Rejected

Suicide is a leading cause of death and morbidity worldwide, yet few interventions are available to mitigate its risk. Barriers to effective treatments involve a limited understanding of factors that predict the onset of suicidal thoughts and behaviors. In the context of suicide risk, stress is a precipitating factor that is largely overlooked in the literature. Indeed, the pathophysiology of stress and suicide are heavily interconnected, underscoring the need to target the stress system in suicide prevention. In this review, we integrate findings from the preclinical and clinical literature that links stress and suicide. We focus specifically on the effects of stress on underlying biological functions and processes associated with suicide, allowing for the review of research using animal models. Owing to the rapid anti-suicidal effects of ()-ketamine, we discuss its ability to modulate various stress-related endophenotypes of suicide, as well as its potential role in preventing suicide in those with a history of chronic life stress (e.g., early life adversity). We highlight future research directions that could advance our understanding of stress-related effects on suicide risk, advocating a dimensional, endophenotype approach to suicide research.

Pancreatic pseudocysts remain a feared complication of acute or chronic pancreatitis and are often characterized by collections of fluids due to underlying damage to the pancreatic ducts, culminating in a walled-off region bereft of an epithelial layer but surrounded by granulation tissue. While fungal infections of pancreatic pseudocysts are rarely encountered, candida albicans remains the most frequently implicated organism.

A young male patient presents with widespread pain and varying chronic inflammatory symptoms for three years and idiopathic low bone density for more than ten years. Based on the patient's clinical history, the patient has been diagnosed with an hypermobile Ehlers-Danlos syndrome, postural orthostatic tachycardia syndrome, and mast cell activation disorder trifecta with affiliated inflammation-induced osteoporosis.

This study investigated the impact of McKenzie exercises against deep neck flexor (DNF) combined with scapulothoracic exercises on improving pain severity, cervical mobility, and functional disability.

Cannabinoid-based therapies offer a safer, non-opioid alternative for the management of chronic pain. While most studies focus on the analgesic potential of the main psychoactive component of marijuana, Δ9-tetrahydrocannabinol, fewer studies have investigated the role of the non-psychoactive component, cannabidiol (CBD). CBD has been purported to have analgesic, anti-inflammatory, anticonvulsant, and anxiolytic effects. In addition to having actions at both cannabinoid receptors (CB and CB ), CBD has been shown to interact with both the transient receptor potential vanilloid-1 (TRPV1) and serotonergic (5-HT) receptors. Clinically, CBD's lack of psychoactivity and decreased abuse liability make it an appealing pharmacotherapeutic for the management of chronic pain. Therefore, the purpose of the current study was to determine whether CBD sex- or dose-dependently reverses antinociception in an acute model of thermal pain and/or mechanical allodynia in a model of cisplatin-induced chronic neuropathic pain. Furthermore, we observed the degree to which CB , CB , 5-HT, and TRPV receptors may be mediating these anti-allodynic responses. Male and female wild-type mice were assessed for either the anti-allodynic effects of 0, 1, 3, 10, and 30 mg/kg CBD in a cisplatin-induced model of neuropathic pain or the antinociceptive effects of 0, 1, 3, 10, 30, and 100 mg/kg CBD in a model of acute thermal (tail-flick) pain 60 minutes following CBD administration. To determine the relative contributions of each receptor subtype in mediating the anti-allodynic effects of CBD, male and female mice were pretreated with either: vehicle, the CB inverse agonist SR141716A (10 mg/kg), the CB antagonist SR144528 (10 mg/kg), the TRPV antagonist capsazepine (10 mg/kg), or the 5-HT antagonist methysergide (4 mg/kg) 30 minutes prior to treatment with CBD. Mice were assessed for the effects of the pretreatment alone and in combination with CBD. CBD at a dose of 3 mg/kg was able to partially reverse cisplatin-induced allodynia in male and female mice, while doses of 10 and 30 mg/kg resulted in nearly complete reversal. Our preliminary findings showed that the anti-allodynic effects of 30 mg/kg CBD were completely blocked following pretreatment with SR141716A and SR144528, and partially blocked by capsazepine in both male and female mice. Interestingly, pretreatment with methysergide partially attenuated the anti-allodynic effects of CBD in females alone. In contrast, CBD (0-100 mg/kg) failed to induce antinociception on the tail-flick assay. CBD did induce mild hypothermia with males showing a greater degree of CBD-mediated hypothermia than female mice. Taken together, these findings suggest that CBD may be a more effective treatment option for the management of chronic pain. This study highlights the therapeutic potential of CBD in a model of neuropathic pain and suggests that these effects may have clinical implications for the use of cannabinoids in chronic pain management.

