Rejected

Activation of airway sensory nerves causes respiratory and autonomic reflexes. The majority of the sensory nerves are only sensitive to noxious stimuli, such as inflammation, infection, irritants and pollutants. Activation of these nociceptive sensory nerves evokes protective mechanisms such as apnea, cough and bradycardia that can contribute to disease morbidity. Airway nociceptive sensory nerves are heterogeneous with respect to gene expression and neuroanatomy, and our objective is to characterize the specific reflexes evoked by activation of specific afferent subsets. To selectively activate these vagal afferent subpopulations in vivo, mice were exposed to nebulized selective stimuli such as capsaicin (transient receptor potential (TRP) vanillin 1 (V1) agonist), allyl isothiocyanate (AITC, TRP ankyrin 1 (A1) agonist) and clozapine-N-oxide (CNO, selective agonist for the designer receptors exclusively activated by designer drugs (DREADD) stimulatory receptor hM3Dq). hM3Dq expression was selectively expressed in sensory subpopulations under the control of cre recombinase in TRPV1-cre (all nociceptors) and Tac1-cre (peptidergic nerves). ECGs were recorded via radiotelemetry following implantation of biopotential sensing modules, and respiration was measured via whole body plethysmography. Our data indicate that stimulation of nociceptive subpopulations selectively evokes bradypnea and bradycardia in freely moving wild type mice.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, which leads to poor quality of life due to the debilitating effect of inflammation. Clinical trials in rheumatoid arthritis targeting the cytokine, granulocyte macrophage-colony stimulating factor (GM-CSF) are showing promise although its mode of action remains largely unknown. We have previously shown that that GM-CSF drives CCL17 production via a new interferon regulatory factor 4 (IRF4)-dependent pathway in human monocytes and mouse macrophages, as well as in vivo. Importantly, in arthritis and pain models IRF4-regulated CCL17 formation mediates the proinflammatory and algesic actions of GM-CSF. Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressive agents broadly used in anti-inflammatory therapy, albeit with adverse side effects associated with long-term usage. The negative consequences of GC therapy provide an impetus for research into gaining insights into the molecular mechanisms of GC action on immune cells. We report here that GM-CSF-induced CCL17 expression is inhibited by dexamethasone, a synthetic GC, in human monocytes and mouse macrophages. Moreover, we provide evidence for the first time that dexamethasone suppresses GM-CSF-induced IRF4 expression via regulating the expression and activity of JMJD3, which demethylates trimethylated-H3K27. Further, we demonstrate that dexamethasone suppresses the expression of JMJD3, via the recruitment of GC receptor-alpha to the negative GC response element in the upstream region of JMJD3 gene. Significantly, we measured elevated levels of CCL17 in synovial fluid from patients with RA compared to healthy controls. Using synovial fluid mononuclear cells from RA patients, we provide molecular evidence for the anti-inflammatory actions of GCs through epigenetic regulation of IRF4 expression and downstream inhibition of CCL17 production. The delineated pathway potentially provides new therapeutic options for the treatment of inflammatory diseases and their associated pain.

