Molecules in Medical Science (MIMS)
Below are some examples of how the basic science in the MIMS course relates to everyday clinical problems in veterinary medicine.
Dogs and cats get diabetes mellitus, but cattle and horses very rarely do. The original work of Banting and Best was actually performed using experimental dogs. Signs in dogs and cats ar similar to human symptoms (polyuria, polydypsia, ketosis, weight loss etc). Diabetes in dogs has been shown to be associated with MHC subtype (See Kennedy et al., Tissue Antigens. 2006 Dec; 68(6):467-76) and appears as autoimmune destruction of pancreas in many cases. IL-4 polymorphisms are also associated with diabetes in some breeds and in some human populations (Short et al., J Heredity, 2007, 98(5): 518-25)
Biological macromolecules, protein structure and enzyme catalysis
Scrapie in sheep is an example of changed protein folding in prion disease, resulting in fatal pathology of the CNS. Changing a single amino-acid in the PrP protein makes folding more or less likely. (Bujdoso et al. (2005) Structural differences between allelic variants of the ovine prion protein revealed by molecular dynamics simulations. Proteins, 610, 840–849). Selecting rams with particular base pairs at specific loci can code for resistance to scrapie (see National Scrapie Plan on DEFRA website).
Bioenergetics and Metabolism
Ruminants rely on gluconeogenesis to maintain glucose homeostasis, as glucose and simple sugars are broken down in the rumen. Lactational ketosis in dairy cows is an example of dietary energy deficit, in which proprionate, a principle substrate for gluconeogenesis via the citric acid cycle, is deficient in the diet. Lipolysis produces acetyl coA, which cannot be metabolised via the citric acid cycle resulting in production of ketone bodies e.g. β-hydroxybutyrate and acetone. Clinical signs include loss of milk production and neurological signs, due to hypoglycaemia and isopropyl alcohol intoxication.
Hyperlipidemia occurs in ponies on poor quality diets, become anorexic or which experience high metabolic loads due to pregnancy. Such animals frequently have a history of obesity. Hyperlipidemia may be managed by maintaining energy intake, reducing energy requirement by inducing parturition, and supplementing insulin to counter the effects of insulin resistance. Feeding non-rumen degradable protein in sheep in late pregnancy, permits amino acids from bacterial protein synthesised in the rumen to be de-aminated by the liver and used for gluconeogenesis. This is important in late pregnancy as other gluconeogenic substrates such as proprionate may be in short supply due to reduced appetite and increase glucose demand by foetuses.
Copper deficiency in pregnant sheep can lead to swayback in the lambs as a result of myelination defects in the central nervous system. Cobalamin transport defects can occur in beagles, border collies and giant schnauzers. Ruminants need dietary cobalt for microbial synthesis of vitamin B12 in the rumen.
Phytochemicals and oxidative stress
Vitamin E reduces production of peroxides formed as a result of oxidative stress during exercise, glutathione peroxidase (which is selenium dependent) scavenges any peroxides formed. Deficiency of vitamin E and selenium in ruminants, results in severe peroxide mediated myopathy.
Membranes and hormones.
Lysosomal storage diseases show that things can go wrong and that protein trafficking can put them right. An example showing both breakdown and repair of endocytosis is mucopolysaccharidosis VI in cats and mucopolysaccharidosis I and VII in dogs - see papers of M Haskins - lysosome targetting through mannose 6 phosphate receptor.
Malignant hyperthermia results from a genetic defect in skeletal muscle calcium
homeostasis, which can be triggered by stress, anaesthetics or depolarising muscle relaxants. Ryanodine receptor mutations have been described in dogs and pigs (porcine stress syndrome). Landrace and Pietrain breeds of pigs are susceptible to malignant hyperthermia, as are horses, double muscled cattle and deer. Attempts of mitochondria to sequester the increased muscle calcium levels, results in uncoupling of oxidative phosphorylation. Capture myopathy seen in wild animals appears to be of similar aetiology.
Other membrane bound receptor mutations include IL2Ra mutation in Corgi SCID; opsin mutations in dominant RP (mastiffs) etc., ion channel mutations e.g. hyperkalemic periodic paralysis (quarter horses), extracellular structural proteins etc: canine and bovine leukocyte adhesion deficiencies etc..
There are many veterinary examples of hormone deficiencies, such as pituitary dwarfism (in German shepherd dogs and Carelian bear dogs), hypothyroidism (seen in many dog breeds), and hypoadrenocorticalism etc.
Parturition of dairy cows results in sudden increased demand for calcium for milk production, lead to clinical hypocalcaemia (milk fever) which can be fatal.
Several methods of manipulating calcium levels have been tried, including
1. Feeding high calcium diet during pregnancy (- does not work as suppresses PTH production resulting in more milk fever cases).
2. Low calcium levels in the diet during pregnancy to promote elevated PTH levels then switch to high calcium diet at calving (- works, but timing of diet change is critical).
3. Injecting high risk cows with vitamin D analogue in last week of pregnancy (-works, but timing is critical and repeating the injection leads to calcification of kidneys).
4. Increasing free plasma calcium by producing a metabolic acidosis through dietary manipulation of cation, anion balance (works, but still requires supplementary calcium at calving and in lactation).
High grade canine mast cell tumours have a very high incidence of a mutated
c-KIT which is juxtamembrane receptor protein. When mutated it then has
constitutive activity as a tyrosine kinase which then drives the cell cycle.
There is now a c-kit tyrosine kinase inhibitor licensed for veterinary use
(MasivetR) that dramatically improves the response rate. This is the first
of the new generation of cytostatic drugs that are coming into oncology
practice targeted at a very specific gene mutation.
A veterinary example of genes maintained by selection would be the maintenance of the ridgeback in the face of dermoid sinus by artificial selection in the Rhodesian and Thai ridgebacked dogs. (see Salmon Hillbertz, Nat Genet. 2007 Nov. 39(11): 1318-20). The selection pressure in hyperkalemic periodic paralysis in American quarter horses, is not defined by a breed standard, but by the need for muscular definition in the show ring (Naylor JM. J Am Vet Med Assoc. 1994 Mar 15;204(6):926-8). Genetic aspects of nutrition in the form of quantitative food conversion traits, are better worked out in farm animals than they are for humans.