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Adrian Frank

Professor Adrian Frank, PhD, was born 1927 in Budapest in a family of physicians. However, his maternal grandfather was an engineer, in fact the industrialist who introduced the inventions of the Nobel laurate Gustaf Dalén on continental Europe (the AGA system of acetylene use). At the age of 12, Adrian Frank decided to live in Sweden, at 15 he added the Swedish language to his college training, and at 20, in the autumn of 1947, he joined the Royal Institute of Technology in Stockholm. Since 1965, he has worked at the Department of Chemistry, National Veterinary Institute, Uppsala, Sweden. With experience from different fields of chemistry (more than 100 scientific papers, 23 of which since his formal age retirement 1992), Frank has devoted a special interest in trace element chemistry of domestic and wild animals. Below, he summarizes some of his research on deficiency states in animals, of special interest to hunters, meat-eaters, and primary health care.

Introduction
In the January issue 2004, the respected journal Science of the Total Environment presents a study of cobalt- and vitamin B₁₂-deficient moose (Alces alces) in Nova Scotia (N.S.), Canada (1).

Background
For nearly 100 years moose in eastern North America have been affected by a wasting disease. The symptoms were special, the etiology unknown and the diagnosis undetermined. Microbiological investigations 50-70 years ago did not lead the studies forward. In the 1960s, a parasitic worm Parelaphostrongylus tenuis was found in the sick animals, but not even this could explain all the cases. Thus, some other agent too was suspected to contribute to the disease. A disturbed nutritional balance was also suggested, however, without any proof (2, 3).

Similar symptoms in Sweden and Nova Scotia
Comprehensive studies of scientific literature of the American moose disease revealed the clinical signs reminding of the new type of moose disease in Sweden, also called Älvsborg disease, observed and described very first under the 1980s (4).

The pH increase in the soil due to liming undertaken to counteract the noxious effects of acid rain in this region changed the balance between Cu and Mo in soil and forage plants of moose. Changed nutritional imbalance between Cu and Mo in the feed of moose was suggested to cause the moose disease (5). Ruminants are sensitive for change of ratio between Cu and Mo in the forage plants. Relative or absolute increase of Mo can result in Cu deficiency and/or molybdenosis with disturbances of the Cu metabolism. It can result in inhibition of Cu-containing enzymes e.g. myocardial cytochrome c oxidase (6), and in toxic endocrinopathy (7) that even can lead to death. The disease is comprehensively described for domestic ruminants such as sheep, goat and cattle (8). The clinical signs of Älvsborg disease include loss of appetite, emaciation, loss of fear of man, neurological disturbances and locomotoric hindrance of the hind legs, going in circles, sometimes even blindness (9).

The investigations of the Älvsborg disease are documented in 8 original articles (10).

Purpose
Due to similarity in anamnestic pattern of both moose diseases some identical etiology was suspected. Therefore wildlife officials in N.S. were contacted to receive tissue samples from sick moose for chemical investigations.

Sampling
Hunting in N.S. is limited due to fear for moose extinction and has been banned in the province since 1981. Tissue material from not more than 18 sick moose was collected from different parts of (N.S.) during a period of about two years and was sent to Sweden for analysis (Dept. of Chemistry, National Veterinary Institute, Uppsala, Sweden).

Results
Trace element analyses performed with ICP and ICP-MS revealed that half of the investigated moose suffered from Co-deficiency in contrast to the Swedish moose affected by molybdenos. Co is part of vitamin B₁₂; therefore, the concentration of B₁₂ was determined microbiologically. Also the concentration of methylmalonic acid (MMA) in blood was investigated and sometimes was found very high. Propionic acid, important as energy source of ruminants, is metabolized via MMA to succinic acid by using B₁₂ as co-factor. Accumulation of propionic acid and MMA in blood, the cause of loss of appetite was often seen in sick moose. Consequently, one more parameter could be added in favor of Co- and B₁₂-deficiency.