Chronic pain is a serious public health concern with an economic burden of $600 million annually and personal burden for approximately 100 million Americans. Prescription opioids (mu opioid receptor agonists) are the "gold standard" for treating moderate to severe pain despite their well-documented adverse effects (dependence, respiratory depression, constipation). Of all prescription medications, opioids are abused most widely, and fatal overdoses have reached epidemic levels. Thus, there is a dire need for safer, more effective treatments for pain. One strategy for improving the margin of safety of opioids is combining them with other analgesic drugs to decrease the opioid dose needed for pain relief, thereby avoiding adverse effects that occur with larger doses. The NMDA receptor antagonist ketamine has been used safely and effectively to treat pain, but only under a narrow range of conditions (in emergency departments, post-operative recovery, and combat casualty). The current studies used a model of acute pain (warm water tail withdrawal) and a model of chronic inflammatory pain (Von Frey paw withdrawal) to determine the antinociceptive effects of morphine and ketamine alone and in mixtures (in 3:1, 1:1, and 1:3 ratios) in 16 male Sprague Dawley rats. Given alone, both morphine (1-10 mg/kg) and ketamine (3.2-32 mg/kg) dose-dependently increased tail withdrawal latency, with morphine having greater potency and efficacy as compared to ketamine. Similarly, given alone, both morphine (0.56-5.6 mg/kg) and ketamine (3.2-32 mg/kg) dose-dependency increased force required to elicit a paw withdrawal response, with morphine having greater potency as compared to ketamine. ED values were used to determine the doses for mixtures. In mixtures, the potency of morphine or ketamine to produce antinociception was enhanced by 2-3 fold as compared to either drug given alone. Dose-equivalence and dose-additivity analyses showed that the effects of morphine:ketamine mixtures were additive. Furthermore, morphine:ketamine mixtures that relieved pain also were tested in an assay of constipation in a separate group of 8 rats. While both morphine (1-10 mg/kg) alone and ketamine (3.2-32 mg/kg) alone dose-dependently decreased fecal output, morphine:ketamine mixtures did not enhance constipation. Therefore, morphine:ketamine mixtures appear to selectively enhance antinociception. It remains unknown whether morphine:ketamine mixtures have other adverse effects (abuse, physical dependence, respiratory depression) and whether interactions between morphine and ketamine on these outcomes might be related to the ratio of each drug in mixtures. Morphine:ketamine mixtures might have greater therapeutic potential than mu opioids alone for treating moderate to severe pain, but only if adverse effects of each drug are not enhanced.

Sepsis is an intense immune response to infection that contributes to the pathophysiological process of acute lung injury (ALI). Inflammation and oxidative stress serve an important role in the development of ALI. Leonurine (LEO) is a natural phenolic alkaloid extracted from , which possesses anti-inflammatory and antioxidative properties. Therefore, the aim of the present study was to explore the effect of LEO on sepsis-induced ALI and to investigate its underlying mechanism. MTT and Cell Counting Kit-8 assays were performed to measure cell viability. The levels of reactive oxygen species, lactate dehydrogenase and malondialdehyde, as well as the activity of superoxidase dismutase, were quantified using commercial assay kits. The expression levels of specific inflammatory cytokines were measured by using ELISA. In addition, western blotting was employed to assess the expression levels of cytokines, including TNF-α, IL-6, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1. The findings demonstrated that LEO increased the viability of lipopolysaccharide (LPS)-stimulated BEAS-2B human lung epithelial cells in a dose-dependent manner. Additionally, LEO suppressed LPS-induced oxidative stress and inflammatory cytokine release in BEAS-2B cells. Treatment with Nrf2 inhibitor reversed the effects of LEO treatment on LPS-induced oxidative stress and inflammatory response in BEAS-2B cells. Taken together, the data of the present study indicated that LEO attenuated LPS-induced ALI through the inhibition of oxidative stress and inflammation regulated by the Nrf2 signaling pathway. Therefore, LEO may be a novel and effective agent for the prevention of sepsis-induced ALI.

Fibromyalgia is a chronic pain condition manifested by chronic generalized pain, fatigue, disordered sleep, and cognitive difficulties, persistent for at least 3 months. Other common complaints/conditions include symptoms of irritable bowel syndrome, headaches, intermittent paresthesias, and various mood disorders. Women are more commonly affected than men. The treatment approach should be individualized and focused on associated mood disorders, sleep, exercise, correction of maladaptive responses to pain, and coping with stress.

COVID-19 mRNA vaccines have demonstrated excellent short-term safety in phase 3 trials. However, no kidney transplant recipients (KTR) were included. The aim of the study was to assess the safety and tolerability of COVID-19 mRNA vaccines in KTR.

