Rejected

To assess patient satisfaction and functional outcomes of primary suture anchor repair with local soft tissue advancement for both acute and chronic thumb ulnar collateral ligament (UCL) injuries.

Management of refractory headache, particularly medication-overuse headache (MOH), is often difficult. In the management of MOH, it is important to determine the underlying primary headaches. Therefore, history taking and medical examinations are crucial for the diagnosis of headache type. Patient education and appropriate preventive therapy are beneficial in ameliorating MOH. As migraine is an underlying primary headache, the use of calcitonin gene-related peptide antibodies should be considered.

The proper function of airway vagal afferent nerves is essential for the dynamic regulation of breathing and initiation of adequate airway defensive reflexes. A better understanding of the mechanisms controlling their activation bears physiological and pathological significance. The voltage-gated potassium (K ) channels exert powerful controls on the neuronal excitability. Yet their expression and functions in the bronchopulmonary vagal afferent neurons remain largely unexplored. In this study we characterized the expression profile and inhibitory function of α-dendrotoxin (α-DTX)-sensitive D-type K channels composed of members of K 1subfamily of α-subunits in mouse bronchopulmonary nodose neurons using a combination of single-neurons RT-PCR, patch clamp recording, ex-vivo extracellular recording and two-photon microscopic Ca imaging techniques. The results showed that the vast majority of retrogradely labeled lung-specific nodose neurons expressed Kcna1, 2 and 6 coding for the α-DTX-sensitive K 1.1, 1.2 and 1.6 α-subunits, respectively. The D-type K current (I ), defined as the α-DTX-sensitive K current, was recorded in 14/15 bronchopulmonary nodose neurons. It started to be activated at -65.7±4.3 mV with 50% channel activation at -24 ± 14 mV. I opened rapidly in response to depolarization (activation time constants <10 ms at voltage ≥-15 mV), and displayed no inactivation during 600 ms at subthreshold/ threshold voltages and little or slow inactivation at more positive potentials (≥-5 mV). Inhibition of I with 50 nM α-DTX depolarized mouse pulmonary nodose neurons, increased input resistance, lowered the minimal depolarizing current needed to evoke an action potential, and increased the number and frequency of action potential firing in response to depolarizing current injections. Application of a bolus of 100 nM α-DTX to the afferent terminals in the mouse lungs via trachea led to overt activation in 49% of capsaicin-sensitive nodose neurons and in 32% of capsaicin-insensitive nodose neurons as detected by two-photon microscope. Further study with extracellular recording revealed that the application of an α-DTX bolus evoked action potential discharges in 8/19 (42%) nodose C-fibers terminating in the mouse lungs with a peak firing frequency of 4.4 ± 3.9 Hz. These results indicate that both the soma and terminals of bronchopulmonary nodose afferent nerves express functional I characterized by low-threshold, fast activation, and lack of or slow inactivation. With these unique biophysical properties, I channels act as an activation brake on the airway vagal afferent nerves by stabilizing the resting membrane potential and by counterbalancing the subthreshold depolarizing forces. Down-regulation of I , as occurs in many inflammatory diseases, may result in a heightened excitability of airway vagal afferent nerves causing exaggerated dyspnea, excessive mucous secretion, bronchoconstriction and chronic unproductive coughs associated with airway inflammation.

Transcutaneous vagus nerve stimulation (tVNS) is an effective, non-invasive method of electrically stimulating the vagus nerve without surgical procedures and it is FDA-approved to treat cluster headache and migraine. One approach of tVNS is to stimulate the auricle branch of the vagus nerve (tVNS ) by sending a small electrical current through the tragus of the ear. Previous evidence indicates that heart rate (HR) is lowered, indices of heart rate variability (HRV) are increased, and muscle sympathetic nerve activity is decreased following 10-15 min of tVNS . However, these previous investigations did not control for respiration, which can influence autonomic activity. Thus, we tested the hypotheses that tVNS would lower heart rate and increase indices of HRV that reflect cardiac parasympathetic activity during paced breathing (PB).

