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Summary Polysaccharide storage myopathy (PSSM) was first described in 1992 in Quarter Horses, Appaloosa and Paint-related breeds with clinical signs of exertional rhabdomyolysis. The disease is characterised by the accumulation of excessive glycogen and diastase-resistant amylopectin polysaccharide inclusions within skeletal muscle fibres. The discovery of a mutation in the glycogen synthase 1 (GYS1) gene in some, but not all, horses with the disease suggested that PSSM represents a group of diseases with similar pathology but different aetiologies and that the pathogenesis is more complex than initially thought. Type 1 PSSM (PSSM1) refers to horses with the GYS1 mutation and has subsequently been identified in a large number of breeds found in Europe and North America. Clinical presentations associated with PSSM1 can vary and increased muscle enzyme activity at rest or following exercise often accompanies PSSM1; however, such changes may not be present in all cases. A diagnosis of PSSM is made on the basis of histopathology or specifically PSSM1 is diagnosed by genotyping horses for the GYS1 mutation. Cases usually respond well to management changes, in particular a diet low in starch and high in fat when it is accompanied by regular exercise.

SummaryReasons for performing study Acorn toxicity has been anecdotally reported to cause fatal colitis and colic in horses but reports in the scientific literature are sparse. Objectives This study reports the diagnosis, treatment, prognosis and outcome of 9 cases with suspected acorn toxicity admitted to 2 referral hospitals. Study design Retrospective case series. Methods Case records from 2004 to 2013 were reviewed. Horses were included in the study if they met 3 of 4 criteria: exposure to acorns; clinical and laboratory data suggesting alimentary or renal dysfunction; acorn husks in the faeces or gastrointestinal tract; and necropsy and histopathological findings consistent with acorn toxicity. Data collected included case history, clinical presentation, clinicopathological data, ultrasonographic findings, case progression, and necropsy and histopathological findings. Results Nine horses met the inclusion criteria. Five cases presenting with haemorrhagic diarrhoea deteriorated rapidly and were subjected to euthanasia or died. Four cases showed signs of colic with gas distension, displacement of the large colon and diarrhoea. Three of these (33%) survived with medical management, the fourth was subjected to euthanasia. Post mortem examination of 6 cases demonstrated submucosal oedema of the large intestine and caecum (n = 6), acute tubular nephrosis (n = 6), diffuse necrohaemorrhagic and ulcerative typhlocolitis and enteritis (n = 4), and small intestinal oedema (n = 3). Conclusions Acorn ingestion may be associated with typhylocolitis leading to diarrhoea, colic and acute renal tubular nephrosis. Recovery is possible in mildly affected cases; more severe cases show hypovolaemia, intractable pain, renal dysfunction and cardiovascular failure, and often succumb to the disease process. Disease is only seen in a small proportion of the population exposed to acorns and there seems to be an increased occurrence in certain years. Further investigation into factors predisposing to disease is required, but limiting exposure to acorns in the autumn seems prudent.

SummaryReasons for performing study Ex vivo evidence suggests that cyclo-oxygenase (COX) 2-preferential inhibitor nonsteroidal anti-inflammatory drugs (NSAIDs), such as meloxicam, have a less detrimental effect on intestinal healing than flunixin meglumine (FM). Whether this translates to a beneficial effect in horses with naturally occurring strangulating small intestinal (SSI) lesions is unknown. Objectives To compare the clinical outcome of horses with naturally occurring SSI lesions treated with meloxicam or FM. Study design Randomised prospective study. Methods Cases presenting to the Royal Veterinary College Equine Referral Hospital and Bell Equine Veterinary Clinic during 2010 and 2011 in which an SSI lesion was identified at exploratory laparotomy were eligible for inclusion. Horses received either 1.1 mg/kg bwt FM or 0.6 mg/kg bwt meloxicam i.v. q. 12 h. Clinical outcomes and clinical and laboratory parameters associated with endotoxaemia were compared between groups. Results Sixty cases were enrolled, 32 horses received FM and 28 received meloxicam. There was no difference in signalment, physical examination or surgical factors between groups. The overall survival to discharge was 81%; there was no difference in survival (P = 0.14) or incidence of post operative ileus (P = 0.25) between groups. There was no significant difference between the plasma lipopolysaccharide (LPS) concentrations at 0 h (P = 0.18) or 48 h (P = 0.60); however, there was a significant difference between neutrophil count at 48 h (P

SummaryReasons for performing study Clinical impression suggested that pony and miniature breeds (collectively referred to as ponies) presenting to a referral hospital for investigation of gastrointestinal disease had higher blood lactate concentrations on admission than large breed horses. Objectives The study tested the hypothesis that ponies with gastrointestinal disease had higher blood lactate concentrations on admission than large breed horses with similar disease severity. Study design Retrospective case–control study. Methods Medical records from September 2006 to July 2011 were reviewed for ponies with a primary presenting complaint of gastrointestinal disease. Two larger breed horses with gastrointestinal disease were selected as controls for each case. Data collected included case details, historical and clinicopathological findings, diagnosis and outcome. Results Information was collected on 50 ponies and 100 horses. Ponies had higher mean ± s.d. respiratory rates (27 ± 13 vs. 21 ± 13 beats/min; P = 0.01) and rectal temperatures (37.9 ± 0.6 vs. 37.4 ± 0.6°C; P = 0.006) and a longer median duration of clinical signs prior to presentation (10 h [1–72 h] vs. 6 h [1–120]; P

Background Type 1 polysaccharide storage myopathy (PSSM1), an equine glycogen storage disorder caused by a gain of function mutation (R309H) in the gene encoding glycogen synthase (GYS1), is associated with the accumulation of amylase-resistant alpha-crystalline polysaccharide inclusions within skeletal muscle. Several glycogenoses in humans have a cardiac phenotype, and reports exist of horses with PSSM and polysaccharide inclusions in cardiac muscle. Hypothesis/Objectives To investigate the hypothesis that horses with PSSM1 display a cardiac phenotype. Our objectives were to compare plasma cardiac troponin I (cTnI) concentration and the incidence of cardiac arrhythmias in PSSM1 homozygotes, heterozygotes, and control horses. Methods One hundred and twenty-five Belgian and Percheron horses under the same management were genotyped for the R309H GYS1 mutation. From these, 8 age-, breed-, and sex-matched cohorts of each genotype were identified. Plasma cTnI concentration and incidence of cardiac arrhythmias (determined by 24-hour Holter ECG) were compared between the groups. Results Although some PSSM1-affected horses had mildly increased plasma cTnI concentrations, there was no significant difference in cTnI concentrations between groups. There were no significant differences in the incidence of ectopic beats, cardiac conduction intervals or mean heart rate between groups. Conclusions and clinical importance We found no evidence of clinically relevant cardiac myocyte injury or arrhythmias in horses with PSSM1. Additional study is required to determine whether myocardial function may be compromised in this disorder.

