Mechano-sensitivity of ß2-adrenoceptors enhances constitutive activation of cAMP generation that is inhibited by inverse agonists.

The concept of agonist-independent signalling that can be attenuated by inverse agonists is a fundamental element of the cubic ternary complex model of G protein-coupled receptor (GPCR) activation. This model shows how a GPCR can exist in two conformational states in the absence of ligands; an inactive R state and an active R* state that differ in their affinities for agonists, inverse agonists, and G-protein alpha subunits. The proportion of R* receptors that exist in the absence of agonists determines the level of constitutive receptor activity. In this study we demonstrate that mechanical stimulation can induce ß2-adrenoceptor agonist-independent Gs-mediated cAMP signalling that is sensitive to inhibition by inverse agonists such as ICI-118551 and propranolol. The size of the mechano-sensitive response is dependent on the cell surface receptor expression level in HEK293G cells, is still observed in a ligand-binding deficient D113A mutant ß2-adrenoceptor and can be attenuated by site-directed mutagenesis of the extracellular N-glycosylation sites on the N-terminus and second extracellular loop of the ß2-adrenoceptor. Similar mechano-sensitive agonist-independent responses are observed in HEK293G cells overexpressing the A2A-adenosine receptor. These data provide new insights into how agonist-independent constitutive receptor activity can be enhanced by mechanical stimulation and regulated by inverse agonists.

The Epidemiology of Skateboarding Injuries: A 10-Year Review at a Major Australian Centre.

Aims The purpose of this study was to attempt to quantify the impact of skateboarding-related injuries on our local orthopaedic service. Method Every presentation to the emergency departments of Gold Coast health public hospitals was retrospectively reviewed to determine whether these were skateboarding-related injuries. Between 2008 and 2018, 5,026 injuries were identified. Patient demographics, mechanism of injury, anatomic location of the injury, treatment, and medical specialty providing treatment were collected and analysed. Results Our investigation demonstrated that skateboarding injuries are common and cause significant trauma in a large percentage of cases. These injuries place a high demand on orthopaedic and emergency departments. This cohort demonstrated a male-to-female ratio of over 4:1. The most common injury type was fracture (44%), of which the upper limb (56%) was the most commonly affected anatomical region. Injuries to the wrist and hand account for 57% of all upper limb injuries, and ankle injuries account for 45% of lower limb injuries. Traumatic brain injuries and concussions account for 62% of all head injuries in this cohort. The mean age was 19 years, with a predominance of 18-25 years old. Only 14% of injuries occurred in those 30 and older. Definitive orthopaedic care, involving inpatient admissions and/or outpatient clinic follow-up, was required in at least 48% of cases, whilst 50% were able to be treated in the emergency department. Additionally, 86% of head injuries were able to be managed in the emergency department, and 11% required specialist neurosurgical management. Conclusion Skateboard-related injuries represent a significant burden of trauma to the local community, predominantly musculoskeletal injuries within the adolescent and young male adult population. This research may direct future strategies for harm minimization, specifically targeted at this demographic of patients.

CXCL17 is an allosteric inhibitor of CXCR4 through a mechanism of action involving glycosaminoglycans.

CXCL17 is a chemokine principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages and has antimicrobial properties. CXCL17 is also implicated in the pathology of inflammatory disorders and progression of several cancers, and its expression is increased during viral infections of the lung. However, the exact role of CXCL17 in health and disease requires further investigation, and there is a need for confirmed molecular targets mediating CXCL17 functional responses. Using a range of bioluminescence resonance energy transfer (BRET)-based assays, here we demonstrated that CXCL17 inhibited CXCR4-mediated signaling and ligand binding. Moreover, CXCL17 interacted with neuropillin-1, a VEGFR2 coreceptor. In addition, we found that CXCL17 only inhibited CXCR4 ligand binding in intact cells and demonstrated that this effect was mimicked by known glycosaminoglycan binders, surfen and protamine sulfate. Disruption of putative GAG binding domains in CXCL17 prevented CXCR4 binding. This indicated that CXCL17 inhibited CXCR4 by a mechanism of action that potentially required the presence of a glycosaminoglycan-containing accessory protein. Together, our results revealed that CXCL17 is an endogenous inhibitor of CXCR4 and represents the next step in our understanding of the function of CXCL17 and regulation of CXCR4 signaling.

