Re-evaluating the placebo response in recent canine dietary epilepsy trials.

The placebo response is a common phenomenon. Limited evidence is available about its magnitude in canine epilepsy trials, even though it can significantly influence the efficacy evaluation of new treatments. It was hypothesised that the placebo response is diminished when epilepsy trials are conducted in a prospective crossover design. Seizure data spanning six months from three previous multicenter epilepsy studies were analysed. The monthly seizure frequency of 60 dogs diagnosed with idiopathic epilepsy was calculated, comparing baseline data with placebo treatment. Furthermore, differentiation was made between dogs randomised to the placebo group early (Phase 1: first 3 months) or later during the study (Phase 2: second 3 months).The analysis did not reveal any placebo response in terms of monthly seizure frequency. Instead, an increase was noted during the placebo treatment period, with a mean of 2.95 seizures per month compared to 2.30 seizures per month before study entry (p = 0.0378). Additionally, a notable phase effect was observed. Dogs receiving the placebo in the second study phase exhibited a significant increase in monthly seizure frequency compared to baseline (p = 0.0036). Conversely, no significant difference from baseline was observed for dogs receiving the placebo in the first study phase. These findings underscore the considerable variability in placebo responses observed in trials for canine epilepsy, contrasting with previous limited data. The identified phase effect should be carefully considered in the design and evaluation of canine epilepsy trials to ensure a more accurate assessment of efficacy for new treatments.

Success Rate After 2-Stage Spacer-Free Total Hip Arthroplasty Exchange and Risk Factors for Reinfection: A Prospective Cohort Study of 187 Patients.

BACKGROUND: Two-stage prosthesis exchange is the treatment of choice for chronic periprosthetic joint infection (PJI) of a total hip arthroplasty (THA), especially when the bone and surrounding soft tissues are compromised or difficult-to-treat pathogens are implicated. The aims of our study were as follows: (1) to determine the outcome of 2-stage prosthesis exchange for the treatment of PJI after THA and (2) to determine the risk factors for reinfection leading to subsequent revision surgeries after reimplantation. METHODS: We prospectively enrolled 187 consecutive patients who underwent a 2-stage THA exchange with resection arthroplasty for PJI from 2013 to 2019. The mean (± SD) duration of follow-up was 54.2 ± 24.9 months (range, 36 to 96), and the mean interval until reimplantation was 9.8 ± 8.9 weeks (range, 2 to 38). All patients remained in a spacer-free girdlestone situation between the 2 stages of treatment. Patients who remained infection-free after their 2-stage treatment were considered to have achieved treatment success. RESULTS: The overall success rate was 85.6%. The cumulative probability of reinfection was 11.5% after one year and 14% after 2 years after reimplantation. High virulence or difficult-to-treat pathogens were significant and independent risk factors for reinfection (HR [hazard ratio] = 3.71, 95% CI [confidence interval]: 1.47 to 9.36, P = .006 and HR = 3.85, 95% CI: 1.73 to 8.57, respectively, P = .001), as was previous 2-stage hip prosthesis exchange (HR = 3.58, 95% CI: 1.33 to 9.62, P = .01). Overall reoperation and revision rates were 26.2 and 16.6%, respectively. Re-infected patients had an 80% higher probability of reoperation than noninfected ones (P < .001, log-rank = 102.6), and they were 55% more likely to undergo revision surgery during their follow-up (P < .001, log-rank = 55.4). CONCLUSIONS: Reinfection rates after 2-stage spacer-free THA revision for PJI still remain high but are comparable to those including cement spacers. Patients who have had prior failed 2-stage implant exchanges or are infected by high-grade or difficult-to-treat pathogens are at high risk for treatment failure.

Long-lasting antiseizure effects of chronic intrasubthalamic convection-enhanced delivery of valproate.