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the presence of anti-nuclear antibodies as well as a broad array of clinical manifestations spanning nearly every organ system. Neuropsychiatric syndromes affect over one half of SLE patients, presenting most commonly as cognitive dysfunction or headache. The pathophysiology of neuropsychiatric lupus is not fully understood; however, a critical mechanism has been identified, which involves passage of inflammatory cytokines and anti-brain antibodies through the blood-brain barrier. We previously developed a mouse model to study the effects of anti-dsDNA antibodies that cross-react with the NMDA receptor (NMDAR), termed DNRAbs, which are present in approximately 30% of SLE patients and whose presence in the CSF is associated with non-focal CNS manifestations of neuropsychiatric lupus. In this mouse model, non-spontaneously autoimmune mice are immunized with DWEYS peptide, a DNA mimotope that elicits production of DNRAb antibodies, which act as positive allosteric modulators of the NMDAR. DNRAbs only enter the brain when the blood-brain barrier is porous; so, we administer LPS, which breaches the blood-brain barrier in the hippocampus. In this model, we discovered two stages of brain injury. In the first stage, lasting up to a week, we observed excitotoxic neuronal death, secondary to DNRAb-mediated NMDAR activation. In the second stage, lasting months, we identified an inflammatory homeostasis, consisting of microglial activation, loss of dendritic arborization in surviving hippocampal neurons, and neuronal secretion of HMGB1, a chromatin protein that can be secreted to act as a damage-associated molecular pattern (DAMP). Once secreted by neurons, HMGB1 interacts with two important receptors -RAGE and TLR4 – inducing a cascade of downstream inflammatory events. In addition, HMGB1 binds to the GluN2B subunit of NMDARs and the complement component C1q, forming a molecular bridge that facilitates synaptic pruning. Here we show that HMGB1 acts directly on microglia, where it activates microglia through RAGE and TLR4 signaling. We found that HMGB1 stimulates microglia to secrete IFNa, transcriptionally upregulating interferon regulatory factors, including IRF7. We also show that IFNa secreted by microglia acts in an autocrine fashion, regulating IFN-response genes such as MX1; IFNa also induces C3 and C1q transcription in microglia. HMGB1 also stimulates microglia to secrete TNFa and IL-1b, which enhances the inflammatory milieu in surrounding neurons. In addition, we found that the ACE-inhibitor captopril reverses dendritic pruning in DWEYS-immunized mice– – an essential component of the second stage of DNRAb-related damage – by regulating expression of the inhibitory receptor LAIR1 in microglia. Whereas captopril reverses dendritic pruning in DWEYS-immunized wildtype mice, captopril has no such effect on LAIR1 knockout mice. We are currently analyzing RNA sequencing data from microglia isolated from captopril-treated, DWEYS immunized mice, to characterize the transcriptional program responsible for this process.

Myofascial syndrome is a common cause of chronic musculoskeletal pain and results in dysfunction of the affected muscles. It is characterized by myofascial trigger points (MTPs) which are clinically identified by palpation of a muscle or fascial taut band. Previous publications have found MTPs to coincide with neuromuscular junctions at the innervation zone (IZ). The fibularis longus syndrome is one of the most frequent myofascial syndrome of the lower limbs and occurs due to a wide variety of etiologies, most commonly, overuse and ankle sprain. Referred pain and tenderness caused by the trigger points of the FL muscle are located above, behind and below the lateral malleolus and may extend along the lateral aspect of the foot and leg.

