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Background: Registry data for total hip arthroplasty (THA) has allowed optimal fixation methods, bearing surfaces and many other factors to be assessed. We describe 10-year THA outcomes from an Irish perspective using regional THA registry data for the first time., Aims: We assess the main predictors of revision in primary total hip arthroplasty (THA) using regional registry data., Methods: This was a prospective study of registry data from a National Orthopaedic Hospital for all THAs with 10-year follow-up data. All metal-on-metal THAs and resurfacings were excluded from the analysis. All-cause revision was the primary outcome. Univariate and multivariate analyses controlling for confounding variables were performed to assess predictor impact on primary and secondary outcomes., Results: A total of 1697 THAs were performed in 1553 patients. The three significant predictors for all-cause revision were fixation type (p < 0.01), surface bearing type (p < 0.01) and femoral head size (p < 0.05). The lowest 10-year all-cause revision rates were seen in cemented THRs at 1.2%. Ceramic-on-poly bearings had the lowest revision rate at 0.9%. The 22.225-mm head sizes had a significantly lower revision rate than other head sizes (p < 0.05). The causes for revision in order of decreasing frequency were infection (0.7%), dislocation (0.4%), periprosthetic fracture (0.2%) and aseptic loosening (0.1%). There were two re-revisions at 10 years in total., Conclusions: Based on this registry and other emerging registry data, the shift towards uncemented THAs may not be fully supported. We also acknowledge that ceramic-on-polyethylene bearings afford the lowest revision rates in this registry.

Addictive behaviors, including relapse, are thought to depend in part on long-lasting drug-induced adaptations in dendritic spine signaling and morphology in the nucleus accumbens (NAc). While the influence of activity-dependent actin remodeling in these phenomena has been studied extensively, the role of microtubules and associated proteins remains poorly understood. We report that pharmacological inhibition of microtubule polymerization in the NAc inhibited locomotor sensitization to cocaine and contextual reward learning. We then investigated the roles of microtubule end-binding protein 3 (EB3) and SRC kinase in the neuronal and behavioral responses to volitionally administered cocaine. In synaptoneurosomal fractions from the NAc of self-administering male rats, the phosphorylation of SRC at an activating site was induced after 1 d of withdrawal, while EB3 levels were increased only after 30 d of withdrawal. Blocking SRC phosphorylation during early withdrawal by virally overexpressing SRCIN1, a negative regulator of SRC activity known to interact with EB3, abolished the incubation of cocaine craving in both male and female rats. Conversely, mimicking the EB3 increase observed after prolonged withdrawal increased the motivation to consume cocaine in male rats. In mice, the overexpression of either EB3 or SRCIN1 increased dendritic spine density and altered the spine morphology of NAc medium spiny neurons. Finally, a cocaine challenge after prolonged withdrawal recapitulated most of the synaptic protein expression profiles observed at early withdrawal. These findings suggest that microtubule-associated signaling proteins such as EB3 cooperate with actin remodeling pathways, notably SRC kinase activity, to establish and maintain long-lasting cellular and behavioral alterations following cocaine self-administration. SIGNIFICANCE STATEMENT Drug-induced morphological restructuring of dendritic spines of nucleus accumbens neurons is thought to be one of the cellular substrates of long-lasting drug-associated memories. The molecular basis of these persistent changes has remained incompletely understood. Here we implicate for the first time microtubule function in this process, together with key players such as microtubule-bound protein EB3 and synaptic SRC phosphorylation. We propose that microtubule and actin remodeling cooperate during withdrawal to maintain the plastic structural changes initially established by cocaine self-administration. This work opens new translational avenues for further characterization of microtubule-associated regulatory molecules as putative drug targets to tackle relapse to drug taking., (Copyright © 2019 the authors.)

Background and Aims: Current best practice states that hip fracture patients should undergo surgery within 48 hours to minimise perioperative complications. There are 10 emergency departments (EDs) in Ireland that receive hip fracture patients without a trauma and orthopaedic surgery unit on site. Idle periods and duplicated preoperative investigations can lead to a prolonged time to surgery. The aim of this study was to identify the effect of admission route on the time to surgery, length of stay and pressure ulcer development in patients who sustain a hip fracture in Ireland., Methods: A retrospective cohort study was performed, using 2013 and 2014 data from the Irish Hip Fracture Database. Age, gender and ASA grade were identified as confounders and adjusted for accordingly., Results: Of the 3893 hip fractures identified, indirect admissions via hospital transfer occurred in 8.6% of cases. Surgery was performed within 48 h in 72.0% of indirect admission and 73.7% of direct admission cases (p = 0.502). The length of stay was significantly prolonged for patients admitted via hospital transfer (25.6 compared to 19.6 days, p < 0.001)., Conclusion: Delayed discharges post hip fracture have been shown to expose patients to increased perioperative morbidity and mortality rates, as well as reduced rehabilitation potential and less chance of returning home on discharge. This has significant cost implications for the health service and justifies the introduction of hospital bypass protocols for patients with hip fractures.