Intracerebral drug delivery is an experimental approach for the treatment of drug-resistant epilepsies that allows for pharmacological intervention in targeted brain regions. Previous studies have shown that targeted pharmacological inhibition of the subthalamic nucleus (STN) via modulators of the GABAergic system produces antiseizure effects. However, with chronic treatment, antiseizure effects are lost as tolerance develops. Here, we report that chronic intrasubthalamic microinfusion of valproate (VPA), an antiseizure medication known for its wide range of mechanisms of action, can produce long-lasting antiseizure effects over three weeks in rats. In the intravenous pentylenetetrazole seizure-threshold test, seizure thresholds were determined before and during chronic VPA application (480 µg/d, 720 µg/d, 960 µg/d) to the bilateral STN. Results indicate a dose-dependent variation in VPA-induced antiseizure effects with mean increases in seizure threshold of up to 33%, and individual increases of up to 150%. The lowest VPA dose showed a complete lack of tolerance development with long-lasting antiseizure effects. Behavioral testing with all doses revealed few, acceptable adverse effects. VPA concentrations were high in STN and low in plasma and liver. In vitro electrophysiology with bath applied VPA revealed a reduction in spontaneous firing rate, increased background membrane potential, decreased input resistance and a significant reduction in peak NMDA, but not AMPA, receptor currents in STN neurons. Our results suggest an advantage of VPA over purely GABAergic modulators in preventing tolerance development with chronic intrasubthalamic drug delivery and provide first mechanistic insights in intracerebral pharmacotherapy targeting the STN.

A six-month prospective, randomised, double-blinded, placebo-controlled, crossover, dietary trial design to investigate the potential of psychobiotics on seizure semiology and comorbidities in canine epilepsy: study protocol.

BACKGROUND: Epilepsy is the most common chronic neurological disease in dogs. More than two-thirds of these patients suffer from associated behavioural comorbidities. The latter could have their origin in partially overlapping pathomechanisms, with the intestinal microbiome as a potential key link between them. The current arsenal of drugs for epilepsy management remains limited. Most canine patients continue to have seizures despite treatment and the occurrence of comorbidities is not sufficiently addressed, limiting quality of life of affected dogs and owners. Therefore, novel additional epilepsy management options are urgently needed. The microbiome-gut-brain axis may serve as a new target for the development of innovative multimodal therapeutic approaches to overcome current shortcomings in epilepsy management. METHODS: A six-month prospective, randomised, double-blinded, placebo-controlled, crossover, dietary trial was designed to investigate the potential of the psychobiotic Bifidobacterium longum on behavioural comorbidities in canine epilepsy. Seizure semiology will be evaluated as a secondary outcome measure. Thirty-four privately owned dogs are planned to be included in the ongoing study meeting the following inclusion criteria: Dogs displaying increased anxiety/fear behaviour since the start of the idiopathic epilepsy. Tier II confidence level of the International Veterinary Epilepsy Task Force for the diagnosis of idiopathic epilepsy, with a maximum seizure interval of 3 month and a minimum of three generalised seizures within that period and chronically treated with at least one antiseizure drug without improvement in seizure frequency Each dog will receive the allocated supplement (probiotic vs. placebo) alongside its normal diet for a 3-month period. After a three-week wash out period, the second phase starts by administering the respective other supplement for another 3 months. DISCUSSION: The current study considers modern high-quality standards for epilepsy medication trials. Common biasing effects should be limited to a possible minimum (regression-to-the mean effect, placebo effect, observer effect), ensuring a high validity and accuracy of the acquired results, thus enabling a representative nature of the efficacy of Bifidobacterium longum as add-on supplement for dogs suffering from epilepsy and its comorbidities. This publication should provide a description of the study procedure and data acquisition methods, including prognosed statistical analysis.

Scopolamine prevents aberrant mossy fiber sprouting and facilitates remission of epilepsy after brain injury.