Association of the FGF4L2 retrogene with fibrocartilaginous embolic myelopathy in dogs.

BACKGROUND: Fibrocartilaginous embolic myelopathy (FCE) is a well-documented condition in dogs although rarely reported in chondrodystrophic breeds. Genetic associations have not been defined. OBJECTIVES: Define the association of the chondrodystrophy-associated FGF4L2 retrogene with histopathologically confirmed cases of FCE. ANIMALS: Ninety-eight dogs with a histopathologic diagnosis of FCE. METHODS: Retrospective multicenter study. Dogs were genotyped for the FGF4L2 and FGF4L1 retrogenes using DNA extracted from formalin-fixed, paraffin-embedded tissue. Associations between breed, FCE and retrogene status were investigated with reference to a hospital population and known breed and general population allele frequencies. RESULTS: FGF4L2 genotype was defined in 89 FCE cases. Fibrocartilaginous embolic myelopathy was present in 22 dogs from FGF4L2-segregating breeds with allele frequencies of ≥5%; however, all dogs were wild type. Two Labrador retrievers with FCE carried FGF4L2 alleles. Frequency of the FGF4L2 allele was significantly (P < .001) and negatively associated with FCE relative to predicted hospital-population dogs. FCE was overrepresented in Boxer, Great Dane, Yorkshire Terrier, Bernese Mountain Dog, Miniature Schnauzer, Rottweiler, and Shetland Sheepdog breeds. CONCLUSIONS AND CLINICAL IMPORTANCE: Study data based on genotypically and histopathologically defined cases support the historical observation that FCE is uncommon in chondrodystrophic dog breeds. FGF4 plays an important role in angiogenesis and vascular integrity; anatomical studies comparing chondrodystrophic and non-chondrodystrophic dogs might provide insight into the pathogenesis of FCE.

ACVIM Consensus Statement on the management of status epilepticus and cluster seizures in dogs and cats.

BACKGROUND: Seizure emergencies (ie, status epilepticus [SE] and cluster seizures [CS]), are common challenging disorders with complex pathophysiology, rapidly progressive drug-resistant and self-sustaining character, and high morbidity and mortality. Current treatment approaches are characterized by considerable variations, but official guidelines are lacking. OBJECTIVES: To establish evidence-based guidelines and an agreement among board-certified specialists for the appropriate management of SE and CS in dogs and cats. ANIMALS: None. MATERIALS AND METHODS: A panel of 5 specialists was formed to assess and summarize evidence in the peer-reviewed literature with the aim to establish consensus clinical recommendations. Evidence from veterinary pharmacokinetic studies, basic research, and human medicine also was used to support the panel's recommendations, especially for the interventions where veterinary clinical evidence was lacking. RESULTS: The majority of the evidence was on the first-line management (ie, benzodiazepines and their various administration routes) in both species. Overall, there was less evidence available on the management of emergency seizure disorders in cats in contrast to dogs. Most recommendations made by the panel were supported by a combination of a moderate level of veterinary clinical evidence and pharmacokinetic data as well as studies in humans and basic research studies. CONCLUSIONS AND CLINICAL RELEVANCE: Successful management of seizure emergencies should include an early, rapid, and stage-based treatment approach consisting of interventions with moderate to preferably high ACVIM recommendations; management of complications and underlying causes related to seizure emergencies should accompany antiseizure medications.

Should We Fix the Fibula in Tibial Plafond Fractures? A Meta-analysis Reviewing the Evidence Base for Fibula Open Reduction and Internal Fixation in Tibial Plafond Fractures.

Open reduction and internal fixation are the standard of care to stabilize tibial plafond fractures. However, it remains uncertain as to whether fixation of the fibula affects the outcome. This study aimed to review the evidence base for comparable outcomes in tibial plafond fractures when undergoing open reduction and internal fixation of ipsilateral fibula fractures compared with open reduction and internal fixation of the tibia alone. A systematic review and meta-analysis of the literature was completed; 4 studies were included for analysis. This study demonstrated no statistically significant differences in the incidence of nonunion (p = .784) or mal-union (p = .416). There was a greater rate of removal of metalwork in the fibula operative group compared to the tibia alone group (p < .001). The current evidence demonstrates that open reduction and internal fixation of ipsilateral fibula fractures in tibial plafond fractures is not necessarily routinely indicated for all fractures.