Objectives: The aim of this study was to describe the anaesthetic management and perianaesthetic complications encountered during hypophysectomy surgery in acromegalic cats. We explored relationships between animal demographic data, the anaesthetic protocol used and presence of perioperative complications., Methods: Cats having undergone hypophysectomy surgery for the treatment of feline acromegaly at a single veterinary referral hospital were identified from hospital records. The anaesthesia records and clinical notes of these animals were retrospectively reviewed. Descriptive statistics were produced and binary logistic regression run to assess for any relationship between patient factors, anaesthetic management and complications during the perioperative period., Results: Perianaesthetic complications identified included hypothermia, hypotension, bradycardia and airway obstruction. Mortality at 24 h post-anaesthesia was 8%. The use of alpha (α) 2 agonists was associated with a lower incidence of hypotension. Fentanyl infusion was associated with a higher incidence of airway obstruction compared with remifentanil. Subjectively assessed anaesthetic recovery quality had an association with the number of days spent in the intensive care ward postoperatively., Conclusions and Relevance: The anaesthetic management described seems effective for hypophysectomy surgery in cats. Intraoperative complications were common and, while not apparently associated with 24 h patient outcome, drugs and equipment to manage these complications should be available.

This article was originally published under standard licence, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the paper have been modified accordingly.

Can food be addictive? What does it mean to be a food addict? Do common underlying neurobiological mechanisms contribute to drug and food addiction? These vexing questions have been the subject of considerable interest and debate in recent years, driven in large part by the major health concerns associated with dramatically increasing body weights and rates of obesity in the United States, Europe, and other regions with developed economies. No clear consensus has yet emerged on the validity of the concept of food addiction and whether some individuals who struggle to control their food intake can be considered food addicts. Some, including Fletcher, have argued that the concept of food addiction is unsupported, as many of the defining features of drug addiction are not seen in the context of feeding behaviors. Others, Kenny included, have argued that food and drug addiction share similar features that may reflect common underlying neural mechanisms. Here, Fletcher and Kenny argue the merits of these opposing positions on the concept of food addiction.

New gene editing technologies are enabling exploration of previously intractable features of genetic risk for drug addiction. A recent study using this technology reveals new insights into how a mutation linked to tobacco dependence influences the addictive properties of nicotine., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The prevalence of GH-secreting pituitary tumors in domestic cats ( Felis catus ) is 10-fold greater than in humans. The predominant inhibitory receptors of GH-secreting pituitary tumors are somatostatin receptors (SSTRs) and D 2 dopamine receptor (DRD2). The expression of these receptors is associated with the response to somatostatin analog and dopamine agonist treatment in human patients with acromegaly. The aim of this study was to describe pathological features of pituitaries from domestic cats with acromegaly, pituitary receptor expression, and investigate correlates with clinical data, including pituitary volume, time since diagnosis of diabetes, insulin requirement, and serum IGF1 concentration. Loss of reticulin structure was identified in 15 of 21 pituitaries, of which 10 of 15 exhibited acinar hyperplasia. SSTR1 , SSTR2 , SSTR5 , and DRD2 mRNA were identified in the feline pituitary whereas SSTR3 and SSTR4 were not. Expression of SSTR1 , SSTR2 , and SSTR5 was greater in acromegalic cats compared with controls. A negative correlation was identified between DRD2 mRNA expression and pituitary volume. The loss of DRD2 expression should be investigated as a mechanism allowing the development of larger pituitary tumors.

The dorsal hypothalamic area regulates increases in body temperature in response to stress, but precise mechanisms are unclear. A new study suggests that glutamatergic neurons in this brain area regulate this action and, surprisingly, may also be involved in blushing., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The ability to recognize and avoid noxious stimuli is essential for survival. The factors that determine whether a given stimulus is considered positive or negative are complex and not fully understood. In this issue of the JCI, Klawonn and colleagues demonstrate that melanocortin 4 receptor (MC4R) signaling is critical for proper responses to negative stimuli. Mice lacking MC4R were shown to have a surprising preference for aversive stimuli compared with WT animals. Moreover, the authors provide evidence that avoidance behaviors are mediated by hypothalamic POMC neurons signaling to striatal dopamine D1 receptor-expressing medium spiny neurons. Together, these results provide important insight into the regulation of responses to aversive stimuli.

