Rejected

Pain is a major symptom of many medical conditions with diverse etiologies. World Health Organization (WHO) indicates that 1 in 5 adults globally suffers from pain. Thus, there is a great demand on finding alternative interventions whether to be used alone or in combination with opioids or NSAIDs. In this preclinical study, we evaluated the antinociceptive effect of serratiopeptidase; a well-known proteolytic enzyme with proven anti-inflammatory effect and questionable analgesic effect; in the presence and absence of ibuprofen. Isobolographic analysis for drug combination was used to determine whether combination effects were synergistic. Intraperitoneal injection of 1.8 % of lactic acid and intraplantar injection of Complete Freund's Adjuvant (CFA) were used to assess acute and chronic inflammatory pain in adult male Sprague-Dawley rats. Both ibuprofen (10-32 mg/kg) and serratiopeptidase (1-3.2 mg/kg) showed a significant antinociceptive effect on lactic acid-induced stretching. Also, only ibuprofen (32 mg/kg) showed significant increase in the number of reward bottle activations using Orofacial Pain Assessment Device (OPAD) for the assessment of acid-depressed feeding behavior. Moreover, only ibuprofen (32 mg/kg) increased paw withdrawal threshold significantly in CFA-induced mechanical allodynia using von Frey filaments. Combination treatments of ibuprofen and serratiopeptidase resulted in a subadditive (antagonistic) interaction on lactic acid-stimulated body stretching behavior. However, synergistic interaction resulted by drug combination on lactic acid-depressed feeding behavior and on CFA-induced mechanical allodynia. In addition, the coadministration of serratiopeptidase with ibuprofen in showed a significant decrease in the duration of CFA-induced mechanical allodynia. These data suggest that the administration of serratiopeptidase with ibuprofen may produce synergistic antinociceptive effect in chronic inflammatory conditions and pain-depressed behaviors such as food consumption. Further clinical tests may be needed to assess this synergistic effect in human subjects.

Nociceptive transmission at the spinal cord is modulated by descending pain inhibitory systems originating in the brainstem that interact with neural cardiovascular pathways, such as baroreceptor input. However, data regarding antinociceptive properties of cardiopulmonary baroreceptors are largely mixed, and no studies have examined cardiopulmonary baroreceptor modulation of pain perception in patients with chronic pain. Therefore, we tested the hypothesis that cardiopulmonary baroreceptor unloading would reduce pain perception in chronic back pain (CBP) patients and healthy participants. Mechanical pressure pain threshold (algometer on the upper trapezius) and pain perception of a repetitive heat stimulus (thermode on the anterior forearm) was tested in 12 CBP patients and 8 healthy controls during supine lower body negative pressure (LBNP) of -10 mmHg and 0 mmHg (control condition). Pressure pain threshold during LBNP was significantly increased compared with the control condition in CBP patients (270 ± 31 vs. 240 ± 27 kPa, P=0.04) and healthy controls (293 ± 59 vs. 259 ± 50 kPa, P=0.02), indicating reduced pain perception. Similarly, the average pain rating (scale 0-100) of the repetitive heat stimulus was significantly reduced during LBNP compared with the control condition in CBP patients (42 ± 6 vs. 48 ± 6, P<0.01). However, no significant change was observed in average pain rating of the repetitive heat stimulus during LBNP in healthy controls (38 ± 5 vs. 37 ± 7, P=0.89). Together, these preliminary findings suggest reduced pain perception during cardiopulmonary baroreceptor unloading with a potentially greater effect in patients with CBP compared with healthy individuals.

Migraine is a common brain disorder characterized by recurrent episodes of headache. It is a complex and multifactorial disease with a higher prevalence in females than in males. Several risk factors have been associated to migraine disease as genetic factors, sex and age. The pathophysiology of migraine is still unclear; however, it has been proven that NOD-like receptor protein 3 (NLRP3) inflammasome pathway overactivation as well as p-ERK/p-CREB axis contribute to migraine pathogenesis. Therefore, the aim of this study was to investigate the effect of BAY-117082, a NLRP3 inflammasome inhibitor and p-ERK/p-CREB modulator, in an in vivo model of nitroglycerin (NTG)-induced migraine. Migraine model was induced by NTG intraperitoneal administration at dose of 10 mg/kg diluted in 0.9% saline. Mice were treated intraperitoneally with BAY-117082 at doses of 1 mg/kg, 5 mg/kg, and 10 mg/kg, 5 minutes after NTG injection. Mice were sacrificed 4 h following NTG injection; the whole brain with the rostral spinal cord was removed to perform several analysis. Our results demonstrated that, following behavioral tests for pain and photophobia, BAY-117082 treatment at doses of 5 mg/kg and 10 mg/kg reduced pain attacks induced by NTG more than BAY-117082 at the dose of 1 mg/kg. Moreover, the treatment with BAY-117082 at doses of 5 mg/kg and 10 mg/kg significantly reduced histological damage in the trigeminal nerve nucleus and significantly decreased inflammosome activation by reduction of NLRP3, ASC, IL-1β and TNF-α expression. Additionally, the treatment with BAY-117082 at doses of 5 mg/kg and 10 mg/kg significantly modulated p-ERK/p-CREB axis activation through the reduction of p-ERK, p-AKT, p-CREB and p-PI3K expression. Therefore, the obtained results offer new insight into the role of NLRP3 inflammasome pathway and p-ERK/p-CREB axis in migraine pathogenesis, suggesting that BAY-117082 could be considered a novel therapeutic strategy to treat migraine.

