Rejected

Acetaminophen is a popular, universally used, over-the-counter pain medication contained in more than 600 different products and available in a plethora of dosage forms. Acetaminophen is an important adjunct to manage postoperative dental pain in combination with a nonsteroidal anti-inflammatory drug such as ibuprofen. For the treatment of more severe pain, acetaminophen is often formulated with non-opioid and opioid agents. Because of the accessibility of acetaminophen and its widespread use, dental practitioners need to be cognizant of any significant safety concerns that may be associated with this drug, including acetaminophen toxicity. This article discusses the history of acetaminophen, its pharmacology, metabolism, and toxicity, as well as strategies to help address some of the potential safety issues with this medication, including unintentional overdosing.

While pain is frequent manisfestation of several disease processes, chronic pain has been described as an established disorder with debilitating ramifications on health and lifestyle. The currently available analgesics for the treatment of chronic pain are often ineffective and accompanied by undesirable adverse effects, which invites for safer and more efficacious alternatives. Adenosine is a naturally-occurring purinergic nucleoside that is involved in cell signaling in multiple tissue types. Although the activation of adenosine receptors can affect nociceptive, inflammatory, and neuropathic pain states, the specific regulatory functions of its subtypes (A1, A2A, A2B and A3 receptors) are not fully understood. The aim of this work was to investigate the role played by different adenosine receptor ligands on inflammatory pain conditions. Inflammatory pain was induced by intra-plantar injection of Complete Freund's Adjuvant (CFA) into the left hindpaw of adult male Sprague Dawley rats. Von Frey filaments were applied to the mid-plantar aspect of the left hind paw using the "up-down" method to determine the CFA-induced mechanical allodynia (expressed as paw withdrawal threshold, PWT). Neither the A2A selective agonist CGS 21680 hydrochloride (0.1, 0.32 and 1 mg/kg) nor the A2B selective agonist BAY 60-6583 (0.1, 0.32 and 1 mg/kg) produced any significant reversal of the PWT. However, both the A1 selective agonist (±)-5'-Chloro-5'-deoxy-ENBA, and the A3 selective agonist 2-Cl-IB-MECA produced a significant reversal of the PWT at the highest dose of 1 mg/kg, suggesting antinociceptive effects of the A1 and A3 adenosine receptors. Co-administration of the selective antagonists of A1 and A3 receptors PSB36 (1 mg/ml) and MRS-3777 (1 mg/ml); respectively, significantly reduced the anti-nociceptive effects of both (±)-5'-Chloro-5'-deoxy-ENBA, and 2-Cl-IB-MECA (1 mg/kg) on PWT one hour post-drug administration. Both the A2A selective antagonist ZM 241385 and the A2B selective antagonist PSB 603 produced a significant reversal of the PWT at the highest dose of 1 mg/kg. In conclusion, A1, A2A, A2B and A3 adenosine receptors are involved in mediating inflammatory pain states, and represent promising targets for the treatment of chronic pain conditions.

Opioid receptors are important regulators of pain, and opioid drugs like morphine are used in a wide variety of clinical settings throughout the world. In spite of their clear utility and efficacy concerning the treatment of pain, the addictive nature of opioids limits their use as an option for the treatment of chronic pain. This illustrates the great medical and social need to improve opioid therapy, both enhancing analgesia and reducing side effects like addiction. More recently, we showed that Heat shock protein 90 (HSP90), a molecular chaperone that participates in a vast array of critical molecular processes in the cell, has been implicated as an important modulator of opioid-induced pain relief within the spinal cord. We found that inhibition of HSP90 improved the therapeutic index of opioids, boosting pain relief and reducing side effects. In an effort to elucidate the molecular pathways responsible for these benefits, we performed proteomic analysis of spinal cord tissue from male and female CD-1 mice treated with intrathecal Vehicle or 17-AAG (0.5 nmol, 24 hrs), an HSP90 inhibitor. We found that the signaling molecule delta-catenin2 was reduced by 27.6% by 17-AAG treatment in spinal tissue. Since delta-catenin2 stabilizes and enables Wnt signaling, this suggests that Wnt signaling is also reduced by HSP90 inhibition. As Wnt has been shown to promote pain, this fits with our model that suppressed Wnt/Catenin signaling could enhance opioid pain relief after HSP90 inhibition. We thus report here our efforts to test this hypothesis by using a Wnt activator (AMBMP) and Wnt inhibitor (JW74) combined with 17-AAG and morphine in a mouse tail flick pain model; we also report our efforts to confirm molecular Wnt signaling changes in spinal cord by Western Blot and qPCR for Wnt itself along with established Wnt signaling targets VEGF-A and LEF1. Together these studies will establish a new mechanistic node linking HSP90 to the regulation of opioid pain relief in the spinal cord. This will enhance our basic science understanding of this system and could lead to novel therapeutic targets.