Each of the co-authors worked with Athina Markou, at different stages of our careers and in different capacities, to develop, optimize, and use animal models of drug addiction and, more generally, mental health disorders such as anxiety, depression, and schizophrenia. Here, we briefly summarize some of our work with Athina, primarily involving the use of the intracranial self-stimulation and intravenous drug self-administration procedures. This work established that excessive consumption of addictive drugs can induce profound dysfunction in brain reward circuits. Such drug-induced reward deficits are likely to play a key role in precipitating the emergence of compulsive drug-seeking behaviors. We also summarize findings suggesting that perturbations in glutamatergic transmission contribute to brain reward deficits in drug-dependent animals and that metabotropic glutamate receptors are potential targets for the development of novel medications to facilitate long-term drug abstinence and prevention of relapse., (Copyright © 2018 Society of Biological Psychiatry. All rights reserved.)

Conserved across vertebrates, the habenular nuclei are a pair of small symmetrical structures in the epithalamus. The nuclei functionally link the forebrain and midbrain by receiving input from and projecting to several brain regions. Each habenular nucleus comprises two major asymmetrical subnuclei, the medial and lateral habenula. These subnuclei are associated with different physiological processes and disorders, such as depression, nicotine addiction, and encoding aversive stimuli or omitting expected rewarding stimuli. Elucidating the functions of the habenular nuclei at the molecular level requires knowledge of their neuropeptide complement. In this work, three mass spectrometry (MS) techniques-liquid chromatography (LC) coupled to Orbitrap tandem MS (MS/MS), LC coupled to Fourier transform (FT)-ion cyclotron resonance (ICR) MS/MS, and matrix-assisted laser desorption/ionization (MALDI) FT-ICR MS-were used to uncover the neuropeptide profiles of the rodent medial and lateral habenula. With the assistance of tissue stabilization and bioinformatics, a total of 262 and 177 neuropeptides produced from 27 and 20 prohormones were detected and identified from the medial and lateral habenula regions, respectively. Among these neuropeptides, 136 were exclusively found in the medial habenula, and 51 were exclusively expressed in the lateral habenula. Additionally, novel sites of sulfation, a rare post-translational modification, on the secretogranin I prohormone are identified. The results demonstrate that these two small brain nuclei have a rich and differentiated peptide repertoire, with this information enabling a range of follow-up studies.

Chronic use of drugs of abuse results in neurochemical, morphological and behavioral plasticity that underlies the emergence of compulsive drug seeking and vulnerability to relapse during periods of attempted abstinence. Identifying and reversing addiction-relevant plasticity is seen as a potential point of pharmacotherapeutic intervention in drug-addicted individuals. Despite considerable advances in our understanding of the actions of drugs of abuse in the brain, this information has thus far yielded few novel treatment options addicted individuals. MicroRNAs are small noncoding RNAs that can each regulate the translation of hundreds to thousands of messenger RNAs. The highly pleiotropic nature of miRNAs has focused attention on their contribution to addiction-relevant structural and functional plasticity in the brain and their potential utility as targets for medications development. In this review, we discuss the roles of miRNAs in synaptic plasticity underlying the development of addiction and then briefly discuss the possibility of using circulating miRNA as biomarkers for addiction., (© 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Cocaine-associated environmental cues can precipitate craving and relapse in addicted individuals even after years of abstinence, but the molecular mechanisms by which maladaptive drug memories are generated remain unclear. New findings suggest that histone deacetylase 5 (HDAC5) plays a key role in this process., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Repeated exposure to drugs of abuse can produce adaptive changes that lead to the establishment of dependence. It has been shown that allelic variation in the α5 nicotinic acetylcholine receptor (nAChR) gene CHRNA5 is associated with higher risk of tobacco dependence. In the brain, α5-containing nAChRs are expressed at very high levels in the interpeduncular nucleus (IPN). Here we identified two nonoverlapping α5 + cell populations (α5- Amigo1 and α5- Epyc ) in mouse IPN that respond differentially to nicotine. Chronic nicotine treatment altered the translational profile of more than 1,000 genes in α5- Amigo1 neurons, including neuronal nitric oxide synthase ( Nos1 ) and somatostatin ( Sst ). In contrast, expression of few genes was altered in the α5- Epyc population. We show that both nitric oxide and SST suppress optically evoked neurotransmitter release from the terminals of habenular (Hb) neurons in IPN. Moreover, in vivo silencing of neurotransmitter release from the α5- Amigo1 but not from the α5- Epyc population eliminates nicotine reward, measured using place preference. This loss of nicotine reward was mimicked by shRNA-mediated knockdown of Nos1 in the IPN. These findings reveal a proaddiction adaptive response to chronic nicotine in which nitric oxide and SST are released by a specific α5 + neuronal population to provide retrograde inhibition of the Hb-IPN circuit and thereby enhance the motivational properties of nicotine., Competing Interests: The authors declare no conflict of interest.