Prevention or modification of acquired epilepsy in patients at risk is an urgent, yet unmet, clinical need. Following acute brain insults, there is an increased risk of mesial temporal lobe epilepsy (mTLE), which is often associated with debilitating comorbidities and reduced life expectancy. The latent period between brain injury and the onset of epilepsy may offer a therapeutic window for interfering with epileptogenesis. The pilocarpine model of mTLE is widely used in the search for novel antiepileptogenic treatments. Recent biochemical studies indicated that cholinergic mechanisms play a role in the epileptogenic alterations induced by status epilepticus (SE) in this and other models of mTLE, which prompted us to evaluate whether treatment with the muscarinic antagonist scopolamine during the latent period after SE is capable of preventing or modifying epilepsy and associated behavioral and cognitive alterations in female Sprague-Dawley rats. First, in silico pharmacokinetic modeling was used to select a dosing protocol by which M-receptor inhibitory brain levels of scopolamine are maintained during prolonged treatment. This protocol was verified by drug analysis in vivo. Rats were then treated twice daily with scopolamine over 17 days after SE, followed by drug wash-out and behavioral and video/EEG monitoring up to ~6 months after SE. Compared to vehicle controls, rats that were treated with scopolamine during the latent period exhibited a significantly lower incidence of spontaneous recurrent seizures during periods of intermittent recording in the chronic phase of epilepsy, less behavioral excitability, less cognitive impairment, and significantly reduced aberrant mossy fiber sprouting in the hippocampus. The present data may indicate that scopolamine exerts antiepileptogenic/disease-modifying activity in the lithium-pilocarpine rat model, possibly involving increased remission of epilepsy as a new mechanism of disease-modification. For evaluating the rigor of the present data, we envision a study that more thoroughly addresses the gender bias and video-EEG recording limitations of the present study.

OV329, a novel highly potent γ-aminobutyric acid aminotransferase inactivator, induces pronounced anticonvulsant effects in the pentylenetetrazole seizure threshold test and in amygdala-kindled rats.

OBJECTIVE: An attractive target to interfere with epileptic brain hyperexcitability is the enhancement of γ-aminobutyric acidergic (GABAergic) inhibition by inactivation of the GABA-metabolizing enzyme GABA aminotransferase (GABA-AT). GABA-AT inactivators were designed to control seizures by raising brain GABA levels. OV329, a novel drug candidate for the treatment of epilepsy and addiction, has been shown in vitro to be substantially more potent as a GABA-AT inactivator than vigabatrin, an antiseizure drug approved as an add-on therapy for adult patients with refractory complex partial seizures and monotherapy for pediatric patients with infantile spasms. Thus, we hypothesized that OV329 should produce pronounced anticonvulsant effects in two different rat seizure models. METHODS: We therefore examined the effects of OV329 (5, 20, and 40 mg/kg ip) on the seizure threshold of female Wistar Unilever rats, using the timed intravenous pentylenetetrazole (ivPTZ) seizure threshold model as a seizure test particularly sensitive to GABA-potentiating manipulations, and amygdala-kindled rats as a model of difficult-to-treat temporal lobe epilepsy. RESULTS: GABA-AT inactivation by OV329 clearly increased the threshold of both ivPTZ-induced and amygdala-kindled seizures. OV329 further showed a 30-fold greater anticonvulsant potency on ivPTZ-induced myoclonic jerks and clonic seizures compared to vigabatrin investigated previously. Notably, all rats were responsive to OV329 in both seizure models. SIGNIFICANCE: These results reveal an anticonvulsant profile of OV329 that appears to be superior in both potency and efficacy to vigabatrin and highlight OV329 as a highly promising candidate for the treatment of seizures and pharmacoresistant epilepsies.

Canine olfactory detection and its relevance to medical detection.

The extraordinary olfactory sense of canines combined with the possibility to learn by operant conditioning enables dogs for their use in medical detection in a wide range of applications. Research on the ability of medical detection dogs for the identification of individuals with infectious or non-infectious diseases has been promising, but compared to the well-established and-accepted use of sniffer dogs by the police, army and customs for substances such as money, explosives or drugs, the deployment of medical detection dogs is still in its infancy. There are several factors to be considered for standardisation prior to deployment of canine scent detection dogs. Individual odours in disease consist of different volatile organic molecules that differ in magnitude, volatility and concentration. Olfaction can be influenced by various parameters like genetics, environmental conditions, age, hydration, nutrition, microbiome, conditioning, training, management factors, diseases and pharmaceuticals. This review discusses current knowledge on the function and importance of canines' olfaction and evaluates its limitations and the potential role of the dog as a biomedical detector for infectious and non-infectious diseases.

Scent dog identification of SARS-CoV-2 infections in different body fluids.

