Safety, Tolerability, and Dose-Limiting Toxicity of Lacosamide in Patients With Painful Chronic Pancreatitis: Protocol for a Phase 1 Clinical Trial to Determine Safety and Identify Side Effects.

BACKGROUND: Chronic abdominal pain is the hallmark symptom of chronic pancreatitis (CP), with 50% to 80% of patients seeking medical attention for pain control. Although several management options are available, outcomes are often disappointing, and opioids remain a mainstay of therapy. Opioid-induced hyperalgesia is a phenomenon resulting in dose escalation, which may occur partly because of the effects of opioids on voltage-gated sodium channels associated with pain. Preclinical observations demonstrate that the combination of an opioid and the antiseizure drug lacosamide diminishes opioid-induced hyperalgesia and improves pain control. OBJECTIVE: In this phase 1 trial, we aim to determine the safety, tolerability, and dose-limiting toxicity of adding lacosamide to opioids for the treatment of painful CP and assess the feasibility of performance of a pilot study of adding lacosamide to opioid therapy in patients with CP. As an exploratory aim, we will assess the efficacy of adding lacosamide to opioid therapy in patients with painful CP. METHODS: Using the Bayesian optimal interval design, we will conduct a dose-escalation trial of adding lacosamide to opioid therapy in patients with painful CP enrolled in cohorts of size 3. The initial dose will be 50 mg taken orally twice a day, followed by incremental increases to a maximum dose of 400 mg/day, with lacosamide administered for 7 days at each dose level. Adverse events will be documented according to Common Terminology Criteria for Adverse Events (version 5.0). RESULTS: As of December 2023, we have currently enrolled 6 participants. The minimum number of participants to be enrolled is 12 with a maximum of 24. We expect to publish the results by March 2025. CONCLUSIONS: This trial will test the feasibility of the study design and provide reassurance regarding the tolerability and safety of opioids in treating painful CP. It is anticipated that lacosamide will prove to be safe and well tolerated, supporting a subsequent phase 2 trial assessing the efficacy of lacosamide+opioid therapy in patients with painful CP, and that lacosamide combined with opiates will lower the opioid dose necessary for pain relief and improve the safety profile of opioid use in treating painful CP. TRIAL REGISTRATION: Clinicaltrials.gov NCT05603702; https://clinicaltrials.gov/study/NCT05603702. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/50513.

Effect of reactive oxygen, nitrogen, and sulfur species on signaling pathways in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease in which fats, lipids, cholesterol, calcium, proliferating smooth muscle cells, and immune cells accumulate in the intima of the large arteries, forming atherosclerotic plaques. A complex interplay of various vascular and immune cells takes place during the initiation and progression of atherosclerosis. Multiple reports indicate that tight control of reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) production is critical for maintaining vascular health. Unrestricted ROS and RNS generation may lead to activation of various inflammatory signaling pathways, facilitating atherosclerosis. Given these deleterious consequences, it is important to understand how ROS and RNS affect the signaling processes involved in atherogenesis. Conversely, RSS appears to exhibit an atheroprotective potential and can alleviate the deleterious effects of ROS and RNS. Herein, we review the literature describing the effects of ROS, RNS, and RSS on vascular smooth muscle cells, endothelial cells, and macrophages and focus on how changes in their production affect the initiation and progression of atherosclerosis. This review also discusses the contribution of ROS, RNS, and RSS in mediating various post-translational modifications, such as oxidation, nitrosylation, and sulfation, of the molecules involved in inflammatory signaling.

Integrated Feedforward and Feedback Mechanisms in Neurovascular Coupling.

Neurovascular coupling (NVC) is the mechanism that drives the neurovascular response to neural activation, and NVC dysfunction has been implicated in various neurologic diseases. NVC is driven by (1) nonmetabolic feedforward mechanisms that are mediated by various signaling pathways and (2) metabolic feedback mechanisms that involve metabolic factors. However, the interplay between these feedback and feedforward mechanisms remains unresolved. We propose that feedforward mechanisms normally drive a swift, neural activation-induced regional cerebral blood flow (rCBF) overshoot, which floods the tissue beds, leading to local hypocapnia and hyperoxia. The feedback mechanisms are triggered by the resultant hypocapnia (not hyperoxia), which causes cerebral vasoconstriction in the neurovascular unit that counterbalances the rCBF overshoot and returns rCBF to a level that matches the metabolic activity. If feedforward mechanisms function improperly (eg, in a disease state), the rCBF overshoot, tissue-bed flooding, and local hypocapnia fail to occur or occur on a smaller scale. Consequently, the neural activation-related increase in metabolic activity results in local hypercapnia and hypoxia, both of which drive cerebral vasodilation and increase rCBF. Thus, feedback mechanisms ensure the brain milieu's stability when feedforward mechanisms are impaired. Our proposal integrates the feedforward and feedback mechanisms underlying NVC and suggests that these 2 mechanisms work like a fail-safe system, to a certain degree. We also discussed the difference between NVC and cerebral metabolic rate-CBF coupling and the clinical implications of our proposed framework.

Using AI to Write a Review Article Examining the Role of the Nervous System on Skeletal Homeostasis and Fracture Healing.