Summary This report describes the unusual diagnosis of a retrobulbar syncytial meningioma in a 16-year-old Thoroughbred gelding. The horse initially presented with unilateral left sided exophthalmos and apparent blindness characterised by unilaterally absent menace and pupillary light responses. Magnetic resonance imaging (MRI) identified a well-defined soft tissue mass intimately associated with the opticnerve.BasedonthecharacteristicMRIappearance,a meningioma was suspected. The eye was enucleated under general anaesthesia and partial excision of the mass was achieved. Histopathology confirmed the diagnosis and the horse underwent a course of adjuvant radiotherapy. Twelve months following surgery the horse is back in work, no neurological abnormalities have been detected and follow-up computed tomographic imaging of the skull has revealed mild bone sclerosis with no remnants of the mass identified. eve_112 503..510

Summary The variation over 24 h of plasma glutamine concentration in nonexercising horses was studied in 3 Thoroughbreds (TB) fed at 1600 h and 0700 h. This indicated a small but regular change associated with feeding. Starting at a mean of 482 μmol/l at 1600 h the concentration increased to 522 μmol/l at 2000 h, falling to 476 μmol/l at 1600 h and increasing again to 525 μmol/l at 2000 h. ‘Normal’ values were established in 19 part-bred TB horses, lacking clinical signs or remarkable pathology and in light training, by sampling weekly at 1000 h over a 10 week period. The mean concentration was 491 μmol/l. Values were normally distributed with 95% confidence range between horses of 469–512 μmol/l. The s.d. of values within-horse was 28 μmol/l. The acute effect of exercise was investigated in 5 TB horses during i) an exercise simulating the road and tracks phase of a 3-day-event and ii) a sustained high-intensity exercise test (115% VO2max until the pace was no longer maintained). In both tests a transient increase was produced as a direct result of exercise, followed by a decline to a nadir at approximately 3 h post exercise. Pre-exercise resting concentrations, following either test, were approaching pre-values by 24 h recovery. The effect of viral challenge was studied in 6 TB horses exposed to an aerosol of equine influenza virus, subtype H3N8 (A/equine-2 subtype) which caused mild clinical signs. A significant fall in the 1000 h plasma glutamine concentration from a mean of 463 to 342 μmol/l by the 6th day was seen in 5 horses. A more gradual decline was observed in the 6th horse. These findings indicate a similar response to viral challenge in the horse to that in man.

Plasma NH3, formed during intense exercise, results principally from the deamination of AMP in muscle. Its formation during exercise may be influenced both by the pool of fibres recruited and by changes in the intracellular environment affecting ADP homeostasis. This study compared incremental and constant speed exercise as possible protocols for the investigation of plasma NH3 accumulation with intense exercise. Six trained Thoroughbred horses, one of which had recently been operated on for recurrent laryngeal neuropathy, undertook a step-wise treadmill test with 1 min incremental steps of 6, 8, 10, 11 and 12 m/s (7.5% incline). Two and 4 weeks later horses performed a constant-speed, maximum-exercise tolerance test at 115% VO2max (7.5% incline). Blood samples from the jugular vein were drawn at 20 s intervals in all 3 tests, for plasma NH3 and lactate. There were marked differences between and within horses in their time dependant lactate and NH3 responses to exercise. Three of the 6 horses studied showed a distinct threshold for onset of plasma NH3 accumulation with incremental exercise. Distinct thresholds for the onset of NH3 accumulation were apparent also in 5 of the 6 horses during exercise at constant rate. The present study demonstrates clearly the practicality of measuring NH3 concentration curves, even during a short incremental step test which has the advantage that other measures relating to cardiovascular and respiratory functions can be measured simultaneously.

Summary Reasons for performing study: The aetiology of temporohyoid osteoarthropathy (THO) is unknown; both primary infectious and degenerative causes have been suggested. Hypothesis: There is a significant association between increasing age and severity of temporohyoid joint degeneration. To examine the histopathology of the temporohyoid articulation in aged horses and to compare the appearance of the joint with computed tomography (CT) and peripheral quantitative CT (pQCT). Methods: pQCT scans of the temporohyoid articulations were obtained bilaterally from 31 horses (range age 1–44 years) post mortem and images were graded by 2 blinded observers on 2 occasions for the presence of osteophytes, irregularity of the joint surface and mineralisation. Eight heads had been examined previously by CT, with the images similarly graded for the shape and density of the proximal stylohyoid bones, bone proliferation surrounding the joint, mineralisation of the tympanohyoid cartilage and the relationship of the petrous temporal bone to the stylohyoid bone. Sixteen temporohyoid joints were then evaluated histologically. Results: There was significant association between the mean pQCT degeneration score and age (rho = 0.75; P

Summary The priority in treating the equine patient with acute diarrhoea is to stabilise the haemodynamic aberrations secondary to the fluid and electrolyte losses. Once this has been initiated and the patient is stabilised ancillary treatments may be beneficial. Besides the well established effects of NSAIDs and polymixin B on systemic inflammation, recent studies suggest that the use of DTOS to bind bacterial toxins and Saccharomyces boulardii to reduce the severity and duration of diarrhoea may be beneficial. The justification for using probiotic products is scant. There is no evidence to suggest that systemic use of antimicrobials benefits equine patients with colitis, with the exception of metronidazole in cases of clostridial diarrhoea. In light of their potentially detrimental effects, their use can, in the opinion of the authors, not be advocated. Better understanding of the pathways of systemic inflammation and more selective anti-inflammatory drugs may be of great benefit in the future.

Summary A 2-day-old filly foal presented with signs of depression, recumbency and inappetence. Blood analyses revealed hypoalbuminaemia, hyperfibrinogenaemia, hyperglycaemia and hyperkalaemia. The foal deteriorated despite intensive treatment and was subjected to euthanasia. At post mortem examination, the urinary bladder, ureters and kidneys appeared normal grossly. Histologically both kidneys showed disorganised development with the presence of structures inappropriate for a foal of this age, including primitive glomeruli, immature renal tubules and persistent metanephric ducts. Based on these findings a diagnosis of bilateral renal dysplasia was made.

