia.
Plasma copper levels in lambs are low at birth but rise to adult levels by 1 to 7 days of age. The primary reserve of copper is the liver, and blood copper concentrations remain near normal until hepatic copper concentrations are markedly decreased. Since serum copper is a poor indicator of copper deficiency, the preferred diagnostic sample is hepatic copper concentration.5 Copper deficiency may be due to dietary deficiency or decreased copper absorption from the large intestine of sheep. Excess molybdenum or sulfates can lead to the formation of insoluble cupric molybdates or copper thiomolybdates in the rumen. Excessive calcium, especially limestone, and iron reduce copper absorption. Excess cadmium and zinc reduce hepatic copper concentrations probably through both decreased absorption and competition with copper for hepatic metallothionein.
AFIP Diagnoses:
1. Cerebrum: Neuronal necrosis, cortical, acute, diffuse, with edema, breed unspecified, ovine.
2. Cerebrum, vessels: Necrosis and mineralization, multifocal.

Note: Some sections contain small numbers of lymphocytes and plasma cells multifocally in the meninges.
Conference Note: Participants identified similar histopathological changes as described by the contributor, and considered various causes of metabolic polioencephalomalacia in the differential diagnosis, including nutritional deficiencies (thiamine, copper), water deprivation/salt excess, and several toxicities (lead, amprolium, thiaminase containing plants, excess dietary sulfur).
Menke's disease in humans is an X-linked recessive disorder in which there is severe hypocupremia due to defective intestinal absorption of copper; copper levels are high in the intestinal wall, but decreased in the liver and brain. The disease shares many clinicopathological features with copper deficiency in animals, and is characterized by severe mental retardation, growth retardation, and skin abnormalities that cause the hair to have a kinky or steely appearance.
Contributor: Department of Pathology, Cornell University, Ithaca, NY 14853.
1. Maas J, Smith BP: Copper deficiency in ruminants. In: Large Animal Internal Medicine, 2nd edition, Smith BP, ed., pp. 904-908, Mosby, St. Louis, MO, 1996.
2. Summers BA, Cummings JF, DeLahunta A: Degenerative diseases of the central nervous system. In: Veterinary Neuropathology, Summers BA, Cummings JF, DeLahunta A, eds., pp. 273-277, Mosby, St. Louis, MO, 1995.
3. Roberts HE, Williams BM: Cerebral oedema in lambs associated with hypocuprosis and its relationship to swayback. I. Field, clinical, gross anatomical and biochemical observations. J Comp Pathol 76:279-283, 1966.
4. Roberts HE, Williams BM: Cerebral oedema in lambs associated with hypocuprosis and its relationship to swayback. II. Histopathological findings. J Comp Pathol 76:285-290, 1966.
5. Puls R: Copper, sheep. In: Mineral Levels in Animal Health, Puls R, ed., 2nd edition, pp. 105-109, Sherpa International.
6. Gould DH: Polioencephalomalacia. J Anim Sci 76:309-314, 1998.
7. Duchen LW, Jacobs JM: Nutritional deficiencies and metabolic disorders. In: Greenfield's Neuropathology, Adams JH, Duchen LW, eds., 5th ed., pp. 850-852, Oxford University Press, New York, 1992.
8. Jones TC, Hunt RD, King NW: Nutritional deficiencies. In: Veterinary Pathology, 6th ed., pp. 805-806, Williams and Wilkins, Baltimore, MD, 1997.

Case II - HN1311 (AFIP 2651908)

Signalment: Five-year-old, male, French bulldog.
History: This dog was referred to an animal hospital at the beginning of April because the dog showed depression since the end of March. Arrhythmia was recognized. Dirofilaria immitis was not detected in the blood sample, and abdominal and thoracic radiographs showed no abnormalities. Rectal temperature was 38.6°C. The dog had been treated with dexamethasone sodium phosphate to reduce the clinical signs. However, dyspnea and tiring on exercise recurred over the following three weeks. At the beginning of May, the dog showed severe bradycardia (heart rates: 40-50 beats per minute) and collapsed with severe dyspnea. Because the dog demonstrated decerebrate rigidity before death, necropsy was performed to examine the central nervous system.
Gross Pathology: The brain showed moderate edematous swelling accompanied by flattening of the cerebral cortical gyri and narrowing of the sulci. The posterior portion of the cerebellar vermis was mildly herniated through the foramen magnum. In transverse section through the mamillary bodies, a single mass, measuring 1.5 x 2.0 x 1.5 cm, was found, located primarily in the moderately-dilated right lateral ventricle. The increased cerebrospinal fluid was cloudy, pinkish, and mucinous in viscosity. The mass was soft, gelatinous, and grayish white.