PURPOSE OF REVIEW: Three review articles have been written that discuss the roles of the central and peripheral nervous systems in fracture healing. While content among the articles is overlapping, there is a key difference between them: the use of artificial intelligence (AI). In one paper, the first draft was written solely by humans. In the second paper, the first draft was written solely by AI using ChatGPT 4.0 (AI-only or AIO). In the third paper, the first draft was written using ChatGPT 4.0 but the literature references were supplied from the human-written paper (AI-assisted or AIA). This project was done to evaluate the capacity of AI to conduct scientific writing. Importantly, all manuscripts were fact checked and extensively edited by all co-authors rendering the final manuscript drafts significantly different from the first drafts. RECENT FINDINGS: Unsurprisingly, the use of AI decreased the time spent to write a review. The two AI-written reviews took less time to write than the human-written paper; however, the changes and editing required in all three manuscripts were extensive. The human-written paper was edited the most. On the other hand, the AI-only paper was the most inaccurate with inappropriate reference usage and the AI-assisted paper had the greatest incidence of plagiarism. These findings show that each style of writing presents its own unique set of challenges and advantages. While AI can theoretically write scientific reviews, from these findings, the extent of editing done subsequently, the inaccuracy of the claims it makes, and the plagiarism by AI are all factors to be considered and a primary reason why it may be several years into the future before AI can present itself as a viable alternative for traditional scientific writing.

Role of the Neurologic System in Fracture Healing: An Extensive Review.

PURPOSE OF REVIEW: Despite advances in orthopedics, there remains a need for therapeutics to hasten fracture healing. However, little focus is given to the role the nervous system plays in regulating fracture healing. This paucity of information has led to an incomplete understanding of fracture healing and has limited the development of fracture therapies that integrate the importance of the nervous system. This review seeks to illuminate the integral roles that the nervous system plays in fracture healing. RECENT FINDINGS: Preclinical studies explored several methodologies for ablating peripheral nerves to demonstrate ablation-induced deficits in fracture healing. Conversely, activation of peripheral nerves via the use of dorsal root ganglion electrical stimulation enhanced fracture healing via calcitonin gene related peptide (CGRP). Investigations into TLR-4, TrkB agonists, and nerve growth factor (NGF) expression provide valuable insights into molecular pathways influencing bone mesenchymal stem cells and fracture repair. Finally, there is continued research into the connections between pain and fracture healing with findings suggesting that anti-NGF may be able to block pain without affecting healing. This review underscores the critical roles of the central nervous system (CNS), peripheral nervous system (PNS), and autonomic nervous system (ANS) in fracture healing, emphasizing their influence on bone cells, neuropeptide release, and endochondral ossification. The use of TBI models contributes to understanding neural regulation, though the complex influence of TBI on fracture healing requires further exploration. The review concludes by addressing the neural connection to fracture pain. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.

Cracking the Code: The Role of Peripheral Nervous System Signaling in Fracture Repair.

PURPOSE OF REVIEW: The traditionally understated role of neural regulation in fracture healing is gaining prominence, as recent findings underscore the peripheral nervous system's critical contribution to bone repair. Indeed, it is becoming more evident that the nervous system modulates every stage of fracture healing, from the onset of inflammation to repair and eventual remodeling. RECENT FINDINGS: Essential to this process are neurotrophins and neuropeptides, such as substance P, calcitonin gene-related peptide, and neuropeptide Y. These molecules fulfill key roles in promoting osteogenesis, influencing inflammation, and mediating pain. The sympathetic nervous system also plays an important role in the healing process: while local sympathectomies may improve fracture healing, systemic sympathetic denervation impairs fracture healing. Furthermore, chronic activation of the sympathetic nervous system, often triggered by stress, is a potential impediment to effective fracture healing, marking an important area for further investigation. The potential to manipulate aspects of the nervous system offers promising therapeutic possibilities for improving outcomes in fracture healing. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.

Do Not Lose Your Nerve, Be Callus: Insights Into Neural Regulation of Fracture Healing.

PURPOSE OF REVIEW: Fractures are a prominent form of traumatic injury and shall continue to be for the foreseeable future. While the inflammatory response and the cells of the bone marrow microenvironment play significant roles in fracture healing, the nervous system is also an important player in regulating bone healing. RECENT FINDINGS: Considerable evidence demonstrates a role for nervous system regulation of fracture healing in a setting of traumatic injury to the brain. Although many of the impacts of the nervous system on fracture healing are positive, pain mediated by the nervous system can have detrimental effects on mobilization and quality of life. Understanding the role the nervous system plays in fracture healing is vital to understanding fracture healing as a whole and improving quality of life post-injury. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.

Propranolol treatment during repetitive mild traumatic brain injuries induces transcriptomic changes in the bone marrow of mice.

Introduction: There are 1.5 million new mild traumatic brain injuries (mTBI) annually in the US, with many of the injured experiencing long-term consequences lasting months after the injury. Although the post injury mechanisms are not well understood, current knowledge indicates peripheral immune system activation as a causal link between mTBI and long-term side effects. Through a variety of mechanisms, peripheral innate immune cells are recruited to the CNS after TBI to repair and heal the injured tissue; however, the recruitment and activation of these cells leads to further inflammation. Emerging evidence suggests sympathetic nervous system (SNS) activity plays a substantial role in the recruitment of immune cells post injury. Methods: We sought to identify the peripheral innate immune response after repeated TBIs in addition to repurposing the nonselective beta blocker propranolol as a novel mTBI therapy to limit SNS activity and mTBI pathophysiology in the mouse. Mice underwent repetitive mTBI or sham injury followed by i.p. saline or propranolol. Isolated mRNA derived from femur bone marrow of mice was assayed for changes in gene expression at one day, one week, and four weeks using Nanostring nCounter® stem cell characterization panel. Results: Differential gene expression analysis for bone marrow uncovered significant changes in many genes following drug alone, mTBI alone and drug combined with mTBI. Discussion: Our data displays changes in mRNA at various timepoints, most pronounced in the mTBI propranolol group, suggesting a single dose propranolol injection as a viable future mTBI therapy in the acute setting.