OBJECTIVE To produce a clonal equine myoblast cell line that retains the ability to divide for multiple passages and differentiate into multinucleated myotubes during specific conditions. SAMPLE Cultured primary equine skeletal muscle-derived cells from a healthy Thoroughbred. PROCEDURES Cell cultures were transfected by electroporation with a plasmid (pNIT) that expresses the temperature-sensitive simian vacuolating virus 40 large T antigen (TAg), which can be controlled by a doxycycline-responsive promoter. Cells that stably integrated the TAg were selected and expanded to passage 25. For each passage, differentiation and fusion properties of the cells were determined and immunocytochemical analyses were performed to evaluate expression of TAg and other muscle-specific proteins. Optimum conditions that led to cell differentiation into myotubes were also determined. RESULTS Compared with nontransfected control cells, myogenic, desmin-positive cells expressed the TAg when incubated at 33°C and could be maintained in culture for numerous passages. Reduced expression of TAg was identified in cells incubated at 37°C or when incubated with doxycycline at 33°C. Expression of TAg was not detected when cells were incubated with doxycycline at 37°C, and when serum was withdrawn from the culture medium, those clones differentiated into a pure population of multinucleated myotubes. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that production of an immortalized clonal equine skeletal muscle cell line was possible. A clonal equine skeletal muscle cell line will be a valuable in vitro tool for use in equine physiology and disease research.

Summary Reasons for performing study: Videoendoscopy of the upper respiratory tract (URT) during high-speed treadmill exercise has proved to be invaluable in the assessment of URT dysfunction in racehorses. However, very little information exists regarding dynamic airway collapse in other sport horses used in nonracing equestrian disciplines. Objectives: To evaluate the videoendoscopic findings at rest and during exercise in a mixed population of sport horses referred for investigation of poor athletic performance and/or abnormal respiratory noise. Methods: Videoendoscopy of the upper airway was performed at rest and during high-speed treadmill exercise in 93 horses. Results: Dynamic airway obstructions were diagnosed in 77% of horses and were frequently complex in nature. The most common forms of dynamic collapse included soft palate dysfunction (54%), dynamic laryngeal collapse (38%), axial deviation of the aryepiglottic folds (24%) and pharyngeal wall collapse (18%). In the majority of horses, no obvious abnormalities were identified at rest. Enforced poll flexion was found to be a contributing factor in 24% of cases. Conclusions: Dynamic obstructions of the URT were a common cause of poor performance and/or abnormal respiratory noise in sport horses referred for investigation of performance problems. Potential relevance: This study highlights the importance of videoendoscopic evaluation of the URT during exercise in horses utilised for equestrian sports where exercise during competition is submaximal in nature.

Acorn toxicity has been anecdotally reported to cause fatal colitis and colic in horses but reports in the scientific literature are sparse.This study reports the diagnosis, treatment, prognosis and outcome of 9 cases with suspected acorn toxicity admitted to 2 referral hospitals.Retrospective case series.Case records from 2004 to 2013 were reviewed. Horses were included in the study if they met 3 of 4 criteria: exposure to acorns; clinical and laboratory data suggesting alimentary or renal dysfunction; acorn husks in the faeces or gastrointestinal tract; and necropsy and histopathological findings consistent with acorn toxicity. Data collected included case history, clinical presentation, clinicopathological data, ultrasonographic findings, case progression, and necropsy and histopathological findings.Nine horses met the inclusion criteria. Five cases presenting with haemorrhagic diarrhoea deteriorated rapidly and were subjected to euthanasia or died. Four cases showed signs of colic with gas distension, displacement of the large colon and diarrhoea. Three of these (33%) survived with medical management, the fourth was subjected to euthanasia. Post mortem examination of 6 cases demonstrated submucosal oedema of the large intestine and caecum (n = 6), acute tubular nephrosis (n = 6), diffuse necrohaemorrhagic and ulcerative typhlocolitis and enteritis (n = 4), and small intestinal oedema (n = 3).Acorn ingestion may be associated with typhylocolitis leading to diarrhoea, colic and acute renal tubular nephrosis. Recovery is possible in mildly affected cases; more severe cases show hypovolaemia, intractable pain, renal dysfunction and cardiovascular failure, and often succumb to the disease process. Disease is only seen in a small proportion of the population exposed to acorns and there seems to be an increased occurrence in certain years. Further investigation into factors predisposing to disease is required, but limiting exposure to acorns in the autumn seems prudent.

Recent great advances in the neuropharmacology of the emetic pathways have led to better therapy and improved insight into pathophysio­ logical processes in patients undergoing chemo- and radiotherapy. This arti­ cle gives an overview of the area, outlines current controversies, and makes recommendations for future clinical studies.

Clinical impression suggested that pony and miniature breeds (collectively referred to as ponies) presenting to a referral hospital for investigation of gastrointestinal disease had higher blood lactate concentrations on admission than large breed horses.The study tested the hypothesis that ponies with gastrointestinal disease had higher blood lactate concentrations on admission than large breed horses with similar disease severity.Retrospective case-control study.Medical records from September 2006 to July 2011 were reviewed for ponies with a primary presenting complaint of gastrointestinal disease. Two larger breed horses with gastrointestinal disease were selected as controls for each case. Data collected included case details, historical and clinicopathological findings, diagnosis and outcome.Information was collected on 50 ponies and 100 horses. Ponies had higher mean ± s.d. respiratory rates (27 ± 13 vs. 21 ± 13 beats/min; P = 0.01) and rectal temperatures (37.9 ± 0.6 vs. 37.4 ± 0.6°C; P = 0.006) and a longer median duration of clinical signs prior to presentation (10 h [1-72 h] vs. 6 h [1-120]; P0.001). Median blood lactate concentrations on admission were higher in ponies than in horses (2.8 mmol/l [0.7-18.0] vs. 1.6 mmol/l [0.4-8.1]; P = 0.001). All other parameters relating to colic severity were not significantly different between groups, although more horses underwent exploratory laparotomy (19/50 ponies and 55/100 horses; P = 0.05). Median blood lactate concentrations in ponies with large intestinal disease, nonstrangulating lesions, undergoing medical treatment and surviving ponies were significantly higher than in horses in the same category. In contrast to horses, no differences in blood lactate concentrations exist between ponies with medical vs. surgical treatment, strangulating and nonstrangulating lesions and surviving and nonsurviving ponies.Ponies might present with higher blood lactate concentrations than horses and might falsely be suspected of having a surgical lesion or a poorer prognosis if veterinarians are not aware of breed differences.

