A randomised factorial design clinical trial to investigate the impact of parenteral long acting oxytetracycline, foot trimming and flunixine meglumine on time to recovery from lameness and foot lesions in sheep lame with footrot

Background: Internationally, foot trimming is used by most farmers and parenteral antibacterials by some, to treat sheep with footrot. Non steroidal anti-inflammatory drugs (NSAID) are sometimes used. No clinical trials have compared these treatments. Objectives: To investigate the above treatments on time to recovery from lameness and foot 5 lesions in sheep with footrot. Animals: 53 sheep with footrot on a commercial farm in England. Methods: In a randomised factorial design, the sheep were allocated to treatment groups. The 8 treatments were oxytetracycline spray to all sheep (positive control) and one or more of: parenteral administration of long acting oxytetracycline, flunixine meglumine and foot trimming on day 1 or day 6 of diagnosis. Follow-up was for 15 days. Time to recovery from lameness and lesions was investigated with discrete- time survival models. Results: There was significant association (p<0.05) between recovery from lameness and lesions. Sheep receiving antibacterials parenterally recovered faster from lameness (odds ratio (OR): 4.92 (1.20-20.10)) and lesions (OR: 5.11 (1.16-22.4)) than positive controls whereas sheep foot trimmed on day 1 (lameness- OR: 0.05 (0.005-0.51); lesions- OR: 0.06 (0.008-0.45)) or day 6 of diagnosis (lameness-OR: 0.07 (0.01-0.72); lesions- OR: 0.07 (0.01-0.56)) recovered slowly than positive controls. NSAID had no significant effect on recovery. Conclusions and Clinical Importance: If foot trimming on day 1 or 6 of diagnosis was stopped and parenteral antibacterials were used, then over 1 million sheep/annum lame with footrot in the UK, would recover more rapidly with benefits to productivity. Globally, this figure would be 21 much higher

Albumin Extravasation During Surgery

This thesis is concerned with the measurement of changes in the circulation during the period of surgery. A loss of albumin from the circulation is to be expected from observations and experiments made in the postoperative period. In this thesis a sensitive measurement technique is described which allows extravasation of albumin to be studied in patients undergoing elective surgery. Radio-isotope labelled albumin and radio-isotope labelled red cells are injected; the ratio between the two is not affected by blood loss or infusion and the ratio is therefore used as a measure of albumin extravasation. To measure the relative loss of albumin from the circulation the isotopes were administered some days prior to surgery to allow distribution and equilibration of the albumin. To measure the rate of loss of albumin (capillary permeability) the isotopes were administered at the time of surgery. The results indicate that major surgery under general anaesthesia is accompanied by a loss of albumin from the circulation, an increased capillary permeability to albumin and a fall in plasma volume that is greater than can be explained on the basis of blood loss and greater than would be expected on the basis of the reduction in red cell volume. The results suggest that patients who receive only glucose and salt solutions intravenously during major surgery will usually suffer a contraction in their blood volumes unless unacceptably large volumes of fluid are infused

Footrot and interdigital dermatitis in sheep: Farmer satisfaction with current management, their ideal management and sources used to adopt new strategies

The aims of this research were to identify management practices that sheep farmers currently use to treat and prevent footrot in sheep and whether they consider that these are successful management tools and to find out how sheep farmers would ideally like to manage footrot in their flock. Over 90% of lameness in sheep in the UK is caused by Dichelobacter nodosus, which presents clinically as interdigital dermatitis (ID) alone or with separation of hoof horn (FR). A questionnaire was sent to 265 farmers to investigate their current management and their satisfaction with current management of the spectrum of clinical presentations of footrot. Farmers were also asked their ideal management of footrot and their interest in, and sources of information for, change. Approximately 160 farmers responded. Farmers satisfied with current management reported a prevalence of lameness ≤5%. These farmers caught and treated lame sheep within 3 days of first seeing them lame, and treated sheep with FR and ID with parenteral antibacterials. Farmers dissatisfied with their management reported a prevalence of lameness >5%. These farmers practised routine foot trimming, footbathing and vaccination against footrot. Whilst 89% of farmers said they were satisfied with their management of FR over 34% were interested in changing management. Farmers identified veterinarians as the most influential source for new information. Farmers reported that ideally they would control FR by culling/isolating lame sheep, sourcing replacements from non-lame parents, trimming feet less, using antibacterial treatments less and using vaccination more. Footbathing was a commonly used management that was linked with dissatisfaction and that also was listed highly as an ideal management. Consequently, some of the ideal managements are in agreement with our understanding of disease control (culling and isolation, sourcing healthy replacements) but others are in contrast with our current knowledge of management and farmers self-reporting of satisfaction of management of footrot (less use of antibacterial treatment, more footbathing and vaccination). One explanation for this is the theory of cognitive dissonance where belief follows behaviour, i.e. farmers report that they believe an ideal which is what they are currently doing, even if the management is sub-optimal