Laboratory Results: None.
Contributor's Diagnosis and Comments: Cerebrum: Malignant oligodendroglioma, French bulldog, canine.
Microscopically, the tumor consists of diffuse proliferation of neoplastic oligodendroglial cells. The neoplastic cells have small, round, hyperchromatic nuclei with poorly stained cytoplasm, and the cells infiltrate into the cortex. Rarely, atypical astrocytes are scattered among the neoplastic oligodendrocytes. The neoplasm has abundant vascular proliferation with occasional glomeruloid pattern, and there is severe multifocal extensive necrosis, with thrombosis and hemorrhages. Neoplastic oligodendroglial cells generally infiltrate into the adjacent white matter and perivascular spaces. Perivascular cuffing and satellitosis of neurons by neoplastic cells are often seen. Mitotic figures are frequently observed at the periphery of the neoplasm.
Immunohistochemistry demonstrated that the neoplastic oligodendrocytes were positive for S-100 protein, vimentin, neuron specific enolase (NSE), and neurofilament protein (NFP). Myelin basic protein (MBP) and glial fibrillar acidic protein were not detected in these cells. Small numbers of GFAP-positive astrocytes that had oval, large nuclei and abundant eosinophilic cytoplasm were noted around proliferated vessels.
Oligodendroglioma appears to be the most common primary brain tumor in middle-aged and old dogs. A predilection for brachycephalic dog breeds, such as the present case, has been recognized in glial tumors. The tumor is usually located in the cerebral white matter, particularly around the lateral ventricles. Clinically, the dogs show depression, blindness, ataxia, and change in temperament from nerve damage. Microscopically, oligodendrogliomas have a very characteristic honeycomb pattern, and the tumor cells have small, round, hyperchromatic nuclei with poorly stained cytoplasm. Occasionally, multifocal mineralization and proliferation of blood vessels are also observed throughout the neoplasm.
The neoplasm was considered to be malignant because of the findings of frequent mitotic figures, nuclear pleomorphism, glomeruloid vascular tufts, and extensive necrosis. The results of immunohistochemical staining of canine oligodendroglioma with antibody against MBP are generally negative. Many oligodendrogliomas show a mixture with GFAP-positive astroglial cells. The interpretation of the finding is controversial whether the astrocytes indicate a capacity for immature oligodendrocytes to express astrocytic differentiation or reactive astrocytes. In our case, the astrocytes within the neoplasm appear to be reactive astrocytes since we could not find intermediate cells, and the cells proliferated especially preferentially around the proliferating blood vessels.
AFIP Diagnosis: Cerebrum: Oligodendroglioma, anaplastic, French bulldog, canine.
Conference Note: This case was studied in consultation with the Department of Neuropathology. All conference participants identified a primary central nervous system (CNS) neoplasm of glial origin. The diagnosis of high grade astrocytoma was considered based on histomorphologic findings of a poorly circumscribed, infiltrative neoplasm with extensive areas of necrosis, relatively high mitotic rate, and prominent proliferation of glomeruloid vessels.
In immunohistochemical studies performed at the AFIP, neoplastic cells were negative for synaptophysin and neurofilament protein (NFP). While the majority of the neoplasm was negative for glial fibrillary acidic protein (GFAP), there were a few GFAP-positive cells, most often located adjacent to vessels.
Anaplastic (malignant) oligodendroglioma and astrocytoma share several histomorphological features, including high cellularity, necrosis, high mitotic rate, and prominent proliferation of glomeruloid vessels; thus, distinguishing between these two glial neoplasms may be difficult. As noted by the contributor, the presence of intermingled astrocytic cells is common in anaplastic oligodendrogliomas and may further complicate the histologic picture. Fortunately, neoplastic cells in oligodendrogliomas generally have distinguishing features such as round, hyperchromatic, nuclei surrounded by small amounts of clear to lightly stained cytoplasm, and distinct cell borders. In addition, the branching capillary proliferation ("chicken-wire" pattern) is characteristic of an oligodendroglioma. These histologic features combined with results of immunohistochemistry support the diagnosis of oligodendroglioma in this case.
Contributor: Laboratory of Comparative Pathology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
1. Rubinstein LJ: Tumors of neuroglial cells. In: Atlas of Tumor Pathology: Tumors of the Central Nervous System, Rubinstein LJ, ed., 2nd series, Fascicle 6, pp. 85-104, Armed Forces Institute of Pathology, Washington DC, 1972.
2. Summers BA, Cummings JF, DeLahunta A: Tumors of the central nervous system. In: Veterinary Neuropathology, Summers BA, Cummings JF, DeLahunta A, eds., pp. 370-373, Mosby, St. Louis, MO, 1995.
3. Bailey CS, Higgins RJ: Characteristics of cisternal cerebrospinal fluid associated with primary brain tumors in the dog: A retrospective study. J Amer Vet Med Assoc 188:414-417, 1986.
4. Taylor RF, Bucci TJ: Oligodendroglioma in a dog. J Small Anim Pract 13:41-46, 1972.
5. Triolo AJ, Howard MO, Miles KG: Oligodendroglioma in a 15-month-old dog. J Amer Vet Med Assoc 205:986-988, 1994.
6. Vandevelde M, Fankhauser R, Luginbuhl H: Immunocytochemical studies in canine neuroectodermal brain tumors. Acta Neuropathol 66:111-116, 1985.
7. Wilson RB, Beckman SL: Mucinous oligodendroglioma of the spinal cord in a dog. J Amer Anim Hosp Assoc 31:26-28, 1995.
8. Koestner A, et al.: Histological classification of tumors of the nervous system of domestic animals. In: World Health Organization Histological Classification of Tumors of Domestic Animals, Schulman FY, ed., 2nd series, volume 5, pp. 17-21, Armed Forces Institute of Pathology, Washington DC, 1999.