Equine type 1 polysaccharide storage myopathy (PSSM1), a common glycogenosis associated with an R309H founder mutation in the glycogen synthase 1 gene (GYS1), shares pathological features with several human myopathies. In common with related human disorders, the pathogenesis remains unclear in particular, the marked phenotypic variability between affected animals. Given that affected animals accumulate glycogen and alpha-crystalline polysaccharide within their muscles, it is possible that physical disruption associated with the presence of this material could exacerbate the phenotype. The aim of this study was to compare the histopathological changes in horses with PSSM1, and specifically, to investigate the hypothesis that the severity of underlying pathology, (e.g. vacuolation and inclusion formation) would (1) be higher in homozygotes than heterozygotes and (2) correlate with clinical severity. Resting and post-exercise plasma creatine kinase (CK) and aspartate aminotransferase (AST) enzyme activity measurements and muscle pathology were assessed in matched cohorts of PSSM1 homozygotes, heterozygotes or control horses. Median (interquartile range (IR)) resting CK activities were 364 (332-764) U/L for homozygotes, 301 (222-377) U/L for heterozygotes and 260 (216-320) U/L for controls, and mean (+/- SD) AST activity for homozygotes were 502 (+/116) U/L, for heterozygotes, 357 (+/-92) U/L and for controls, 311 (+/-64) U/L and were significantly different between groups (P = 0.04 and P = 0.01 respectively). Resting plasma AST activity was significantly associated with the severity of subsarcolemmal vacuolation (rho = 0.816; P = 0.01) and cytoplasmic inclusions (rho = 0.766; P = 0.01). There were fewer type 2× and more type 2a muscle fibres in PSSM1-affected horses. Our results indicate that PSSM1 has incomplete dominance. Furthermore, the association between plasma muscle enzyme activity and severity of underlying pathology suggests that physical disruption of myofibres may contribute to the myopathic phenotype. This work provides insight into PSSM1 pathogenesis and has implications for related human glycogenoses.

The main function of emesis is to remove toxins from the body. The emetic response will also be triggered by cancer chemotherapy and radiotherapy or surgery under general anaesthesia. The mechanism of activation of the vomiting system is dependent on stimulation of gastrointestinal (mechanoreceptors and chemoreceptors) and/or central pathways which activate the chemoreceptor trigger zone in the area postrema. Postoperative emesis is activated by a range of factors before, during and after anaesthesia. The precise mechanism of action of any one of the influencing factors can only be speculated as there has been very little basic research into this area, due largely to the lack of an appropriate model for postoperative nausea and vomiting. The range of agents used in the prevention and treatment of emesis are effective to varying degrees, but some are associated with poor side effect profiles making them particularly unsuitable for prophylactic use. Newer antiemetics, which selectively antagonise 5-HT3 receptors, have proved effective and well tolerated in the treatment of chemotherapy-induced emesis and postoperative nausea and vomiting.

Dumuis and colleagues (1988) in their investigation of a 5-HT receptor positively linked to adenylate cyclase in the central nervous system, concluded that the receptor was not 5-HT1, 5-HT2 or 5-HT3-like and suggested that it belonged to a new class of 5-HT receptor called 5-HT4. A similar, if not identical receptor was located by Craig and Clark (1990) in the guinea pig ileum and a functional role for the peripheral 5-HT4 receptor has since been established in many species to mediate muscle contraction or relaxation within the gut and positive inotropic effects in the heart. In contrast, a functional role for central 5-HT4 receptors has remained obscure. Using measurements of rodent behaviour in the mouse light and dark test box and rat social interaction, anxiolytic agents such as diazepam and putative anxiolytic agents such as the 5-HT1A and 5-HT3 receptor ligands 8-OH-DPAT and low doses of tropisetron release behaviour suppressed by the aversive situation. 5-Hydroxytryptophan has the opposite effect exacerbating the behavioural response to the aversive situation. But an anxiolytic profile is revealed by co-treatment with ritanserin plus 5-hydroxytryptophan. The drug-induced anxiolytic profiles are inhibited by SDZ205-557 and a high dose of tropisetron. Both compounds are 5-HT3/5-HT4 receptor antagonists yet the selective 5-HT3 receptor antagonist ondansetron fails to inhibit the drug-induced anxiolytic profiles.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dehydration on thermoregulatory and metabolic responses were studied in six horses during 40 min of exercise eliciting approximately 40% of maximal O2 consumption and for 30 min after exercise. Horses were exercised while euhydrated (C), 4 h after administration of furosemide (FDH; 1.0 mg/kg i.v.) to induce isotonic dehydration, and after 30 h without water (DDH) to induce hypertonic dehydration. Cardiac output was significantly lower in FDH (144.1 +/- 8.0 l/min) and in DDH (156.6 +/- 6.9 l/min) than in C (173.1 +/- 6.2 l/min) after 30 min of exercise. When DDH, FDH, and C values were compared, dehydration resulted in higher temperatures in the middle gluteal muscle (41.9 +/- 0.3, 41.1 +/- 0.2, and 40.6 +/- 0.2 degrees C, respectively) and pulmonary artery (40.8 +/- 0.3, 40.1 +/- 0.2, and 39.7 +/- 0.2 degrees C, respectively). Temperatures in the superficial thoracic vein and subcutaneous sites on the neck and back and peak sweating rates on the neck and back were not significantly different in DDH and C. In view of higher core temperatures during exercise after dehydration and decrease in cardiac output without concomitant increases in peripheral temperatures or reduced sweating rates, we conclude that the impairment of thermoregulation was primarily due to decreased transfer of heat from core to periphery.