Post-acute sequelae of COVID-19, commonly known as long-COVID, is defined as a persistent symptom(s) that is unexplainable by alternative diagnosis and lasts beyond three months after the onset of COVID-19. Several studies have now identified long-COVID in >50% of COVID-19 patients, emphasizing the need for elucidating mechanisms underlying these symptoms. Pain is a prevalent symptom in long-COVID patients and presents as headache, persistent muscle pain, joint pain, stomach pain, chest pain, respiratory discomfort, and dysesthesia or paresthesia. Understanding the molecular underpinnings of pain maintenance in these patients could provide information on novel therapeutic strategies. Our lab has previously identified novel treatments for pain due to peripheral inflammation from dysesthesia-inducing mechanisms associated with acute SARS-CoV-2 (SCV2) respiratory infection in hamsters (1-4 days post-infection, dpi). We have also previously demonstrated the validity of long-term infection of hamsters (30-60 dpi) as a pre-clinical model of long-COVID. By utilizing the Von Frey assay, we found that SCV2, but not Influenza A, causes mechanical hypersensitivity at 28 dpi in both male and female hamsters. Bulk RNA sequencing of 31 dpi thoracic dorsal root ganglia (DRGs) revealed a unique transcriptional perturbation signature (168 DEGs, 47 up & 121 down, p-adj.<0.1), despite viral clearance at approximately 7 dpi. Ingenuity Pathway Analysis of this sequencing (853 DEGs, p-nom.<0.05) identified several injury-related canonical pathways, including Production of NO & ROS in Macrophages, Signaling by Rho Family GTPases, mTOR Signaling, Estrogen Receptor Signaling, and Ephrin Receptor Signaling. The Enrichr DisGeNET browser associated these transcriptional changes with clinical neurodegeneration phenotypes, including Amyotrophic Lateral Sclerosis, Alzheimer's Disease, Neurodegenerative Disorders, and Parkinson Disease. Of note, TUNEL staining did not demonstrate any sign of SCV2-induced sensory neuron apoptosis at 31 dpi. Further investigation of the sequencing dataset revealed a broad downregulation of TubbmRNA isoforms and Mbp, suggesting microtubule and myelin dysregulation. We also observed a drastic increase in Scn8areads, which could point to Na 1.6-induced DRG neuron hyperexcitability. In conclusion, our findings suggest that SCV2 leaves a lasting hypersensitivity-associated transcriptomic signature in DRGs despite early viral clearance that appears to be associated with neurodegeneration mechanisms. As we continue investigating the mechanisms underlying SCV2-induced actions in DRGs and peripheral nerves, we will also use an upstream regulator analysis of our RNA sequencing data to identify promising therapeutic targets.

Emergence of severe acute respiratory syndrome coronavirus 2 infections and the resultant disease, COVID-19 led the world into 238 million cases and 4.8 million deaths over the first 22 months of the pandemic. While numerous vaccines have been developed to combat this pandemic, limited literature is available regarding the comparison of these vaccines. This study aims to systematically review and evaluate the immunogenicity and safety of COVID-19 vaccines compared with control arms in the healthy adult population.

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory condition that may involve multiple organ systems. Although the antinuclear antibody (ANA) test is positive in nearly every case of SLE, it is not specific for this disease and must be interpreted in the appropriate clinical context. Key features that warrant ANA testing include unexplained multisystem inflammatory disease, symmetric joint pain with inflammatory features, photosensitive rash, and cytopenias. ANA staining patterns and more specific autoantibody testing may be helpful in diagnosis of suspected SLE or ANA-associated disease. For patients with nonspecific symptoms, such as malaise and fatigue, ANA testing is of limited value.

The COVID-19 pandemic has challenged neurologists since its early days. Neurology consultation services were then overloaded by emergency department and intensive-care patients with acute neurological syndromes. These complications are better explained today, but the growing number of patients with reported longstanding neurological symptoms constitute an emerging, complex, and still poorly understood phenomenon.

Coronavirus disease 2019 (COVID-19) vaccination campaigns are trying to curb the pandemic by vaccinating as many individuals and as quickly as possible. The speed of immunization depends upon the availability of the vaccine and vaccine uptake by the communities, which in turn is related to vaccine hesitancy, the safety/efficacy profile of the vaccines, and adverse events following immunization (AEFI).

Thoracic epidural analgesia (TEA) is an effective analgesic technique for breast surgery, although it has many associated complications. Ultrasound (US)-guided erector spinae plane (ESP) block requires less technical expertise, is safe and may be an alternative to TEA. We aimed to compare the efficacy of TEA with US-guided continuous ESP block for post-operative analgesia in patients undergoing modified radical mastectomy (MRM) surgeries.

The initial electrocardiogram finding in the setting of acute myocardial infarction typically shows either persistent ST-segment elevation or non-ST-segment elevation. In young adults, when coronary angiography is performed, can further classify the patient with an occluded vessel and those with non-occluded coronary arteries. In these subgroups, myocardial infarction can be explained on the basis of coronary artery thrombosis, embolization, spontaneous coronary artery dissection, myocardial bridging, coronary aneurysms, ectasia, anomalous origin of coronary arteries coronary microvascular dysfunction, and vasospasm, or a combination of these factors. We describe a 37-year-old male with a history of chest pain and electrocardiographic evidence of acute myocardial infarction who worked many hours under the sun before being presented to the emergency department. The initial laboratory tests showed evidence of acute kidney injury. He underwent a rescue coronary angiogram due to failed initial medical reperfusion therapy with Tenecteplase, which revealed occluded of the distal left anterior descending (LAD) artery with a minor lesion in proximal LAD and right coronary artery. Our patient experienced acute myocardial infarction owing to severe dehydration. This case is important as it highlights that severe dehydration can be considered one of the triggering factors for acute myocardial infarction in young men who are at risk. Proper hydration could be a preventive measure.