Clinicopathological features of peripheral odontogenic fibromas in dogs and risk factors for their laboratory diagnosis.

OBJECTIVES: To explore clinicopathological features of peripheral odontogenic fibromas in dogs and risk factors for their diagnosis. MATERIALS AND METHODS: Data of cases with a histopathological diagnosis of peripheral odontogenic fibromas were obtained from a UK-based diagnostic laboratory and retrospectively reviewed. Prevalence amongst all biopsy submissions was assessed using binomial tests and Clopper-Pearson intervals. Age at diagnosis was assessed using t-test for independent samples. Lesion location, sex, and neuter status were assessed using χ2 and post hoc binomial tests. Breed odds ratios were calculated using univariable logistic regression modelling. RESULTS: The prevalence of peripheral odontogenic fibromas amongst all biopsy submissions was 2.8% (1001 of 35,328, 95% confidence interval [CI]: 2.7 to 3.0). The mean (sd) age was 8.1 (±2.7) years. The most affected quadrant was the rostral maxilla (40.1%). The ratio of maxillary to mandibular lesions was 1.3:1 (95% CI: 1.1 to 1.5), and for cases of multiple peripheral odontogenic fibromas the ratio of maxillary to mandibular lesions was 2.4:1 (95% CI: 1.1 to 5.6). Males had 1.2 times the odds of suffering of peripheral odontogenic fibromas compared to females (odds ratio [OR]: 1.2, 95% CI: 1.1 to 1.4). Neutering was associated with an increased risk of diagnosis (OR: 1.6, 95% CI: 1.3 to 1.9). Breeds with increased odds of peripheral odontogenic fibromas compared to crossbreed dogs included boxers (OR: 3.78, 95% CI: 2.80 to 5.09), border terriers (OR: 3.21, 95% CI: 2.10 to 4.91) and Basset Hounds (OR: 3.18, 95% CI: 1.58 to 6.44). Breeds with increased odds of multiple simultaneous peripheral odontogenic fibromas compared to crossbreed dogs included: Boxers (OR: 12.02, 95% CI: 7.13 to 20.24), border terriers (OR: 5.05, 95% CI: 2.32 to 11.43) and Staffordshire Bull terriers (OR: 2.42, 95% CI: 1.33 to 4.41). CLINICAL SIGNIFICANCE: Knowledge of clinicopathological features and at-risk breeds for peripheral odontogenic fibroma development can assist clinicians with making a diagnosis. The identification of risk factors provides targets for future research investigating peripheral odontogenic fibroma pathogenesis.

Nitric oxide, a biological double-faced janus--is this good or bad?

Nitric oxide (NO) is a biological messenger molecule produced by one of the essential amino acids L-arginine by the catalytic action of the enzyme NO synthase (NOS). The dual role of NO as a protective or toxic molecule is due to several factors, such as; the isoform of NOS involved, concentration of NO and the type of cells in which it is synthesised, the availability of the substrate L-arginine, generation of guanosine 3,5'-cyclic monophosphate (cGMP) from soluble guanylate cyclase and the overall extra and intracellular environment in which NO is produced. NOS activation as a result of trauma (calcium influx) or infection leads to NO production, which activates its downstream receptor sGC to synthesise cGMP and/or leads to protein nitrosylation. This may lead to one or more systemic effects including altered neurotransmission which can be protective or toxic, vaso/bronchodilatation in the cardiovascular and respiratory systems and enhanced immune activity against invading pathogens. In addition to these major functions, NO plays important role in thermoregulation, renal function, gastrointestinal motility, endocrine function, and various functions of the urogenital system ranging from renin secretion to micturation; spermatogenesis to penile erection; and ovulation to implantation and parturition. A schematic summary of the functions of NO and the various isoforms of NOS expressed in body systems is shown in figure 1. In this review, the historical background, biochemistry and biosynthesis of NO and its enzymes together with the mechanism of NO actions in physiology and pathophysiology are discussed.

Neuronal nitric oxide synthase and nerve growth factor expression in the enteric nervous system.