SPINAL ataxia is a common presenting sign in horses with neurological disease in the UK and in most cases the signs are attributed to spinal cord compression. This report describes an unusual, but perhpas overlooked degenerative cause of spinal ataxia in horses in which diagnosis was confirmed at

The aetiology of temporohyoid osteoarthropathy (THO) is unknown; both primary infectious and degenerative causes have been suggested.There is a significant association between increasing age and severity of temporohyoid joint degeneration. To examine the histopathology of the temporohyoid articulation in aged horses and to compare the appearance of the joint with computed tomography (CT) and peripheral quantitative CT (pQCT).pQCT scans of the temporohyoid articulations were obtained bilaterally from 31 horses (range age 1-44 years) post mortem and images were graded by 2 blinded observers on 2 occasions for the presence of osteophytes, irregularity of the joint surface and mineralisation. Eight heads had been examined previously by CT, with the images similarly graded for the shape and density of the proximal stylohyoid bones, bone proliferation surrounding the joint, mineralisation of the tympanohyoid cartilage and the relationship of the petrous temporal bone to the stylohyoid bone. Sixteen temporohyoid joints were then evaluated histologically.There was significant association between the mean pQCT degeneration score and age (rho = 0.75; P0.0001), between the pQCT and CT score (rho = 0.63; P = 0.01) and between the degenerative changes identified within each temporohyoid joint within each horse (rho = 0.81; P0.0001). Age-associated changes included the development of a club shape by the proximal stylohyoid bone, rounding of the synostosis with the petrous temporal bone and extension of osteophytes from the petrous temporal bone to envelope the stylohyoid head and bridge the joint. In no horse was there any evidence of osteomyelitis within the petrous temporal bone, stylohyoid bone or tympanohyoid cartilage.This study provides evidence that age is associated with increasing severity of degenerative changes in the equine temporohyoid joint and that similar changes are commonly found bilaterally.The changes identified appear similar, albeit milder to the changes reported in horses with THO, suggesting that degenerative, rather than infectious causes may underlie the aetiology of THO. Future work should be directed at examining the histopathology of clinical THO cases.

Background: In paediatric inpatients, medication errors occur as frequently as 1 in 4.2 drug orders, with up to 80% of these being prescribing errors. Context: The children’s unit of a district general hospital in West Yorkshire, UK. Key measures for improvement: Prescribing errors and preventable adverse drug events Strategies for change: (1) The introduction of a junior doctor prescribing tutorial. (2) The introduction of a bedside prescribing guideline. Effects of change: The introduction of the junior doctor prescribing tutorial decreased the prescribing errors by 46%. The introduction of a bedside prescribing guideline did not decrease prescribing errors but may have been helpful to those doctors unable to attend a prescribing tutorial. Lessons learnt: By investing time and providing appropriate written resources, we have been able to reduce our paediatric prescribing errors on the children’s ward by almost half.

No Abstract. NQJHM Vol. 8 (2) 1998: pp. 139-142

Summary Reasons for performing study:Pharmacological benefits of glutamine supplementation have been shown in athletically and clinically stressed human subjects. In the horse, infection and intense exercise have also been shown to significantly decrease plasma glutamine concentrations, but little is known on how best to supplement. Objective:To evaluate whether ingestion of different foodstuffs, with or without L-glutamine (G) or a peptide (Pep) containing 31.5% w/w G in a water-stable form, could affect plasma glutamine concentrations (P-GC). Materials and methods:Nine feeds (molassed sugar beet-pulp (mSB); naked oats (nO); commercial mix (CM); mSB with 30 or 60 mg/kg bwt G or the G-molar equivalent of Pep; and CM with 60 mg/kg bwt G or equivalent Pep) were offered to 6 healthy mature horses on different days following overnight food restriction. The changes in P-GC were monitored for 8 h post feeding. Results: After 1.5 h mean ± s.d. ΔP-GC were -0.9 ± 10.2% (mSB), +12.5 ± 7.1% (nO) and +44.7 ± 15.9% (CM; P

Summary Reasons for performing study: The reliability of diagnoses of obstructive conditions of the upper respiratory tract (URT) based on examinations performed at rest vs. at exercise is controversial. Objective: To compare diagnosis of URT by endoscopy at rest with that achieved during high-speed treadmill exercise (HSTE). Hypothesis: Endoscopy of URT at rest, when performed in isolation from other simpler techniques is unreliable in the prediction of dynamic respiratory obstructions. Methods: Endoscopic findings of 600 Thoroughbred racehorses during quiet breathing were compared with findings during high-speed treadmill exercise. Other parameters were also assessed for their specificity in diagnosis. Results: Endoscopy of the resting horse showed low sensitivity (0.15) in the diagnosis of dorsal displacement of the soft palate (DDSP) and palatal instability (PI). When endoscopy and reported noises were taken together there was still a 35% misdiagnosis rate. Although there was significant association between resting laryngeal function score (LFS) and dynamic vocal cord and/or arytenoid cartilage collapse at exercise, 19% of horses with a grade 4/5 LFS were able to attain and maintain full abduction during exercise and 7% of those with ‘normal’grades 1 or 2 LFS at rest showed dynamic laryngeal collapse when exerted. Sensitivity of the diagnostic model was greatly increased (80%) when a history of inspiratory noise and palpable intrinsic muscle atrophy were included. Conclusions and potential relevance: Endoscopy of the upper respiratory tract of static horses is unreliable in the diagnosis of dynamic obstructions of the URT and should not be used in isolation in surgical decision-making or in the assessment of horses at the time of sale.

Summary Dorsal displacement of the soft palate (DDSP) is one of the most common obstructive conditions of the upper respiratory tract in the racehorse. The present study was conducted to determine the effects of intermittent dorsal displacement of the soft palate (DDSP) on ventilation and respiratory airflow during high intensity exercise. Videoendoscopic recordings were made of the nasopharynx and larynx simultaneously with measurements of airflow and respiratory gas exchange, during high-speed treadmill exercise in 9 horses with confirmed intermittent DDSP admitted for clinical investigation of poor racing performance. In all horses, DDSP resulted in a reduction in minute ventilation (VE) (P