Case III - 10376-98 (AFIP 2640589)

one 2x2 gross color photo transparency
Signalment: Ovine, male, cross-bred, 2-week-old.
History: This lamb became lethargic within 8 hours of being let out to pasture for the first time. He did not nurse but seemed more alert after treatment with antibiotic and B-vitamin injections. Two days after the onset of clinical signs, he began circling to the left, and by the next day he was non-ambulatory, laterally recumbent, and paddling with opisthotonos and nystagmus. The lamb was humanely euthanized.
Gross Pathology: The cerebrum was edematous, and the cerebellar vermis was slightly herniated through the foramen magnum. On transverse section, bilaterally symmetric areas of hemorrhage and malacia were observed in the cerebellar peduncles, midbrain including rostral colliculi, thalamus, internal capsule, and basal ganglia. Using a standard dipstick test, the urine was positive for glucose.
Laboratory Results: None.
Contributor's Diagnosis and Comments: Cerebellar peduncles: Necrosis, hemorrhage, and edema, bilaterally symmetric, acute, consistent with ovine focal symmetrical encephalomalacia caused by Clostridium perfringens type D toxin(s).
This case is an example of ovine focal symmetrical encephalomalacia. Necrotic lesions were acute enough that the primary inflammatory cell response was neutrophilic. The pathogenesis of lesions in the brain of affected lambs involves increased capillary permeability associated with binding of epsilon toxin and swelling of astrocyte end-feet. Toxin production occurs in the gut where proliferation of Clostridium perfringens type D is favored by certain changes in diet. Glucosuria is associated with hyperglycemia.
AFIP Diagnosis: Cerebellum, peduncles: Necrosis, hemorrhage, and edema, bilaterally symmetrical, extensive, breed unspecified, ovine.
Conference Note: Clostridium perfringens is an anaerobic, spore-forming, Gram-positive bacillus that causes disease through elaboration of exotoxins within the gastrointestinal tract. There are five strains of the organism (types A, B, C, D, and E) based upon the elaboration of one or more of four exotoxins designated as alpha, beta, epsilon, and iota. Alpha toxin is a phospholipase C that is produced by all five strains of C. perfringens and causes hemolysis and necrosis. Clostridium perfringens types B and C produce beta toxin which is associated with increased vascular permeability and necrosis. Epsilon toxin is elaborated by types B and D as a nontoxic protoxin and is converted to a potent toxin by proteolytic enzymes, leading to increased vascular permeability and tissue necrosis. Iota toxin is produced by type E as a protoxin and is converted to an active form by proteolytic enzymes, causing increased vascular permeability and necrosis.
Enterotoxemia caused by C. perfringens type D is a common disease of sheep and goats, and has been reported in calves. In sheep, the disease most frequently occurs in fattening lambs and is known as "overeating disease", or as "pulpy kidney disease" (named for the rapid postmortem autolysis of the kidneys in some animals dying from the condition). In sheep, the disease is predominately characterized by central nervous system (CNS) signs and lesions, exemplified by the cerebellar changes in this case. In the gastrointestinal tract, there is peritoneal hemorrhage, mucosal congestion of the intestines, and superficial desquamation of the intestinal epithelium; numerous bacilli are found in the intestinal contents. In goats, the disease primarily occurs in the gastrointestinal tract, and CNS signs and lesions occur less frequently than in sheep. Additionally, lesions in the gastrointestinal tract of goats more commonly affect the colon, rather than the small intestine.
Contributor: Animal Disease Diagnostic Laboratory, ADDL-1175, Purdue University, West Lafayette, IN 47907.
1. Summers BA, Cummings JF, de Lahunta A: Degenerative diseases of the central nervous system. In: Veterinary Neuropathology, Summers BA, Cummings JF, de Lahunta A, eds., pp. 269-270, Mosby Year-Book, St. Louis, MO, 1995.
2. Jones TC, Hunt RD, King NW: Diseases caused by bacteria. In: Veterinary Pathology, Jones TC, Hunt RD, King NW, eds., 6th ed., pp. 420-422. Williams & Wilkins, Baltimore, MD, 1997.