The role of nitric oxide (NO) in various systems of the body has gained prominence since the last decade. The dual role of NO either as a toxic or protective molecule depends on the concentrations of NO being produced, the isoform of NO synthase involved and the type of cell in which NO produced. The protective roles of NO appear to be mediated via cross talk between neurotrophic pathways. In view of this, in this paper, the role of NO in the enteric system is discussed with respect to neuronal nitric oxide synthase expression in neurons associated with the gut and the nerve growth factor and its receptor, tyrosine kinase A expression in the lamina epithelialis.

First demonstration of protective immunity against foetopathy in cattle with latent Neospora caninum infection.

The parasite Neospora caninum is an important cause of abortion in cattle world-wide. Chronically infected dams transmit the parasite transplacentally and infected foetuses may be aborted or born chronically infected but clinically normal. Chronically infected cows repeatedly transmit the parasite to foetuses in several pregnancies and some may abort more than once suggesting that the immune response in these cattle is compromised during pregnancy. To investigate the nature of the immune response in chronically infected cattle, five naturally, chronically infected cows were challenged with N. caninum tachyzoites at 10 weeks of gestation. No foetopathy occurred and all five delivered live calves at full-term. In four naive pregnant cows challenged at the same time, all four foetuses died within 3-5 weeks of challenge. Of the five live calves born to the chronically infected challenged cows, three were transplacentally infected with N. caninum. The kinetics of the maternal anti-N. caninum antibody responses during gestation suggested that these transplacental infections were not the result of the superimposed challenge, but the result of the recrudescence of the maternal chronic infection-which occurred concurrently in non-challenged, chronically infected pregnant controls. These data provide the first experimental evidence that protective immunity occurs in neosporosis. They also suggest that whilst immunity to a pre-existing infection will protect against an exogenous challenge, this protective immunity will not prevent transplacental infection. This implies that a subtle form of concomitant immunity exists in chronically infected cattle and has important implications for vaccine development.

Postanaesthetic cerebral necrosis in five horses.

After being anaesthetised for between one hour 40 minutes and seven hours, five adult horses developed acute neurological signs and extensive cerebrocortical necrosis. Four of them had had abdominal surgery for colic and one had had repeated orthopaedic interventions. Between five hours and seven days after the surgery, all five horses suddenly developed severe signs of a predominantly prosencephalic disturbance: bilateral blindness with normal pupillary light responses, abnormal behaviour varying from propulsive pacing to head pressing profound lethargy and generalised seizures. They were euthanased between 24 hours and three weeks after the onset of these signs. In three of the cases a gross examination of the brain revealed patchy malacia of the cerebral grey matter and some discolouration of the adjacent white matter. Microscopical examination revealed lesions that varied from laminar neuronal necrosis in the grey matter of the cerebral cortex to more diffuse necrosis of the cortex and underlying white matter. Four of the five cases had had a period of hypercapnea while anaesthetised, and two of them (and possibly a third) had also had hypoxaemia.

Bax and caspases are inhibited by endogenous nitric oxide in dorsal root ganglion neurons in vitro.

Axotomised dorsal root ganglia (DRG) neurons show an increased expression of neuronal nitric oxide synthase (nNOS) compared with neurons from the intact ganglia. Increased nNOS expression resulted in synthesis of nitric oxide (NO) and the subsequent activation of cGMP in satellite glia cells surrounding the DRG neuron soma. In dissociated DRG we have demonstrated that the increase in nNOS expression is regulated by nerve growth factor and that the subsequent inhibition of NO production or cGMP synthesis precipitates apoptosis of neurons expressing nNOS and some non-nNOS neurons. Hence, NO or the NO-cGMP cascade appears to have a neuroprotective action in trophic factor-deprived DRG neurons. In the present study, using immunocytochemistry, we have investigated some of the factors associated with apoptosis that are activated when nNOS activity is blocked with NOS inhibitor in DRG neurons in vitro. Marked elevation of bax was observed within a few hours of NOS inhibition in nNOS containing neurons, whereas pretreatment of cultures with l-arginine completely abolished this effect in almost all nNOS neurons and 8-bromo-cGMP in some neurons. The apoptosis precipitated by NOS inhibition was also partially prevented by a number of caspase inhibitors; of those a caspase-9 blocker was the most effective. These observations further support the neuroprotective role of NO/NO-cGMP in stressed DRG neurons in an autocrine fashion that involves the suppression of bax, caspase-3 and -9 activation.