Mechanisms and Management of Breathlessness in Chronic Heart Failure

Background: The pathophysiology of dyspnoea (‘breathlessness’) is poorly understood and treatment options limited. This is particularly true for heart failure in which dyspnoea is a cardinal symptom, even when the heart failure is optimally managed. This thesis aims to untangle mechanisms and utilise this knowledge to optimise heart failure management. It focuses on the potential of nebulised furosemide as an adjunct treatment, given its excellent safety record and existing evidence that it modulates dyspnoea via direct action on lungs. Methods: A multi-dimensional questionnaire was used to survey the prevalence of dyspnoea in the heart failure community. A randomised, double blind, placebo-controlled crossover trial (RCT) was then performed in healthy participants to determine the specific components of dyspnoea that are relieved by the action of furosemide on the lungs. This study led to the design of a feasibility RCT in patients with heart failure using the visual analogue scale (VAS) ratings of the ‘air hunger’ (AH) component of dyspnoea as the primary outcome measure. The RCT itself; i) addressed other issues that could account for variability in relief seen in previous studies, ii) explored blood biomarkers of heart failure in relation to dyspnoea and iii) provided guidance for future definitive clinical trials. Results: 1) 47% of patients experienced dyspnoea in the community. Dyspnoea-12 scores correlated with New York Heart Association class, with many in class III experiencing dyspnoea at rest. 2) Nebulised furosemide specifically relieved AH induced in healthy participants but did not affect the 'work/effort' component. Relief was only with nebulised, not intravenous furosemide. 3) Breathing furosemide quickly or slowly did not alter dyspnoea relief, but ventilation was not matched. 4) Cardiopulmonary exercise testing (CPET) produced an average VO2peak of 54±15% predicted, with a measurable anaerobic threshold in 73% of tests and raised dyspnoea to 42±19%VAS. 5) Nebulised furosemide resulted in no significant improvements in exercise capacity. 6) Cardiac biomarkers increased appropriately and returned to baseline within 1 hour of exercise. The maximal absorption efficiency of nebulised furosemide was 2%. Conclusion: 1) Dyspnoea is a prevalent symptom in heart failure, comparable to chronic obstructive pulmonary disease. The NYHA classification may require clarification regarding presence of breathlessness at rest. 2) Relief of dyspnoea with nebulised furosemide occurs via a mechanism within the lungs and should be targeted at those in whom ‘air hunger’ predominates. 3) CPET is a feasible method for dyspnoea assessment in heart failure. 4) Fully powered RCT of nebulised furosemide in heart failure are warranted taking on board the preliminary information gathered in this thesis to optimise treatment effect

A within farm clinical trial to compare two treatments (parenteral antibacterials and hoof trimming) for sheep lame with footrot

From observational studies, farmers who use parenteral antibacterials to promptly treat all sheep with footrot (FR) or interdigital dermatitis (ID) have a prevalence of lameness of <2% compared with a prevalence of 9% lameness reported by farmers who treat lame sheep by trimming affected feet. We tested the hypothesis that prompt treatment of sheep lame with naturally developing FR or ID with parenteral and topical antibacterials reduces the prevalence and incidence of lameness with these conditions compared with less frequent treatment with trimming of hoof horn and applying topical antibacterials. A further hypothesis was that reduction of ID and FR would improve productivity. A lowland sheep flock with 700 ewes was used to test these hypotheses in an 18-month within farm clinical trial with four groups of ewes: two intervention and two control. The duration and severity of lameness was used to categorise sheep into three weighted scores of lameness (WLS): never lame (WLS0), mildly lame/lame for <6 days (WLS1) and severely or chronically lame (WLS2). The intervention reduced the prevalence of lameness due to FR and ID in ewes and lambs and the incidence of lameness in ewes. The WLS was also significantly lower in sheep in the intervention groups. Ewes with a higher WLS were subsequently significantly more likely to have a body condition score <2.5 and to have lame lambs. Significantly more ewes lambed and successfully reared more lambs that were ready for slaughter at a younger age in the intervention versus control groups. There was an increase in the gross margin of £630/100 ewes mated in the intervention group, including the cost of treatment of £150/100 ewes mated. We conclude that prompt parenteral and topical antibacterial treatment of sheep lame with ID and FR reduced the prevalence and incidence of these infectious conditions and led to improved health, welfare and productivity

A case report of lameness in two dairy goat herds: a suspected combination of nutritional factors concurrent with treponeme infection