Repeated closed-head mild traumatic brain injury-induced inflammation is associated with nociceptive sensitization.

BACKGROUND: Individuals who have experienced mild traumatic brain injuries (mTBIs) suffer from several comorbidities, including chronic pain. Despite extensive studies investigating the underlying mechanisms of mTBI-associated chronic pain, the role of inflammation in long-term pain after mTBIs is not fully elucidated. Given the shifting dynamics of inflammation, it is important to understand the spatial-longitudinal changes in inflammatory processes following mTBIs and their effects on TBI-related pain. METHODS: We utilized a recently developed transgenic caspase-1 luciferase reporter mouse model to monitor caspase-1 activation through a thinned skull window in the in vivo setting following three closed-head mTBI events. Organotypic coronal brain slice cultures and acutely dissociated dorsal root ganglion (DRG) cells provided tissue-relevant context of inflammation signal. Mechanical allodynia was assessed by mechanical withdrawal threshold to von Frey and thermal hyperalgesia withdrawal latency to radiant heat. Mouse grimace scale (MGS) was used to detect spontaneous or non-evoked pain. In some experiments, mice were prophylactically treated with MCC950, a potent small molecule inhibitor of NLRP3 inflammasome assembly to inhibit injury-induced inflammatory signaling. Bioluminescence spatiotemporal dynamics were quantified in the head and hind paws, and caspase-1 activation was confirmed by immunoblot. Immunofluorescence staining was used to monitor the progression of astrogliosis and microglial activation in ex vivo brain tissue following repetitive closed-head mTBIs. RESULTS: Mice with repetitive closed-head mTBIs exhibited significant increases of the bioluminescence signals within the brain and paws in vivo for at least one week after each injury. Consistently, immunoblotting and immunofluorescence experiments confirmed that mTBIs led to caspase-1 activation, astrogliosis, and microgliosis. Persistent changes in MGS and hind paw withdrawal thresholds, indicative of pain states, were observed post-injury in the same mTBI animals in vivo. We also observed enhanced inflammatory responses in ex vivo brain slice preparations and DRG for at least 3 days following mTBIs. In vivo treatment with MCC950 significantly reduced caspase-1 activation-associated bioluminescent signals in vivo and decreased stimulus-evoked and non-stimulus evoked nociception. CONCLUSIONS: Our findings suggest that the inflammatory states in the brain and peripheral nervous system following repeated mTBIs are coincidental with the development of nociceptive sensitization, and that these events can be significantly reduced by inhibition of NLRP3 inflammasome activation.

Returning to education after childhood acquired brain injury: Learning from lived parental experience.

BACKGROUND: Returning to education (RtE) after an acquired brain injury (ABI) can be stressful for children/young people (CYP) and families. While much can be done to support RtE, there has been limited exploration of the lived experience of parents/carers about what can both help and hinder the process. OBJECTIVE: The aim was to understand more about RtE from parents' perspectives to inform best practice and facilitate improvements in service delivery. METHODS: A service evaluation explored parent/carer views about the RtE process and the support received from healthcare professionals at a regional centre in the UK. Questionnaires (n = 59) were sent to parents of patients treated for an ABI in the last two years. RESULTS: 31 parents (response rate = 51%) completed the survey. Results highlight the many challenges of RtE. Thematic analysis of responses revealed six key themes: Parental mindset and growth; What do they need now?; Specialist support and information; Talk and share; Challenges of new and hidden needs; and Don't forget them! CONCLUSION: Parents offer crucial insight into the challenges of the RtE process. Their feedback highlights important factors for service development and reminds professionals of the key components of an effective return.

Long-Term Treatment with Gadopentetic Acid or Gadodiamide Increases TRPC5 Expression and Decreases Adriamycin Nuclear Accumulation in Breast Cancer Cells.

