Serum N-Terminal Type III Procollagen Propeptide: An Indicator of Growth Hormone Excess and Response to Treatment in Feline Hypersomatotropism.

BACKGROUND: N-terminal type III procollagen propeptide (PIIINP) is a biomarker of soft tissue proliferation. Hypersomatotropism (HS) is associated with soft tissue proliferation. HYPOTHESIS: Serum PIIINP is increased in cats with HS and decreases with effective treatment, and may be an additional tool in the diagnosis and treatment of feline HS. ANIMALS: Cats with uncomplicated diabetes mellitus (DM; n = 30) and with HS-induced DM (HSDM; n = 30). Pre- and posttreatment samples were available from 5 cats undergoing radiotherapy (RT) and 16 cats undergoing hypophysectomy (HPX). METHODS: Retrospective and prospective cross-sectional study. Analytical performance of a serum PIIINP ELISA was assessed and validated for use in cats. PIIINP and insulin-like growth factor 1 (IGF-1) radioimmunoassays (RIA) were performed pre- and post-treatment in cats with DM and HSDM. PIIINP and IGF-1 were compared between cats treated by RT and HPX. RESULTS: Serum PIIINP concentrations were significantly higher (P < .001) in HSDM cats (median, 19.6 ng/mL; range, 1.7-27.9) compared to DM cats (median, 5.0 ng/mL; range, 2.1-10.4). A cut-off of 10.5 ng/mL allowed differentiation between DM and HSDM cats with 87% sensitivity and 100% specificity (area under the curve [AUC], 0.91; 95% confidence interval [CI], 0.82-1). After RT, PIIINP increased significantly (P = .043) with no significant change in IGF-1 concentrations. After HPX, serum PIIINP (P = .034) and IGF-1 concentrations (P < .001) decreased significantly. CONCLUSION AND CLINICAL IMPORTANCE: PIIINP concentrations are increased in cats with untreated HSDM compared to those with DM, demonstrating the effect of excess GH on soft tissue. PIIINP concentrations decreased after HPX in most HSDM cats.

Risk factors for early post-operative neurological deterioration in dogs undergoing a cervical dorsal laminectomy or hemilaminectomy: 100 cases (2002-2014).

Early post-operative neurological deterioration is a well-known complication following dorsal cervical laminectomies and hemilaminectomies in dogs. This study aimed to evaluate potential risk factors for early post-operative neurological deterioration following these surgical procedures. Medical records of 100 dogs that had undergone a cervical dorsal laminectomy or hemilaminectomy between 2002 and 2014 were assessed retrospectively. Assessed variables included signalment, bodyweight, duration of clinical signs, neurological status before surgery, diagnosis, surgical site, type and extent of surgery and duration of procedure. Outcome measures were neurological status immediately following surgery and duration of hospitalisation. Univariate statistical analysis was performed to identify variables to be included in a multivariate model. Diagnoses included osseous associated cervical spondylomyelopathy (OACSM; n = 41), acute intervertebral disk extrusion (IVDE; 31), meningioma (11), spinal arachnoid diverticulum (10) and vertebral arch anomalies (7). Overall 54% (95% CI 45.25-64.75) of dogs were neurologically worse 48 h post-operatively. Multivariate statistical analysis identified four factors significantly related to early post-operative neurological outcome. Diagnoses of OACSM or meningioma were considered the strongest variables to predict early post-operative neurological deterioration, followed by higher (more severely affected) neurological grade before surgery and longer surgery time. This information can aid in the management of expectations of clinical staff and owners with dogs undergoing these surgical procedures.

Clinical reasoning in canine spinal disease: what combination of clinical information is useful?