Introduction Measurement of incorporation of stable isotope-containing amino acids into muscle is the gold-standard technique for measuring muscle protein synthesis (MPS), but its use in assessing MPS in horses has not been evaluated. Determination of MPS requires steady-state tracer plasma enrichment and serial muscle biopsy. Given that MPS is often assessed in response to exercise and that muscle biopsy in the standing horse typically requires sedation, the influence of exercise and sedation on tracer kinetics was determined. Methods Three mature Thoroughbred geldings received 0.1 mg/kg D5-phenylalanine (D5-Phe) IV and plasma D5-Phe enrichment was measured over 3 hrs. Pharmacokinetic modeling determined the rate of appearance and phenylalanine pool size, from which a loading dose and infusion rate that would achieve a steady 5–10% enrichment were calculated. Subsequently, steady-state was confirmed by measuring plasma enrichment during 6 hours of infusion after loading. Horses then received the same dose and completed a 12-minute exercise test and were sedated with xylazine 0.4 mg/kg IV. Plasma D5-Phe enrichment was determined every 5–15 minutes for 2 hours after both exercise and sedation. Results The mean rate of phenylalanine appearance in the horse was 56 umol/kg/hr (SD 24) and mean phenylalanine pool size 41 umol/kg (SD 8.8). A loading dose of 3.3 umol/kg and an infusion rate of 4.5 umol/kg/hr D5-phenylalanine was calculated and subsequently, confirmed to achieve steady state tracer concentration at 5.6–9.1% APE in sedentary horses. Exercise caused a transitory, and sedation a more prolonged reduction in plasma enrichment (up to 20%). Conclusions D5-phenylalanine is a suitable metabolic tracer in the horse as a steady-state can be achieved, however interventions should be taken into account. Ethical Animal Research The study was performed in in accordance with the local Ethics Committee approval and Home office project license (PPL 70/7523) under the UK A(SP)A Act 1986. Sources of funding: Boehringer Ingelheim. Competing interests: R Naylor is completing a PhD studentship sponsored by Boehringer Ingelheim.

Gaddum and Picarelli(1957), using the guinea pig ileum, were the first researchers to show that 5-hydroxytryptamine (5-HT) can mediate a neuronal depolarising response and release of acetylcholine. A clarification of the nature and function of the receptor mediating the response to 5-HT has subsequently taken some 40 years. The present chapter reviews the beginnings of a pharmacological understanding of this receptor and the therapeutic implications of drugs which have affinity for it.

1. The effects of 5-HT and 5-HT agonists to induce contraction and the 5-HT receptors mediating these effects were investigated in the proximal, central and terminal intestinal segments of Suncus murinus. 2. The contraction curves to 5-HT (3 nM - 30 microM) were shifted to the right by methysergide (1 microM) and ritanserin (0.1 microM), without affecting the maximum response. 3. In the central and terminal segments (but not the proximal segments) ondansetron (1 microM) and atropine (1 microM) significantly attenuated the contractions to higher concentrations of 5-HT. The selective 5-HT4 receptor antagonist SB204070 (1 nM), failed to modify 5-HT induced contractions in any segment examined. 4. 5-carboxamidotryptamine, alpha-methyl-5-HT and 5-methoxytryptamine (0.003 - 3.0 microM) induced contractions but unlike 5-HT, higher concentrations of these three agents failed to increase the response or were associated with a decrease in response. 2-methyl-5-HT (0.03 - 1.0 microM) was ten times less potent than 5-HT to induce contraction but achieved the same maximum response. 5. The contractions induced by the lower concentrations of 2-methyl-5-HT (0.03 - 1.0 microM) in all segments were markedly reduced or abolished by methysergide (1.0 microM); the response to the higher concentrations of 2-methyl-5-HT (3 - 30.0 microM) were markedly reduced by atropine (1.0 microM) and ondansetron (1.0 microM). 6. In all segments examined, tetrodotoxin (1 microM) significantly reduced the 5-HT-induced contraction. 7. It is concluded that the 5-HT-induced contraction was mediated via 5-HT2 (ritanserin sensitive) receptors in all regions of the intestine, with 5-HT3 (ondansetron sensitive) receptors mediating an additional major component in the central and terminal regions.

Thermoregulation may limit exercise performance under hot and humid conditions. This study compared heart rate (HR), respiratory rate (RR), rectal temperature (Tr), packed cell volume (PCV) and total plasma protein concentration (TPP) during a submaximal incremental field exercise test under high vs. low ambient temperature and relative humidity. Ten horses were tested 3 times in summer (July) and 3 times in autumn (September). Heart rate was measured continuously, the other variables at rest and immediately after 4 min at 3.5, 4.5 and 7.0 m/s, separated by 3 min rest intervals, and after 5 and 10 min recovery. Data for all variables were significantly greater during exercise and recovery in the hot vs. cool conditions, respectively: after 4 min at 7.0 m/s, HR was 135+/-1 and 123+/-1/min (P

Recent great advances in the neuropharmacology of the emetic pathways have led to better therapy and improved insight into pathophysiological processes in patients undergoing chemo- and radiotherapy. This article gives an overview of the area, outlines current controversies and makes recommendations for future clinical studies.

The anxiolytic potential of the selective sigma2 ligand 1-[4-[1-(4-Fluorophenyl)-1H-indol-3-yl]-1-butyl]spiro[isobenzofuran-1(3H),4-piperidine] [corrected] (Lu 28-179) was assessed in various animal models of anxiety in rodents. Lu 28-179 facilitated the exploratory behavior of mice and rats in the black and white two-compartment box over a large dose range. In the rat, the minimal effective dose (MED) was 0.18 nmol/kg (0.1 microg/kg), and in the mouse, the MED was 0.00018 nmol/kg (0.1 ng/kg). The anxiolytic-like effect was maintained after treatment with 1 microg/kg/day for up to 14 days, and no anxiogenic-like effects were seen upon withdrawal from repeated treatment. Lu 28-179 increased the time that pairs of rats spent in active social interaction (unfamiliar high-light conditions), MED = 0.1 ng/kg. Daily treatment with Lu 28-179 (1.8 nmol/kg = 1 microg/kg/day) for up to 4 weeks increased the social interaction time significantly compared with controls, and no anxiogenic-like effects were seen upon withdrawal. Furthermore, Lu 28-179 reversed shock-induced suppression of drinking in the rat (MED = 18,000 nmol/kg = 10 mg/kg). Lu 28-179 did not inhibit footshock-induced ultrasonic vocalization in the rat or isolation-induced aggressive behavior in the mouse. Lu 28-179 was over 100 times more potent than diazepam in the rat and mouse black and white test box and the rat social interaction test, whereas the potency of Lu 28-179 was comparable to that of lorazepam in reversal of shock-induced suppression of drinking. Lu 28-179 neither induced sedation nor impaired motor coordination, even at high doses (70,000 nmol/kg = 40 mg/kg). In conclusion, Lu 28-179 exerts potent and long-lasting anxiolytic-like effects in rodents without inducing sedation and withdrawal anxiogenesis.