Gadopentetic acid and gadodiamide are paramagnetic gadolinium-based contrast agents (GBCAs) that are routinely used for dynamic contrast-enhanced magnetic resonance imaging (MRI) to monitor disease progression in cancer patients. However, growing evidence indicates that repeated administration of GBCAs may lead to gadolinium (III) cation accumulation in the cortical bone tissue, skin, basal ganglia, and cerebellum, potentially leading to a subsequent slow long-term discharge of Gd3+. Gd3+ is a known activator of the TRPC5 channel that is implicated in breast cancer's resistance to chemotherapy. Herein, we found that gadopentetic acid (Gd-DTPA, 1 mM) potentiated the inward and outward currents through TRPC5 channels, which were exogenously expressed in HEK293 cells. Gd-DTPA (1 mM) also activated the Gd3+-sensitive R593A mutant of TRPC5, which exhibits a reduced sensitivity to GPCR-Gq/11-PLC dependent gating. Conversely, Gd-DTPA had no effect on TRPC5-E543Q, a Gd3+ insensitive TRPC5 mutant. Long-term treatment (28 days) of human breast cancer cells (MCF-7 and SK-BR-3) and adriamycin-resistant MCF-7 cells (MCF-7/ADM) with Gd-DTPA (1 mM) or gadodiamide (GDD, 1 mM) did not affect the IC50 values of ADM. However, treatment with Gd-DTPA or GDD significantly increased TRPC5 expression and decreased the accumulation of ADM in the nuclei of MCF-7 and SK-BR-3 cells, promoting the survival of these two breast cancer cells in the presence of ADM. The antagonist of TRPC5, AC1903 (1 µM), increased ADM nuclear accumulation induced by Gd-DTPA-treatment. These data indicate that prolonged GBCA treatment may lead to increased breast cancer cell survival owing to the upregulation of TRPC5 expression and the increased ADM resistance. We propose that while focusing on providing medical care of the best personalized quality in the clinic, excessive administration of GBCAs should be avoided in patients with metastatic breast cancer to reduce the risk of promoting breast cancer cell drug resistance.

Repeated mild traumatic brain injury in mice elicits long term innate immune cell alterations in blood, spleen, and brain.

Mild traumatic brain injury is an insidious event whereby the initial injury leads to ongoing secondary neuro- and systemic inflammation through various cellular pathways lasting days to months after injury. Here, we investigated the impact of repeated mild traumatic brain injury (rmTBI) and the resultant systemic immune response in male C57B6 mice using flow cytometric methodology on white blood cells (WBCs) derived from the blood and spleen. Isolated mRNA derived from spleens and brains of rmTBI mice was assayed for changes in gene expression at one day, one week, and one month following the injury paradigm. We observed increases in Ly6C+, Ly6C-, and total monocyte percentages in both blood and spleen at one month after rmTBI. Differential gene expression analysis for the brain and spleen tissues uncovered significant changes in many genes, including csf1r, itgam, cd99, jak1,cd3ε, tnfaip6, and nfil3. Additional analysis revealed alterations in several immune signaling pathways over the course of one month in the brain and spleen of rmTBI mice. Together, these results indicate that rmTBI produces pronounced gene expression changes in the brain and spleen. Furthermore, our data suggest that monocyte populations may reprogram towards the proinflammatory phenotype over extended periods of time after rmTBI.

Dihydroceramides Derived from Bacteroidetes Species Sensitize TRPV1 Channels.

Bacterial colonization of open wounds is common, and patients with infected wounds often report significantly elevated pain sensitivity at the wound site. Transient Receptor Potential Vanilloid Type 1 (TRPV1) channels are known to play an important role in pain signaling and may be sensitized under pro-inflammatory conditions. Bacterial membrane components, such as phosphoethanolamine dihydroceramide (PEDHC), phosphoglycerol dihydroceramide (PGDHC), and lipopolysaccharide (LPS), are released in the environment from the Gram-negative bacteria of the Bacteroidetes species colonizing the infected wounds. Here, we used intracellular calcium imaging and patch-clamp electrophysiology approaches to determine whether bacterially derived PEDHC, PGDHC, or LPS can modulate the activity of the TRPV1 channels heterologously expressed in HEK cells. We found that PEDHC and PGDHC can sensitize TRPV1 in a concentration-dependent manner, whereas LPS treatment does not significantly affect TRPV1 activity in HEK cells. We propose that sensitization of TRPV1 channels by Bacteroidetes-derived dihydroceramides may at least in part underlie the increased pain sensitivity associated with wound infections.

Racial Differences in Head Pain and Other Pain-Related Outcomes After Mild Traumatic Brain Injury.

Recent research suggests that mild traumatic brain injury (TBI) may exert deleterious effects on endogenous pain modulatory function, potentially underlying the elevated risk for persistent headaches following injury. Accumulating research also shows race differences in clinical and experimental pain, with African Americans (AA) generally reporting more severe pain, worse pain modulation, and greater pain sensitivity compared with Caucasians. However, race differences in pain-related outcomes following mild TBI have rarely been studied. The purpose of this study was to explore race differences in endogenous pain modulation, pain sensitivity, headache pain, and psychological factors among AA and Caucasian individuals with mild TBI in the first month following injury compared with healthy controls and across time. Patients with mild TBI were recruited from local emergency department trauma centers. Sixty-three participants with mild TBI (AAs: n = 23, Caucasians: n = 40) enrolled in this study and completed study sessions at 1-2 weeks and 1-month post-injury. Forty-one mild-TBI-free control participants (AAs: n = 11, Caucasians: n = 30), matched on age and sex, completed one study session. Assessments included a Headache Survey, Pain Catastrophizing Scale, Center for Epidemiological Studies-Depression Scale (CES-D), and quantitative sensory testing (QST) to measure endogenous pain modulatory function. QST included conditioned pain modulation (CPM) to measure endogenous pain inhibitory function and temporal summation (TS) of pain and pressure pain thresholds (PPTs) of the head to measure pain sensitization and sensitivity. Two-way analysis of variance (ANOVA) was used to determine whether the outcome measures differed as a function of race, mild TBI, and time. Mediation analysis was used to explore potential mediators for the race differences in headache pain intensity. The results showed that AA participants with mild TBI reported significantly greater headache pain and pain catastrophizing and exhibited higher pain sensitivity and worse pain modulation on QST compared with Caucasian participants with mild TBI. These same race differences were not observed among the healthy TBI-free control sample. The mediation analyses showed complete mediation for the relation between race and headache pain intensity by pain catastrophizing at 1-2 weeks and 1-month post-injury. Overall, the results of this study suggest that AAs compared with Caucasians are characterized by psychological and pain modulatory profiles following mild TBI that could increase the risk for the development of intense and persistent headaches following injury.