BACKGROUND: The main strategy to contain the current SARS-CoV-2 pandemic remains to implement a comprehensive testing, tracing and quarantining strategy until vaccination of the population is adequate. Scent dogs could support current testing strategies. METHODS: Ten dogs were trained for 8 days to detect SARS-CoV-2 infections in beta-propiolactone inactivated saliva samples. The subsequent cognitive transfer performance for the recognition of non-inactivated samples were tested on three different body fluids (saliva, urine, and sweat) in a randomised, double-blind controlled study. RESULTS: Dogs were tested on a total of 5242 randomised sample presentations. Dogs detected non-inactivated saliva samples with a diagnostic sensitivity of 84% (95% CI: 62.5-94.44%) and specificity of 95% (95% CI: 93.4-96%). In a subsequent experiment to compare the scent recognition between the three non-inactivated body fluids, diagnostic sensitivity and specificity were 95% (95% CI: 66.67-100%) and 98% (95% CI: 94.87-100%) for urine, 91% (95% CI: 71.43-100%) and 94% (95% CI: 90.91-97.78%) for sweat, 82% (95% CI: 64.29-95.24%), and 96% (95% CI: 94.95-98.9%) for saliva respectively. CONCLUSIONS: The scent cognitive transfer performance between inactivated and non-inactivated samples as well as between different sample materials indicates that global, specific SARS-CoV-2-associated volatile compounds are released across different body secretions, independently from the patient's symptoms. All tested body fluids appear to be similarly suited for reliable detection of SARS-CoV-2 infected individuals.

Scent dog identification of samples from COVID-19 patients - a pilot study.

BACKGROUND: As the COVID-19 pandemic continues to spread, early, ideally real-time, identification of SARS-CoV-2 infected individuals is pivotal in interrupting infection chains. Volatile organic compounds produced during respiratory infections can cause specific scent imprints, which can be detected by trained dogs with a high rate of precision. METHODS: Eight detection dogs were trained for 1 week to detect saliva or tracheobronchial secretions of SARS-CoV-2 infected patients in a randomised, double-blinded and controlled study. RESULTS: The dogs were able to discriminate between samples of infected (positive) and non-infected (negative) individuals with average diagnostic sensitivity of 82.63% (95% confidence interval [CI]: 82.02-83.24%) and specificity of 96.35% (95% CI: 96.31-96.39%). During the presentation of 1012 randomised samples, the dogs achieved an overall average detection rate of 94% (±3.4%) with 157 correct indications of positive, 792 correct rejections of negative, 33 incorrect indications of negative or incorrect rejections of 30 positive sample presentations. CONCLUSIONS: These preliminary findings indicate that trained detection dogs can identify respiratory secretion samples from hospitalised and clinically diseased SARS-CoV-2 infected individuals by discriminating between samples from SARS-CoV-2 infected patients and negative controls. This data may form the basis for the reliable screening method of SARS-CoV-2 infected people.

Nucleic acid-based biomarkers in body fluids of patients with urologic malignancies.

This review focuses on the promising potential of nucleic acids in body fluids such as blood and urine as diagnostic, prognostic, predictive and monitoring biomarkers in urologic malignancies. The tremendous progress in the basic knowledge of molecular processes in cancer, as shown in the companion review on nucleic acid-based biomarkers in tissue of urologic tumors, provides a strong rationale for using these molecular changes as non-invasive markers in body fluids. The changes observed in body fluids are an integrative result, reflecting both tissue changes and processes occurring in the body fluids. The availability of sensitive methods has only recently made possible detailed studies of DNA- and RNA-based markers in body fluids. In addition to these biological aspects, methodological aspects of the determination of nucleic acids in body fluids, i.e. pre-analytical, analytical and post-analytical issues, are particularly emphasized. The characteristic changes of RNA (differential mRNA and miRNA expression) and DNA (concentrations, integrity index, mutations, microsatellite and methylation alterations) in serum/plasma and urine samples of patients suffering from the essential urologic cancers of the prostate, bladder, kidney and testis are summarized and critically discussed below. To translate the promising results into clinical practice, laboratory scientists and clinicians have to collaborate to resolve the challenges of harmonized and feasible pre-analytical and analytical conditions for the selected markers and to validate these markers in well-designed and sufficiently powered multi-center studies.