Case report: Traumatic hemorrhagic cervical myelopathy in a dog.

A 1.5-year-old female entire French bulldog was referred for neurological evaluation, further diagnostic tests, and treatment 24 h after a road traffic accident. Initial emergency treatment, diagnostic tests, and stabilization had been performed by the referring veterinarian. Neurological examination revealed severe spastic non-ambulatory tetraparesis and was consistent with a C1-5 myelopathy. A magnetic resonance imaging (MRI) study revealed an irregular to elongated ovoid intramedullary lesion centered over the body of C2. The lesion showed marked signal heterogeneity with a central T2W and T2* hyperintense region, surrounded by a hypointense rim on both sequences. The lesion appeared heterogeneously T1W hypointense. The lesion was asymmetric (right-sided), affecting both white and gray matter. The C2-3 intervertebral disk appeared moderately degenerate with a Pfirrmann grade of 3. No evidence of vertebral fracture or luxation was found on radiographs or MRI of the vertebral column. Additional soft tissue abnormalities in the area of the right brachial plexus were suggestive of brachial plexus and muscle injury. A diagnosis of traumatic hemorrhagic myelopathy at the level of C2 and concurrent brachial plexus injury was formed. Conservative treatment was elected and consisted of physiotherapy, bladder care with an indwelling urinary catheter, repeated IV methadone based on pain scoring (0.2 mg/kg), oral meloxicam 0.1 mg/kg q24h, and oral gabapentin 10 mg/kg q8h. The dog was discharged after 4 days, with an indwelling urinary catheter and oral medication as described. The catheter was replaced two times by the referring veterinarian and finally removed after 10 days. Thereafter, voluntary urination was seen. During the 2 months after the road traffic accident, slow recovery of motor function was seen. The right thoracic limb recovery progressed more slowly than the left limb, also showing some lower motor neuron signs during follow-up. This was judged to be consistent with a right-sided brachial plexus injury. The dog was reported ambulatory with mild residual ataxia and residual monoparesis of the right thoracic limb at the last follow-up 3 months post-injury. This case report highlights the MRI-based diagnosis of traumatic hemorrhagic myelopathy in a dog. A fair short-term outcome was achieved with conservative treatment in this case.

What is the best method of fixation for minimally displaced subcapital neck of femur fractures? A systematic review.

BACKGROUND: Femoral neck fractures are a common cause of morbidity and mortality in the community. Minimally displaced subcapital necks of femoral fractures are usually managed with internal fixation, although there is debate as to which method is superior. This systematic review aimed to compare the outcomes of different fixation methods in the management of this common fracture. METHODS: This systematic review was conducted in accordance with PRISMA statement guidelines. The databases searched were MEDLINE (Ovid), Cochrane Central Register of Controlled Trials, and EMBASE (Ovid). The study quality and risk of bias were assessed using the Newcastle-Ottawa Quality Assessment Scale, and relevant data were extracted and synthesised. RESULTS: Nine articles met the inclusion criteria. A total of 819 patients were included in this study. Eight of the nine studies were case series, and one was a randomised control trial. The mean risk of bias was 7.4/9 for non-randomised articles. The fixation methods used in the included studies were dynamic hip screw (DHS), cannulated screws, Smith-Peterson nail, hooknail, Moore's pins, and Knowle's pins. DHS was found to be a superior method of fixation and was supported by a clinical trial. It has high rates of union (99 %), low rates of avascular necrosis (<1 %), and low rates of fixation failure (<1 %). CONCLUSIONS: Based on the available data, DHS appears to be the superior method of fixation for the minimally displaced subcapital neck of femoral fractures. Given the general low level of evidence currently available, additional clinical trials are needed in this area.

Magnetic resonance imaging characteristics of atlanto-axial subluxation in 42 dogs: Analysis of joint cavity size, subluxation distance, and craniocervical junction anomalies.

