Rejected

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.

Chronic pancreatitis is an inflammatory condition resulting in fibrosis and consequent destruction of pancreatic tissue and loss of exocrine and endocrine function. Despite being an uncommon disease in adults, its incidence in children is significantly lower. Crucial surgical intervention is considered in pediatric cases where pain management and reducing the risk of future cancer development are of concern. The efficacy of the Rochelle-Partington modification of the Puestow procedure in remedying chronic pancreatitis has shown satisfactory long-term results, especially in pediatric cases, however, not without side effects. A 13-year-old girl who suffers from recurrent abdominal pain attributed to chronic pancreatitis underwent the Rochelle-Partington modification of the Puestow procedure to mitigate her symptoms. The postoperative course was complicated by small bowel obstruction necessitating revision of the enteroenteric anastomosis. After three years since surgery, the patient remains pain-free, well-nourished, and leads a normal life without the interruption of her daily activities. While still left to be seen if the modified Puestow procedure serves to be the superior choice in the treatment of chronic pancreatitis, it remains a safe choice for surgical treatment among adolescents. Sustaining pancreatic function is essential in pediatric cases where the long-term quality of life is concerned to reduce chronic pain and maintain nutrition.

Introduction Up to 30% of terminally ill cancer patients experiencing intense pain might be refractory to opioid treatment. Complex cancer pain can be a mixture of somatic, visceral, and neuropathic pain with few or no effective alternatives to ameliorate pain. Radiosurgery to treat refractory pain in cancer has been reported with different degrees of success. Radiomodulation in pain could be defined as a fast (<72 h), substantial (>50%) pain relief by focal irradiation to a peripheric, and/or central mediated pain circuitry. Based on our previous experience, mixed, refractory cancer pain is usually unresponsive to single target irradiation of the hypophysis. We treated three patients using a multi-target approach. Methods Three terminally ill oncological patients experiencing refractory, complex, mixed pain from bone, abdomen, thorax, and brachial plexus were treated with triple target irradiation which consisted of irradiating with a maximum dose (Dmax) of 90 Gy to the hypophysis using either an 8 mm collimator with gamma ray (Infini) (Shenzhen, China: Masep Medical Company) or a 7.5 circular collimator with Cyberknife (Sunnyvale, CA: Accuray Inc.), the other two targets were the mesial structures of the thalamus bilaterally using a 4 mm collimator with Infini and the 5 mm circular collimator with CK delivering 90 Gy Dmax to each region. Patients had a VAS of 10 despite the best medical treatment. A correlation was made between the 45 Gy and 20 Gy isodose curves of the two different technologies to the Morel stereotactic atlas of the thalamus and basal ganglia for further understanding of dose distribution reconstructions in accordance with the São Paulo-Würzburg atlas of the Human Brain Project were performed. Lastly, a scoping review of the literature regarding radiosurgery for oncological pain was performed. Results Radiomodulation effect was achieved in all patients; case 1 had a VAS of five at 72 h, three at 15 days, and three at the time of death (21 days after treatment). Case 2 had a VAS of six at 72 h, five at 15 days, and four at the time of death (29 days after treatment). Case 3 had a VAS of five at 72 h, six at 15 days, and six at the time of death (30 days). Morphine rescues for cases 1 and 2 were reduced to 84%, and 70% for case 3. Overall, there were no adverse effects to treatment although excessive sleepiness was reported by one patient. After reading the title and abstract, only 14 studies remained eligible for full-text evaluation, and only nine studies met inclusion criteria after full-text reading. For most reports (seven), the target was the hypophysis and in two reports, the target was the thalamus either with single or bilateral irradiation. Conclusions In complex, for refractory oncological pain of mixed nature (nociceptive, neuropathic, and visceral), very few, if any, treatment alternatives are currently available. We provide a small proof of concept that multitarget intracranial radiosurgery might be effective in ameliorating pain in this population. The doses administered per target are the lowest that have shown effectiveness thus far, a different strategy might be needed as opposed to single target "large" dose approach that has been tried in the past for complex mixed refractory oncological pain. By no means, in our experience, these treatments traduce in elimination of pain, clinical results might make pain to be more bearable and respond better to pain medication.

Pyoderma gangrenosum is an uncommon ulcerative auto-inflammatory dermatosis. Numerous studies suggest cutaneous side effects of the COVID-19 vaccine. Pyoderma gangrenosum has been reported as one of the rare side effects of the COVID-19 vaccine. In this report, a 36-year-old male was admitted to a hospital due to a progression of pyoderma gangrenosum on the lateral aspect of his upper arm which had developed eight months ago, following the first dose of Sinopharm BBIBP COVID-19 vaccine. The reported symptoms included headache, blurred vision, palpitation, fatigue on exertion, documented fever, chills and productive cough with yellow sputum, possibly due to the inflammatory effect of pyoderma gangrenosum. In the past, the patient's face had several abnormal skin lesions similar to the newly developed lesion. In addition, the newly developed lesion did not regress despite using medication. COVID-19 vaccinations could potentially trigger pyoderma gangrenosum, especially in patients with a past medical history of similar lesions in different body parts. Therefore, we recommend inquiring about the past medical history of pyoderma gangrenosum or abnormal skin lesions prior to vaccination.