Nucleic acid-based tissue biomarkers of urologic malignancies.

Molecular biomarkers play an important role in the clinical management of cancer patients. Biomarkers allow estimation of the risk of developing cancer; help to diagnose a tumor, ideally at an early stage when cure is still possible; and aid in monitoring disease progression. Furthermore, they hold the potential to predict the outcome of the disease (prognostic biomarkers) and the response to therapy (predictive biomarkers). Altogether, biomarkers will help to avoid tumor-related deaths and reduce overtreatment, and will contribute to increased survival and quality of life in cancer patients due to personalized treatments. It is well established that the process of carcinogenesis is a complex interplay between genomic predisposition, acquired somatic mutations, epigenetic changes and genomic aberrations. Within this complex interplay, nucleic acids, i.e. RNA and DNA, play a fundamental role and therefore represent ideal candidates for biomarkers. They are particularly promising candidates because sequence-specific hybridization and amplification technologies allow highly accurate and sensitive assessment of these biomarker levels over a broad dynamic range. This article provides an overview of nucleic acid-based biomarkers in tissues for the management of urologic malignancies, i.e. tumors of the prostate, testis, kidney, penis, urinary bladder, renal pelvis, ureter and other urinary organs. Special emphasis is put on genomic, transcriptomic and epigenomic biomarkers (SNPs, mutations [genomic and mitochondrial], microsatellite instabilities, viral and bacterial DNA, DNA methylation and hydroxymethylation, mRNA expression, and non-coding RNAs [lncRNA, miRNA, siRNA, piRNA, snRNA, snoRNA]). Due to the multitude of published biomarker candidates, special focus is given to the general applicability of different molecular classes as biomarkers and some particularly promising nucleic acid biomarkers. Furthermore, specific challenges regarding the development and clinical implementation of nucleic acid-based biomarkers are discussed.

ChatGPT May Offer an Adequate Substitute for Informed Consent to Patients Prior to Total Knee Arthroplasty-Yet Caution Is Needed.

Prior to undergoing total knee arthroplasty (TKA), surgeons are often confronted with patients with numerous questions regarding the procedure and the recovery process. Due to limited staff resources and mounting individual workload, increased efficiency, e.g., using artificial intelligence (AI), is of increasing interest. We comprehensively evaluated ChatGPT's orthopedic responses using the DISCERN instrument. Three independent orthopedic surgeons rated the responses across various criteria. We found consistently high scores, predominantly exceeding a score of three out of five in almost all categories, indicative of the quality and accuracy of the information provided. Notably, the AI demonstrated proficiency in conveying precise and reliable information on orthopedic topics. However, a notable observation pertains to the generation of non-existing references for certain claims. This study underscores the significance of critically evaluating references provided by ChatGPT and emphasizes the necessity of cross-referencing information from established sources. Overall, the findings contribute valuable insights into the performance of ChatGPT in delivering accurate orthopedic information for patients in clinical use while shedding light on areas warranting further refinement. Future iterations of natural language processing systems may be able to replace, in part or in entirety, the preoperative interactions, thereby optimizing the efficiency, accessibility, and standardization of patient communication.

Canine Electroencephalography Electrode Positioning Using a Neuronavigation System.

BACKGROUND: Studies in people suggest that surface electroencephalography (EEG) electrode positions vary across participants and that the consistency of these positions is electrode-, region-, and examiner-dependent. The aim was to investigate the variability in EEG electrode positions to their underlying cortical regions (CRs) in dogs using a neuronavigation system and evaluate the use of said system in electrode positioning, via a cadaver study with 22 dogs. CT scans and MRI were performed for each dog. These were uploaded onto a neuronavigation system where the desired CRs were annotated. The electrode positions were marked on the heads, which were positioned using only a previously established guide and anatomical landmarks. Using the neuronavigation system, alignment or deviations from the desired CRs were noted. Fifty-three percent of all the marked electrode positions showed an alignment with the desired CRs. Thirty-three percent showed no alignment, and fourteen percent showed partial alignment. Three percent deviated to different cortical lobes. Placement via the neuronavigation system enabled reliable and replicable electrode positioning and CR alignment. The standard for EEG electrode placement in dogs is subjected to a high variance. A neuronavigation system can aid in more precise electrode placements. Specific gyri cannot accurately be evaluated on EEG without imaging-controlled electrode placement.