Recent great advances in the neuropharmacology of the emetic pathways have led to better therapy and improved insight into pathophysiological processes in patients undergoing chemo- and radiotherapy. This article gives an overview of the area, outlines current controversies and makes recommendations for future clinical studies.

1. The 5-HT receptor involved in the effect of mucosal application of 5-HT to facilitate peristalsis was investigated in the isolated guinea pig ileum. 2. An application of 5-HT (3-100 microM) to the mucosal surface (by inclusion of 5-HT in the Krebs-Henseleit solution passing through the lumen of the ileum) caused a concentration related facilitation of peristalsis characterized by a reduction in the peristaltic threshold. 3. Peristalsis was not modified by methiothepine (0.1 microM), ritanserin (0.1 microM), ondansetron (5 microM), granisetron (1 microM) or SB 204070 (0.1 microM) administered alone to the mucosal surface. 4. The concentration-response curve to mucosally applied 5-HT was not altered by the mucosally applied 5-HT1/2 receptor antagonist methiothepine (0.1 microM), the 5-HT2 receptor antagonist ritanserin (0.1 microM) or the 5-HT4 receptor antagonist SB 204070 (0.1 microM). However, the mucosally applied 5-HT3 receptor antagonists ondansetron (5 microM) and granisetron (1 microM) shifted the response curves to mucosally applied 5-HT to the right in a parallel and surmountable manner. The pD2 values in the absence and presence of ondansetron were 5.42 +/- 0.07 and 4.12 +/- 0.10, respectively, (n = 6) and that of granisetron were 5.45 +/- 0.12 and 4.50 +/- 0.10 respectively, (n = 5). 5. Serosally applied ondansetron (5 microM) or granisetron (1 microM) had no effect on the concentration-response curve to mucosally applied 5-HT. However, the serosally applied ondansetron and granisetron antagonised the facilitatory effect of serosally applied 5-HT (10 microM) when administered in the presence of serosally applied SB 204070 (0.1 microM). 6. It is concluded that the facilitatory effect of mucosally applied 5-HT to reduce the peristaltic threshold in the guinea pig ileum is mediated via a 5-HT3 receptor located on the mucosal and not the serosal side of the ileum.

1. The ability of 5-HT2 and 5-HT4 receptor antagonists to modify the disinhibitory profile of diazepam and other agents was investigated in male BKW mice in the light/dark test box. 2. The 5-HT2A/2B/2C receptor antagonists ritanserin, MDL11939 and RP62203 and also methysergide, which failed to modify mouse behaviour when administered alone, caused dose-related enhancements (4 to 8 fold) in the potency of diazepam to disinhibit behavioural responding to the aversive situation of the test box. 3. Ritanserin was shown to enhance the disinhibitory potency of other benzodiazepines, chlordiazepoxide (4 fold), temazepam (10 fold) and lorazepam (10 fold), the 5-HT1A receptor ligands, 8-OH-DPAT (25 fold), buspirone (100 fold) and lesopitron (500 fold), the 5-HT3 receptor antagonists, ondansetron (100 fold) R(+)-zacopride (100 fold) and S(-)-zacopride (greater than a 1000 fold), the substituted benzamides, sulpiride (10 fold) and tiapride (5 to 10 fold) and the cholecystokinin (CCK)A receptor antagonist, devazepide (100 fold). It also reduced the onset of action of disinhibition following treatment with the 5-HT synthesis inhibitor parachlorophenylalanine. Ritanserin failed to enhance the disinhibitory effects of the CCKB receptor antagonist CI-988, the angiotensin AT1 receptor antagonist losarten or the angiotensin converting enzyme inhibitor ceranapril. 4. The 5-HT4 receptor antagonists SDZ205-557, GR113808 and SB204070 caused dose-related reductions in the disinhibitory effect of diazepam, returning values to those shown in vehicle treated controls. The antagonists failed to modify mouse behaviour when administered alone. 5. GR113808 was also shown to cause a dose-related antagonism of the disinhibitory effects of chlordiazepoxide, lorazepam, 8-OH-DPAT, buspirone, lesopitron, ondansetron, R(+)-zacopride, sulpiride, tiapride, devazepide, CI-988, losarten, ceranapril and parachlorophenylalanine. 6. It was concluded that in BKW mice (a) the failure of 5-HT2 and 5-HT4 receptor antagonists when administered alone to modify behaviour in the light/dark test indicates an absence of an endogenous 5-HT tone at the 5-HT2 and 5-HT4 receptors and (b) the enhancement by the 5-HT2 receptor antagonists and attenuation by the 5-HT4 receptor antagonists of drug-induced disinhibition indicates a plurality of 5-HT receptor involvement in the mediation of drug-induced disinhibitory profiles in the mouse.

CHOLESTEROL granulomata – benign choroid plexus masses often detected at equine postmortem examinations – are sometimes associated with central neurological signs (Ivoghli and others 1977, Johnson and others 1993, Jackson and others 1994, King 1997). Antemortem diagnosis was impossible until advent of magnetic resonance imaging (Maulet and others 2008) and CT (Vink-Nooteboom and others 1998, Vanschandevijl and others 2008). These two cases are the first to illustrate diagnosis using standing (unanaesthetised) CT (CT Lightspeed QX/i; GE medical systems) and describe the long-term follow-up of one case, revealing that the prognosis for some cases is fair. Case 1: A 12-year-old Irish Draught cross gelding was presented with a 10-day history of intermittent lethargy and abnormal head carriage. On presentation, episodes of generalised muscle rigidity and ataxia were noticed by the owner; the horse was obtunded with reduced tongue tone and drooping of the lower lip and reluctant to flex or extend the neck and back. Neurological signs had improved following administration of methylprednisolone, penicillin and flunixin meglumine. On presentation to the Royal Veterinary College, the horse was obtunded; menace responses were reduced bilaterally, but pupillary light reflexes were intact. Mild superficial gluteal muscle fasciculations were evident. The horse had an exaggerated guarding response to deep palpation of the neck at C5 to C7. The neuroanatomical localisation suggested forebrain involvement, but based on cervical discomfort on …