Stanford's Division of Clinical Anatomy offered a virtual, week-long Clinical Anatomy Summer Program (CASP) to pre-health students interested in learning clinical anatomy, enabling the exploration of Virtual Reality (VR) as a supplemental teaching and learning modality. Students attended lectures, clinical case presentations, and hour-long VR lab demonstrations featuring anatomical models via Engage platform. Students were provided support with setup, operation, and troubleshooting of Oculus Quest 1 headsets and the Engage application. The goal of this study is to evaluate the effectiveness of VR in anatomy teaching, understand the impact VR may have on the overall quality of the learning experience, and assess potential drawbacks to the usage of VR technology as a teaching tool.

Opioid use disorder (OUD) can be defined as the continued use of opioids despite the negative physical, psychological, and social consequences that result from its use. Since the 1970s, several strategies have been approved by the Food and Drug Administration (FDA) to treat OUD and reverse opioid overdose. Despite their implementation and other exhaustive efforts and resources expended by the scientific and public health communities, the increase in opioid use disorder (OUD) in the United States continues to have staggering economic and quality of life impacts. Decades of research has established that chronic activation of the N-methyl-D-aspartate (NMDA) receptor is a major driving force of the neuroplastic pathology that underlies opioid use disorder. The therapeutic potential of antagonism of the NMDA receptor has been explored, however due to the ubiquity of the receptor, several off-site side-effects have hindered development. In recent years, the endogenous NMDA receptor antagonist agmatine has come under consideration for its therapeutic potential in combatting CNS disorders such as neuropathic chronic pain as well as OUD, without producing unwanted side-effects. Female ICR mice (21-30g) were separated into dosing groups and oriented to self-administration operant chambers in which they were able to press either for oral oxycodone reward (30 mg/L, 200 mg/L, or 1,000 mg/L) or inactive control (H2O + quinine) over 12 hours. Animals were sacrificed and perfused with tissue fixative for later molecular analysis of reward pathways. Animals with the 30 mg/L and 200 mg/L dose option showed consistently higher responding compared to animals pressing for 1,000 mg/L and control. Notably, animals in the 200 mg/L group showed an almost immediate increase in lever presses while the animals in the 30 mg/L group showed a slow increase in responding over time when compared to inactive control. We next sought to characterize agmatine's ability to prevent oxycodone self-administration, with 200 mg/L of oral oxycodone selected as the reward dose based on the previous data. Mice were given daily i.p. injections of either agmatine or saline immediately prior to self-administration sessions. Mice who received agmatine pre-treatment demonstrated significantly reduced drug-seeking compared to animals who received saline pre-treatment. Following completion of the experiment, animals were sacrificed and perfused for molecular analysis. These data support that agmatine may have therapeutic potential in preventing opioid use disorder. Future studies will focus on comparative molecular analysis between oxycodone-exposed mice with or without agmatine.

Opioid use is associated with increased risk of chest infection due to opioid suppression of immune function, ventilation, cough, and secretion mobilization. Buprenorphine is a highly lipophilic, semi-synthetic partial agonist of the mu opioid receptor. Intramuscular buprenorphine is commonly used for post-operative analgesia at a dose range of 0.01-0.04 mg/kg in the cat. While buprenorphine is considered to have a low side effect profile, its effects on the pharyngeal phase of swallow are unknown. We hypothesized that administration of opioid would result in clinically meaningful decline of pharyngeal swallow function. Experiments were performed on healthy adult cats (12 months old). Animals were administered intramuscular buprenorphine (0.015 mg/kg) q12 hours for 48 hours. One hour after the last dose was given, videofluoroscopic swallow studies were performed to evaluate the effects of the drug on swallow function. Animals were presented with 40% by volume barium sulfate in tuna water mixed to a thin consistency, and all animals ate voluntarily. Images were recorded in the lateral plane at 30 frames/second and compared to control feeding assessments using the Global Dysphagia Scale (GDS), a novel tool developed to rate swallow function in the cat. The GDS consists of an Airway Invasion Scale (AIS) and relevant components of the Modified Barium Swallow Impairment Profile (MBSImP), a standardized protocol for swallow assessment. The AIS is a 10-point scale where scores of 0-1 are normal, scores of 2-4 indicate laryngeal penetration, and scores of 5-9 indicate tracheobronchial aspiration. Four components of the MBSImP were included: Initiation of the pharyngeal swallow, pharyngeal stripping wave, pharyngoesophageal segment opening, and pharyngeal residue. The GDS rating was derived by adding the AIS and MBSImP sub-totals. During control assessments mean GDS was 5.5 ± 1.3, and aspiration was not detected in any animal. On buprenorphine, mean GDS was 11.25 ± 4.2, and 50% of animals exhibited large volume tracheobronchial aspiration. In conclusion, after 48 hours on buprenorphine, airway protection during swallow failed without appreciable response in 50% of animals (no cough, throat clear, or cessation of eating). Our success in producing dysphagia (significant but varying by animal) with relatively small doses of opioid has potential implications for predicting aspiration pneumonia in post-surgical clinical cases.