What Did We Learn About Fracture Pain from Animal Models?

Progress in bone fracture repair research has been made possible due to the development of reproducible models of fracture in rodents with more clinically relevant fracture fixation, where there is considerably better assessment of the factors that affect fracture healing and/or novel therapeutics. However, chronic or persistent pain is one of the worst, longest-lasting and most difficult symptoms to manage after fracture repair, and an ongoing challenge remains for animal welfare as limited information exists regarding pain scoring and management in these rodent fracture models. This failure of adequate pre-clinical pain assessment following osteotomy in the rodent population may not only subject the animal to severe pain states but may also affect the outcome of the bone healing study. Animal models to study pain were also mainly developed in rodents, and there is increasing validation of fracture and pain models to quantitatively evaluate fracture pain and to study the factors that generate and maintain fracture pain and develop new therapies for treating fracture pain. This review aims to discuss the different animal models for fracture pain research and characterize what can be learned from using animal models of fracture regarding behavioral pain states and new molecular targets for future management of these behaviors.

Performance of Echocardiographic Algorithms for Assessment of High Aortic Bioprosthetic Valve Gradients.

BACKGROUND: Bioprosthetic aortic valve dysfunction (BAVD) is a challenging diagnosis. Commonly used algorithms to classify high-gradient BAVD are the 2009 American Society of Echocardiography, 2014 Blauwet-Miller, and 2016 European Association of Cardiovascular Imaging algorithms. We sought (1) to evaluate the accuracy of existing algorithms against objectively proven BAVD and (2) to propose an improved algorithm. METHODS: This was a retrospective study of 266 patients with objectively proven BAVD (pathology of explanted valves, four-dimensional computed tomography prior to transcatheter valve-in-valve replacement, or therapeutically confirmed bioprosthetic thrombosis) who were treated. Of those, 191 had obstruction, 48 had regurgitation, 15 had mixed stenosis and regurgitation, and 12 had patient-prosthesis mismatch (PPM). Normal controls were matched 1:1 (age, prosthesis size, and type), of which 43 had high gradients (PPM in 30, high flow in nine, and normal prosthesis in nine). Algorithm assignment was based on the echocardiogram leading to BAVD diagnosis and the predischarge "fingerprint" echocardiogram after surgical or transcatheter aortic valve replacement. A novel algorithm (Mayo Clinic algorithm) incorporating valve appearance in addition to Doppler parameters was developed to improve observed deficiencies. RESULTS: The accuracy of existing algorithms was suboptimal (2009 American Society of Echocardiography, 62%; 2014 Blauwet-Miller, 62%; 2016 European Association of Cardiovascular Imaging, 57%). The most common overdiagnosis was PPM (22%-29% of patients and controls with high gradients). The novel Mayo Clinic algorithm correctly identified the mechanism in 256 of 307 patients and controls (83%). Recognition of regurgitation was substantially improved (42 of 47 patients, 89%), and the number of PPM misdiagnoses was significantly reduced (five patients). CONCLUSION: Currently recommended algorithms misclassify a significant number of BAVD patients. The accuracy was improved by a newly proposed algorithm.

Effectiveness of maturity of Rubus occidentalis on hyperalgesia induced by acidic saline injection in rats.

BACKGROUND: Rubus occidentalis, also known as black raspberry, contains several bioactive components that vary depending on the maturity of the fruit. The goal of this study was to evaluate the efficacy of immature Rubus occidentalis extract(iROE) on acid-induced hyperalgesia, investigate the mechanism involved, and compare the antihyperalgesic effect of immature and mature ROEs. METHODS: In adult male Sprague-Dawley rats, chronic muscle pain was induced via two injections of acidic saline into one gastrocnemius muscle. To evaluate the dose response, the rats were injected intraperitoneally with 0.9% saline or iROE (10, 30, 100, or 300 mg/kg) following hyperalgesia development. To evaluate the mechanism underlying iROE-induced analgesia, the rats were injected intraperitoneally with saline, yohimbine 2 mg/kg, dexmedetomidine 50 µg/kg, prazosin 1 mg/kg, atropine 5 mg/kg, mecamylamine 1 mg/kg, or naloxone 5 mg/kg 24 h after hyperalgesia development, followed by iROE 300 mg/kg administration. To compare immature versus mature ROE, the rats were injected with mature ROE 300 mg/kg and immature ROE 300 mg/kg after hyperalgesia development. For all experiments, the mechanical withdrawal threshold(MWT) was evaluated using von Frey filaments before the first acidic saline injection, 24 h after the second injection, and at various time points after drug administration. Data were analysed using multivariate analysis of variance(MANOVA) and the linear mixed-effects model(LMEM). We compared the MWT at each time point using analysis of variance with the Bonferroni correction. RESULTS: The iROE 300 mg/kg injection resulted in a significant increase in MWT compared with the control, iROE 30 mg/kg, and iROE 100 mg/kg injections at ipsilateral and contralateral sites. The iROE injection together with yohimbine, mecamylamine, or naloxone significantly decreased the MWT compared with iROE alone, whereas ROE together with dexmedetomidine significantly increased the MWT. According to MANOVA, the effects of immature and mature ROEs were not significantly different; however, the LMEM presented a significant difference between the two groups. CONCLUSIONS: Immature R. occidentalis showed antihyperalgesic activity against acid-induced chronic muscle pain, which may be mediated by the α2-adrenergic, nicotinic cholinergic, and opioid receptors. The iROE displayed superior tendency regarding analgesic effect compared to mature ROE.

