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Modern management practices will affect equine health and welfare positively and with these life expectancy, with the consequence an increasing number of older horses. Neoplasms are one of the most diagnosed diseases in geriatric horses, with penile and preputial squamous cell carcinoma (SCC) the most common neoplasm of the external genitalia. The overall aim of this thesis was to perform a comprehensive study on penile and preputial SCC in horses, including the course of the disease, etiological factors, pathogenesis and outcome of treatment, to serve as a basis for guideline development. Chapter 2 represents a review of the literature on equine penile and preputial tumours that outlines the most important characteristics of this disorder that are relevant for the development of guidelines for a standardised diagnostic and therapeutic approach. Chapters 3 and 4 contain retrospective analyses. A large group of horses with penile and preputial neoplasia were evaluated to find relationships between factors such as age, castration status, type and site of the lesion and involvement of lymph nodes and stage, and course of the disease. Common presenting clinical signs were irregularities on the integument of the penis and prepuce, and purulent or sanguineous discharge from preputial orifice. SCC is the most common urogenital tumour and occurs primarily in older horses. Horses with poorly differentiated SCCs tend to have a higher incidence of regional metastases and a greater chance that the treatment would be unsuccessful. Therefore, pathology of lymph nodes is a valuable diagnostic exercise and grading of SCC can help predict prognosis and guide selection of treatment. The expression of COX-1, COX-2 and mPGES-1 in equine penile and preputial normal tissue, papillomas and SCC is investigated in relation to the degree of inflammation and the differentiation grade of the tumour (chapter 5). Retrospective study using archived material shows that expression of COX-1 and COX-2 in penile and preputial SCC in the horse is poor and COX inhibitors may thus be of little value for prevention or treatment. mPGES-1 is more prominently expressed in well-differentiated tissue compared with poorly differentiated tissue, but further research on the role of mPGES-1 in carcinogenesis is needed. Chapter 6 describes the relationship various tumour characteristics and their possible role as a prognosticator. Equus caballus papillomavirus type 2 (EcPV2) DNA was detected in 89.4% of horses. No differences in quantitative expression of E2, E6 and L1 oncogenes between well and poorly differentiated tumours were found. Expression of p53 and occurrence of metastasis were significantly positively correlated to a less differentiated subtype. Comparable to chapter 4, this study shows also that horses with less differentiated tumours were more likely to die of the disease and that that tumour grading appears to be an important prognosticator for survival and a predictor for presence of metastases. Based on tumour grading and staging, a standardised approach for the management of penile and preputial tumours in the horse is finally proposed.

Healing of tendon lesions, a common disorder in the equine species, is slow and often inadequate because the resulting scar tissue cannot meet the functional demands posed by the everyday athletic activity of many horses, making re-injury the most common and often fatal complication after initial trauma. Many therapies have been tried over time, but none of them thus far has succeeded in significantly improving the functional recovery rate in horses after suffering from a tendon injury. The healing trajectory of tendon injuries can be divided in three partially overlapping phases: the inflammation phase, the proliferative phase and the maturation phase. These phases are charactersied by biological porcesses specific to the phase of healing. Up to now very little attempts have been made to distinguish between these phases when applying a therapy to an injured tendon. In this thesis a specific therapy for each of the stages was studied, although it is acknowledged that therapies might exhibit effects in more than one phase of the healing trajectory. During the inflammatory phase there is an initial enlargement of original the lesion due to proteolytic and biomechanical influences. In an in vitro mechanical study it was shown that this lesion propagation after tendon injury may be mitigated by immobilisation during the early phase of repair, although in vitro work remains necesarry to confirm these findings. The proliferative phase is characterised by cell proliferation and synthesis of extracellular matrix components, such as collagen and glycosaminoglycans. These processes can possibly be enhanced by treatment with platelet rich plasma (PRP), an autologous concentrate of growth factor containing platelets. PRP treatment was evaluated in a blinded placebo-controlled experimental study, in which artificially induced tendon lesions were treated with PRP or placebo and tissue was harvested after 24 weeks. PRP improevd biochemical, biomechanical and histological properies of the treated tendons. Doppler ultrasonography revealed large differences in vascularisation between treated and untreated tendons. Computerised Ultrasonography was used to monitor the healing process and appeared capable of predicting outcome at a relatively early stage of the healing process and revealed clues about some of the mechanisms of action. Extracorporeal Shock Wave Therapy (ESWT), a technique based on physical intervention, was used in vivo on healthy equine tendons. It could be shown that, after an initial boost of metabolic activity in the tendon tissue, there was a long-term (6 weeks after treatment) negative effect on cell-matabolism. Further, a rather severe disorganisation of the normal tendon architecture. Both findings warrant caution in the clinical use of this technique, but might also explain the positive effects ESWT appears to have on more chronic tendon lesions. The thesis concludes that a staged approach for the treatment of tendon injuries is likely to improve the final prognosis of horses that are recoverring from a tendon injury, although functional healing of tendon injuries will remain a problem in equestrian sports and additional research is necessary. Improvement of prognosis can be expected by a proactive approach including early immobilisation and application of novel intratendinous treatments.