(E)-5-(Pyrimidin-5-yl)-1,2,3,4,7,8-hexahydroazocine (TC299423) is a novel agonist for nicotinic acetylcholine receptors (nAChRs). We examined its efficacy, affinity, and potency for α6β2 ∗ (α6β2-containing), α4β2 ∗ , and α3β4 ∗ nAChRs, using [ 125 I]-epibatidine binding, whole-cell patch-clamp recordings, synaptosomal 86 Rb + efflux, [ 3 H]-dopamine release, and [ 3 H]-acetylcholine release. TC299423 displayed an EC 50 of 30-60 nM for α6β2 ∗ nAChRs in patch-clamp recordings and [ 3 H]-dopamine release assays. Its potency for α6β2 ∗ in these assays was 2.5-fold greater than that for α4β2 ∗ , and much greater than that for α3β4 ∗ -mediated [ 3 H]-acetylcholine release. We observed no major off-target binding on 70 diverse molecular targets. TC299423 was bioavailable after intraperitoneal or oral administration. Locomotor assays, measured with gain-of-function, mutant α6 (α6L9'S) nAChR mice, show that TC299423 elicits α6β2 ∗ nAChR-mediated responses at low doses. Conditioned place preference assays show that low-dose TC299423 also produces significant reward in α6L9'S mice, and modest reward in WT mice, through a mechanism that probably involves α6(non-α4)β2 ∗ nAChRs. However, TC299423 did not suppress nicotine self-administration in rats, indicating that it did not block nicotine reinforcement in the dosage range that was tested. In a hot-plate test, TC299423 evoked antinociceptive responses in mice similar to those of nicotine. TC299423 and nicotine similarly inhibited mouse marble burying as a measure of anxiolytic effects. Taken together, our data suggest that TC299423 will be a useful small-molecule agonist for future in vitro and in vivo studies of nAChR function and physiology.

The lateral hypothalamus is known to drive food consumption during periods of hunger. A new study suggests that the lateral hypothalamus may also participate in the formation and storage of memories about events in the environment that predict the availability of food., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

To truly reduce the rates of chronic kidney disease, a root cause of kidney damage, obesity, must be targeted. Weight loss is often unsustainable because imbalances in satiety regulators are frequently not addressed to ensure maintenance of weight loss. In a recent study, gastric bypass surgery rebalanced satiety signals through resensitization of the gut-brain axis in obesity. This research may lead to noninvasive strategies to reduce obesity and obesity-related kidney disease., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Moloney leukemia virus 10 (Mov10) is an RNA helicase that mediates access of the RNA-induced silencing complex to messenger RNAs (mRNAs). Until now, its role as an RNA helicase and as a regulator of retrotransposons has been characterized exclusively in cell lines. We investigated the role of Mov10 in the mouse brain by examining its expression over development and attempting to create a Mov10 knockout mouse. Loss of both Mov10 copies led to early embryonic lethality., Results: Mov10 was significantly elevated in postnatal murine brain, where it bound retroelement RNAs and mRNAs. Mov10 suppressed retroelements in the nucleus by directly inhibiting complementary DNA synthesis, while cytosolic Mov10 regulated cytoskeletal mRNAs to influence neurite outgrowth. We verified this important function by observing reduced dendritic arborization in hippocampal neurons from the Mov10 heterozygote mouse and shortened neurites in the Mov10 knockout Neuro2A cells. Knockdown of Fmrp also resulted in shortened neurites. Mov10, Fmrp, and Ago2 bound a common set of mRNAs in the brain. Reduced Mov10 in murine brain resulted in anxiety and increased activity in a novel environment, supporting its important role in the development of normal brain circuitry., Conclusions: Mov10 is essential for normal neuronal development and brain function. Mov10 preferentially binds RNAs involved in actin binding, neuronal projection, and cytoskeleton. This is a completely new and critically important function for Mov10 in neuronal development and establishes a precedent for Mov10 being an important candidate in neurological disorders that have underlying cytoarchitectural causes like autism and Alzheimer's disease.