Physical activity behavior in the first month after mild traumatic brain injury is associated with physiological and psychological risk factors for chronic pain.

OBJECTIVE: The purpose of this study was to determine whether self-reported physical activity (PA) in the first month after mild traumatic brain injury (mTBI) predicts endogenous pain modulatory function and pain catastrophizing at 1 to 2 weeks and 1 month after injury in patients with mTBI. METHODS: Patients with mild traumatic brain injury completed study sessions at 1 to 2 weeks and 1 month after injury. Assessments included a headache survey, Pain Catastrophizing Scale, International Physical Activity Questionnaire-Short Form, and several quantitative sensory tests to measure endogenous pain modulatory function including conditioned pain modulation (CPM), temporal summation, and pressure pain thresholds of the head. Hierarchical linear regressions determined the relationship between the PA variables (predictors) and pain catastrophizing and pain modulation variables (dependent variables) cross-sectionally and longitudinally, while controlling for potential covariates. RESULTS: In separate hierarchical regression models, moderate PA, walking, and total PA at 1 to 2 weeks after injury predicted pain inhibition on the CPM test at 1 month, after controlling for significant covariates. In addition, a separate regression revealed that minutes sitting at 1 month predicted CPM at 1 month. Regarding predicting pain catastrophizing, the regression results showed that sitting at 1 to 2 weeks after injury significantly predicted pain catastrophizing at 1 month after injury. CONCLUSION: Greater self-reported PA, especially moderate PA, 1 to 2 weeks after injury longitudinally predicted greater pain inhibitory capacity on the CPM test at 1 month after injury in patients with mTBI. In addition, greater sedentary behavior was associated with worse pain inhibition on the CPM test and greater pain catastrophizing at 1 month after injury.

Continuing professional development for veterinarians in a changing world.

The veterinary profession has time and again successfully adapted to new challenges and developments, with considerable evolution of the skills needed. Different contexts, production systems and societal requirements continue to shape the profession, resulting in an increasing demand for specialisation, interdisciplinary collaboration along value chains, and preparedness for the omnipresent risk of emerging diseases. To keep up with changes, new insights, advances in research and novel ways to address challenges, continuing professional development (CPD) and the adaptation and updating of the veterinary curriculum have been essential to maintain and enhance the quality and performance of Veterinary Services. This paper reviews actors involved in the provision of Veterinary Services and discusses how vital CPD is in addressing current and future challenges, by focusing on veterinarians and allied veterinary professionals. The authors examine how providers of CPD contribute to the system and how the internal and external factors of a cohort or individual affect the quality and impact of capacity development. The paper further examines the landscape of veterinary CPD in terms of organisational structures, pedagogical approaches, the transition from input- to outcome-based learning, modern delivery tools, and the demands on the different actors involved in the delivery of animal health services. The authors conclude that CPD is essential if the quality of Veterinary Services is to keep pace with the ever-increasing and evolving demands of the 21st century. A CPD programme should therefore be constructed in a way that is tailored to the needs of veterinary professionals and to the requirements of their workplace, whether they work with animal keepers, livestock value chains, national governments or international regulatory bodies. An optimised and successful veterinary sector requires an evidencebased CPD programme that keeps those professionals who are involved in the delivery of animal health services both competent and relevant in a changing world.