Establishment and maintenance of a longitudinal study of bovine spongiform encephalopathy (the ULiSES scheme).

This paper addresses the issues of tracing and compliance encountered in setting up and maintaining a UK-wide 5-year observational study of beef cattle. The 5-year prospective study was initiated in 1997 to investigate the occurrence of bovine spongiform encephalopathy (BSE) in a single herd of pedigree Aberdeen Angus cattle, in which BSE had been detected at low prevalence. The study was given the acronym ULiSES (University of Liverpool Spongiform Encephalopathy Scheme). All cattle present on the farm at the start of the scheme were registered as members of the study population (n=320), as were all calves subsequently born on the farm (n=350). Animals that were sold (n=291) were traced and monitored at destination farms. Farmers were requested to give advance notification of slaughter of any ULiSES animal and an attempt was made to collect post-mortem samples of nervous tissue, peripheral lymphoid tissue and striated muscle from all animals in the scheme at the time of slaughter, death or euthanasia. Sections of medulla were examined (by standard histopathological techniques) for the presence of spongiform change. Remaining samples were stored at -70 degrees C for future investigation by alternative tests. At the halfway point of the scheme in October 1999, 75.2% (506/673) of the study population was still alive; 42% (284) of the population was still alive on the study farm and 33% (222) was distributed on other farms throughout the UK. Complete sets of specimens had been recovered from 77% (129/167) of dead animals. All brainstem sections were negative by histopathological examination. No suspect cases of BSE were reported in ULiSES animals. Failure to recover specimens occurred principally in animals which had left the study farm. The main cause of specimen loss was a failure of compliance in a small number of individuals who had purchased large numbers of ULiSES animals, and subsequently slaughtered them without contacting the University. Despite this, farmer compliance was generally high. The ULiSES scheme shows the feasibility of a country-wide longitudinal observational study spanning a period of several years and indicates the large impact of small numbers of non-compliant individuals.

Cutaneous alternariosis in a cat.

A 10-year-old male domestic shorthaired cat had a chronic, slowly enlarging subcutaneous mass on the right side of its nose. At the time of presentation, the nasal airflow was severely impeded on the affected side. The cat had been treated medically with various drugs. Oral itraconazole had been the most effective in reducing the size of the mass, but had caused hepatotoxicity and had to be withdrawn. The mass was finally removed surgically, and a diagnosis of granulomatous cellulitis caused by Alternaria alternata (phaeohyphomycosis) was established, based on histopathology and fungal isolation. There has been no recurrence of the lesion after 21 months and the cat remains clinically well at the time of writing. Subcutaneous phaeohyphomycosis caused by A alternata has not, to the authors' knowledge, been previously described in small domestic animals in the UK.

Histological characterization of an ependymoma in the fourth ventricle of a cat.

A tumour occupying the fourth ventricle in a 3-year-old cat was removed surgically and characterized as a tanycytic ependymoma on the basis of histological features of low cellularity, inconspicuous perivascular pseudorosettes and fascicular architecture. Immunohistochemical analysis of sections revealed that the neoplastic cells were immunoreactive for glial fibrillary acidic protein (GFAP), vimentin and S-100. The histological and immunohistochemical findings were similar to those of human tanycytic ependymoma, a subclassification of ependymoma not previously described in domestic species.

Trapidil-mediated inhibition of CNS remyelination results from reduced numbers and impaired differentiation of oligodendrocytes.