Background: Atlanto-axial (AA) subluxation can be a complex syndrome in dogs. Accurate identification and assessment of this condition are key to providing treatment and resolution. Aim: The purpose of this retrospective study was to describe the magnetic resonance imaging (MRI) characteristics of AA subluxation and associated neurologic deficits. Methods: A multicenter review of dogs with a diagnosis of AA subluxation was conducted, evaluating signalment, neurologic grade, duration of signs, and MRI characteristics. MRI characteristics included degree of spinal cord compression and joint subluxation, integrity of odontoid ligaments, presence of a dens, spinal cord signal intensity, and presence of syringohydromyelia, hydrocephalus, and Chiari-like malformation. A control population with normal AA joints was also evaluated. MR images of 42 dogs with AA subluxation were compared to 26 age and breed-matched control dogs. Results: Affected dogs had a median age of 27 months and a median weight of 2.7 kg, and the most commonly affected breed was the Yorkshire terrier (47.5%). Spinal cord signal hyperintensity, increased AA joint size, and cross-sectional cord compression at the level of the dens and mid-body C2 were associated with AA subluxation. No associations were found between cord compression, the appearance of the dens, or cord signal intensity and neurologic grade. Affected dogs did not have a higher incidence of Chiari-like malformation, syringohydromyelia, or hydrocephalus than control dogs, and their neurologic grade was not associated with MRI findings. Lack of dens and/or odontoid ligaments was associated with larger subluxations. Conclusion: Dogs with clinical signs of AA subluxation were significantly more likely to have intramedullary hyperintensity at the level of compression ( p = 0.0004), an increased AA joint cavity size ( p = 0.0005), and increased spinal cord compression at the level of dens and mid-body C2 (p ≤ 0.05). The authors suggest an AA joint cavity size >1.4 mm and a subluxation distance >2.5 mm as cutoffs for MRI diagnosis of AA subluxation in dogs. No differences were noted between dogs with AA subluxation and control dogs regarding syringohydromyelia, hydrocephalus, and Chiari-like malformation.

Case report: Surgical treatment and long-term successful outcome of a spinal intramedullary vascular malformation in a dog.

A 3.5-year-old male intact Staffordshire terrier crossbreed dog was presented with a one-week history of progressive paraparesis with fecal and urinary incontinence. Neurological examination was consistent with a T3-L3 myelopathy. A magnetic resonance imaging study revealed the presence of a well-circumscribed hemorrhagic space-occupying lesion at the level of T12, suspected to be a vascular malformation, such as cavernoma or arteriovenous fistula, primary hematoma or hamartoma; less likely considerations included hemorrhagic inflammation or hemorrhagic primary or secondary neoplasia. A dorsal laminectomy, durotomy, and midline dorsal myelotomy were performed with a surgical microscope, and the vascular lesion was identified and removed. Histological examination of surgical samples yielded fibrin, hemorrhage, hematoidin pigment, and some neural tissue. Although a lining wall was visualized during surgery consistent with a vascular malformation, there was no histological confirmation of such a structure, hampering definitive classification of the lesion. There was no gross or histopathological evidence that would support a diagnosis of a hamartoma or benign neoplasia. The dog was paraplegic with intact nociception the day following surgery. Ambulation was recovered within 2 weeks. Progressive and complete recovery of neurological function was seen over the next 12 weeks. No recurrence of neurological dysfunction was seen over a 12-month follow-up period. Surgical treatment should be considered in dogs with spinal intramedullary vascular lesions which can have a successful long-term outcome.

Glioma with cribriform plate involvement in 6 dogs.

Distinct patterns of local infiltration are a common feature of canine oligodendroglioma and astrocytoma, and typically involve the surrounding neuroparenchyma, ventricles, or leptomeninges. Infiltration of adjacent extraneural sites is rare and has not been well documented in veterinary medicine. Here we describe 6 canine gliomas with cribriform plate involvement (compression or infiltration) and caudal nasal invasion confirmed by neuroimaging, autopsy, and/or histology. All affected dogs were adults (9-12-y-old), and 3 were brachycephalic. Clinical signs were associated with the brain tumor, with no respiratory signs reported. Magnetic resonance imaging in 2 patients revealed a rostral intraparenchymal telencephalic mass with extension into the cribriform plate. All dogs were euthanized. Gross changes consisted of poorly demarcated, white or pale-yellow, soft, and, in oligodendrogliomas, gelatinous, intraparenchymal masses that expanded the rostral portions of the telencephalon and adhered firmly to the ethmoid bone and cribriform plate. Gliomas were classified as high-grade oligodendrogliomas (4 cases) and high-grade astrocytomas (2 cases) based on histology and immunohistochemistry for OLIG2 and GFAP. In all cases, there was evidence of cribriform plate invasion and, in one case, additional invasion of the caudal nasal cavity.

