Assessing the Effects of Parthenolide on Inflammation, Bone Loss, and Glial Cells within a Collagen Antibody-Induced Arthritis Mouse Model.

Rheumatoid arthritis is characterised by a chronic inflammatory response resulting in destruction of the joint and significant pain. Although a range of treatments are available to control disease activity in RA, bone destruction and joint pain exist despite suppression of inflammation. This study is aimed at assessing the effects of parthenolide (PAR) on paw inflammation, bone destruction, and pain-like behaviour in a mild collagen antibody-induced arthritis (CAIA) mouse model. CAIA was induced in BALB/c mice and treated daily with 1 mg/kg or 4 mg/kg PAR. Clinical paw inflammation was scored daily, and mechanical hypersensitivity was assessed on alternate days. At end point, bone volume and swelling in the paws were assessed using micro-CT. Paw tissue sections were assessed for inflammation and pre-/osteoclast-like cells. The lumbar spinal cord and the periaqueductal grey (PAG) and rostral ventromedulla (RVM) regions of the brain were stained for glial fibrillary acidic protein (GFAP) and ionised calcium-binding adaptor molecule 1 (IBA1) to assess for glial reactivity. Paw scores increased in CAIA mice from days 5-10 and were reduced with 1 mg/kg and 4 mg/kg PAR on days 8-10. Osteoclast-like cells on the bone surface of the radiocarpal joint and within the soft tissue of the hind paw were significantly lower following PAR treatment (p < 0.005). GFAP- and IBA1-positive cells in the PAG and RVM were significantly lower following treatment with 1 mg/kg (p < 0.0001 and p = 0.0004, respectively) and 4 mg/kg PAR (p < 0.0001 and p = 0.001, respectively). In the lumbar spinal cord, IBA1-positive cells were significantly lower in CAIA mice treated with 4 mg/kg PAR (p = 0.001). The findings indicate a suppressive effect of both low- and moderate-dose PAR on paw inflammation, osteoclast presence, and glial cell reactivity in a mild CAIA mouse model.

DAT isn't all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling.

The initial reinforcing properties of drugs of abuse, such as cocaine, are largely attributed to their ability to activate the mesolimbic dopamine system. Resulting increases in extracellular dopamine in the nucleus accumbens (NAc) are traditionally thought to result from cocaine's ability to block dopamine transporters (DATs). Here we demonstrate that cocaine also interacts with the immunosurveillance receptor complex, Toll-like receptor 4 (TLR4), on microglial cells to initiate central innate immune signaling. Disruption of cocaine signaling at TLR4 suppresses cocaine-induced extracellular dopamine in the NAc, as well as cocaine conditioned place preference and cocaine self-administration. These results provide a novel understanding of the neurobiological mechanisms underlying cocaine reward/reinforcement that includes a critical role for central immune signaling, and offer a new target for medication development for cocaine abuse treatment.

Perineuronal net structure as a non-cellular mechanism contributing to affective state: A scoping review.

Affective state encompasses emotional responses to our physiology and influences how we perceive and respond within our environment. In affective disorders such as depression, cognitive adaptability is challenged, and structural and functional brain changes have been identified. However, an incomplete understanding persists of the molecular and cellular mechanisms at play in affective state. An exciting area of newly appreciated importance is perineuronal nets (PNNs); a specialised component of extracellular matrix playing a critical role in neuroprotection and synaptic plasticity. A scoping review found 24 studies demonstrating that PNNs are still a developing field of research with a promising general trend for stress in adulthood to increase the intensity of PNNs, whereas stress in adolescence reduced (potentially developmentally delayed) PNN numbers and intensity, while antidepressants correlated with reduced PNN numbers. Despite promising trends, limited research underscores the need for further exploration, emphasizing behavioral outcomes for validating affective states. Understanding PNNs' role may offer therapeutic insights for depression and inform biomarker development, advancing precision medicine and enhancing well-being.

Opioid activation of toll-like receptor 4 contributes to drug reinforcement.

Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4(-/-) mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.

Gender-specific effects of COVID-19 lockdowns on scientific publishing productivity: Impact and resilience.