Background: Two dairy goat farms with high level of lameness in lactating animals were presented for further investigation. Farm 1 and Farm 2 presented with 37 and 67 % morbidity, respectively. Both farms had an all year round indoor system, feeding ad libitum concentrate with forage available at all times. Case presentation: The lameness was found to be based in the foot. Previous treatments consisting of biweekly footbathing with zinc sulphate, spraying lesions with oxytetracycline spray and packing lesions with copper crystals on a single occasion and single injections with long acting oxytetracycline had not been successful. Mild cases had signs of haemorrhaging in the white line or on the sole of the foot. Moderate cases showed under running of the wall horn or small areas of exposed sole corium. Severe cases would consist of horn or wall separation with the corium exposed and infected. In extreme cases only the wall horn of the claw remained, with a large area of necrotic tissue in the centre and no healthy corium visible. Only one animal was seen to have interdigital lesions. Polymerase chain reaction (PCR) and culture of swabs taken from exposed corium and the interdigital space were negative for Dichelobacter nodosus but PCR for treponemes were positive in both the adults and the youngstock tested. Due to the high level of concentrate in the diet of these goats, nutrition was thought to contribute to the problem. Transcutaneous rumen fluid samples were taken and pH was measured on both farms, with 35 % of the samples below pH value 5.5. Conclusion: No definite diagnosis could be made. However, the results suggest both treponemes and nutrition play a role in the aetiology of the lameness. The initial sole or wall horn lesions were thought to be secondarily infected by treponemes. Further investigation is needed to definitively diagnose the cause and contributing factors for this lamenes

Factors associated with changes of state of foot conformation and lameness in a flock of sheep

The aim of this research was to investigate transitions between foot conformation, lameness and footrot in sheep. Data came from one lowland flock of approximately 700 ewes studied for 18 months. Multilevel multistate analyses of transitions between good and poor foot conformation states in ewes, and lame and non-lame states in ewes and lambs were conducted. Key results were that the longer sheep had feet in good conformation, the more likely they were to stay in this state; similarly, the longer a ewe was not lame the more likely she was not to become lame. Ewes with poor foot conformation were more likely to become lame (OR: 1.83 (1.24-2.67)) and to be > 4 years (OR: 1.50(1.09-2.05)). Ewes with footrot were less likely to move to good foot conformation (OR: 0.48 (0.31-0.75)) and were more likely to become lame (OR: 3.81(2.60-5.59)). Ewes lame for > 4 days and not treated with parenteral antibacterials had a higher risk of developing (OR: 2.00 (1.08-3.61)), or remaining in (OR: 0.49 (0.29-0.95)) poor foot conformation compared with ewes never lame. Treatment of ewes lame with footrot with parenteral antibacterials increased the probability of transition from a lame to a non-lame state (OR: 1.46 (1.05-2.02)) and these ewes, even if lame for > 4 days, were not more likely to develop poor foot conformation. The risk of a ewe becoming lame increased when at least one of her offspring was lame (OR: 2.03 (1.42-2.92)) and when the prevalence of lameness in the group was ≥ 5% (OR: 1.42 (1.06-1.92)). Lambs were at increased risk of becoming lame when they were male (OR: 1.42 (1.01-2.01)), single (OR: 1.86 (1.34-2.59)) or had a lame dam or sibling (OR: 3.10 (1.81-5.32)). There were no explanatory variables associated with lambs recovering from lameness. We conclude that poor foot conformation in ewes increases the susceptibility of ewes to become lame and that this can arise from untreated footrot. Treatment of ewes lame with footrot with parenteral antibacterials leads to recovery from lameness and prevents or resolves poor foot conformation which then reduces the susceptibility to further lameness with footrot

Multiple locus VNTR analysis highlights that geographical clustering and distribution of Dichelobacter nodosus, the causal agent of footrot in sheep, correlates with inter-country movements

Dichelobacter nodosus is a Gram-negative, anaerobic bacterium and the causal agent of footrot in sheep. Multiple locus variable number tandem repeat (VNTR) analysis (MLVA) is a portable technique that involves the identification and enumeration of polymorphic tandem repeats across the genome. The aims of this study were to develop an MLVA scheme for D. nodosus suitable for use as a molecular typing tool, and to apply it to a global collection of isolates. Seventy-seven isolates selected from regions with a long history of footrot (GB, Australia) and regions where footrot has recently been reported (India, Scandinavia), were characterised. From an initial 61 potential VNTR regions, four loci were identified as usable and in combination had the attributes required of a typing method for use in bacterial epidemiology: high discriminatory power (D > 0.95), typeability and reproducibility. Results from the analysis indicate that D. nodosus appears to have evolved via recombinational exchanges and clonal diversification. This has resulted in some clonal complexes that contain isolates from multiple countries and continents; and others that contain isolates from a single geographic location (country or region). The distribution of alleles between countries matches historical accounts of sheep movements, suggesting that the MLVA technique is sufficiently specific and sensitive for an epidemiological investigation of the global distribution of D. nodosus