The Safety and Efficacy of Microporous Polysaccharide Hemospheres in Terms of the Complication Rates in Total Hip Arthroplasty for Femoral Neck Fractures: A Control-Matched Retrospective Cohort.

AIMS: This study aimed to assess the safety and efficacy of microporous polysaccharide hemospheres (MPSHs) in managing blood loss and reducing the risk of postoperative haematoma and early periprosthetic joint infection (PJI) following total hip arthroplasty (THA) for femoral neck fracture (FNF), in the context of the existing treatment challenges. METHODS: A control-matched retrospective analysis of 163 patients undergoing unilateral primary THA for displaced FNF between 2020 and 2023 was performed. The study group consisted of 74 patients who received MPSH administered intraoperatively. The control group consisted of 89 patients who received no topical haemostatics. One-to-one case-control matching between groups was performed. The primary outcome was a perioperative change in the haematologic values (haemoglobin, red blood cell count, haematocrit, platelet concentration) and transfusion rate. The secondary outcomes were the incidence of postoperative local haematoma formation, prolonged wound secretion, surgical site infection (SSI), and PJI within 3 months of surgery. RESULTS: Our analysis found no statistically significant differences in the haematologic parameters between the control and study cohorts. The changes in the haemoglobin concentration were not significant between the control group (3.18 ± 1.0 g/dL) and the treatment group (2.87 ± 1.15 g/dL) (p = 0.3). There were no significant differences (p = 0.24) in the haematocrit and red blood cell concentration (p = 0.15). The platelet levels did not significantly differ (p = 0.12) between the groups. Additionally, we found no significant discrepancy in the incidence of early PJI or blood transfusion rates between the groups. No adverse effects following MPSH use were recorded in the study group. CONCLUSIONS: Routine use of MPSH in THA for FNF management appears to be safe, with no observed adverse events related to Arista® use. Although there was a tendency towards reduced blood loss in the Arista® AH group, MPSH did not significantly impact bleeding complications, local haematoma formation, or subsequent PJI.

Comparing standard screening questionnaires of canine behavior for assessment of cognitive dysfunction.

Background: Canine cognitive dysfunction (CCD) is a common, yet underdiagnosed neurodegenerative disease affecting older dogs. Treatment is most effective when started early, so identifying mild cognitive decline in the earlier stages of the disease is considered important. Hypothesis/objective: To compare the results of three different standard screening questionnaires [Canine Dementia Scale (CADES), Canine Cognitive Assessment Scale (CCAS), and Canine Cognitive Dysfunction Rating Scale (CCDR)] for CCD diagnosis. Trainability, pain sensitivity, and fear were additionally assessed with the Canine Behavioral Assessment and Research Questionnaire (C-BARQ) in order to evaluate associations between the three dementia scales and behavior. Methods: An online survey containing all the mentioned questionnaires was designed for and distributed among owners of elderly dogs. Results: Data from 597 dogs were analyzed. Overall, the scores of the three CCD questionnaires correlated well with each other, especially those of the CADES and CCAS. The CADES was more sensitive in identifying dogs with already mild to moderate cognitive impairment, while the others classified them as still undergoing normal aging. CCD scores increased for all questionnaires with age with spatial orientation being a key feature in CCD development. Trainability assessed with the C-BARQ decreased significantly with severity of CCD signs, while pain sensitivity increased. Fear and anxiety was pronounced in animals with mild but not with severe CCD. These associations based on the C-BARQ were more clearly observable in relation to CADES and CCDR than CCAS. Conclusion/clinical relevance: The choice of screening questionnaire impacts the evaluation of cognitive status and severity of CCD. Thresholds for severity classification differ significantly and may have an impact on reliable assessment. Further longitudinal studies are required to determine which of the questionnaires investigated in this study is best suited for early detection of CCD.