RATIONALE: The SARS-CoV2 pandemic led to drastic social restrictions globally. Early data suggest that women in science have been more adversely affected by these lockdowns than men, with relatively fewer scientific articles authored by women. However, these observations test broad populations with many potential causes of disparity. Australia presents a natural experimental condition where several states of similar demographics and disease impact had differing approaches in their social isolation strategies. The state of Victoria experienced 280 days of lockdowns from 2020 to 2021, whereas the comparable state of New South Wales experienced 107 days, most of these in 2021, and other states even fewer restrictions. OBJECTIVE AND METHODS: To assess how the gender balance changed in Australian biomedical publishing with the lockdowns, we created a custom workflow to analyse PubMed data from more than 120,000 published articles submitted in 2019-2021 from Australian authors. RESULTS: Broadly, Australian women have been incredibly resilient to the challenges faced by the lockdowns. There was an increase in the number of published articles submitted in 2020 that was equally due to women as men, including from Victoria. On the other hand, articles specifically addressing COVID-19 were significantly less likely to be authored by women than those on other topics, a finding not likely due to particular gender imbalance in virology or viral epidemiology, since publications on HIV followed similar patterns to previous years. By 2021, this imbalance had reversed, with more COVID-19-related papers authored by women than men. CONCLUSIONS: These data suggest women from Victoria were less able to rapidly transition to new research early in the pandemic but had accommodated to the new conditions by 2021. This work indicates we need strategies to support women in science as the pandemic continues and to continue to monitor the situation for its impact on vulnerable groups.

Review: What innovations in pain measurement and control might be possible if we could quantify the neuroimmune synapse?

It has taken more than 40 years for the fields of immunology and neuroscience to capture the potential impact of the mechanistic understanding of how an active immune signalling brain might function. These developments have grown an appreciation for the immunocompetent cells of the central nervous system and their key role in the health and disease of the brain and spinal cord. Moreover, the understanding of the bidirectional communication between the brain and the peripheral immune system has evolved to capture an understanding of how mood can alter immune function and vice versa. These concepts are rapidly evolving the field of psychiatry and medicine as a whole. However, the advances in human medicine have not been capitalised upon yet in animal husbandry practice. Of specific attention are the implications that these biological systems have for creating and maintaining heightened pain states. This review will outline the key concepts of brain-immune communication and the immediate opportunities targeting this biology can have for husbandry practices, with a specific focus on pain.

Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4.

BACKGROUND AND PURPOSE: The toll-like receptor TLR4 is involved in neuropathic pain and in drug reward and reinforcement. The opioid inactive isomers (+)-naltrexone and (+)-naloxone act as TLR4 antagonists, reversing neuropathic pain and reducing opioid and cocaine reward and reinforcement. However, how these agents modulate TLR4 signalling is not clear. Here, we have elucidated the molecular mechanism of (+)-naltrexone and (+)-naloxone on TLR4 signalling. EXPERIMENTAL APPROACH: BV-2 mouse microglial cell line, primary rat microglia and primary rat peritoneal macrophages were treated with LPS and TLR4 signalling inhibitors. Effects were measured using Western blotting, luciferase reporter assays, fluorescence microscopy and ELISA KEY RESULTS: (+)-Naltrexone and (+)-naloxone were equi-potent inhibitors of the LPS-induced TLR4 downstream signalling and induction of the pro-inflammatory factors NO and TNF-α. Similarly, (+)-naltrexone or (+)-naloxone inhibited production of reactive oxygen species and increased microglial phagocytosis, induced by LPS. However, (+)-naltrexone and (+)-naloxone did not directly inhibit the increased production of IL-1ß, induced by LPS. The drug interaction of (+)-naloxone and (+)-naltrexone was additive. (+)-Naltrexone or (+)-naloxone inhibited LPS-induced activation of IFN regulatory factor 3 and production of IFN-ß. However, they did not inhibit TLR4 signalling via the activation of either NF-κB, p38 or JNK in these cellular models. CONCLUSIONS AND IMPLICATIONS: (+)-Naltrexone and (+)-naloxone were TRIF-IFN regulatory factor 3 axis-biased TLR4 antagonists. They blocked TLR4 downstream signalling leading to NO, TNF-α and reactive oxygen species. This pattern may explain, at least in part, the in vivo therapeutic effects of (+)-naltrexone and (+)-naloxone.

Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain.