All modern vaccines share the risk of neurological adverse effects. Only a few cases of Parsonage-Turner syndrome (PTS), an uncommon peripheral nerve condition associated with coronavirus disease 2019 (COVID-19) immunization, have been reported to date. We describe a case of COVID-19 vaccine-induced PTS and provide a brief literature review. A 78-year-old male non-smoker with a medical history of coronary artery disease presented with non-exertional, constant chest pain for one hour and new onset of bilateral hand weakness for three days. He had no neurological disease or allergies and denied any recent trauma or infection. Three weeks before the onset of the symptoms, the patient received a second dose of the BNT162b2 COVID-19 vaccine, which was administered 21 days after the first dose. Physical examination was significant for weakness in right-hand grip and wrist flexion. There were no other motor deficits, upper motor neuron signs, bulbar weakness, or sensory deficits. Diagnostic workup for the underlying diabetes mellitus, infections, or other autoimmune diseases was negative. Imaging workup revealed no demyelination, fracture deformity, traumatic subluxation, or compressive myelopathy. Nerve conduction studies, including needle electromyography, showed decreased motor unit recruitment in the bilateral first dorsal interosseous and right deltoid, biceps, and triceps muscles confirming PTS. The patient was treated with 40 mg/day of oral prednisone and occupational therapy to maintain range of motion and activities of daily living. PTS is also known as neuralgic amyotrophy, brachial plexus neuritis, brachial plexopathy, and shoulder-girdle syndrome. It is characterized by asymmetrical, chronic, resistant upper extremity neuropathic pain and neurological defects such as paralysis and paresthesia. There are two different types of PTS: non-hereditary and inherited. The etiology and pathophysiology of PTS are not fully understood. Various aspects such as genetic, environmental, and immunological predisposition may play a role in developing the syndrome. Infections, vaccines, and injuries are typical causes of non-hereditary forms. After the COVID-19 epidemic and the commencement of a global immunization effort, similar instances happened. Presently there is no available test that unequivocally confirms or excludes PTS itself. Electrodiagnostic study and imaging modalities help to rule out other differential diagnoses. Also, there is no specific treatment available; however, it may resolve independently of treatment with supportive care.

Introduction A chronic daily headache (CDH) comprises a group of headaches occurring at least 15 days per month for three or more consecutive months. We retrospectively investigated the effectiveness of the hybrid treatment strategy for CDH using medicine combined with Western medication. Methods We retrospectively investigated 43 consecutive first-visit CDH patients. In addition to Western acute and prophylactic medications, we prescribed three types of medicines: , , and  depending on the patients' symptoms. Headache impact test-6 (HIT-6), monthly headache days (MHD), monthly migraine days (MMD), and monthly acute medication intake days (AMD) before, 1- and 3-months after starting the hybrid medications were assessed as outcomes. Results Thirty-six women and seven men were included. The median age was 51 years old. Nine were chronic migraine (CM), 22 were episodic migraine and tension-type headaches (EM+TTH), and 12 were chronic TTH. Twenty-seven patients also had medication overuse headaches (MOH). The medians of HIT-6 before, one and three months after treatment were 63, 48, and 40, respectively. Those of MHD were 20, 5, and 2. Those of MMD were 2, 0, and 0. Those of AMD were 15, 0, and 0. Significant reductions in HIT-6, MDH, MMD, and AMD were observed one and three months after starting treatment. Similar trends were observed in the EM+TTH and MOH patients as subgroup analyses. Conclusion The hybrid medication strategy of and Western medicines for CDH is safe and effective in terms of both acute and prophylactic medications with rapid efficacy.

The patient was a 70-year-old woman who underwent transurethral resection of bladder tumor in May 2020. She was diagnosed with urothelial carcinoma (high grade, pT1 by pathology). We started bacillus Calmette-Guerin (BCG) intravesical infusion (80 mg Tokyo strain) in August of the same year after a second transurethral resection. Pain during urination persisted during the administration of BCG, and it worsened after the completion of six doses. The patient was hospitalized with back and neck pain and difficulty in physical movement. At the time of admission, bilateral conjunctivitis was observed. The patient was diagnosed with reactive arthritis associated with BCG intravesical injection therapy, as three typical symptoms were observed (bilateral conjunctivitis, urethritis, polyarthritis). The patient was treated with prednisolone and non-steroidal anti-inflammatory drugs for arthritis, but the symptoms did not improve. We administered salazosulfapyridine and her reactive arthritis improved.