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Summary Peroxisome proliferator-activated receptor alpha (PPARα) ligands are medications used to treat hyperlipidaemia and atherosclerosis. Increasing evidence suggests that these agents are immunosuppressive. In the following studies we demonstrate that WY14,643, a PPARα ligand, attenuates expression of anti-glomerular basement membrane disease (AGBMD). C57BL/6 mice were fed 0·05% WY14,643 or control food and immunized with the non-collagenous domain of the α3 chain of Type IV collagen [α3(IV) NC1] in complete Freund's adjuvant (CFA). WY14,643 reduced proteinuria and greatly improved glomerular and tubulo-interstitial lesions. However, the PPARα ligand did not alter the extent of IgG-binding to the GBM. Immunohistochemical studies revealed that the prominent tubulo-interstitial infiltrates in the control-fed mice consisted predominately of F4/80+ macrophages and WY14,643-feeding decreased significantly the number of renal macrophages. The synthetic PPARα ligand also reduced significantly expression of the chemokine, monocyte chemoattractant protein (MCP)-1/CCL2. Sera from mice immunized with AGBMD were also evaluated for antigen-specific IgGs. There was a significant increase in the IgG1 : IgG2c ratio and a decline in the intrarenal and splenocyte interferon (IFN)-γ mRNA expression in the WY14,643-fed mice, suggesting that the PPARα ligand could skew the immune response to a less inflammatory T helper 2-type of response. These studies suggest that PPARα ligands may be a novel treatment for inflammatory renal disease.

Recurrent colic occurs frequently in the general horse population but little evidence exists about what factors place horses at greater risk of recurrent colic.To quantify time-varying and non time-varying risk factors for recurrent colic among horses attended by first-opinion veterinary surgeons in northwest England.Nested case-control study.A nested case-control study was conducted on data from a prospective longitudinal cohort study of 127 horses recruited subsequent to an episode of medical colic. Data were collected on management and recurrent colic episodes at 4-monthly intervals by telephone questionnaires. All recurrent colic episodes were selected as cases; controls were unmatched and randomly selected from all horse-time at risk. Data relating to the 30 days prior to the date of colic or control selection were used to determine exposure status. Multivariable logistic regression analyses were used to determine risk factors for recurrent colic.In total, 59 cases and 177 controls were included. The final model showed that horses that displayed crib-biting/windsucking (odds ratio [OR] 10.1, 95% confidence interval [CI] 2.5-41.0) or weaving behaviour (OR 3.9, 95% CI 1.5-10.1) had an increased risk of recurrence of colic. Increasing time at pasture reduced the risk of recurrence (OR 0.99, 95% CI 0.99-1.0). A significant interaction was found suggesting that the risk associated with crib-biting/windsucking may be modified by feeding fruit/vegetables; however, further research is required before recommendations for feeding practices can be made.This study suggests that sufficient access to pasture may be an important means of reducing recurrent colic risk. The behavioural risk factors highlight individuals who may be at increased risk of recurrent colic and whose colic prevention strategies should be carefully managed.

Risk factors for large colon volvulus (LCV) in the horse have not been previously reported. Knowledge of these risk factors may allow the introduction of measures that could be taken to minimise the incidence of LCV.To investigate risk factors for LCV in the horse.A prospective, multicentre, unmatched case-control study was conducted over a 24 month period in the UK. Data on 69 cases and 204 control horses, from 4 veterinary hospitals, were obtained via telephone questionnaires. Multivariable logistic regression was used to identify associations between horse and management-level variables and the likelihood of LCV.Increasing height, multiple colic episodes in the previous 12 months and mares, with a greater odds ratio in mares that had previously foaled, were associated with increased risk of LCV. Receiving medication (excluding anthelmintic treatment) in the previous 7 days and quidding behaviour were also associated with increased risk. Management-level variables associated with greater risk of LCV were an increase in the hours of stabling in the previous 14 days, an increasing number of horses on the premises, and 3 or more people involved in the horse's care. Variables related to nutrition associated with increased risk of LCV were being fed hay, being fed sugar-beet, a change in pasture in the previous 28 days, and an alteration in the amount of forage fed in the last 7 days.This study has identified factors that may assist in the recognition of horses with increased risk of LCV and factors that might be altered to minimise the incidence of LCV.Clinicians can use this information to identify horses at risk of LCV and to provide evidence-based advice to owners of these horses.