Tobacco smokers titrate their nicotine intake to avoid its noxious effects, sensitivity to which may influence vulnerability to tobacco dependence, yet mechanisms of nicotine avoidance are poorly understood. Here we show that nicotine activates glucagon-like peptide-1 (GLP-1) neurons in the nucleus tractus solitarius (NTS). The antidiabetic drugs sitagliptin and exenatide, which inhibit GLP-1 breakdown and stimulate GLP-1 receptors, respectively, decreased nicotine intake in mice. Chemogenetic activation of GLP-1 neurons in NTS similarly decreased nicotine intake. Conversely, Glp1r knockout mice consumed greater quantities of nicotine than wild-type mice. Using optogenetic stimulation, we show that GLP-1 excites medial habenular (MHb) projections to the interpeduncular nucleus (IPN). Activation of GLP-1 receptors in the MHb-IPN circuit abolished nicotine reward and decreased nicotine intake, whereas their knockdown or pharmacological blockade increased intake. GLP-1 neurons may therefore serve as 'satiety sensors' for nicotine that stimulate habenular systems to promote nicotine avoidance before its aversive effects are encountered.

Hankir and colleagues (2017) show that gastric bypass surgery in rats enhances the sensitivity of cells in the gut to dietary lipids. In turn, these cells signal to stimulate dopamine neurotransmission in the striatum to inhibit fat consumption. The findings have important implications for the development of non-invasive therapeutics for obesity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Synovial chrondomatosis is a rare disorder characterised by the development of hyaline cartilage from the synovial membrane. Large isolated lesions in the Hoffa's fat pad are an uncommon entity., Presentation of Case: A 33 year old gentleman presented complaining of progressive knee pain associated with an enlarging lesion on the anterior aspect of the right knee, with associated locking and giving way. Examination revealed a firm 4×5cm lesion adjacent to the patellar tendon. Subsequent CT and MRI demonstrated a lesion in the inferior aspect of Hoffa's fat pad, with a second lesion adjacent to the proximal tibiofibular joint, in addition to advanced degenerative changes and a meniscal tear. He proceeded to excisional biopsy. Histological analysis was consistent with a solitary synovial osteochondroma. There were no atypical features suggestive of malignancy., Discussion: Synovial chondromatosis is a rare disorder affecting the synovial joints. The underlying pathophysiology is thought to be metaplastic change of the synovium to hyaline cartilaginous tissue. Transformation to malignancy has been described but is uncommon with an estimated risk of 5%. It is 1.5-2 times as prevalent in males versus females. Symptoms which patients may complain of include pain;locking and giving way; and palpable masses. The management usually entails removal of the mass lesion with or without accompanying synovectomy. Recurrence of disease may occur in up to 15-23% of patients., Conclusion: Synovial chrondromatosis is a rare but well recognised condition. Long term follow up is advised in view of the risk of recurrence and malignant transformation., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The idea that interconnected neuronal ensembles code for specific behaviors has been around for decades; however, recent technical improvements allow studying these networks and their causal role in initiating and maintaining behavior. In particular, the role of ensembles in drug-seeking behaviors in the context of addiction is being actively investigated. Concurrent with breakthroughs in quantifying ensembles, research has identified a role for synaptic glutamate spillover during relapse. In particular, the transient relapse-associated changes in glutamatergic synapses on accumbens neurons, as well as in adjacent astroglia and extracellular matrix, are key elements of the synaptic plasticity encoded by drug use and the metaplasticity induced by drug-associated cues that precipitate drug-seeking behaviors. Here, we briefly review the recent discoveries related to ensembles in the addiction field and then endeavor to link these discoveries with drug-induced striatal plasticity and cue-induced metaplasticity toward deeper neurobiological understandings of drug seeking., (© 2017 Elsevier B.V. All rights reserved.)