In the central nervous system, bidirectional signaling between glial cells and neurons ('neuroimmune communication') facilitates the development of persistent pain. Spinal glia can contribute to heightened pain states by a prolonged release of neurokine signals that sensitize adjacent centrally projecting neurons. Although many persistent pain conditions are disproportionately common in females, whether specific neuroimmune mechanisms lead to this increased susceptibility remains unclear. This review summarizes the major known contributions of glia and neuroimmune interactions in pain, which has been determined principally in male rodents and in the context of somatic pain conditions. It is then postulated that studying neuroimmune interactions involved in pain attributed to visceral diseases common to females may offer a more suitable avenue for investigating unique mechanisms involved in female pain. Further, we discuss the potential for primed spinal glia and subsequent neurogenic inflammation as a contributing factor in the development of peripheral inflammation, therefore, representing a predisposing factor for females in developing a high percentage of such persistent pain conditions.

Common compartment syndromes in athletes. Treatment and rehabilitation.

Compartment syndromes in athletes are rare, but they can also be limb-threatening events. Chronic exertional compartment syndrome (CECS) is a less emergent form where symptoms recur with repetitive loading or exertional activities. CECS is the most common form of compartment syndrome seen in athletes. Acute compartment syndromes may also occur in athletes secondary to direct trauma or may develop from pre-existing CECS. The leg is by far the most common site of compartment syndrome in athletes. The thigh, forearm, and foot are the next most common sites, although any fascially limited compartment can be affected. Awareness of the clinical presentation and pathophysiology of compartment syndromes can help the examiner make a prompt and accurate diagnosis. The treatment of acute compartment syndrome is emergent while the treatment of CECS is not. Conservative treatment and rehabilitation can be successful in treating CECS. Acute compartment syndromes must be treated immediately with surgical decompression. With CECS, if conservative treatment fails, surgical decompression is also indicated. Some authors have suggested that the results of surgical fasciotomy and rate of return to sport for athletes with CECS has not been uniform. If the diagnosis is accurate and carefully documented, a high degree of success with athletes returning to sport can be expected.

Common sports injuries in young tennis players.

Tennis is a popular racquet sport played by boys, girls, men and women. Tennis players frequently begin playing in childhood and may continue playing into late adulthood. Preadolescent and adolescent players have open growth plates and a reduced muscle power, lower level of coordination and smaller stature compared with adult players. The physical characteristics of the young tennis player mean that unique demands are placed on the developing athlete which can, in turn, be associated with different types and patterns of injury. The most common types of injury in tennis players of all ages are muscle sprains and ligament sprains secondary to overuse. These are a particular problem in the adolescent age group because, in general, this group begin playing with a lower level of physical conditioning. Fortunately, injuries in younger players are usually not longstanding and the overuse (chronic) problems seen in older players, such as patellar tendinosis and tennis elbow, are less common in younger players. Anatomically, lower extremity injuries are twice as common as those to the upper extremity or spine, with ankle injury being the most common. Prevention of injury in young tennis players, or at least a reduction in the incidence, is possible. Some traumatic injuries, including contusions, abrasions, lacerations and fractures, may be unavoidable as a result of aggressive play, but others may be prevented by monitoring equipment and the court surface to ensure a safe field of play. The prime target of prevention in young tennis players should be overuse injuries. The principles of 'overload' and staged involvement are of particular importance in this age group. A gradual, progressive increase in the intensity of tennis practice, the slow introduction of new court surfaces and a staged progression in the teaching of tennis skills can help to reduce the incidence of injury in young tennis players.

Knee injuries in female athletes.

Female athletes are at increased risk for certain sports-related injuries, particularly those involving the knee. Factors that contribute to this increased risk are the differences in sports undertaken and in gender anatomy and structure. Gender differences include baseline level of conditioning, lower extremity alignment, physiological laxity, pelvis width, tibial rotation and foot alignment. Sports like gymnastics and cheerleading create a noncontact environment, but can result in significant knee injuries. In quick stopping and cutting sports, females have an increased incidence of anterior cruciate ligament (ACL) injury by noncontact mechanisms. Patellofemoral (PF) disorders are also very common in female athletes. Awareness of these facts helps the sports medicine professional make an accurate diagnosis and institute earlier treatment-focused rehabilitation with or without surgery. Further prospective and retrospective research is needed in areas of epidemiology, mechanisms, severity and types of knee injuries. The goal is to lessen the severity of certain knee injuries and to prevent others.

Low back pain in elite rhythmic gymnasts.