In a previous study, we described the inhibitory effects of the growth factor-antagonist, trapidil, on spontaneously occurring oligodendrocyte remyelination in the rat spinal cord following lysolecithin-induced demyelination [30]. The objective of the present study was to further investigate the mechanisms of trapidil-mediated impairment of remyelination and thus obtain greater insight into the steps at which growth factors may be involved in remyelination. To this end, an ultrastructural analysis of the cellular composition of lesions from control and trapidil-treated animals was undertaken. Demyelination was created in the dorsal funiculus of 6-week-old female rats by the injection of 1.0 microliter of 1% lysolecithin. The animals received daily intraperitoneal injections of trapidil (80 mg/kg) or saline for 21 days, beginning on the day of lesion induction. Quantitative electron microscopic examination of lesions from both groups of animals showed that trapidil-treated lesions had reduced numbers of oligodendrocytes (P = 0.02) with a higher relative proportion of immature phenotypes, but increased numbers of microglia (P = 0.0009) and dystrophic axons (P0.02). In addition, the numbers of myelin lamellae around remyelinated axons were fewer in trapidil-treated animals. These results suggest that trapidil-mediated impairment of CNS remyelination is due to a blockage of growth factor-mediated proliferation and/or recruitment of remyelinating cells. Furthermore, the presence of oligodendrocytes with a more immature phenotype and the decreased thickness of the myelin sheaths of remyelination in the trapidil-treated animals indicate an impairment of growth factor-mediated differentiation.

The effects of the growth factor-antagonist, trapidil, on remyelination in the CNS.

In this study we describe the effects of trapidil, a putative platelet-derived growth factor-antagonist, on spontaneously occurring remyelination in rat spinal cord. Demyelination was created in the dorsal funiculus of 6- and 11-week-old female rats by the direct injection of 1.0 microliter of 1% lysolecithin. The animals received daily intra-peritoneal injections of either trapidil or saline for 21 days, commencing on the day of lesion induction. The 11-week-old rats receiving trapidil (60 mg/kg) showed a significant decrease in the extent of oligodendrocyte remyelination. Moreover, those axons that were remyelinated by oligodendrocytes tended to have thinner myelin sheaths than axons remyelinated by oligodendrocytes in the control group. In the 6-week-old group, the dose of trapidil which inhibited oligodendrocyte remyelination in the 11-week-old animals had a minimal effect on the extent of oligodendrocyte remyelination and no effect on the quality of myelin sheath formation. A higher dose of trapidil (80 mg/kg) was required before significant impairment of oligodendrocyte remyelination was achieved in the younger age group, implying an age-dependent effect of growth factor-inhibition of CNS remyelination. These results indicate an important role for growth factors, and in particular PDGF, in the orchestration of oligodendrocyte remyelination in the rodent CNS.

Contrasting effects of mitogenic growth factors on oligodendrocyte precursor cell migration.

We have examined the effects of the mitogenic growth factors platelet derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and glial growth factor-2 (GGF-2) on oligodendrocyte precursor migration. In an agarose drop migration assay PDGF and bFGF stimulated migration while GGF-2 had no effect. The migration-enhancing effect of bFGF cannot be blocked by neutralising antibodies against PDGF, confirming that this effect is direct and not mediated via upregulation of PDGF receptors. Based on our results, we propose a model in which the differing effects of PDGF and GGF-2 ensure appropriate numbers of oligodendrocyte precursor cells in the vicinity of axons to be myelinated during development.

Malignant histiocytosis in three Bernese mountain dogs.

Malignant histiocytosis is a rare disease which is characterised by the neoplastic proliferation of tissue macrophages (histiocytes) leading to excessive phagocytosis of erythrocytes. The clinical signs and pathological findings in three Bernese mountain dogs are described. Two of the dogs had the same sire. The disease has been established as a familial problem in Bernese mountain dogs in other countries, although it has not been previously recorded in the United Kingdom.

Herpes simplex oesophagitis.

A patient is described with oesophageal ulceration due to herpes simplex virus type I. The endoscopic, light, electron microscopic, and immunohistochemical appearances are described and the literature of this under-diagnosed entity is reviewed.