La profession vétérinaire s'est adaptée à maintes reprises et avec succès à de nouveaux défis et évolutions qui ont nécessité la mobilisation d'un grand nombre de compétences nouvelles. La diversité des contextes, des systèmes de production et des exigences sociétales impose à la profession vétérinaire des transformations continues, avec pour conséquences une demande croissante de spécialisation et de collaborations interdisciplinaires le long des chaînes de valeur et la nécessité de mieux se préparer au risque omniprésent de maladies émergentes. Face aux changements intervenus, aux nouvelles connaissances, aux progrès de la recherche et aux nouvelles manières de relever les défis, la formation professionnelle continue (FPC) et l'adaptation et actualisation des cursus d'enseignement vétérinaire ont joué un rôle déterminant pour maintenir et améliorer la qualité et les performances des Services vétérinaires. Les auteurs font le point sur les divers prestataires de services vétérinaires et examinent le rôle essentiel de la FPC pour relever les défis actuels et futurs, en mettant l'accent sur les vétérinaires et les professions connexes travaillant en lien avec les vétérinaires. Ils analysent la contribution des fournisseurs de FPC au système de santé animale, ainsi que l'influence sur la qualité et l'impact du renforcement des capacités d'un certain nombre de facteurs internes et externes à l'échelle des cohortes ou des individus. Les auteurs décrivent également le paysage de la FPC dans le domaine vétérinaire et plus particulièrement les structures organisationnelles, les approches pédagogiques, la transition d'un apprentissage axé sur les contenus à un apprentissage axé sur les résultats, les outils modernes de formation et les exigences imposées aux différents prestataires de services de santé animale dans un monde en constante évolution. En conclusion, les auteurs insistent sur l'importance cruciale de mettre en place des dispositifs de formation professionnelle continue destinés au secteur vétérinaire, afin que la qualité des services fournis soit à la hauteur des exigences croissantes et en constante évolution du 21e siècle. Les programmes de FPC doivent donc être conçus en veillant à s'adapter aux besoins des vétérinaires et des professionnels des domaines connexes concernant les compétences spécifiques qu'ils doivent déployer en fonction des exigences de leur activité, qu'ils travaillent auprès des gardiens d'animaux, des professionnels des filières issues de l'élevage, des gouvernements nationaux ou des organismes internationaux chargés de l'élaboration de normes. Un secteur vétérinaire optimisé et performant nécessite un programme de FPC fondé sur des données concrètes afin que les vétérinaires et les autres prestataires de services de santé animale puissent maintenir leur niveau de compétences ainsi que la pertinence de leurs interventions au regard des exigences évolutives d'un monde en pleine transformation. La profession vétérinaire s'est adaptée à maintes reprises et avec succès à de nouveaux défis et évolutions qui ont nécessité la mobilisation d'un grand nombre de compétences nouvelles. La diversité des contextes, des systèmes de production et des exigences sociétales impose à la profession vétérinaire des transformations continues, avec pour conséquences une demande croissante de spécialisation et de collaborations interdisciplinaires le long des chaînes de valeur et la nécessité de mieux se préparer au risque omniprésent de maladies émergentes. Face aux changements intervenus, aux nouvelles connaissances, aux progrès de la recherche et aux nouvelles manières de relever les défis, la formation professionnelle continue (FPC) et l'adaptation et actualisation des cursus d'enseignement vétérinaire ont joué un rôle déterminant pour maintenir et améliorer la qualité et les performances des Services vétérinaires. Les auteurs font le point sur les divers prestataires de services vétérinaires et examinent le rôle essentiel de la FPC pour relever les défis actuels et futurs, en mettant l'accent sur les vétérinaires et les professions connexes travaillant en lien avec les vétérinaires. Ils analysent la contribution des fournisseurs de FPC au système de santé animale, ainsi que l'influence sur la qualité et l'impact du renforcement des capacités d'un certain nombre de facteurs internes et externes à l'échelle des cohortes ou des individus. Les auteurs décrivent également le paysage de la FPC dans le domaine vétérinaire et plus particulièrement les structures organisationnelles, les approches pédagogiques, la transition d'un apprentissage axé sur les contenus à un apprentissage axé sur les résultats, les outils modernes de formation et les exigences imposées aux différents prestataires de services de santé animale dans un monde en constante évolution. En conclusion, les auteurs insistent sur l'importance cruciale de mettre en place des dispositifs de formation professionnelle continue destinés au secteur vétérinaire, afin que la qualité des services fournis soit à la hauteur des exigences croissantes et en constante évolution du 21e siècle. Les programmes de FPC doivent donc être conçus en veillant à s'adapter aux besoins des vétérinaires et des professionnels des domaines connexes concernant les compétences spécifiques qu'ils doivent déployer en fonction des exigences de leur activité, qu'ils travaillent auprès des gardiens d'animaux, des professionnels des filières issues de l'élevage, des gouvernements nationaux ou des organismes internationaux chargés de l'élaboration de normes. Un secteur vétérinaire optimisé et performant nécessite un programme de FPC fondé sur des données concrètes afin que les vétérinaires et les autres prestataires de services de santé animale puissent maintenir leur niveau de compétences ainsi que la pertinence de leurs interventions au regard des exigences évolutives d'un monde en pleine transformation. La profession vétérinaire s'est adaptée à maintes reprises et avec succès à de nouveaux défis et évolutions qui ont nécessité la mobilisation d'un grand nombre de compétences nouvelles. La diversité des contextes, des systèmes de production et des exigences sociétales impose à la profession vétérinaire des transformations continues, avec pour conséquences une demande croissante de spécialisation et de collaborations interdisciplinaires le long des chaînes de valeur et la nécessité de mieux se préparer au risque omniprésent de maladies émergentes. Face aux changements intervenus, aux nouvelles connaissances, aux progrès de la recherche et aux nouvelles manières de relever les défis, la formation professionnelle continue (FPC) et l'adaptation et actualisation des cursus d'enseignement vétérinaire ont joué un rôle déterminant pour maintenir et améliorer la qualité et les performances des Services vétérinaires. Les auteurs font le point sur les divers prestataires de services vétérinaires et examinent le rôle essentiel de la FPC pour relever les défis actuels et futurs, en mettant l'accent sur les vétérinaires et les professions connexes travaillant en lien avec les vétérinaires. Ils analysent la contribution des fournisseurs de FPC au système de santé animale, ainsi que l'influence sur la qualité et l'impact du renforcement des capacités d'un certain nombre de facteurs internes et externes à l'échelle des cohortes ou des individus. Les auteurs décrivent également le paysage de la FPC dans le domaine vétérinaire et plus particulièrement les structures organisationnelles, les approches pédagogiques, la transition d'un apprentissage axé sur les contenus à un apprentissage axé sur les résultats, les outils modernes de formation et les exigences imposées aux différents prestataires de services de santé animale dans un monde en constante évolution. En conclusion, les auteurs insistent sur l'importance cruciale de mettre en place des dispositifs de formation professionnelle continue destinés au secteur vétérinaire, afin que la qualité des services fournis soit à la hauteur des exigences croissantes et en constante évolution du 21e siècle. Les programmes de FPC doivent donc être conçus en veillant à s'adapter aux besoins des vétérinaires et des professionnels des domaines connexes concernant les compétences spécifiques qu'ils doivent déployer en fonction des exigences de leur activité, qu'ils travaillent auprès des gardiens d'animaux, des professionnels des filières issues de l'élevage, des gouvernements nationaux ou des organismes internationaux chargés de l'élaboration de normes. Un secteur vétérinaire optimisé et performant nécessite un programme de FPC fondé sur des données concrètes afin que les vétérinaires et les autres prestataires de services de santé animale puissent maintenir leur niveau de compétences ainsi que la pertinence de leurs interventions au regard des exigences évolutives d'un monde en pleine transformation.