3. Barker IK, Van Dreumel AA, Palmer N: The alimentary system. In: Pathology of Domestic Animals, Jubb KVF, Ken-nedy PC, Palmer N, eds., 4th ed., vol. 2, pp. 241-244, Academic Press, San Diego, CA, 1993.
4. Uzal FA, Kelly WR: Effects of the intravenous administration of Clostridium perfringens type D epsilon toxin on young goats and lambs. J Comp Path 116:63-71, 1997.
5. Uzal FA, Kelly WR: Experimental Clostridium perfringens type D enterotoxemia in goats. Vet Pathol 35:132-140, 1998.

Case IV - 98-6312 (AFIP 2641154)

one 2x2 photo transparency
Signalment: 22-month-old, spayed, female, Australian Cattle Dog.
History: There was onset of seizures at 14 months of age, with gradual progression of thoracic limb weakness, spontaneous nystagmus, and incoordination.
Gross Pathology: There was marked bilateral atrophy of scapular muscles of thoracic limbs. Foci of malacia, 2 to 5 mm in diameter, were found in the midbrain, pons, medulla oblongata and cerebellum involving the caudal colliculi, lateral vestibular and lateral cuneate nuclei, and the entire gray matter of the cervical intumescence.
Laboratory Results: MRI demonstrated hyperechoic lesions associated with malacic foci.
Contributor's Diagnosis and Comments: Poliomyelomalacia, diffuse, severe.
This dog was submitted for necropsy with a tentative diagnosis of hereditary polioencephalomyelopathy based on the clinical signs and supportive MRI findings. Postmortem findings in this dog were strikingly similar to those previously described. To date, this disorder has been reported in the literature affecting three Australian Cattle Dogs. Similar to this dog, previous dogs had initial signs of seizures, with progression of neurologic signs to thoracic limb weakness and stiffness, followed by lateral recumbency. In addition to the spinal cord lesions, this dog had grossly apparent malacic lesions affecting multiple nuclei in the brain stem and cerebellum. The severe spinal cord changes were restricted to the cervical intumescence in this dog. However, in previously described cases, the lumbosacral intumescence was also involved.
Lesions in the previous dogs were bilaterally symmetrical and identified in the caudal colliculi, lateral vestibular nuclei, lateral cuneate nuclei, and lateral reticular nuclei, extending into the ventral gray columns of C1 and the cervical and lumbosacral intumescences. The lesions in the spinal intumescences were the most severe. Early lesions consisted of degenerative changes of vacuolation within myelin sheaths and glial cells, with astrocyte and microglial proliferation, which were identi-fiable microscopically but not grossly. The gross lesions in the grey matter of the spinal cord had microscopic changes of rarefaction of neuropil which was reduced to a loose meshwork of blood vessels, astrocytic processes, and naked axons. A remarkable feature was the retention of large motor neurons in the rarefied neuropil, which is also present in this case.
The affected dogs in the previous report were produced by non-affected parents. Pedigree analysis showed that the affected dogs were genetically closely related. Testing for simple autosomal recessive inheritance indicated consistency with a disease controlled by a simple Mendelian autosomal recessive gene with complete penetrance. The genetic rela-tionship of the dog in this case to the previous cases is unknown, and siblings in this mating could not be located or were unaffected.
The pathogenesis of lesion development in this poliomyeloencephalopathy is unknown. The bilaterally symmetrical na-ture of the lesions suggests a neurodegenerative process or toxicosis. It is unlikely ischemic in nature, as large motor neurons were surviving in the malacic lesions. Other malacic diseases in animals include focal symmetrical spinal poliomalacia syndrome of sheep (cause unknown), focal symmetrical spinal poliomalacia of pigs associated with sele-nium toxicosis, polioencephalomalacia of ruminants, thiamine deficiency in carnivores, nigropallidal encephalomalacia of horses associated with ingestion of Centaurea sp., salt poisoning, leukoencephalomalacia of horses associated with fumonisins, and lead poisoning.