Epilepsy is more than a simple seizure disorder: Parallels between human and canine cognitive and behavioural comorbidities.

Psychiatric and cognitive comorbidities have been known to play a major role in human epilepsy for a long time. People with epilepsy (PWE) frequently express signs of varying psychiatric and cognitive disorders affecting their quality and quantity of life (QoL/QaoL). Over the last few years, research on behavioural comorbidities and their effect on the underlying disease have been performed in canine epilepsy. The following article reviews manifestations of comorbidities in canine epilepsy with an emphasis on patterns of clinical signs and their effects on QoL and QaoL. Cognitive and behavioural alterations in epileptic dogs are mainly represented by fear-/anxiety related behaviour and cognitive impairment (CI). Reduced trainability and altered reactions to daily situations are common results of comorbid changes posing obstacles in everyday life of owners and their dog. In addition, clinical signs similar to attention deficit hyperactivity disorder (ADHD) in humans have been reported. Canine attention-deficit-hyperactivity-disorder-like (c-ADHD-like) behaviour should, however, be evaluated critically, as there are no official criteria for diagnosis of ADHD or ADHD-like behaviour in dogs, and some of the reported signs of c-ADHD-like behaviour could be confused with anxiety-associated behaviour. Many intrinsic and extrinsic factors could potentially influence the development of behavioural and cognitive comorbidities in canine epilepsy. In particular, seizure frequency/severity, signalment and factors concerning disease management, such as pharmacotherapy and nutrition, are closely linked with the presence of the aforementioned comorbid disorders. Further studies of behavioural alterations in epileptic dogs are needed to comprehend the complexity of clinical signs and their multifactorial origin.

Epilepsy is more than a simple seizure disorder: Causal relationships between epilepsy and its comorbidities.

This review draws connections between the pathogenesis of canine epilepsy and its most commonly recognised comorbidities: cognitive impairment (CI), attention deficit hyperactivity disorder (ADHD)-like behaviour, fear and anxiety. Uni/bidirectional causalities and the possibility of a common aetiology triggering both epilepsy and the associated diseases are considered. Research on this topic is sparse in dogs, so information has been gathered and assessed from human and laboratory animal studies. Anatomical structures, functional connections, disrupted neurotransmission and neuroinflammatory processes collectively serve as a common foundation for epilepsy and its comorbidities. Specific anatomical structures, especially parts of the limbic system, such as the amygdala and the hippocampus, are involved in generating seizures, as well as cognitive- and behavioural disorders. Furthermore, disturbances in inhibitory and excitatory neurotransmission influence neuronal excitability and networks, leading to underlying brain dysfunction. Functional magnetic resonance imaging (fMRI), interictal epileptiform discharges (IEDs), and electroencephalography (EEG) have demonstrated functional brain connections that are related to the emergence of both epilepsy and its various comorbidities. Neuroinflammatory processes can either cause or be a consequence of seizures, and inflammatory mediators, oxidative stress and mitochondrial dysfunction, can equally evoke mood disorders. The extensive relationships contributing to the development and progression of seizures and comorbid cognitive and behavioural conditions illustrate the complexity of the disease that is epilepsy.

MicroRNA expression analysis in peripheral blood and soft-tissue of patients with periprosthetic hip infection.