ELEVATED triglyceride concentrations are a common consequence of negative energy balance in equids (Naylor and others 1980). They are most often observed in overweight ponies, miniature horses and donkeys experiencing an increased energy demand, anorexia or subsequent to an underlying disease promoting the release of inflammatory mediators, which promote lipid catabolism. Clinical signs of equine dyslipidaemias are non specific, and can be masked by, or attributed to, any underlying disease process if present (Mogg and Palmer 1995); therefore, clinically significant increases in triglyceride concentrations may go undetected. Rapid diagnosis of elevated triglyceride concentration is important to allow prompt initiation of therapy, which is important for a successful outcome (Burden and others 2011). The Accutrend Plus (Roche Diagnostics; AP) is a handheld monitor marketed for the measurement of blood cholesterol, glucose, lactate and triglyceride concentrations in human beings (Moses and others 1996, Luley and others 2000). The lactate function has been validated for use in horses (Tennent-Brown and others 2007) while the triglyceride function has been validated for use in dogs and cats (Kluger and others 2010a, b). The device costs approximately £250 and each test around £2.40. Currently, no point-of-care monitors are validated to measure blood triglyceride concentrations in horses. A point-of-care monitor with the facility to measure triglyceride concentrations would be useful in diagnosing dyslipidaemias and monitoring the response …

From a consideration of the above evidence, it is possible to hypothesize that the 5-HT3 receptors, which are located both in the gut and in the AP/NTS, may play an important and perhaps pivotal part in the mechanism(s) of action of chemotherapy and radiotherapy to induce emesis in animals and humans and represent the anti-emetic sites of action of ondansetron and related agents (see Fig. 1). The value of ondansetron and the 5-HT3 receptor antagonists has been to greatly improve the treatment of nausea and emesis in the cancer patient and to cause a renaissance in emesis research. The 5-HT3 receptor antagonists have helped to redefine the phases of chemotherapy induced emesis and establish the first clear neurotransmitter links in the emetic reflex. It has also encouraged the analysis of emetic mechanisms that will identify further points for pharmacological intervention that may ultimately provide "broad spectrum" anti-emetic agents. Such compounds would further improve the quality of life and treatment of the cancer patient, leading to increased success in the treatment of malignant tumours.

The effects of dehydration and 40 min of exercise at approximately 40% of maximal O2 consumption on plasma volume (PV) and blood volume (BV) were studied in six horses. Horses were exercised while euhydrated (C); 4 h after administration of furosemide (1.0 mg/kg i.v.; FDH), which induced isotonic dehydration; and after 30 h without water (DDH), which caused hypertonic dehydration. Dehydration resulted in decreases of 6.3 and 9.9% for PV and BV, respectively, with FDH and 10.7 and 8.5%, respectively, with DDH. During exercise in C, PV and BV increased by 12.7 and 20.0%, respectively; during exercise with FDH, they increased by 11.7 and 26.1%, respectively; and during exercise with DDH, PV decreased by 1.3% from predehydration values, while BV increased by 18.7%. Hematocrit and total plasma protein concentration rose to higher values throughout exercise in FDH and DDH than in C; plasma [Na+] was higher in DDH than in FDH and C, [Cl-] was higher in DDH and lower in FDH than in C, and [K+] was lower in FDH and DDH than in C through exercise and recovery. From these results, we conclude that increases in PV and BV are normal features of low-intensity exercise in the horse. The increases in BV not only augment O2 carriage but also help maintain circulating volume. These increases can be modified by preexercise dehydration, the nature of which affects the extent of modification.

Pharmacological manipulations to enhance 5-HT synthesis and release have been reported to reduce alcohol intake. However, recent evidence indicates that 5-HT3 receptor antagonists may also exert a similar effect in a number of species. This report reviews the existing data which implicates a central role for 5-HT3 receptors in the control of psychoactive substance abuse.

5-HT3 receptor antagonists such as ondansetron, granisetron, ICS205-930 and zacopride are highly effective in the ferret, cat or dog to prevent emesis caused by cisplatin and other chemotherapeutic agents, and radiation treatment. The anti-emetic effects may be mediated centrally in the area postrema and associated structures of the emetic reflex such as the nucleus tractus solitarius, which have a very high density of 5-HT3 receptors. Additional sites of action may be found on the 5-HT3 receptors located on the vagus nerve or enteric neuronal elements in the gastro-intestinal tract. The precise site(s) and mechanism(s) of action of different cytotoxic treatments to induce emesis remains to be determined, but appears to involve a common action on a 5-HT3 system. The 5-HT3 receptor antagonists do not impair normal behaviour and, in particular, fail to affect the extrapyramidal motor system and do not cause sedation. Of potential benefit, the 5-HT3 receptor antagonists have an anxiolytic profile of action in rodent and primate models. The 5-HT3 receptor antagonists are revealed as an important group of drugs to prevent emesis induced by a wide range of cytotoxic treatments.

5-HT3 receptors have an exclusive neuronal location and evidence is presented of their involvement in behaviour. 5-HT3 receptor antagonists such as ondansetron, tropisetron and zacopride have provided the critical pharmacological tools to reveal a potent and efficacious ability to regulate disturbed behaviour. Thus the 5-HT3 receptor antagonists will restore to normal rodent and primate behaviour disturbed by increasing limbic dopamine function, aversive situations, cognitive impairments and drug abuse. The remarkable feature of their action is a failure to modify normal behaviour. This unique pharmacological signature has ensured a wide interest in the potential role of the 5-HT3 receptor antagonists in the treatment of schizophrenia, anxiety, age related memory impairment and the problems of withdrawal from drugs of abuse. The preclinical data and preliminary clinical observations are presented.

Ondansetron is a highly potent and selective antagonist at 5-HT3 receptors. Its anti-emetic actions were first revealed by its ability to antagonize retching and vomiting induced by chemotherapy and radiotherapy in animals and man. Subsequently, the availability of labelled 5-HT3 receptor ligands allowed identification of 5-HT3 receptors, located at highest densities in the area postrema, nucleus tractus solitarius (NTS), in other areas of the brain, and on afferent terminals of the vagus nerve. Postoperative nausea and vomiting may be caused by various factors: the anaesthetic, associated drugs, the surgical procedure, movement of the patient, sex, weight and pain. These factors mediate their effects via the higher brain circuits, the vestibular nuclei, the chemoreceptor trigger zone in the area postrema, or the upper gastrointestinal tract via the vagus nerve, influencing motor and visceral emetic outputs in the hind-brain. It is hypothesized that ondansetron blocks nausea and vomiting by 5-HT3 receptor antagonism at two specific sites: (i) centrally, in the area postrema/NTS; and (ii) peripherally on vagus nerve terminals. The absence of other pharmacological effects of ondansetron ensures an absence of side-effects.