The pattern of long-term survival and specific factors associated with long-term survival have not previously been evaluated in horses with a strangulating large colon volvulus (LCV).To provide data on the long-term survival of horses with LCV and to identify pre-, intra- and post operative variables associated with survival.Clinical data and long-term follow-up information were obtained from 116 horses with a strangulating LCV (≥360°) undergoing general anaesthesia. Two multivariable Cox proportional hazards models for post operative survival time were developed: Model 1 included all horses and evaluated preoperative variables and Model 2 included horses that survived anaesthesia and evaluated pre-, intra- and post operative variables.The study population comprised 116 horses. Eighty-nine (76.7%) survived general anaesthesia. Of these, the percentage that survived until discharge, to one year and to 2 years was 70.7%, 48.3% and 33.7%, respectively. Median survival time for horses that survived general anaesthesia was 365 days. In Model 1 increased preoperative packed cell volume (PCV) was significantly associated with reduced post operative survival (hazard ratio [HR] 1.08, 95% confidence interval [CI] 1.05-1.11). However, this effect changed over time. In Model 2 abnormal serosal colour intraoperatively (HR 3.61, 95% CI 1.55-8.44), increased heart rate at 48 h post surgery (HR 1.04, 95% CI 1.02-1.06), and colic during post operative hospitalisation (HR 2.63, 95% CI 1.00-6.95), were all significantly associated with reduced post operative survival.Survival time in horses with a LCV was associated with preoperative PCV, serosal colour, heart rate at 48 h post operatively and colic during post operative hospitalisation.This study provides evidence-based information on the long-term survival of horses with LCV and identifies parameters that may assist decision-making by clinicians and owners.

There is limited information about risk factors and survival associated with disorders of the small colon requiring surgical management.1) To document the types of surgical lesion in horses where pathology of the small (descending) colon was the primary cause of abdominal pain, 2) to describe the short- and long-term survival of these cases and identify factors associated with survival and 3) to identify preoperative variables associated with localisation of a lesion to the small colon.Clinical data and long-term follow-up were obtained for horses that underwent exploratory laparotomy over a 10-year period. Descriptive data were generated for short- and long-term survival and survival analysis performed to identify factors associated with reduced survival. Univariable and multivariable relationships were explored using a Cox proportional hazards model. Preoperative factors associated with increased likelihood of a small colon lesion were explored, using controls randomly selected from horses undergoing exploratory laparotomy for treatment of colic unrelated to the small colon.The study population included 84 horses. Of horses with small colon lesions recovered from anaesthesia, the percentage that survived until discharge, one year and 2 years following surgery, was 91.0, 81.0 and 73.5%, respectively. Median survival time for horses in which a resection had been performed was 1029 vs. 3072 days in the nonresection group. Small colon cases were more likely to have shown a longer duration of colic signs prior to admission (P0.001) and to develop post operative diarrhoea (P = 0.001) when compared with surgical controls.Lesions of the small colon carry a good prognosis for survival following surgery. Resection and anastomosis was the only factor associated with reduced long-term survival.This study provides information about lesion types and post operative survival that may be used to assist informed decision-making when managing these cases.

The hormone, 1,25-(OH)2D3, is metabolized into 1,25-(OH)2-24-OXO-D3, in kidney prior to conversion to its final inactive product, calcitroic acid. Similarly, 1,25-(OH)2-24OXO-16eneD3, is produced in the kidney from the Vitamin D analog, 1,25-(OH)2-16eneD3, but resists further hydroxylation. The analog's metabolite was synthesized and its biologic activity compared to the parent compound. Naive SJL/J mice, 4 weeks old, were immunized with neuroantigen in adjuvant to induce experimental autoimmune encephalomyelitis [EAE]. Treatment with 1,25-(OH)2-24OXO-16eneD3 was given at 0.05, 0.15 and 0.3 microgram I.P., on alternate days, starting 3 days prior and for up to 5 days post immunization and compared to a similar treatment with 0.1 microgram 1,25-(OH)2D3 or 1,25-(OH)2-16eneD3. Suppression of EAE was observed with 0.15 microgram 1,25-(OH)2-24OXO-16eneD3, comparable to the suppression induced with the parent compound and more potent than 1,25-(OH)2D3. However, no hypercalcemia was seen in mice treated with 0.15 microgram of OXO-metabolite (9.7 +/- 0.6 vs 9.3 +/- 1.1 mg/dl, treated vs controls), in contrast to 1,25-(OH)2D3 and 1,25-(OH)2-16eneD3 (11.2 +/- 1.0 and 11.0 +/- 0.9 mg/dl respectively; p0.001). In summary, our results suggest that 1,25-(OH)2-24OXO-16eneD3, a stable intermediary metabolite of the vitamin D analog, 1,25-(OH)2-16eneD3 exerts immunosuppressive activity equal to its parent without causing hypercalcemia in vivo.