Spinal disease in dogs is commonly encountered in veterinary practice. Numerous diseases may cause similar clinical signs and presenting histories. The study objective was to use statistical models to identify combinations of discrete parameters from the patient signalment, history and neurological examination that could suggest the most likely diagnoses with statistical significance. A retrospective study of 500 dogs referred to the Queen Mother Hospital for Animals before June 2012 for the investigation of spinal disease was performed. Details regarding signalment, history, physical and neurological examinations, neuroanatomical localisation and imaging data were obtained. Univariate analyses of variables (breed, age, weight, onset, deterioration, pain, asymmetry, neuroanatomical localisation) were performed, and variables were retained in a multivariate logistic regression model if P<0.05. Leading diagnoses were intervertebral disc extrusion (IVDE, n=149), intervertebral disc protrusion (n=149), ischaemic myelopathy (IM, n=48) and neoplasms (n=44). Multivariate logistic regression characterised IM and acute non-compressive nucleus pulposus extrusions as the only peracute onset, non-progressive, non-painful and asymmetrical T3-L3 myelopathies. IVDE was most commonly characterised as acute onset, often deteriorating, painful and largely symmetrical T3-L3 myelopathy. This study suggests that most spinal diseases cause distinctive combinations of presenting clinical parameters (signalment, onset, deterioration, pain, asymmetry, neuroanatomical localisation). Taking particular account of these parameters may aid decision making in a clinical setting.

Consultant and trainee attitudes towards supervision of operative procedures in the UK and Ireland.

The e-logbook is used to monitor progression through training and to assess training within teaching units. We document consultant and trainee opinions with regards to supervision status, and to inform guidelines for trainees and trainers using the e-logbook. A questionnaire was sent to consultants and trainees in the UK and Ireland. Eight theatre scenarios were described and respondents were asked to state what they felt was the appropriate supervision status for the trainee. Significantly more consultants in the UK use the e-logbook than those based in Ireland (58.5%:14.5%). There were differences in consensus response to the scenarios between consultants and trainees, and between Irish and UK based surgeons. We have documented the opinions of consultants and trainees from across the UK and Ireland with regards to supervision status for trainees under certain theatre situations. This information should support formal guidelines for all users of the logbook.

Biomarkers for smoking cessation.

One way to enhance therapeutic development is through the identification and development of evaluative tools such as biomarkers. This review focuses on putative diagnostic, pharmacodynamic, and predictive biomarkers for smoking cessation. These types of biomarkers may be used to more accurately diagnose a disease, personalize treatment, identify novel targets for drug discovery, and enhance the efficiency of drug development. Promising biomarkers are presented across a range of approaches including metabolism, genetics, and neuroimaging. A preclinical viewpoint is also offered, as are analytical considerations and a regulatory perspective summarizing a pathway toward biomarker qualification.

Intra-abdominal blockage of a ventriculoperitoneal shunt by a suspected mesenteric pseudocyst in a dog.

BACKGROUND: There are few reports of abdominal complications following ventriculoperitoneal (VP) shunt placement for the treatment of hydrocephalus in dogs. CASE REPORT: A 3-year-old dog underwent successful VP shunting for the treatment of hydrocephalus, but re-presented 10 months later with progressive central vestibular syndrome. Magnetic resonance imaging of the brain suggested VP catheter obstruction. The dog was euthanased and on postmortem examination the abdominal tip of the VP catheter was ensheathed and blocked by fibrous mesentery, possibly a pseudocyst. CONCLUSIONS: Abdominal complications are common in humans, with pseudocysts reported in up to 4.5% of cases. This diagnosis should be considered for dogs re-presenting following VP shunt surgery.

Cervical vertebral stenosis associated with a vertebral arch anomaly in the Basset Hound.

OBJECTIVES: To report the clinical presentation, imaging characteristics, treatment results, and histopathological findings of a previously undescribed vertebral malformation in the Basset Hound. ANIMALS AND METHODS: Retrospective case series study. Eighteen Basset Hounds presented for evaluation of a suspected cervical spinal cord problem. All dogs underwent computed tomography myelography or magnetic resonance imaging of the cervical region. RESULTS: Thirteen male and 5 female Basset Hounds between 6 months and 10.8 years of age (median: 1.4 years) were studied. Clinical signs varied from cervical hyperesthesia to nonambulatory tetraparesis. Imaging demonstrated a well-defined and smooth hypertrophy of the dorsal lamina and spinous process of ≥ 2 adjacent vertebrae. Although this bony abnormality could decrease the ventrodorsal vertebral canal diameter, dorsal midline spinal cord compression was predominantly caused by ligamentum flavum hypertrophy. The articulation between C4 and C5 was most commonly affected. Three dogs were lost to follow-up, 10 dogs underwent dorsal laminectomy, and medical management was initiated in 5 dogs. Surgery resulted in a good outcome with short hospitalization times (median: 4.5 days) in all dogs, whereas medical management produced more variable results. Histopathology confirmed ligamentum flavum hypertrophy and demonstrated the fibrocartilaginous nature of this anomaly. CONCLUSIONS AND CLINICAL IMPORTANCE: Dorsal lamina and spinous process hypertrophy leading to ligamentum flavum hypertrophy should be included in the differential diagnosis of Basset Hounds with cervical hyperesthesia or myelopathy. Prognosis after decompressive surgery is favorable. Although a genetic component is suspected, additional studies are needed to determine the specific etiology of this disorder.