AFIP Diagnosis: Spinal cord: Poliomyelomalacia, bilaterally symmetrical, with sparing of motor neurons, Australian Cattle Dog, canine.
Conference Note: The neurodegenerative disorder that affects young Australian Cattle Dogs is characterized by bilateral and symmetrical encephalomyelopathy. The pathogenesis is unknown; however, an autosomal recessive mode of inheritance is suspected. Mitochondrial abnormalities were observed ultrastructurally in astrocytes in the recent study of affected dogs, and mitochondrial injury may play a role in the disease process. The CNS lesions have some resemblance to the human condition known as Leigh's disease.
Leigh's disease is characterized by early onset (less than two years), although adolescent and adult forms have been described. Grossly, lesions predominately occur in the gray matter, are frequently symmetrical, and particularly affect the basal ganglia, diencephalon, and brain stem. Lesions are also often observed in the cerebellum and spinal cord. Microscopically, the lesions are characterized by vascular endothelial proliferation, astrocytosis, and the presence of macrophages. There is the appearance of "loosening of the neuropil", with relative sparing of neuronal perikarya. Several biochemical abnormalities have been identified in Leigh's disease, and most of them are associated with impairment of mitochondrial function. If the pathogenesis of the encephalopathy of Australian Cattle Dogs is determined to be related to primary mitochondrial dysfunction, the condition may serve as an important animal model for the study of related human conditions.
Contributor: Kansas State University, Diagnostic Medicine/Pathobiology, 1800 Dension, VCS Bldg., Manhattan, KS 66506.
1. Brenner O, de Lahunta A, Summers BA, Cummings JF, Cooper BJ, Valentine BA, Bell JS: Hereditary polioencephalomyelopathy of the Australian Cattle Dog. Acta Neuropathol 94:54-66, 1997.
2. Jubb KVF, Huxtable CR: The nervous system. In: Pathology of Domestic Animals, Jubb KVF, Ken-nedy PC, Palmer N, eds., 4th ed., vol. 1, pp. 338-350, Academic Press, San Diego, CA, 1993.
3. Duchen LW, Jacobs JM: Nutritional deficiencies and metabolic disorders. In: Greenfield's Neuropathology, Adams JH, Duchen LW, eds., 5th ed., pp. 847-850, Oxford University Press, New York, 1992.
Wednesday Slide Conference Coordinator:
Ed Stevens, DVM
Captain, United States Army
Registry of Veterinary Pathology*
Department of Veterinary Pathology
Armed Forces Institute of Pathology
(202)782-2615; DSN: 662-2615
* The American Veterinary Medical Association and the American College of Veterinary Pathologists are co-sponsors of the Registry of Veterinary Pathology. The C.L. Davis Foundation also provides substantial
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