The frequency of recurrent colic in the UK equine general practice population is previously unreported. Elucidating risk factors for recurrent colic could provide a basis for clinical decision making and interventions.To determine the incidence rate of and risk factors for recurrent colic.Horse management, prophylactic health care and innate behaviour contribute to the risk of recurrent colic.A cohort of 127 horses was enrolled at the point of a veterinary-diagnosed medical colic episode. Participating owners completed a baseline and 3 follow-up telephone questionnaires over one year. Clinical details of each colic episode were collected with data on management, behaviour and preventive healthcare. Incidence was calculated using time at risk data; non-time varying covariates were assessed for association with recurrent colic using multivariable logistic regression.The recurrence rate was 50 colic events/100 horse years at risk (HYAR). Including only veterinary attended recurrent colic episodes the incidence was 35 colic events per 100 HYAR. A multivariable logistic regression model was built to explore non-time varying risk factors for recurrence collected from baseline data. The model showed that horses that have a known dental problem (OR 5.5, 95% CI 1.3, 23.1) or crib-bite/windsuck (OR 12.1, 95% CI 1.4, 108.1) were at increased risk of recurrence during the year following a colic event.The incidence of recurrence in horses following a medical episode of colic is high in this population and represents a welfare concern. The incidence rate can be used to compare intervention efficacy in similar populations. Identified risk factors could provide the basis for management interventions or highlight at risk individuals.

Epiploic foramen entrapment (EFE) has been associated with reduced post operative survival compared to other types of colic but specific factors associated with reduced long-term survival of these cases have not been evaluated in a large number of horses using survival analysis.To describe post operative survival of EFE cases and to identify factors associated with long-term survival.A prospective, multicentre, international study was conducted using clinical data and long-term follow-up information for 126 horses diagnosed with EFE during exploratory laparotomy at 15 clinics in the UK, Ireland and USA. Descriptive data were generated and survival analysis performed to identify factors associated with reduced post operative survival.For the EFE cohort that recovered following anaesthesia, survival to hospital discharge was 78.5%. Survival to 1 and 2 years post operatively was 50.6 and 34.3%, respectively. The median survival time of EFE cases undergoing surgery was 397 days. Increased packed cell volume (PCV) and increased length of small intestine (SI) resected were significantly associated with increased likelihood of mortality when multivariable analysis of pre- and intraoperative variables were analysed. When all pre-, intra- and post operative variables were analysed separately, only horses that developed post operative ileus (POI) were shown to be at increased likelihood of mortality.Increased PCV, increased length of SI resected and POI are all associated with increased likelihood of mortality of EFE cases. This emphasises the importance of early diagnosis and treatment and the need for improved strategies in the management of POI in order to reduce post operative mortality in these cases.The present study provides evidence-based information to clinicians and owners of horses undergoing surgery for EFE about long-term survival. These results are applicable to university and large private clinics over a wide geographical area.

Crib-biting/windsucking behaviour has important consequences for equine health and welfare. Lay perceptions of health and illness are of interest to medical sociologists, providing important information to medical practitioners, but have infrequently been applied in veterinary research.To demonstrate how lay epidemiology can be applied within veterinary research by exploring the lay perceptions regarding the causes of crib-biting/windsucking behaviour in horses.Informants were recruited from professional and amateur horse owners who had or had not owned/cared for a horse that exhibited crib-biting/windsucking behaviour. In-depth interviews were used to examine perceptions about the development of this behaviour within each group until a 'saturation' of themes emerged.The main themes that emerged as causes of crib-biting/windsucking behaviour were 'boredom', 'stress' and 'habit/addiction'. In the group of owners/carers who did not have direct experience of this type of behaviour, 'copying' from other horses emerged as a strong theme and they stated that they would not wish to own a crib-biting/windsucking horse. In contrast, those who had direct experience of horses demonstrating this behaviour did not believe copying was a cause based on their own observations and would not be put off purchasing or caring for another horse displaying this behaviour.Perceptions about what causes crib-biting/windsucking was influenced by whether or not informants had personal experience of horses demonstrating this behaviour. The three main themes that emerged have some justification based on current research and highlight the need for further investigation into the underlying pathophysiology of crib-biting/windsucking behaviour.Qualitative approaches to health, disease and behaviour have an important role in the medical field and are applicable to veterinary research.

