At an individual level and for global economic reasons, lower back pain is a serious issue. It debilitates, restricts and depresses individuals, often becoming a chronic long-term illness. There are significant economic reasons to address this problem: days off work or reduced performance in addition to the personal sufferer's happiness and quality of life. Treating and curing intervertebral disc (IVD) degeneration, which is the most common cause of pain, is still the major challenge. Orthopaedic surgery approaches do not address the underlying problem causing disc degeneration and can limit the motion of the spine. Regenerative medicine utilizing cells and tissue engineering processes offers significant potential to address a cure. Cell-based therapy could regenerate or at least slow down degeneration, by implanting autologous cells such as mesenchymal stem cells which have proven their ability to self-renew and differentiate into many tissue types. These cells are becoming increasingly easy to harvest as the knowledge base increases and offer, in the not too distant future, a minimally invasive therapeutic regime towards regeneration rather than stabilization.

Copper-sensitive North Ronaldsay sheep represent a possible model for certain hepatic-overload syndromes of infancy and childhood that are clinically, pathologically and genetically distinct from Wilson's disease. The purpose of this study was to simulate in artificially reared lambs the syndrome produced by copper exposure in susceptible human infants. Twenty four North Ronaldsay lambs were assigned to three groups of eight animals, namely, an unsupplemented control group and two trial groups given milk replacer to which copper (CuSO4) had been added at the rate of 5 mg/litre and 10 mg/litre. Four lambs from each group were killed at 40 or 69 days. Livers were fixed in 10% formalin and analysed for copper by mass spectrometry. Paraffin wax-embedded sections were stained with rhodanine for copper and labelled immunohistochemically for alpha smooth muscle actin (ASMA). At 40 days the maximum amounts of copper in the livers of both copper-supplemented groups was 1466-1605 microg/g dry weight (control group 172-201 microg/g Cu dry weight). Histochemically, copper was demonstrated within hepatocytes, together with marked apoptosis. At 69 days there was a florid pericellular fibrosis complemented by strong ASMA immunolabelling, confirming phenotypic modulation of hepatic stellate cells. Such primary copper-induced fibrogenesis confirms the unique status of this animal model in respect of childhood copper toxicosis.

Sheep display a variant phenotype with respect to their susceptibility to copper and derivative pathology. The North Ronaldsay sheep are acutely sensitive to environmental copper while the Cambridge breed is much more copper-tolerant. A study of protein expression in the liver of the two different breeds of sheep as a result of copper challenge would aid in the understanding of their differing pathophysiologies and contribute to knowledge of copper toxicosis in man. In this initial study, Cambridge breed sheep were challenged with oral copper and liver proteins were analyzed by two-dimensional (2-D) gel electrophoresis. Proteins whose expression pattern was modified by copper exposure were then identified by peptide mass fingerprinting using matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. In conclusion, the pattern of changes in protein expression were consistent with an early adaptive response to oxidative challenge. This was followed by evidence of an impaired ability of the liver to compensate as copper loading increased, accompanied by oxidative stress-induced injury.

Ammonium tetrathiomolybdate (TTM) has hitherto been the treatment of choice for chronic copper poisoning in sheep, but the long-term consequences have not been evaluated. This study was based on a flock of copper-poisoned sheep which, after apparently successful treatment with TTM, became infertile and progressively unthrifty and eventually died 2–3 years later. The last five surviving animals were subjected to euthanasia and detailed study. Necropsy revealed marked wasting together with depletion of the pituitary and adrenal glands, testicular atrophy and ovarian cystic follicles. Histopathological examination revealed a non-inflammatory atrophy or degeneration of the adenohypophysis with loss of trophic cells; adrenocortical and testicular atrophy and ovarian degeneration. The regressive changes in the anterior lobe of the pituitary were confirmed by immunocytochemical labelling, which revealed a marked depletion of adrenocorticotrophic hormone (ACTH), follicle stimulating hormone (FSH) and luteinizing hormone (LH) in the affected pituitaries by comparison with healthy controls. Excess molybdenum (Mo) retention (P<0.02) was identified by inductively coupled plasma mass spectrometry (ICPMS) in the pituitaries and atomic absorption spectrometry (AAS) in the adrenals and brains of affected sheep. It was concluded that molybdenum introduced systemically as TTM is retained within the brain, pituitary and adrenal glands and is associated with a toxic endocrinopathy. It is postulated that Mo administered as thiomolybdate adversely affects the hypothalamo-adenohypophyseal system by interfering with trophic hormone release, leading to the cessation of reproductive activity and ultimately the failure of intermediary metabolism. Whether Mo exerts its effect centrally or directly on the pituitary was not established.