Irish National Joint Registry: a concept.

Despite the well-documented benefits, some countries have yet to agree on the establishment of a national joint register. A questionnaire study was undertaken to ascertain the opinions of the consultant orthopaedic surgeons and specialist registrars, regarding establishment of an Irish National Joint Register. The aim was to find out the possible reasons why a national joint register has not been established in Ireland. A 69% first response rate was recorded. Ninety-seven percent believe it is time to set up a registry and 81% say it should be made compulsory for unwilling surgeons and hospitals to participate. Despite the overwhelming support, privacy and liability issues were major concerns. Fifty-eight percent agree that access to registry report by general public can expose surgeons and hospitals to medico-legal implications. Legislation may be required to protect the integrity of a national joint replacement registry to ensure that the data are used as intended.

Cement-in-cement revision hip arthroplasty: an analysis of clinical and biomechanical literature.

INTRODUCTION: The number of revision hip arthroplasties is increasing but several aspects of this procedure could be improved. One method of reducing intra-operative complications is the cement-in-cement technique. This procedure entails cementing a smaller femoral prosthesis into the existing stable cement mantle. The aim of this systematic review is to provide a concise overview of the existing historical, operative, biomechanical and clinical literature on the cement-in-cement construct. RESULTS: Four biomechanical publications exist in authoritative journals and these were reviewed. Simple specimens were produced and these were tested by static means. Although these published tests support the cement-in-cement technique, they cannot be regarded as conclusive. Areas which could be subject to further research are identified. Five clinical publications on patients undergoing cement-in-cement revisions were also reviewed. Patient numbers were generally low (7-53) apart from one study containing 354 patients. Long-term patient follow-up was not available except in Hubble's study (41 patients followed for 8 years). Outcomes of these patients were very satisfactory for the period of follow-up. Three expert reviews of cemented femoral revisions outline the cement in cement procedure. If other Orthopaedic Centres can emulate the results of the clinical research presented, complication rates, operative times and financial costs may be decreased. CONCLUSION: The analysis presented in this paper consolidates the latest biomechanical and clinical information on cement-in-cement revision hip arthroplasty. Although we find evidence to support the use of the method clinically, we do note that the scientific basis needs further investigation.

The dorsal raphé nucleus is a crucial structure mediating nicotine's anxiolytic effects and the development of tolerance and withdrawal responses.

RATIONALE: Smokers frequently report that they obtain anxiety-reducing (anxiolytic) effects from smoking, and this may be one factor which contributes to nicotine dependence. OBJECTIVE: The aim of this study was to investigate the role of the dorsal raphé nucleus (DRN) in mediating the acute anxiolytic effect of nicotine, the development of tolerance to this effect and the anxiogenic response observed on withdrawal from chronic nicotine. METHODS: The social interaction test of anxiety was used to investigate the effects of a range of doses of (-)-nicotine (2.5-4000 ng) following DRN infusion, and whether co-administration of the specific 5-HT1A receptor antagonist WAY 100635 could antagonise the anxiolytic action of nicotine. We then examined the effects of intra-DRN nicotine (2.5-7 ng) following six daily injections of subcutaneous (s.c.) (-)-nicotine (0.1 mg/kg). Finally, we examined whether s.c. or intra-DRN (-)-nicotine could antagonise the anxiogenic response seen 72 h after the termination of 7 days of nicotine treatment. RESULTS: Acute nicotine administration into the DRN produced dose-related effects: low doses (2.5-10 ng) induced an anxiolytic effect, intermediate doses were behaviourally silent (100-1000 ng), and an anxiogenic effect was seen following administration of a high dose (4 micrograms). The anxiolytic effect of (-)-nicotine (5 ng) was reversed by co-administration of a behaviourally inactive dose of WAY 100635 (200 ng). Following 6 days of treatment with s.c. 0.1 mg/kg per day (-)-nicotine, tolerance developed to its anxiolytic action in the DRN. Rats withdrawn for 72 h following this chronic treatment showed an anxiogenic response which was reversed by (-)-nicotine injected s.c. (0.1 mg/kg) or into the DRN (5 ng). CONCLUSIONS: The present findings therefore suggest that the DRN plays an important role in mediating the acute effects of nicotine on anxiety, as measured in the social interaction test, and that the anxiolytic effect is mediated by activation of somatodendritic 5-HT1A autoreceptors. The DRN is also concerned with mediating the development of tolerance to nicotine's anxiolytic effects and because there is an anxiogenic response 72 h after withdrawal from chronic nicotine, this suggests that an oppositional, compensatory mechanism is mediating the tolerance.