More than 50 million Americans suffer from chronic pain. However, the anatomical and physiological mechanisms of peripheral nociceptive processes have not been well elucidated which has seriously impeded the progress of designing novel bioengineering manipulations/treatments for chronic pain. In this study, we performed a comprehensive topographical mapping of pain-related neural circuitry in the flat-mount of whole mouse stomach (male, n=8, 3-5 months). We used Substance P (SP) as a marker for nociceptive axons and applied a combination of state-of-the-art techniques, including flat-mount tissue processing and immunohistochemistry of the whole stomach, confocal microscopy, Zeiss Imager microscopy to determine the distribution and morphology of SP-IR axons and terminals in the whole stomach. We found that 1) SP-IR axons formed extensive terminal networks in both the ventral and dorsal stomachs. 2) SP-IR axons were much denser in the antrum and corpus regions than in the fundus and cardia. 3) SP-IR varicose axons ran in parallel with the circular and longitudinal muscle layers. 4) SP-IR axons innervated blood vessels. 5) SP-IR varicose axons formed terminals wrapping around individual myenteric neurons. 6) There were no confirmed SP-IR myenteric neurons. 7) SP-IR afferent innervation of the stomach showed a similar pattern of SP-IR axons and terminals between the ventral and dorsal stomachs. In control mice (n=8), we injected tracer DiI into the ventral and dorsal stomach muscular layers or Fluorogold injection (i.p) and found that the main extrinsic source of SP-IR afferent axons in the stomach was from the T7-T11 DRG and to a lesser extent the VNG, but not from the celiac ganglia and dorsal motor nucleus of vagus. Our data provide for the first time a comprehensive topographical map for SP-IR axons and terminals in the whole stomach with single cell/axon/synapse resolution. This work will contribute to a 3D digital representation of a brain-stomach nociceptive atlas in a stomach scaffold, thus providing a novel anatomical foundation for functional mapping of nociceptive afferent axons and their pathological remodeling in the stomach. The first two authors contributed equally to this work.

Isolated dislocations of thumb CMC joints are rare injuries with serious functional implications. Patients suffering these injuries will have decreased pinch and grip strength. A high-energy, axially directed force on a flexed thumb typically causes dislocation. Chronically dislocated thumb CMC joints may be due to untreated remote trauma, hypermobility, or connective tissue disorders. Roberts and CMC stress view radiographs help identify joint dislocations. Treatment of these injuries includes closed reduction and immobilization, percutaneous pinning, open reduction with direct repair, and ligament reconstruction. Timely identification, timely treatment, and proper hand therapy often lead to adequate joint stability with minimal residual pain.

Burkitt lymphoma (BL) is one of the highly aggressive non-Hodgkin B-cell lymphomas. The optic nerve can be affected in case of isolated lymphoma or together with the central nervous system (CNS) and systemic lymphoma. We report a rare case of involvement of bilateral optic nerves in BL. A 31-year-old lady who was diagnosed with BL presented with severe intermittent headache and vomiting with blurring of vision in both eyes for one week. Visual acuity on presentation was 6/9 in the right eye and 6/24 in the left eye, with a reduction of the left eye optic nerve functions. Fundoscopy showed swollen optic disc in the right eye and temporal pallor disc in the left. Magnetic resonance imaging of the brain and orbit showed increased leptomeningeal enhancement in the right frontal and temporal lobes and the right optic nerve. Lumbar puncture revealed high opening pressure (50 cmHO). Pleocytosis and the presence of lymphomatous infiltration were noted in cerebrospinal fluid analysis. After the completion of four cycles of chemotherapy, her condition unfortunately deteriorated, and she was subsequently planned for palliative therapy. CNS-directed therapies should be considered given the high risk of CNS relapse.