Probing expression of E-selectin using CRISPR-Cas9-mediated tagging with HiBiT in human endothelial cells.

E-selectin is expressed on endothelial cells in response to inflammatory cytokines and mediates leukocyte rolling and extravasation. However, studies have been hampered by lack of experimental approaches to monitor expression in real time in living cells. Here, NanoLuc Binary Technology (NanoBiT) in conjunction with CRISPR-Cas9 genome editing was used to tag endogenous E-selectin in human umbilical vein endothelial cells (HUVECs) with the 11 amino acid nanoluciferase fragment HiBiT. Addition of the membrane-impermeable complementary fragment LgBiT allowed detection of cell surface expression. This allowed the effect of inflammatory mediators on E-selectin expression to be monitored in real time in living endothelial cells. NanoBiT combined with CRISPR-Cas9 gene editing allows sensitive monitoring of real-time changes in cell surface expression of E-selectin and offers a powerful tool for future drug discovery efforts aimed at this important inflammatory protein.

Multiplex analysis of cytokines in the cerebrospinal fluid of dogs after ischemic stroke reveals elevations in chemokines CXCL1 and MCP-1.

Introduction: Neuroinflammation that occurs in the brain after stroke has been shown to be important to disease pathogenesis and outcomes. The aim of this study was to evaluate a large number of pro- and anti-inflammatory cytokines in dogs with clinically-confirmed, naturally occurring stroke. Materials and methods: Fifteen dogs with a clinical diagnosis of ischemic stroke and ten healthy control dogs were included in the study. A multiplex immunoassay was utilized to evaluate cerebrospinal fluid for GM-CSF, IFN-γ, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-15, IL-18, IP-10, CXCL1, MCP-1, and TNF-α. Results: Mean concentrations of CXCL1 (stroke-436 pg/ml, control-267 pg/ml, p = 0.01) and MCP-1 (stroke-196 pg/ml, control-66 pg/ml, p ≤ 0.0001) were significantly elevated in dogs with stroke when compared with control dogs. Location and type of infarct, duration of clinical signs, and use of anti-inflammatory medications were not associated with differences in cytokine concentration. Discussion: CXCL1 and MCP-1 may play a role in naturally occurring canine stroke and represent targets for future research.

Tanshinone IIA-loaded nanoparticles and neural stem cell combination therapy improves gut homeostasis and recovery in a pig ischemic stroke model.

Impaired gut homeostasis is associated with stroke often presenting with leaky gut syndrome and increased gut, brain, and systemic inflammation that further exacerbates brain damage. We previously reported that intracisternal administration of Tanshinone IIA-loaded nanoparticles (Tan IIA-NPs) and transplantation of induced pluripotent stem cell-derived neural stem cells (iNSCs) led to enhanced neuroprotective and regenerative activity and improved recovery in a pig stroke model. We hypothesized that Tan IIA-NP + iNSC combination therapy-mediated stroke recovery may also have an impact on gut inflammation and integrity in the stroke pigs. Ischemic stroke was induced, and male Yucatan pigs received PBS + PBS (Control, n = 6) or Tan IIA-NP + iNSC (Treatment, n = 6) treatment. The Tan IIA-NP + iNSC treatment reduced expression of jejunal TNF-α, TNF-α receptor1, and phosphorylated IkBα while increasing the expression of jejunal occludin, claudin1, and ZO-1 at 12 weeks post-treatment (PT). Treated pigs had higher fecal short-chain fatty acid (SCFAs) levels than their counterparts throughout the study period, and fecal SCFAs levels were negatively correlated with jejunal inflammation. Interestingly, fecal SCFAs levels were also negatively correlated with brain lesion volume and midline shift at 12 weeks PT. Collectively, the anti-inflammatory and neuroregenerative treatment resulted in increased SCFAs levels, tight junction protein expression, and decreased inflammation in the gut.

"I'd never have that operation again" - a mixed-methods study on how patients react to adverse outcomes following foot and ankle surgery.