Nicotine regulates 5-HT(1A) receptor gene expression in the cerebral cortex and dorsal hippocampus.

The 5-HT(1A) receptor has previously been shown to be important in mediating the behavioural effects of nicotine. It is possible that nicotine administration might regulate the levels of 5-HT receptors in limbic and cortical regions, and such regulations may underlie adaptive responses to nicotine in the central nervous system. The effects of acute and chronic systemic (--)-nicotine administration on 5-HT(1A) receptor gene expression were measured by in situ hybridization, in the rat cerebral cortex, dorsal hippocampus and lateral septum. In the cortex, acute nicotine (0.5 mg/kg i.p.) significantly increased the expression of 5-HT(1A) receptor mRNA 2 h and 24 h after injection. Similarly, acute nicotine significantly increased 5-HT(1A) receptor mRNA in the dentate gyrus (DG), CA3 and CA1 regions of the dorsal hippocampus 2 h and 24 h after injection. Acute nicotine was without effect in the lateral septum. Chronic nicotine (0.5 mg/kg i.p; twice daily for 7 days) significantly decreased 5-HT(1A) receptor mRNA in the cortex 2 h after the final injection, but was without effect at 24 h or 72 h. Chronic nicotine caused no changes in 5-HT(1A) mRNA in the lateral septum or dorsal hippocampus. These data demonstrate that nicotine regulates 5-HT(1A) receptor gene expression in the cortex and hippocampus. The rapid regulation of expression of 5-HT(1A) receptor mRNA leads to the hypothesis that nicotine-induced 5-HT release may alter the postsynaptic sensitivity to 5-HT.

Neurobiology of the nicotine withdrawal syndrome.

The aversive aspects of withdrawal from chronic nicotine exposure are thought to be an important motivational factor contributing to the maintenance of the tobacco habit in human smokers. Much emphasis has been placed on delineating the underlying neurobiological mechanisms mediating different components of the nicotine withdrawal syndrome. Recent studies have shown that both central and peripheral populations of nicotinic acetylcholine receptors (nAChRs) are involved in mediating somatic signs of nicotine withdrawal as measured by the rodent nicotine abstinence scale. However, only central populations of nAChRs are involved in mediating affective aspects of nicotine withdrawal, as measured by elevations in brain-stimulation reward thresholds and conditioned place aversion. Nicotine interacts with several neurotransmitter systems, including acetylcholine, dopamine, opioid peptides, serotonin, and glutamate systems. Evidence so far suggests that these neurotransmitters play a role in nicotine dependence and withdrawal processes. The available evidence also suggests that different underlying neurochemical deficits mediate somatic and affective components of nicotine withdrawal. The aim of the present review is to discuss preclinical findings concerning the neuroanatomical and neurochemical substrates involved in these different aspects of nicotine withdrawal.

Hippocampal and septal injections of nicotine and 8-OH-DPAT distinguish among different animal tests of anxiety.

1. Different animal tests model different anxiety disorders. Thus, the social interaction test is a model of generalised anxiety disorder, plus-maze Trial 1 models elements of panic disorder and Trial 2 in the elevated plus-maze is a model of specific phobia. 2. Studies of the neuroanatomical and neurochemical pathways controlling behaviour in these different tests provides information on the neurobiological mechanisms modulating anxiety disorders. 3. In the social interaction test, nicotine and 8-OH-DPAT had anxiogenic effects when injected into the dorsal hippocampus or the lateral septum. 4. These ligands were without effect on Trial 1 in the plus-maze when injected into the dorsal hippocampus, but had anxiogenic effects when injected into the lateral septum. 5. On Trial 2 in the elevated plus-maze, nicotine had an anxiolytic effect, but 8-OH-DPAT had an anixiogenic effect when injected into the dorsal hippocampus.