Aims: Current diagnostic tools are not always able to effectively identify periprosthetic joint infections (PJIs). Recent studies suggest that circulating microRNAs (miRNAs) undergo changes under pathological conditions such as infection. The aim of this study was to analyze miRNA expression in hip arthroplasty PJI patients. Methods: This was a prospective pilot study, including 24 patients divided into three groups, with eight patients each undergoing revision of their hip arthroplasty due to aseptic reasons, and low- and high-grade PJI, respectively. The number of intraoperative samples and the incidence of positive cultures were recorded for each patient. Additionally, venous blood samples and periarticular tissue samples were collected from each patient to determine miRNA expressions between the groups. MiRNA screening was performed by small RNA-sequencing using the miRNA next generation sequencing (NGS) discovery (miND) pipeline. Results: Overall, several miRNAs in plasma and tissue were identified to be progressively deregulated according to ongoing PJI. When comparing the plasma samples, patients with a high-grade infection showed significantly higher expression levels for hsa-miR-21-3p, hsa-miR-1290, and hsa-miR-4488, and lower expression levels for hsa-miR-130a-3p and hsa-miR-451a compared to the aseptic group. Furthermore, the high-grade group showed a significantly higher regulated expression level of hsa-miR-1260a and lower expression levels for hsa-miR-26a-5p, hsa-miR-26b-5p, hsa-miR-148b-5p, hsa-miR-301a-3p, hsa-miR-451a, and hsa-miR-454-3p compared to the low-grade group. No significant differences were found between the low-grade and aseptic groups. When comparing the tissue samples, the high-grade group showed significantly higher expression levels for 23 different miRNAs and lower expression levels for hsa-miR-2110 and hsa-miR-3200-3p compared to the aseptic group. No significant differences were found in miRNA expression between the high- and low-grade groups, as well as between the low-grade and aseptic groups. Conclusion: With this prospective pilot study, we were able to identify a circulating miRNA signature correlating with high-grade PJI compared to aseptic patients undergoing hip arthroplasty revision. Our data contribute to establishing miRNA signatures as potential novel diagnostic and prognostic biomarkers for PJI.

Fecal supernatants from dogs with idiopathic epilepsy activate enteric neurons.

Introduction: Alterations in the composition and function of the gut microbiome have been reported in idiopathic epilepsy (IE), however, interactions of gut microbes with the enteric nervous system (ENS) in this context require further study. This pilot study examined how gastrointestinal microbiota (GIM), their metabolites, and nutrients contained in intestinal contents communicate with the ENS. Methods: Fecal supernatants (FS) from healthy dogs and dogs with IE, including drug-naïve, phenobarbital (PB) responsive, and PB non-responsive dogs, were applied to cultured myenteric neurons to test their activation using voltage-sensitive dye neuroimaging. Additionally, the concentrations of short-chain fatty acids (SCFAs) in the FS were quantified. Results: Our findings indicate that FS from all examined groups elicited neuronal activation. Notably, FS from PB non-responsive dogs with IE induced action potential discharge in a higher proportion of enteric neurons compared to healthy controls, which exhibited the lowest burst frequency overall. Furthermore, the highest burst frequency in enteric neurons was observed upon exposure to FS from drug-naïve dogs with IE. This frequency was significantly higher compared to that observed in PB non-responsive dogs with IE and showed a tendency to surpass that of healthy controls. Discussion: Although observed disparities in SCFA concentrations across the various FS samples might be associated with the induced neuronal activity, a direct correlation remains elusive at this point. The obtained results hint at an involvement of the ENS in canine IE and set the basis for future studies.

Quantification of spinal ataxia in dogs with thoracolumbar spinal cord injury.

The clinical sign of ataxia is related to several neurological diseases and is seen in conjunction with paresis in dogs with spinal cord injury (SCI). Endeavours to objectify canine spinal ataxia in SCI remain limited. The aim of this clinical study was to determine and quantify differences between gait characteristics of ataxic dogs with thoracolumbar myelopathy and healthy control dogs using a computer-and treadmill-based gait analysis system. Five dogs with spinal ataxia and six healthy dogs underwent video-and computer-assisted gait analysis while walking on a four-ground reaction force plate treadmill system (maximum speed of 0.7 m/s). Spatio-temporal and kinetic gait characteristics regarding the dogs' locomotion were analysed with a focus on the individual coefficient of variation (CV), as a potential measure for quantification of the level of ataxia. Ataxic dogs with thoracolumbar SCI showed no effect on symmetry indices but higher variability in spatio-temporal and kinetic gait parameters mainly in the pelvic, but also in the thoracic limbs. Double support phase of the individual limb was prolonged in SCI dogs at the cost of the single support and swing phase. Reduced peaks of ground reaction forces (GRF) could potentially be explained by reduction of muscle strength, as a strategy of avoiding falling by taking enthusiastic steps, or by alteration of the rhythmogenic spinal circuits between the pelvic and thoracic limb pattern generators.