BACKGROUND: Adverse outcomes arising from foot and ankle surgery, including lack of pain relief, increased disability and perioperative complications are infrequent but inevitable. This mixed-methods study aims to explore the impact of adverse outcomes on patients following nonemergent foot and ankle surgery. METHODS: Patients who underwent foot and ankle surgery over a two-year period were invited to participate in this study if they reported an adverse outcome. Qualitative assessment consisted of individual semi-structured interviews, designed to explore the decision they made to have surgery and the impact of the outcome after surgery. Quantitative assessment was performed using questionnaires on demographics, current analgesia, foot pain, health-related quality of life, psychological health, and regret. RESULTS: Twelve participants (eight women) consented for inclusion in this study. Current foot pain was high in 10 participants, five met the criteria for central sensitisation syndrome and two had clinically significant pain catastrophising. Most participants regretted their decision to have surgery. The three major themes identified were expectations, communication, and alternatives. CONCLUSIONS: Self-reported adverse outcomes following foot and ankle surgery were prevalent and participants in this study consistently complained of persistent pain. Regret was common and reasons cited for their adverse outcomes centred around the feelings of inadequate communication and failure to meet expectations.

Advancements in drug delivery methods for the treatment of brain disease.

The blood-brain barrier (BBB) presents a formidable obstacle to the effective delivery of systemically administered pharmacological agents to the brain, with ~5% of candidate drugs capable of effectively penetrating the BBB. A variety of biomaterials and therapeutic delivery devices have recently been developed that facilitate drug delivery to the brain. These technologies have addressed many of the limitations imposed by the BBB by: (1) designing or modifying the physiochemical properties of therapeutic compounds to allow for transport across the BBB; (2) bypassing the BBB by administration of drugs via alternative routes; and (3) transiently disrupting the BBB (BBBD) using biophysical therapies. Here we specifically review colloidal drug carrier delivery systems, intranasal, intrathecal, and direct interstitial drug delivery methods, focused ultrasound BBBD, and pulsed electrical field induced BBBD, as well as the key features of BBB structure and function that are the mechanistic targets of these approaches. Each of these drug delivery technologies are illustrated in the context of their potential clinical applications and limitations in companion animals with naturally occurring intracranial diseases.

Tanshinone IIA-Loaded Nanoparticle and Neural Stem Cell Therapy Enhances Recovery in a Pig Ischemic Stroke Model.

Induced pluripotent stem cell-derived neural stem cells (iNSCs) are a multimodal stroke therapeutic that possess neuroprotective, regenerative, and cell replacement capabilities post-ischemia. However, long-term engraftment and efficacy of iNSCs is limited by the cytotoxic microenvironment post-stroke. Tanshinone IIA (Tan IIA) is a therapeutic that demonstrates anti-inflammatory and antioxidative effects in rodent ischemic stroke models and stroke patients. Therefore, pretreatment with Tan IIA may create a microenvironment that is more conducive to the long-term survival of iNSCs. In this study, we evaluated the potential of Tan IIA drug-loaded nanoparticles (Tan IIA-NPs) to improve iNSC engraftment and efficacy, thus potentially leading to enhanced cellular, tissue, and functional recovery in a translational pig ischemic stroke model. Twenty-two pigs underwent middle cerebral artery occlusion (MCAO) and were randomly assigned to a PBS + PBS, PBS + iNSC, or Tan IIA-NP + iNSC treatment group. Magnetic resonance imaging (MRI), modified Rankin Scale neurological evaluation, and immunohistochemistry were performed over a 12-week study period. Immunohistochemistry indicated pretreatment with Tan IIA-NPs increased iNSC survivability. Furthermore, Tan IIA-NPs increased iNSC neuronal differentiation and decreased iNSC reactive astrocyte differentiation. Tan IIA-NP + iNSC treatment enhanced endogenous neuroprotective and regenerative activities by decreasing the intracerebral cellular immune response, preserving endogenous neurons, and increasing neuroblast formation. MRI assessments revealed Tan IIA-NP + iNSC treatment reduced lesion volumes and midline shift. Tissue preservation and recovery corresponded with significant improvements in neurological recovery. This study demonstrated pretreatment with Tan IIA-NPs increased iNSC engraftment, enhanced cellular and tissue recovery, and improved neurological function in a translational pig stroke model.

Are models of plantar heel pain suitable for competitive runners? A narrative review.