During exercise, skeletal muscle contraction stimulates mechanically sensitive channels on the sensory endings of thin fiber muscle afferents. Stimulation of these mechanically sensitive channels initiates a reflex, termed the mechanoreflex, which contributes importantly to reflex increases in sympathetic nerve activity (SNA) and mean arterial blood pressure (MAP). In patients and animals with heart failure with reduced ejection fraction (HF-rEF), mechanoreflex activation contributes to exaggerated increases in SNA and is linked to decreased exercise tolerance and increased mortality. The exaggerated mechanoreflex in HF-rEF is partially attributed to an increased responsiveness of thin fiber skeletal muscle afferents to mechanical stimulation. Several lines of evidence demonstrate that signaling within sensory neurons mediated by the non-traditional protein kinase c epsilon (PKCε) isoform augments mechanically activated channel function and produces mechanical hyperalgesia. Whether PKCε-mediated signaling within sensory neurons contributes the exaggerated mechanoreflex in HF-rEF is unknown.

There are 3.8 million sports-related concussions reported annually. Although there is a growing number of sports-related concussions, there is a lack of evidence-based methods to evaluate, treat, predict, and monitor recovery in athletes. Today, concussions are clinically diagnosed using self-reported symptoms and by examining posture, neurocognition, ocular/vestibular control, and various imaging techniques. The Sport Concussion Assessment Tool (SCAT) is widely used on the sideline along with other methods to diagnose a concussion. However, current studies use control groups that are rested (i.e baseline) without considering the effect of intense exercise and contact (not related to head) that a player may have experienced during a game. To obtain this data we developed a mobile tent-based laboratory that permits us to collect data on the field during a rugby match. SCAT3 questionnaires were performed within 3 hours following a rugby match in players who experienced a head injury or completed the match without a head injury. Additional measures included beat-by-beat blood pressure (Finometer), heartrate, common and internal carotid blood flow, and end-tidal CO2 (nasal cannula) during rest, in the seated and supine position. A principal component analysis was performed on the 26 listed symptoms on the SCAT3 and Mann-Whitney U-test on the resulting 4 components. There were a total 209 players (67 female, 142 males; 33 ± 13 years) who just played a match, with 80 who experienced a head injury and 129 controls. Self-reported symptoms were significantly greater in players who experienced a head injury 26.16 ± 17.6 vs control 8.93 ± 11.5, P<.001. A principal component analysis on our entire dataset produced 4 symptom components: (1) Cognitive-Sensory (2) Emotional-Affective (3) Hypersensitive (4) Headache. A Mann-Whitney U-tests showed significant differences between the concussed and control groups for the following symptom components: Cognitive-Sensory (p<0.001), Headache (p<0.001), Emotional-Affective (p<0.004), and Hypersensitive (p<0.001). This data suggests that the SCAT3 symptoms were greater in the players with a head injury, but that some of the control players who just played an intense match also show an increased number of symptoms and severity. Further analysis and violin plots on each of the 4 components showed that the symptom component named "Headache" composed of; Pressure in the Head, Headache, Feeling Slowed down, Dizziness, Don't Feel Right may provide a better indicator of concussion in players that just played an intense match. Future work is needed to examine how these components can be used along with current physiological measures to better assess a concussion in players that just came off the field.

Rapid local heating of the skin elicits biphasic vasodilation. The initial peak in skin blood flow (SkBF) is mediated by sensory nerves (i.e., the axon reflex). Both endothelin (ET and ET ) receptors are located on axon terminals on nociceptor fibers, and therefore may be involved in the sensory nerve mediated vasodilation. Although prior work shows a blunted axon reflex with aging, this has yet to be examined in women, and the role of ET and ET receptors in this initial sensory nerve-mediated vasodilatory response remains unclear.