Discussion
Co-deficiency responsible for B₁₂-deficiency resulted in severe metabolic disturbances in moose. Co- and B₁₂-deficiency in domestic ruminants has been known a long time in e.g. Australia, New Zealand (11) and even in Scotland, Norway and Sweden. Afflicted flocks of sheep were detected at the early 1980s on the Swedish island Gotland (12). However, in a wild ruminant, the moose was recognized probably at the first time (1).

Humans and the monogastric animals in general have to be supplied with the essential vitamin B₁₂ in food, while those with ruminal microbial activity synthesize the vitamin in presence of Co. The availability of Co in the Swedish environment is rather high due to easily weathering minerals such as green stones in basic rocks, while it is definitely lower in N.S. due to the more resistant granitic rocks.

The most characteristic symptom in human B₁₂- deficiency is pernicious anemia, seldom found in ruminants and other animals. Atrophy of mucous membranes and fertility disturbances may also occur in humans (13). Damage of the peripheral nerves and neurological symptoms may be the result of early symptoms of B₁₂-deficiency.

Additionally, we found extremely high Cd concentrations in renal cortex from moose in N.S. (148 mg Cd kg^-1 kidney cortex, wet wt.) probably as the result of acidification. The values were 5 times higher than the highest individual moose kidney value seen in a comprehensive Swedish study from 1982. For the time being, cadmium is not supposed to contribute to the disease.

1. Frank A, McPartlin J,Danielsson R. Nova Scotia Moose mystery – a moose sickness related to cobalt- and vitamin B₁₂ deficiency. Sci Total Environ 2004;318/1-3:89–100.

2. Benson DA. 1955. Nova Scotia Moose Studies, Univ. of Maine (Masters thesis, unpubl.) Orono, Maine, USA: Raymond H. Fogler Library, 242 pp.

3. Benson DA. Moose "Sickness" in Nova Scotia. I. Can J Comp Med 1958;22:244-246.

4. Stéen M, Frank A, Bergsten M, Rehbinder C. En ny sjukdomsbild hos älg. [A new pathological picture of moose disease. In Swedish.] Svensk Veterinärtidn 1989;41:73-77.

5. Frank A, Galgan V, Petersson LR. Secondary copper deficiency, chromium deficiency and trace element imbalance in the moose (Alces alces L.): Effect of anthropogenic activity. Ambio 1994;23:315 - 317.

6. Frank A, Wibom R, Danielsson R. Myocardial cytochrome c oxidase activity in Swedish moose (Alces alces L.) affected by molybdenosis. Sci Total Environ 2002; 290:121-129.

7. Haywood S, Dincer Z, Jasani B, Loughran MJ. Molybdenum-associated Pituitary Endocrinopathy in Sheep Treated with Ammonium Tetrathiomolybdate. J Comp Pathol 2004;130:21–31.

8. Andrew ED, Hart LJ, Stephenson BJ. A comparison of the vitamin B₁₂ and cobalt contents of livers from normal lambs, and others with recent history of mild cobalt deficiency disease. NZ J Agric Res 1959;2:274–282.

9. Frank A. ’Mysterious’ moose disease in Sweden; Similarities to copper deficiency and/or molybdenosis in cattle and sheep. Biochemical background of clinical signs and organ lesions. Sci Total Environ 1998;209:17-26.

10. Frank A. Molybdenosis leading to type 2 diabetes mellitus in Swedish moose. In: Skinner HCW, Berger AR editors. Geology and Health: Closing the Gap. New York, Oxford: Oxford University Press 2003;7981.

11. Lee J, Masters DG, White CL, Grace ND, Judson GJ. Current issues in trace element nutrition of grazing livestock in Australia and New Zealand. Aust J Agric Res. 1999; 50:1341–64.

12. Schwan O, Jacobsson S-O, Frank A, Rudby-Martin L, Petersson LR. Cobalt and copper deficiency in Swedish landrace pelt sheep J Vet Med A 1987;34:709–718.

13. Gräsbeck R. Infertility – folate, cobalamin and other micronutrients [evaluation]. Rondel 2002; 10. URL: http://www.rondellen.net