The equine veterinarian has regained its position in the veterinary profession. Equine veterinarians work in equine practices as well as in mixed practices. In general, it can be said that the backbone of equine work is formed by a relatively small amount of activities for which only a limited number of skills is necessary. There is a rather large discrepancy between the perception by the equine vet of his or her activities and reality. There seem to be hardly any skills that can be claimed as a prerogative for the equine specialist, still, the number of practices where equine specialists work increases. Although the supply of equine care has improved considerably in both quantitative and qualitative terms, this does not mean that market demand is completely met. A survey among top equine sportsmen highlighted ineffective or lacking communication between providers of equine healthcare and insufficient knowledge on the specific treatment of sport horses by the equine veterinarians as main complaints. An analysis of court cases filed against equine practitioners showed that frequent failures include insufficient availability of adequate care in certain defined situations, incompleteness of diagnostic procedures and insufficient information of the client. Technical failures did occur, but account only for a minority of the incidents. State of the art clinics are readily available in the western world, however, a critical economic analysis shows that better equipped practices are no guarantee for economic success and many economically interesting skills can be performed without the availability of hospital conditions. Practising equine veterinary medicine in the Netherlands in agreement with the code of good veterinary practice as agreed upon by the veterinary profession and thereby using only authorised equine veterinary medicinal products is impossible. In most cases equine vets have to recur to the so-called “cascade” or to the list of so-called “essential substances”, which are allowed for the treatment of horses despite being not officially registered, is needed to legitimise the use of medication. In some cases illegitimate use of drugs is the only way out. Seventy-eight percent of the equine vets perceive their work as their hobby, despite the fact that they have long working weeks and admit that they have trouble to balance work and private life. Working with horses poses a serious health risk in terms of accidents and the development of more chronic ailments. Sixty-seven percent of all diseases and injuries amongst equine practitioners are related to work with musculoskeletal problems as most frequent. Driven by a strong motivation, the equine vet appreciates his or her job, is aware of the risks involved and takes them more or less for granted. However, albeit a strong drive based on love for the horse and affection for equestrian activities is an excellent starting point, it is not enough. Economic viability, appreciation of the work by the public and social esteem are important factors for maintaining motivation at long-term. There are several ways for the profession to take action in order to achieve these goals, some of which are discussed in this thesis.

This thesis focussed on the diagnostic use of metabolic products and enzymes found in plasma, urine and muscle of the horse, the identification of which can reveal physiological or pathological changes in muscle metabolism. In this thesis analyses of carbohydrate-, lipid- and protein metabolites have been performed as well as analyses of the purine nucleotide cycle, the creatine metabolism and the oxidative phosphorylation. With these analyses we studied metabolic myopathies in the horse as well as metabolic effects of normal and intensified training and exercise. The application of these diagnostic techniques in treating horses with atypical myopathy revealed the pathogenesis of a new disorder of lipid metabolism in equines, namely acquired multiple acyl-CoA dehydrogenase deficiency (MADD), which appears to have a large and emerging prevalence in Europe and elsewhere. Several hypotheses for prevention and treatment of this disorder are presented in this thesis. The diagnostic analysis of creatine-, carbohydrate- and purine metabolism as well as oxidative phosphorylation was performed in healthy horses and horses with MADD. The goal of this study was to ascertain if, apart from the lipid metabolic disorder, the exogenic toxic insult associated with MADD disrupted any other metabolic cycles or reactions. Examples of general metabolic parameters for myopathic damage found included plasma creatine kinase (CK) and lactic acid, as well as urinary creatine and uric acid. Very low activity of the enzyme phosphoglycerate mutase (PGAM) and severely decreased activity of ATP-synthase were found in some patients. The effects of intense exercise and (intensified) training on protein (amino acids) and lipid (organic acids, carnitines) metabolism were studied. Ten Standardbred horses were trained for 32 weeks, divided into four phases, including a phase of intensified training for five horses. At the end of each phase, a standard exercise test (SET), was performed. Plasma amino acid, fatty acid and carnitine concentrations, before and after each SET, were measured. Training significantly reduced mean plasma aspartic acid concentration, whereas exercise significantly increased the plasma concentrations of alanine, taurine, methionine, leucine, tyrosine and phenylalanine and reduced the plasma concentrations of glycine, ornithine, glutamine, citrulline and serine. Concentrations of lactic acid, total nonesterified fatty acids, 3-OH-isobutyric acid and C2-carnitine were significantly increased following all SETS in exercised horses, whereas beta-hydroxybutyric acid, C3- and C4-carnitine were significantly decreased. No significant effect of training and intensified training was found. Our findings suggest that plasma acylcarnitine profile in the equine species might reflect skeletal muscle carnitine metabolism following exercise thereby providing a possible practical method to investigate potential disorders in carnitine metabolism in horses suffering from myopathy. A study to determine the effect of alfa-tocopherol acetate (vitamin E; 4 mg/kg BW/day) on glucose metabolism, peripheral insulin sensitivity and anti-oxidant status, showed that at this dose neither glucose metabolism nor peripheral insulin sensitivity were significantly altered. In addition, alfa-tocopherol acetate administration did not improve the measured parameters of antioxidant status.