Current treatment strategies for psychiatric disorders remain inadequate. Impeding development of novel therapeutics is our incomplete knowledge of the molecular pathophysiology underlying these disorders. Changes to miRNA function and expression are increasingly being associated with pathological behavioral states. Furthermore, the prospect of using of miRNA expression profiles (the miRNome) as objective psychiatric diagnosis tools is gaining traction. In this review, we focus on recent findings surrounding the link between miRNA function and psychiatric disorders, and outline some of the key challenges that will need to be overcome if the therapeutic potential of these molecular effectors is to be fully realized., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Genome-wide association studies (GWASs) have identified associations between the CHRNA5-CHRNA3-CHRNB4 gene cluster and smoking heaviness and nicotine dependence. Studies in rodents have described the anatomical localisation and function of the nicotinic acetylcholine receptors (nAChRs) formed by the subunits encoded by this gene cluster. Further investigations that complemented these studies highlighted the variability of individuals' smoking behaviours and their ability to adjust nicotine intake. GWASs of smoking-related health outcomes have also identified this signal in the CHRNA5-CHRNA3-CHRNB4 gene cluster. This insight underpins approaches to strengthen causal inference in observational data. Combining genetic and mechanistic studies of nicotine dependence and smoking heaviness may reveal novel targets for medication development. Validated targets can inform genetic therapeutic interventions for smoking cessation and tobacco-related diseases., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Four MRI variables have recently been suggested to be independently associated with a diagnosis of thoracolumbar intervertebral disk extrusion or protrusion. Midline intervertebral disk herniation, and partial intervertebral disk degeneration were associated with intervertebral disk protrusion, while presence of a single intervertebral disk herniation and disk material dispersed beyond the boundaries of the intervertebral disk space were associated with intervertebral disk extrusion. The aim of this retrospective, cross-sectional study was to determine whether using these MRI variables improves differentiation between thoracolumbar intervertebral disk extrusions and protrusions. Eighty large breed dogs with surgically confirmed thoracolumbar intervertebral disk extrusions or protrusions were included. Randomized MRI studies were presented on two occasions to six blinded observers, which were divided into three experience categories. During the first assessment, observers made a presumptive diagnosis of thoracolumbar intervertebral disk extrusion or protrusion without guidelines. During the second assessment they were asked to make a presumptive diagnosis with the aid of guidelines. Agreement was evaluated by Kappa-statistics. Diagnostic accuracy significantly improved from 70.8 to 79.6% and interobserver agreement for making a diagnosis of intervertebral disk extrusion or intervertebral disk protrusion improved from fair (κ = 0.27) to moderate (κ = 0.41) after using the proposed guidelines. Diagnostic accuracy was significantly influenced by degree of observer experience. Intraobserver agreement for the assessed variables ranged from fair to excellent and interobserver agreement ranged from fair to moderate. The results of this study suggest that the proposed imaging guidelines can aid in differentiating thoracolumbar intervertebral disk extrusions from protrusions., (© 2016 American College of Veterinary Radiology.)

Background: Cerebellar cortical degeneration (CCD) is an increasingly recognised neurodegenerative disease process affecting many dog breeds. Typical presentation consists of a progressive cerebellar ataxia, with a variable age at onset and rate of progression between different breeds. Cerebellar histopathological findings typically consist of primary Purkinje neuronal degeneration and loss, with variable secondary depletion of the granular and molecular cell layers. Causative genes have been identified associated with CCD in several breeds, allowing screening for selective breeding to reduce the prevalence of these conditions. There have been no previous reports of CCD in Hungarian Vizslas., Results: Two full-sibling Hungarian Vizsla puppies from a litter of nine presented with a history of progressive ataxia, starting around three months of age. Clinical signs included marked hypermetric and dysmetric ataxia, truncal sway, intention tremors and absent menace responses, with positional horizontal nystagmus in one dog. Routine diagnostic investigations were unremarkable, and magnetic resonance imaging performed in one dog revealed mild craniodorsal cerebellar sulci widening, supportive of cerebellar atrophy. Owners of both dogs elected for euthanasia shortly after the onset of signs. Histopathological examination revealed primary Purkinje neuron loss consistent with CCD. Whole genome sequencing was used to successfully identify a disease-associated splice donor site variant in the sorting nexin 14 gene (SNX14) as a strong causative candidate. An altered SNX14 splicing pattern for a CCD case was demonstrated by RNA analysis, and no SNX14 protein could be detected in CCD case cerebellum by western blotting. SNX14 is involved in maintaining normal neuronal excitability and synaptic transmission, and a mutation has recently been found to cause autosomal recessive cerebellar ataxia and intellectual disability syndrome in humans. Genetic screening of 133 unaffected Hungarian Vizslas revealed the presence of three heterozygotes, supporting the presence of carriers in the wider population., Conclusions: This is the first report of CCD in Hungarian Vizsla dogs and identifies a highly associated splice donor site mutation in SNX14, with an autosomal recessive mode of inheritance suspected.