Background: Plantar heel pain (PHP), or plantar fasciopathy, is a common condition in active and sedentary populations, contributing to short- and long-term reductions in quality of life. The condition's aetiology and pathophysiology are the subjects of a significant body of research. However, much of this research has been conducted with sedentary participants, and comparatively little research exists in a population of highly-trained athletes focused on performance outcomes. Models for PHP and proposed mechanisms, such as high body mass index or systemic disease, are mostly absent from an athletic population. Even less is known about the origins of pain in PHP. Pain is believed to be a complex multifactorial process and may be experienced differently by sedentary and highly active populations, particularly endurance athletes. Consequently, conservative through to surgical treatment for athletes is informed by literature for a different population, potentially hindering treatment outcomes. Aims: The aim of this review, therefore, is to summarise what is known about PHP in athletic populations and propose potential directions for future research. Methods: Embase, PubMed, and Scopus using MeSH search terms for PHP and competitive sport and common synonyms. Discussion: Two explanatory models for PHP were found. These primarily propose mechanical factors for PHP. It remains unclear how gait, body composition, and psychological factors may differ in an athletic population with and without PHP. Therefore, research in these three areas is needed to inform clinical and training interventions for this population.

Pain catastrophising, body mass index and depressive symptoms are associated with pain severity in tertiary referral orthopaedic foot/ankle patients.

INTRODUCTION: Patients with chronic foot/ankle pain are often referred for orthopaedic assessment. Psychological vulnerabilities influence pain states (including foot and ankle), therefore this study aimed to establish the prevalence and relative importance of compromised psychological health to perceived foot/ankle pain severity in people referred to an orthopaedic foot and ankle clinic with non-urgent presentations. METHODS: Patients with triaged non-urgent foot/ankle referrals to the Department of Orthopaedics at Gold Coast University Hospital were recruited over a 12-month period and completed the Manchester-Oxford Foot and Ankle Questionnaire which was the primary measure. Participants also completed questionnaires assessing their anthropometric, demographic and health characteristics (Self-Administered Comorbidity Questionnaire) as well as measures of health-related quality of life (EuroQol-5-Dimensions-5-Level Questionnaire and EQ Visual Analogue Scale) and psychological health (Center for Epidemiological Studies-Depression scale, Pain Catastrophizing Scale and Central Sensitization Inventory). Descriptive statistics were used to summarise participant characteristics and a hierarchical multiple linear regression was employed to establish the extent to which psychological variables explain additional variance in foot/ankle pain severity beyond the effects of participant characteristics (age, sex, body mass index (BMI)). RESULTS: One hundred and seventy-two adults were recruited ((64.0% female), median (IQR) age 60.9 (17.7) years and BMI 27.6 (7.5) kg/m2). Specific psychological comorbidities were prevalent including depressive symptoms (48%), central sensitisation (38%) and pain catastrophising (24%). Age, sex and BMI accounted for 11.7% of the variance in MOXFQ-index and psychological variables accounted for an additional 28.2%. Pain catastrophising was the most significant independent predictor of foot/ankle pain severity (accounting for 14.4% of variance), followed by BMI (10.7%) and depressive symptoms (2.3%). CONCLUSIONS: This study demonstrated that specific psychological comorbidities and increased BMI are common in this cohort and that these factors are associated with the symptoms for which patients are seeking orthopaedic assessment. This knowledge should prompt clinicians to routinely consider the psychosocial components of patient presentations and develop non-operative and pre-operative treatment strategies which consider these factors with the goal of improving overall patient outcomes.

Defining and overcoming the therapeutic obstacles in canine refractory status epilepticus.

Status epilepticus (SE) can be effectively resolved if diagnosis and treatment are addressed at an early stage, although this is not always possible in clinical practice. If untreated, continuous seizure activity leads to refractory SE which does not respond to antiseizure medication. Although refractory SE is a life-threatening emergency, there is a lack of veterinary consensus on its appropriate management. Classical therapeutic approaches often fail to prevent the progression of SE. One of the main reasons for failure or inadequate response, is a lack of understanding of the fundamental progressive pathophysiology occurring during SE. If the therapeutic approach is focussed on the specific pathophysiologic alterations responsible for initiating and maintaining continuous seizure activity, SE could be successfully resolved during its early stages, preventing progression to a refractory state. The aim of this review is to detail the underlying pathophysiology of SE at its different temporal stages in order to determine a more effective therapeutic approach.