BACKGROUND: Rhythmic gymnastics is a sport that blends the athleticism of a gymnast with the grace of a ballerina. The sport demands both the coordination of handling various apparatus and the flexibility to attain positions not seen in any other sport. To attain perfection and reproducibility of their routines, the athletes must practice and repeat the basic elements of their routines thousands of times. In so doing, the athlete places herself at risk of a myriad of overuse injuries, the most common being low back pain. METHODS: To document the presence and severity of low back pain in elite rhythmic gymnasts, a prospective study of seven national team members was undertaken that documented injuries and complaints with daily medical reports over a 7-wk period. These findings were correlated with a retrospective review of 11 elite level gymnasts followed over a 10-month period whose complaints ultimately required evaluation by a physician. RESULTS: Eighty-six percent of the gymnasts in the prospective study complained of back pain at some point over the course of the study. The only injury recorded that required a time loss from sport was a low back injury. The most common complaint requiring a physician's evaluation was low back pain with the diagnoses varying from muscle strains to bony stress reaction or complete fracture of the pars inter-articularis (spondylolysis). No athlete had a spondylolisthesis or ruptured disk. Two had mild scolioses which did not appear to be associated with their low back pain. CONCLUSIONS: It would appear that rhythmic gymnasts are at relative increased risk of suffering low back complaints secondary to their sport.

Comparison of injury patterns in elite hockey players using ice versus in-line skates.

PURPOSE: The purpose of this study was to assess the variation of injury patterns between hockey players who use in-line roller skates versus those who use ice skates. METHODS: Injury surveillance was undertaken on three professional hockey teams. Two performed on in-line skates and one performed on ice skates. Injury patterns including mechanism of injury, anatomic location, time-loss from sport, and injury type were evaluated with respect to the use of type of skate. The number of athletic exposures (AE) was calculated for each athlete to establish a relative risk. All athletes were elite professional athletes, and injuries were recorded and categorized by a certified athletic trainer or physician. RESULTS: Of the 215 games and 1122 athletic exposures evaluated, 142 injuries were recorded that required an evaluation by a physician and 46 of those required a time loss from sport. The total injury rate was similar between the two sports (in-line: 139 per 1000 AE; ice: 119 per 1000 AE) although injuries tended to be more severe in ice hockey (average time loss from sport: ice, 8.3 games; in-line, 6.5 games). CONCLUSIONS: Comparison of injury patterns by anatomic location, mechanism of injury, and injury type were similar between players using the two types of skates except that ice skates were associated with an increase in the number of lacerations, in-line skates were associated with an increased number of injuries secondary to checking and a decreased number of injuries relative to skate equipment, and ice hockey had an increased risk of head and neck injuries compared with hockey on in-line skates.

Improving leaping ability in elite rhythmic gymnasts.

PURPOSE: The purpose of this study was to improve the leaping ability of athletes in rhythmic gymnastics, a high leap demanding sport, using a controlled course of jump training. METHODS: Six elite athletes underwent a course of leap training including pool training and Pilates' Method of Body Conditioning using spring controlled resistance to muscular exertion. Baseline data was obtained on a force plate that measured reaction time, leap height, and explosive power on each athlete before initiating training. RESULTS: After 1 month of training, leap height improved 16.2%, ground reaction time improved 50%, and explosive power improved 220%. With continued maintenance training, no decrease in effect was noted; however, no significant improvement occurred after the first month of training. At 1 yr with discontinuation of the leaping protocol but continued training within the sport, the initial gains were likewise maintained. No injuries occurred during participation in the leaping protocol. CONCLUSIONS: Elite rhythmic gymnasts can safely improve their leaping ability significantly through an intense course of jump training. Continued training with the leaping protocol does not appear to further enhance the benefit; however, the gains appear to be maintained at 4 months and 1 yr post training with or without additional training with the leaping protocol.

Injury surveillance at the USTA Boys' Tennis Championships: a 6-yr study.

Injuries that required physical or medical assistance were recorded for participants at the United States Tennis Association National Boys' Tennis Championships from 1986-1988, 1990-1992 (N = 1440, 240 athletes per year). Over the 6-yr period, a total of 304 athletes (or 21.1%) sustained new or recurrent injuries that required evaluation by the medical team. New injuries alone numbered 145 (incidence rate of 9.9 per 100 athletes). The analysis of injuries showed a higher rate of lower than upper extremity injuries. When evaluated by anatomic regions, back injuries were most common followed by thigh, shoulder, and ankle injuries, respectively. When evaluated by injury type, strains and sprains were most common (71% of all injuries) with fractures and dislocations being rare (1.3% of all injuries). The lower extremity provided the majority of sprain type injuries with 87.5% of ligament sprains coming from the knee and ankle. Injuries with tennis eponyms (i.e., tennis toe, tennis leg, tennis elbow, and tennis shoulder) were rare (0%-5% of all injuries). It would appear that these young elite athletes are at significant risk of injury.