Treatment recommendations differ for dogs with intervertebral disk extrusion vs. intervertebral disk protrusion. The aim of this retrospective, cross-sectional study was to determine whether clinical and magnetic resonance imaging (MRI) variables could be used to predict a diagnosis of thoracolumbar intervertebral disk extrusion or protrusion in dogs. Dogs were included if they were large breed dogs, had an MRI study of the thoracolumbar or lumbar vertebral column, had undergone spinal surgery, and had the type of intervertebral disk herniation (intervertebral disk extrusion or protrusion) clearly stated in surgical reports. A veterinary neurologist unaware of surgical findings reviewed MRI studies and recorded number, location, degree of degeneration and morphology of intervertebral disks, presence of nuclear clefts, disk space narrowing, extent, localization and lateralization of herniated disk material, degree of spinal cord compression, intraparenchymal intensity changes, spondylosis deformans, spinal cord swelling, spinal cord atrophy, vertebral endplate changes, and presence of extradural hemorrhage. Ninety-five dogs were included in the sample. Multivariable statistical models indicated that longer duration of clinical signs (P = 0.01), midline instead of lateralized disk herniation (P = 0.007), and partial instead of complete disk degeneration (P = 0.01) were associated with a diagnosis of intervertebral disk protrusion. The presence of a single intervertebral herniation (P = 0.023) and dispersed intervertebral disk material not confined to the disk space (P = 0.06) made a diagnosis of intervertebral disk extrusion more likely. Findings from this study identified one clinical and four MRI variables that could potentially facilitate differentiating intervertebral disk extrusions from protrusions in dogs., (© 2016 American College of Veterinary Radiology.)

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., (Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia., Methods: We defined schizophrenia risk loci as genomic regions reaching genome-wide significance in the latest Psychiatric Genomics Consortium schizophrenia genome-wide association study (GWAS) of 36 989 cases and 113 075 controls and loss of function variants observed only once among 5079 individuals in an exome-sequencing study of 2536 schizophrenia cases and 2543 controls (Swedish Schizophrenia Study). Using two large and orthogonally created databases, we collated drug targets into 167 gene sets targeted by pharmacologically similar drugs and examined enrichment of schizophrenia risk loci in these sets. We further linked the exome-sequenced data with a national drug registry (the Swedish Prescribed Drug Register) to assess the contribution of rare variants to treatment response, using clozapine prescription as a proxy for treatment resistance., Findings: We combined results from testing rare and common variation and, after correction for multiple testing, two gene sets were associated with schizophrenia risk: agents against amoebiasis and other protozoal diseases (106 genes, p=0·00046, pcorrected =0·024) and antipsychotics (347 genes, p=0·00078, pcorrected=0·046). Further analysis pointed to antipsychotics as having independent enrichment after removing genes that overlapped these two target sets. We noted significant enrichment both in known targets of antipsychotics (70 genes, p=0·0078) and novel predicted targets (277 genes, p=0·019). Patients with treatment-resistant schizophrenia had an excess of rare disruptive variants in gene targets of antipsychotics (347 genes, p=0·0067) and in genes with evidence for a role in antipsychotic efficacy (91 genes, p=0·0029)., Interpretation: Our results support genetic overlap between schizophrenia pathogenesis and antipsychotic mechanism of action. This finding is consistent with treatment efficacy being polygenic and suggests that single-target therapeutics might be insufficient. We provide evidence of a role for rare functional variants in antipsychotic treatment response, pointing to a subset of patients where their genetic information could inform treatment. Finally, we present a novel framework for identifying treatments from genetic data and improving our understanding of therapeutic mechanism., Funding: US National Institutes of Health., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Addiction is a chronically relapsing disorder characterized by compulsive drug use in spite of adverse consequences. Currently, there are very few effective treatments for addiction; in order to develop novel therapies, a clearer understanding of mechanisms underlying addiction is needed. Drugs of abuse induce lasting adaptations in corticostriatal and mesolimbic brain reward circuitry due to long-term alterations in gene expression. microRNAs, a class of non-coding RNAs, are powerful regulators of gene expression that bind to target mRNAs, thereby inhibiting their translation and/or causing degradation. miRNAs are increasingly implicated in gene expression changes underlying normal neuronal function as well as dysfunctions such as addiction and psychiatric disorders. This review summarizes plasticity- and drug-related miRNA expression patterns and functions in the context of corticostriatal circuitry, while proposing future directions that may reveal miRNA-mediated mechanisms regulating addiction-related behaviors in vivo., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background and Purpose: A tourniquet may potentiate rare and devastating arterial complications after total knee replacement (TKR) in patients with peripheral vascular disease (PVD). Most prior studies that evaluated peripheral arterial blood flow primarily used the ankle-brachial index (ABI)., Methods: We assessed the prevalence and risk factors for PVD in a cohort undergoing TKR. Clinical and radiological evaluations, including duplex ultrasonography, were performed one week prior to, and six weeks post-TKR performed under tourniquet control. Forty patients were analysed (20 male, 20 female; mean age 67 yrs, range: 53-80 yrs)., Main Findings: Hypertension (50%) and hypercholesterolaemia (50%) were the most common co-morbidities. Distal pulses were present in all patients preoperatively. Six patients (15%) had arterial calcification on their preoperative knee X-rays. Three patients (7.5%) had moderate PVD. There was no change in blood flow postoperatively in patients with or without PVD (p > 0.05). Vascular stenosis was less than 50% in all patients preoperatively and postoperatively. No postoperative vascular complications occurred., Conclusions: Severe PVD is not common in patients undergoing TKR. Performing total knee replacement under tourniquet control does not adversely affect the vasculature in patients with less than 50% vascular occlusion., (Copyright © 2014 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChR) are important therapeutic candidates as well as valuable research tools. We identified a novel type II PAM, (R)-7-bromo-N-(piperidin-3-yl)benzo[b]thiophene-2-carboxamide (Br-PBTC), which both increases activation and reactivates desensitized nAChRs. This compound increases acetylcholine-evoked responses of α2* and α4* nAChRs but is without effect on α3* or α6* nAChRs (* indicates the presence of other nAChR subunits). Br-BPTC acts from the C-terminal extracellular sequences of α4 subunits, which is also a PAM site for steroid hormone estrogens such as 17β-estradiol. Br-PBTC is much more potent than estrogens. Like 17β-estradiol, the non-steroid Br-PBTC only requires one α4 subunit to potentiate nAChR function, and its potentiation is stronger with more α4 subunits. This feature enables Br-BPTC to potentiate activation of (α4β2)(α6β2)β3 but not (α6β2)2β3 nAChRs. Therefore, this compound is potentially useful in vivo for determining functions of different α6* nAChR subtypes. Besides activation, Br-BPTC affects desensitization of nAChRs induced by sustained exposure to agonists. After minutes of exposure to agonists, Br-PBTC reactivated short term desensitized nAChRs that have at least two α4 subunits but not those with only one. Three α4 subunits were required for Br-BPTC to reactivate long term desensitized nAChRs. These data suggest that higher PAM occupancy promotes channel opening more efficiently and overcomes short and long term desensitization. This C-terminal extracellular domain could be a target for developing subtype or state-selective drugs for nAChRs., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Hunger increases physical activity and stamina to support food-directed foraging behaviors, but underlying mechanisms are unclear. In this issue, Fernandes et al. (2015) show that disruption of leptin-regulated STAT3 signaling in midbrain dopamine neurons increases the rewarding effects of running in mice, which could explain the "high" experienced by endurance runners., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Most patients undergoing total knee arthroplasty (TKA) in Ireland are referred to orthopaedic services by their general practitioners (GPs). We aimed to evaluate Irish GPs' expectations for their patients' perioperative experience and post-operative return to function. A questionnaire was mailed to 350 GPs in all provinces. This included questions relating to GPs' expectations for their patients and their knowledge and sources of information on TKA. 111 completed questionnaires were returned (response rate 31.7%). Overall expectations for functional and psychological outcomes were high, especially regarding pain relief (108 (97.3%)) expected relief from most or all pre-operative pain), mobility (108 (97.3%)) expected patients to walk medium or long distances) and psychological wellbeing (95 (85.5%) considered this somewhat or very important). Only 22 (20.2%) reported receiving any relevant information or training within the previous year. Overall expectations for functional outcomes were high, however greater communication between surgeons and GPs may improve GP information,