Evidence for a complex influence of nicotinic acetylcholine receptors on hippocampal serotonin release.

The effects of nicotine on 5-hydroxytryptamine (5-HT) release from serotonergic nerve endings in rat dorsal hippocampal slices were studied. Nicotine (50-500 microM:) caused a concentration-dependent increase in 5-HT release. This effect was antagonised by mecamylamine (0.5 microM:), indicating an action at nicotinic receptors. Nicotine-evoked 5-HT release was not affected by tetrodotoxin (3 microM:), cadmium chloride (0.1 mM:), or the absence of Ca(2+) or Na(+) in the superfusion medium. Unexpectedly, higher concentrations of mecamylamine alone (1-50 microM:) increased 5-HT release. This suggested the presence of inhibitory input to 5-HT neurones and that these inhibitory neurones possess tonically active nicotinic receptors. The effect of mecamylamine (50 microM:) on 5-HT release was reduced by the muscarinic M(1) receptor agonist, McN-A-343 (100 microM:), but pirenzepine (0.005-1 microM:), which blocks M(1) receptors, alone increased 5-HT release. Hippocampal serotonergic neurones are known to possess both excitatory nicotinic receptors and inhibitory M(1) receptors. Although there may be several explanations for our results, one possible explanation is that nicotine stimulates 5-HT release by activating nicotinic heteroreceptors on 5-HT terminals. Mecamylamine (0.5 microM:) antagonises this effect, but higher concentrations increase 5-HT release indirectly by blocking the action of endogenous acetylcholine on nicotinic receptors situated on cholinergic neurones that provide muscarinic inhibitory input to 5-HT neurones.

The role of 5-HT1A receptors in mediating the anxiogenic effects of nicotine following lateral septal administration.

The purpose of the present study was to determine the role of the 5-HT1A receptors in the lateral septum in the mediation of the anxiogenic effects of nicotine in the social interaction and elevated plus maze tests of anxiety in the rat. Bilateral infusion of (-)-nicotine (4 and 8 microg) and of the 5-HT1A receptor agonist 8-OH-DPAT (200 and 500 ng) into the lateral septum decreased the time spent in social interaction, indicating anxiogenic effects. The anxiogenic effect of 8-OH-DPAT (500 ng) was completely reversed by coadministration of a behaviourally inactive dose of the 5-HT1A receptor antagonist, WAY 100635 (200 ng). The anxiogenic effect of the lower dose of (-)-nicotine (4 microg) was completely reversed by WAY 100635 (200 ng), but the reversal was only partial following administration of 8 microg nicotine. In a second test of anxiety, the elevated plus maze, lateral septal administration of 8-OH-DPAT (500 ng) and nicotine (4 microg) induced anxiogenic effects. In this test, the anxiogenic effect of nicotine (4 microg) was completely reversed by coadministration of WAY 100635 (200 ng). The effects of 8-OH-DPAT demonstrate that stimulation of 5-HT1A receptors in the lateral septum has anxiogenic effects in two animal tests and that the anxiogenic effects of nicotine are mediated at least in part by these 5-HT1A receptors.

Neurobiological mechanisms by which nicotine mediates different types of anxiety.

The effects of nicotine administration into the dorsal hippocampus and lateral septum provide further evidence that different neurochemical and neuroanatomical substrates control behaviour in different animal tests. Thus, in the social interaction test (a model of generalised anxiety disorder), bilateral administration of nicotine (1-4 microg) into both regions has anxiogenic effects in test conditions that generate moderate anxiety. The anxiogenic effects are mediated by a nicotine-evoked increase in 5-hydroxytryptamine (5-HT) release and are reversed by co-administration of the 5-HT(1A) receptor antagonist, N-(2-(6-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)-cyclohex -ane carboxamide trichloride (WAY 100,635). On trial 1 in the elevated plus-maze (which models the escape components of panic disorder), nicotine is without effect when administered to the dorsal hippocampus, but has anxiogenic effects after lateral septal administration. On trial 2 in the elevated plus-maze (a model of specific phobia), nicotine (1 microg) has anxiolytic effects when administered to the dorsal hippocampus, but is ineffective (4 and 8 microg) in the lateral septum.