Ranitidine and duodenal ulceration: a short-term and maintenance study.

Forty-eight patients successfully completed a six-week, double blind, placebo controlled trial of ranitidine hydrochloride 200mg twice daily for active duodenal ulceration. Following endoscopy 68% of the patients taking ranitidine had healed, compared to 35% of those who were taking placebo. Nineteen of the patients who had not healed then took a further six weeks of open active treatment; of these, 14 were successfully treated. Thirty-one of the patients who had healed duodenal ulcers then took ranitidine hydrochloride 100mg at night as a maintenance treatment for one year: 71% remained endoscopically and symptomatically in remission. No serious side effects were encountered.

Studies of the antisecretory activity of morphine in rabbit ileum in vitro.

We studied the influence of morphine on intestinal secretion induced by three different secretogogues in an attempt to elucidate the mechanism for its antisecretory activity. In rabbit ileal mucosa in vitro morphine (10(-4) M) did not influence the electrical response to the subsequent administration of prostaglandin E2 or of acetylcholine but did inhibit the net secretion of chloride provoked by both agents and prevented the reduction of sodium adsorption induced by the prostaglandin. Morphine reduced the peak electrical response to cholera toxin and reduced toxin-induced net chloride secretion. The modes of action of morphine appeared to be by both enhancing adsorption, as it does in control, nonsecreting mucosa, and by inhibiting secretogogue activity.

Mechanisms of histamine stimulated secretion in rabbit ileal mucosa.

Histamine is present in high concentrations in the intestine and we investigated the possibility that it might have a role here in intestinal transport. When added to the basal side of rabbit ileal mucosa in vitro histamine (10(-4)M) induced a short-lived increase in electrical potential difference and short circuit current. It inhibited net chloride absorption but did not influence sodium transport. Alkali secretion, measured by a pH stat technique, was inhibited, suggesting that bicarbonate secretion was reduced. Both the electrical and ion flux responses to histamine were blocked by the H1 receptor blocker diphenhydramine, but not by the H2 receptor blocker cimetidine. The presence of specific H1 histamine receptors was further supported by shifts in the dose-response curve to histamine by four different concentrations of diphenhydramine. Calculation of a pA2 value from these "Schild' plots provided a figure of 7.85, which is similar to that for H1 receptors in other tissues. Aminoguanidine, a histaminase blocker, had no electrical effects alone but shifted the histamine dose response curve to the left. These studies indicate that histamine inhibits chloride absorption and alkali secretion, possibly by influencing a chloride/bicarbonate exchange process, through specific mucosal H1 receptors. Enhancement of histamine effects by a histaminase inhibitor suggests that histaminases are present in the intestinal mucosa and supports the possibility of a role for endogenous histamine in influencing ion transport. The observations indicate a mechanism by which absorption might be impaired in diseases in which histamine is liberated locally in the intestine.

Influence of opiates on ion transport across rabbit ileal mucosa.

Opiates are commonly used as antidiarrheal agents, and endogenous opioids have been demonstrated in the intestine. It seemed important therefore to investigate the effects of morphine on ion transport across intestinal mucosa. In rabbit ileum in vitro morphine (2 x 10(-5) M) induced a significant fall in potential difference and short circuit current but did not influence tissue resistance. Dextromoramide (10(-5) M), an active opiate, mimicked the action of morphine, whereas the inactive isomer levomoramide (10(-5) M) had no effect. Morphine caused a significant increase in chloride absorption, due predominantly to a decrease in the serosa to mucosa flux. No change in sodium transport was detected, but the residual ion flux, possibly representing bicarbonate secretion, was enhanced. Similar response were observed with a synthetic enkephalin analogue (Me-Tyr-D-Met-Gly-Phe-Pro-NH2); but this was more potent than morphine, a significant electrical response being observed at a concentration as low as 10(-8) M. These electrical and ion transport responses to morphine were blocked by naloxone, an effect shown to be competitive in nature. The results suggest that opiate receptors exist in rabbit ileal mucosa and that these influence electrical and ion transport changes across the mucosa.