Chemotherapy-induced neuropathic pain is a prevalent side effect of treatment with anti-neoplastic agents. This debilitating neuropathy is characterized by excessive pain resulting in mechanical and sensory hypersensitivity. There is a critical clinical need to develop non-opioid alternatives to manage chronic pain. A potential alternative for the management of pain is decursinol, a pyranocoumarin compound isolated from the root of the Angelica gigas Nakai (AGN) plant. Pharmacokinetic studies find that clinically, AGN is first metabolized into decursin (D) and decursinol angelate (DA) which are subsequently metabolized into decursinol (DOH). D and DA possess anti-inflammatory, neuroprotective, antinociceptive, and antioxidant modulatory properties. Studies have reported acute analgesic properties of DOH, but tolerance development along with its impact on chronic pain remains unknown. Therefore, the goal of this study was to assess the antinociceptive effects and potential tolerance to once-daily injections of DOH (50 mg/kg) in models of thermal (hot plate and tail-flick), inflammatory (formalin test), and chronic (cisplatin-induced neuropathic; CINP) pain. We hypothesized that DOH has prolonged antinociceptive and anti-inflammatory effects. Antinociception and tolerance were assessed in male mice treated once-daily with either vehicle, DOH (50 mg/kg), or morphine (10 mg/kg; formalin only) intraperitoneally (IP) 30 minutes prior to testing for 14 consecutive days. In the formalin assay, following pretreatment, mice received an intraplanar injection of 2.5% formalin into the right hind paw and nocifensive behaviors were recorded and scored. CINP was induced following four weeks of once-weekly IP injections of cisplatin (5 mg/kg). Following pretreatment, mice with CINP were assessed for mechanical allodynia via an electro-von-Frey anesthesiometer. Daily treatment with 50 mg/kg DOH induced prolonged antinociceptive and anti-inflammatory responses in all nociceptive tests. Evidence of tolerance to DOH in acute thermal nociceptive tests occurred around day 10 for both hot plate and tail-flick. Acute administration of DOH eliminated inflammatory pain to an undetectable level in both the acute and inflammatory phases of the formalin test. Further, there is evidence of tolerance by day 14 in the acute (but not the inflammatory) phase of the formalin test. Likewise, tolerance was slower to develop to the antinociceptive effects of DOH compared to morphine in the formalin assay. In mice with CINP, DOH (50 mg/kg) caused a full reversal of mechanical allodynia with evidence of partial tolerance by day 3 with complete tolerance not occurring until day 14. These data indicate that DOH may serve as a potential non-opioid alternative for the management of pain. Future directions for this study include elucidating the mechanism of action for the antinociceptive effects of DOH.

The pharmacological inhibition of soluble epoxide hydrolase (sEH) has been suggested as a potential therapy for the treatment of pain and inflammatory diseases through the stabilization of epoxyeicosatrienoic acids, endogenous chemical mediators derived from arachidonic acid that show anti-inflammatory and analgesic effects. Although several potent sEH inhibitors (sEHI) have been developed, including clinical candidates AR9281, GSK2256294, and EC5026, so far no sEHI has reached the market. Recently, a new series of benzohomoadamantane-based ureas endowed with potent inhibitory activity for the human and murine sEH was reported. However, their very low microsomal stability prevented further development. Herein, novel series of benzohomoadamantane-based ureas were synthesized, fully characterized, and evaluated as sEHI. Most of them were endowed with subnanomolar inhibitory potencies at the human and murine enzymes. Further in vitro profiling (solubility, cytotoxicity, metabolic stability, CYP450s, hLOX-5, hCOX-2, hERG inhibition, permeability) allowed us to select a candidate for efficacy studies. In summary, these novel results and the previously reported studies using other families of sEHI, strongly suggest that sEH may be a target of clinical interest for the treatment of inflammatory and pain-related disorders. References: 1-Morisseau, C.; Hammock, B. D. Annu.Rev. Pharmacol. Toxicol. 2013, 53, 37-58. 2-Sun, C.-P.; Zhang, X.-Y.; Morisseau, C.; Hwang, S. H.; Zhang, Z.-J.; Hammock, B. D.; Ma, X.-C. J. Med. Chem. 2021, 64, 184-215. 3-Codony, S.; Calvó-Tusell, C.; Valverde, E.; Osuna, S.; Morisseau, C.; Loza, M. I.; Brea, J.; Pérez, C.; Rodríguez-Franco, M. I.; Pizarro-Delgado, J.; Corpas, R.; Griñán-Ferré, C.; Pallàs, M.; Sanfeliu, C.; Vázquez-Carrera, M.; Hammock, B. D.; Feixas, F.; Vázquez, S. J. Med. Chem., 2021, 64, 5429-5446. 4-McReynolds, C.; Morisseau, C.; Wagner, K.; Hammock, B. D. Adv. Exp. Med. Biol. 2020, 1274, 71-99.