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., (British Veterinary Association.)

Neuronal nicotinic acetylcholine receptors containing α4, β2, and sometimes other subunits (α4β2* nAChRs) regulate addictive and other behavioral effects of nicotine. These nAChRs exist in several stoichiometries, typically with two high affinity acetylcholine (ACh) binding sites at the interface of α4 and β2 subunits and a fifth accessory subunit. A third low affinity ACh binding site is formed when this accessory subunit is α4 but not if it is β2. Agonists selective for the accessory ACh site, such as 3-[3-(3-pyridyl)-1,2,4-oxadiazol-5-yl]benzonitrile (NS9283), cannot alone activate a nAChR but can facilitate more efficient activation in combination with agonists at the canonical α4β2 sites. We therefore suggest categorizing agonists according to their site selectivity. NS9283 binds to the accessory ACh binding site; thus it is termed an accessory site-selective agonist. We expressed (α4β2)2 concatamers in Xenopus oocytes with free accessory subunits to obtain defined nAChR stoichiometries and α4/accessory subunit interfaces. We show that α2, α3, α4, and α6 accessory subunits can form binding sites for ACh and NS9283 at interfaces with α4 subunits, but β2 and β4 accessory subunits cannot. To permit selective blockage of the accessory site, α4 threonine 126 located on the minus side of α4 that contributes to the accessory site, but not the α4β2 sites, was mutated to cysteine. Alkylation of this cysteine with a thioreactive reagent blocked activity of ACh and NS9283 at the accessory site. Accessory agonist binding sites are promising drug targets., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)