The hormone, 1,25-dihydroxyvitamin D3 (1,25-[OH]2-D3), inhibits lymphocyte activation in vitro. We studied the ability of the vitamin D metabolite to interfere in vivo with a primary T cell-mediated model of autoimmunity, murine experimental autoimmune encephalomyelitis (EAE). Within 2 wk of antigenic challenge, immunized animals will develop acute paralysis with central nervous tissue inflammation. If mice survive, a rise in antibody titer develops within a month. The administration of 0.1 microgram 1,25-(OH)2-D3 i.p. given every other day for 15 d, starting 3 d before immunization, significantly prevented the development of EAE. The rise in antibody titer to myelin basic protein was also abrogated. Histopathologic lesions of EAE were inhibited by treatment with the sterol. These results suggest a potent immunosuppressive role for 1,25-(OH)2-D3 in vivo in the modulation of a cell-mediated model of autoimmunity.

The clinical features of 71 cases in 70 horses in which part of the small intestine became entrapped in the epiploic foramen are described. The horses' sex, age and breed, the month during which they were affected, and whether they exhibited stereotypic behaviour were compared with the same variables in 1279 horses which suffered other types of surgical colic during the same period. Thoroughbred and thoroughbred cross horses were over-represented among the 70 affected horses. There was no age or sex predilection. Fifty-five (77.5 per cent) of the cases occurred between October and March and 15 (21.1 per cent) occurred in January. The cases were significantly more likely to have a history of crib-biting/windsucking than the control group (odds ratio 7.9, 95 per cent confidence interval 4.1 to 15.3). The condition had recurred in two of the horses. Fifty-eight (81.7 per cent) recovered from surgery and 49 (69 per cent) survived until they were discharged from hospital. The median survival time of 31 of the affected horses discharged from the hospital was 700 days, whereas 417 horses with other types of surgical colic had a median survival time in excess of 1931 days.

1,25-Dihydroxyvitamin D3 [1,25-(OH)2-D3] is known to be an immunosuppressive hormone. This review primarily deals with in vitro and in vivo effects of 1,25-(OH)2-D3 and analogue, 1,25-dihydroxy-16ene-vitamin D3 [1,25-(OH)2-16ene-D3], on T helper subsets type 1 (Th1) or type 2 (Th2) that have distinctive functional characteristics in humans. Th1 secrete interferon (IFN-gamma), interleukin (IL-2) and induce B cells to produce immunoglobulin IgG2a while Th2 secrete IL-4, IL-10 and induce the production of IgG1 and IgE by B cells. The sterol inhibits the secretion of IL-12, a cytokine produced by monocytes and B cells, which leads to the activation and differentiation of Th1. In addition, 1,25-(OH)2-D3 directly inhibits IFN-gamma secretion by Th1 clones while it has little effect on IL-4 secretion by Th2 clones. The analogue, 1,25-(OH)2-16ene-D3, is 100-fold more potent than 1,25-(OH)2-D3 in inhibiting IFN-gamma secretion but also has little effect on IL-4 secretion. In mice, when given in vivo, the sterol prevents the induction of spontaneous and induced autoimmune diseases and inhibits Th1 induce IgG2a responses. These actions of the vitamin D3 compounds suggest that it may have potential therapeutic applications in Th1-mediated clinical situations such as autoimmunity and transplantation.

A computer program to automatically determine lung volume and percentage of emphysema from computed tomographic (CT) chest sections was developed. To test it, the authors reviewed scans obtained in 89 patients. Any computer errors in identification of normal or emphysematous lungs were corrected manually by tracing the boundaries of the lungs or eliminating areas of nonemphysematous lung with a roller ball. The corrected values were compared with the uncorrected values. In 33 patients from the study group, lung volumes and the percentage of emphysema were calculated by using a currently available "voxel highlighting" program. Successful computerized analysis of entire lungs was performed in 1 minute, compared to more than 1 hour for manual analysis. Correlation was high (r = .99) between results obtained manually and those obtained with the computer. Although the difference between uncorrected and corrected values of the percentage of emphysema was statistically significant, this converted to a correction of only 0.1%. The computer program allowed quick, accurate, and reproducible quantification of emphysema.