Endometriosis is a complex gynecological disorder characterized by the ectopic growth of endometrial tissue. Symptoms of endometriosis are known to impair the quality of life of patients, among these symptoms are dysmenorrhea, chronic pelvic pain, and gastrointestinal (GI) issues. These GI issues are one of the common reasons for misdiagnosis with irritable bowel syndrome (IBS), a pain syndrome characterized by abdominal pain, painful bowel movements, diarrhea, and constipation, all of which are often present in endometriosis and persist even after treatment. Enteric glial cells (EGC) are known to play a role in pain associated with IBS, and reactive gliosis has been reported in patients with IBS, but the role of EGC in endometriosis has yet to be elucidated.

Iron deficiency is extremely common in adolescents with heavy menstrual bleeding (HMB) presenting to the emergency department; however, patients are rarely screened for this. The objective of this study was to evaluate screening for iron deficiency in adolescents presenting to the emergency department for HMB.

To explore the causes of ineffective or short-term recurrence (within 3 months)of trigeminal neuralgia treated by percutaneous microballoon compression(PBC), and to examine the reoperative strategies and clincal outcomes of modified PBC. The clinical data of 21 patients with ineffective or short-term recurrence after PBC treatment (5.7% of 369 patient received PBC) admitted to the Department of Neurosurgery,Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University from June 2018 to June 2020 were retrospectively analyzed.There were 8 males and 13 females, mean aged 66.6 years (range:51 to 79 years).Among them,2 patients was ineffective after PBC and 19 patients relapsed within 3 months.The distribution of pain was along V branches in 2 cases,V branches in 3 cases,V+V branches in 1 case,and V+V branches in 15 cases.The mean time of recurrence was 46.8 days (range:23 to 76 days) among the 19 patients with short-term recurrence.The patients were divided into 4 types based on the causes of postoperative ineffectiveness or short-term recurrence.TypeⅠ:extracapsular false pear (1 case);Type Ⅱ:invalid true pear(2 cases);Type Ⅲ:capsular rupture (6 cases);Type Ⅳ:compression blind area (12 cases).The individualized modified PBC operation plans were used according to the types of the patients and the clinical effect and complications of the patients were observed. The pain symptoms of the patients disappeared after the second operation with immediate effective rate of 100%. All patients had mild facial numbness after surgery.Five patients(23.8%,5/21) had masseter muscle weakness, 3 (14.3%,3/21) had peristomatous herpes, 1(4.8%,1/21) had diplopia.No bleeding or other complications occurred.All patients were followed up for at least 12 months (range:13 to 28 months). One patient (4.8%,1/21) (compression blind area type) had pain recurrence 9 months after surgery, and cured by receiving the original modified PBC surgery again with no recurrence after another 13 months' follow-up. None of the other patients relapsed during the follow-up period.Up to the last follow-up,19 cases(90.5%,19/21) were cured,and 2 cases (9.5%,2/21) were relieved. The main reason for ineffective or short-term recurrence of PBC in trigeminal neuralgia patients is the ineffectively compressed of trigeminal ganglion.According to the different types of patients,the use of individualized modified surgical scheme can improve the efficacy of PBC surgery.