La profesión veterinaria siempre ha sabido adaptarse con éxito a las novedades y nuevos problemas que han ido surgiendo, y que requieren la adquisición de nuevos conocimientos y aptitudes. Los diferentes contextos, sistemas productivos y necesidades sociales siguen configurando la profesión veterinaria y generando una creciente demanda de especialización, de colaboración interdisciplinar en todos los eslabones de las cadenas de valor y de preparación ante el omnipresente riesgo que plantean las enfermedades emergentes. El perfeccionamiento profesional continuo (PPC) y la adaptación y actualización de los planes de estudios veterinarios han sido factores esenciales para seguir el ritmo de las transformaciones, las nuevas ideas, los avances científicos y las novedosas respuestas a los problemas y, gracias a ello, mantener y mejorar la calidad y el desempeño de los Servicios Veterinarios. Los autores pasan revista a cuantos agentes intervienen en la prestación de servicios veterinarios y, centrándose en los veterinarios y cuerpos profesionales conexos, exponen la función crucial que cumple el PPC para hacer frente a los problemas de hoy y de mañana. También explican cómo contribuyen al sistema los proveedores de PPC y cómo los factores internos y externos de una cohorte o un individuo afectan a la calidad y la repercusión del desarrollo de capacidades. Además, describen el panorama que ofrece el PPC en veterinaria desde el punto de vista de las estructuras organizativas, los planteamientos pedagógicos, la transición del aprendizaje de asimilación al aprendizaje por resultados, las modernas herramientas de trabajo y las exigencias que deben satisfacer los distintos agentes que intervienen en la prestación de servicios zoosanitarios en un mundo en plena evolución. Los autores concluyen que es de la máxima importancia ocuparse del PPC para que los servicios veterinarios dispensados sigan siendo de calidad y respondiendo a las crecientes y mudables exigencias que trae consigo el siglo XXI. Hay que establecer pues un programa de PPC especialmente adaptado a las necesidades de los veterinarios y cuerpos profesionales conexos, pensando en dotarlos de las competencias necesarias para satisfacer los requisitos propios de su lugar de trabajo, ya obren al servicio de la producción animal, de cadenas de valor ganaderas, de administraciones nacionales o de organismos internacionales de reglamentación. Un sector veterinario optimizado y eficaz requiere un programa de PPC científicamente fundamentado, que sirva a los veterinarios y demás agentes de la prestación de servicios zoosanitarios para seguir siendo a la vez competentes y útiles ante las cambiantes exigencias que les plantea un mundo en plena evolución.

Blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) prevents posttraumatic epileptogenesis in mice.

OBJECTIVE: Effective treatment for the prevention of posttraumatic epilepsy is still not available. Here, we sought to determine whether blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) signaling pathways would prevent posttraumatic epileptogenesis. METHODS: In a mouse undercut model of posttraumatic epilepsy, daily injections of saline, RAGE monoclonal antibody (mAb), or TAK242, a TLR4 inhibitor, were made for 1 week. Their effects on seizure susceptibility and spontaneous epileptic seizures were evaluated with a pentylenetetrazol (PTZ) test in 2 weeks and with continuous video and wireless electroencephalography (EEG) monitoring between 2 and 6 weeks after injury, respectively. Seizure susceptibility after undercut in RAGE knockout mice was also evaluated with the PTZ test. The lesioned cortex was analyzed with immunohistology. RESULTS: Undercut animals treated with RAGE mAb or TAK242 showed significantly higher seizure threshold than saline-treated undercut mice. Consistently, undercut injury in RAGE knockout mice did not cause a reduction in seizure threshold in the PTZ test. EEG and video recordings revealed a significant decrease in the cumulative spontaneous seizure events in the RAGE mAb- or TAK242-treated group (p < 0.001, when the RAGE mAb or TAK242 group is compared with the saline group). The lesioned cortical tissues of RAGE mAb- or TAK242-treated undercut group showed higher neuronal densities of Nissl staining and higher densities of glutamic acid decarboxylase 67-immunoreactive interneurons than the saline-treated undercut group. Immunostaining to GFAP and Iba-1 revealed lower densities of astrocytes and microglia in the cortex of the treatment groups, suggesting reduced glia activation. SIGNIFICANCE: RAGE and TLR4 signaling are critically involved in posttraumatic epileptogenesis. Blocking these pathways early after traumatic brain injury is a promising strategy for preventing posttraumatic epilepsy.