Midline fascial splitting approach to the iliac crest for bone graft. A new approach.

The midline fascial splitting approach is a modified midline approach to the iliac crest for bone graft that takes advantage of the anatomic planes between layers of the dorsal lumbar fascia. Two hundred consecutive grafts were taken by this technique with one superficial infection, two cases of serous hematoma, and three patients with significant postoperative pain at the harvest site, for an overall complication rate of 3%. In comparison, bone grafts were harvested from 200 consecutive patients by the midline subcutaneous approach to the iliac crest with 2 deep infections, 1 cluneal nerve injury, 15 patients with severe and disabling pain at the harvest site, and 12 patients with a serous hematoma, for an overall complication rate of 15%. The midline fascial splitting approach significantly reduced the incidence of postoperative serous hematoma (P < 0.007) as well as the incidence of significant and disabling pain (P < 0.001). In addition, the approach is simple, straightforward, anatomic, and decreases trauma to soft tissues.

Reproducibility of anatomic tibial landmarks for anterior cruciate ligament reconstructions.

We evaluated the reproducibility of landmarks used for accurate anatomic placement of the tibial tunnel in anterior cruciate ligament reconstruction. Landmarks evaluated were the medial tibial eminence, the posterior cruciate ligament, the "over-the-back" position, the true posterior border of the tibia, and the posterior border of the lateral meniscus. Forty-two pairs of cadaveric knees were dissected, and anatomic measurements were made regarding the anterior cruciate ligament insertion and these various landmarks. Statistical analysis was used to confirm reproducibility and significance. Measurements based on the medial tibial eminence and posterior border of the meniscus were particularly erratic. The most reproducible anatomic landmark was the posterior cruciate ligament. The anterior border of the posterior cruciate ligament was consistently 6.7 mm posterior to the posterior border of the anterior cruciate ligament and 10.9 mm posterior to the central sagittal insertion point of the anterior cruciate ligament. The over-the-back position was consistently in contact with the anterior border of the posterior cruciate ligament if the knee was flexed with a posterior-directed force applied. In this position, the over-the-back position was equally reproducible as compared with the posterior cruciate ligament. Measurements gauged from the true posterior border of the tibia gave a second rigid bony landmark but with a wider standard deviation than the posterior cruciate ligament-based landmarks. The relative anterior-posterior dimension of the tibia did not correlate with the relationship between the anterior cruciate ligament and other anatomic landmarks.

Loss of extension after reconstruction of the anterior cruciate ligament.

The most common complication of anterior cruciate ligament (ACL) reconstruction is loss of extension, which is often functionally worse for patients than their preoperative instability. Many preventable surgical and nonsurgical etiologic factors have been identified. Accurate placement of the tibial tunnel, adequate notchplasty, and the routing of the femoral side of the graft are all critical factors. Several studies report that early range-of-motion therapy emphasizing immediate postoperative "hyperextension" and avoiding immobilization in flexion reduces the rate of loss of extension. Initial studies investigating the effect of acute versus chronic ACL reconstruction suggested that acute reconstruction is associated with a higher rate of loss of extension. However, the authors of two recent studies in which modern techniques were used have disputed this conclusion. It is likely that the loss of extension historically seen with acute ACL reconstructions was related to tibial tunnel placement and postoperative immobilization. It is possible that the timing of acute ACL reconstruction has less of an effect than originally postulated. On the basis of the results of several biomechanical studies, it appears that ACL reconstruction may be performed with the knee in full extension during graft placement with excellent results and a very low rate of loss of extension. Use of the descriptive term "loss of extension" is preferred to the often misleading terms "arthrofibrosis" and "flexion contracture."

Upper extremity injuries in young athletes.

With the knowledge base of normal anatomy, development, biomechanics, and differential diagnosis, the sports medicine professional can treat injured young athletes with greater efficiency. In addition, microtraumatic injuries may be prevented by emphasizing safe parameters of participation, proper throwing techniques, and careful monitoring of the amount of practice time and intensity. Gymnasts using apparatus should always have spotters. The height of towers and basket tosses by cheerleaders should be limited by age and ability. Proper pitching techniques, not the fastest pitch or youngest curve, should be taught to baseball players. "Play it safe" should be the rule. Finally, by establishing an early and precise diagnosis, potential complications from injuries can be lessened.