Rejected

Chronic neck pain is a highly prevalent condition. Learning a relaxation technique is recommended by numerous guidelines for chronic neck pain. Smartphone apps can provide relaxation exercises; however, their effectiveness, especially in a self-care setting, is unclear.

Stress is known to cause migraine. This study investigates the effects of neonatal maternal deprivation (MD) and chronic unpredictable stress (CUS) on migraine in rats.

The rat surgical anterior cruciate ligament transection (ACLT) model is commonly used to investigate intra-articular osteoarthritis (OA) therapies, and histological assessment is often the primary outcome measure. However, histological changes do not always correlate well with clinical outcomes. Therefore, this study evaluated functional outcomes in the rat surgical ACLT model and compared intra-articular injection volumes ranging from 20 to 50 μl. Unilateral ACLT was surgically induced and static weight-bearing, mechanical allodynia, motor function, and gait were assessed in four groups of male, Sprague-Dawley rats (n = 6 per group). Intra-articular injections of 20 µl Dulbecco's phosphate-buffered saline (DPBS), 50 µl DPBS, or 50 µl of synthetic biomimetic boundary lubricant were administered once weekly for 3 weeks postoperatively. Structural changes were evaluated histologically at 20 weeks. Rat cadaver knees were injected with 20, 30, 40, or 50 µl of gadolinium solutions and were imaged using magnetic resonance imaging (MRI). Static weight-bearing, mechanical allodynia, and gait parameters in ACLT groups revealed differences from baseline and naïve controls for 4 weeks post-ACLT; however, these differences did not persist beyond 6 weeks. Different intra-articular DPBS injection volumes did not result in functional or histological changes; however, peri-articular leakage was documented via MRI following 50, 40, and 30 µl but not 20 µl gadolinium injections. Statement of clinical significance: Differences in functional parameters were predominantly restricted to early, postoperative changes in the rat surgical ACLT model despite evidence of moderate histologic OA at 20 weeks. Injection volumes of 20-30 µl are more appropriate for investigating intra-articular therapies in the rat knee.

Calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are peptide hormones and their receptors play a critical role in migraine progression and blood pressure control, respectively. CGRP and AM receptors are structurally related since they are the complex of the calcitonin receptor-like receptor (CLR) with the different types of receptor activity-modifying protein (RAMP). Several crystal structures of the CGRP and AM receptor extracellular domain (ECD) used maltose-binding protein (MBP) as a tag protein to facilitate crystallization. Unexpectedly, the recent crystal structures of CGRP receptor ECD showed that the N-terminal tag MBP located in proximity of bound/mutated peptide ligands. This study provided evidence that MBP N-terminally tagged to the CGRP receptor ECD formed chemical interaction with the mutated peptide ligands. Interestingly, N-glycosylation of the CGRP receptor ECD was predicted to prevent MBP docking to the mutated peptide ligands. I found that the N-glycosylation of CLR ECD N123 was the most critical for inhibiting MBP interaction with the mutated peptide ligands. The MBP tag protein interaction was also dependent on the sequence of the peptide ligands. In contrast to the CGRP receptor, the MBP tag was not involved in peptide ligand binding at AM receptor ECD. Here, I provided evidence that N-glycosylation of the CGRP receptor ECD inhibited the tag protein interaction suggesting an additional function of N-glycosylation in the MBP-fused CGRP receptor ECD. This study reveals the importance of using tag protein-free versions of the CGRP receptor for the accurate assessment of peptide binding affinity.

The novel coronavirus, SARS-coV-2, which emerged in Wuhan in November 2019, has increasingly spread worldwide. More than 272 million cases of infection have been identified. COVID-19 affects 223 countries and territories across the world. The principal target of the SARS-CoV-2 infection is the lower respiratory tract. Series of moderate to non-specific severe clinical signs and symptoms that appear two to fourteen days after exposure to SARS-CoV-2 can occur in patients with COVID-19 disease. There is cough, breath deficiency, and at least two of these symptoms: headache, fever, chills, repeated rigor, myalgia, oropharyngitis, anosmia, and ageusia. No therapeutic agents have been validated to have substantial efficacy in the clinical care of COVID-19 patients in large-scale trials, despite worsening infected rates in COVID-19. Early clinical evidence from many sources suggests that treatment with famotidine may decrease COVID-19-related morbidity and mortality. The mechanism by which famotidine could improve the outcomes of COVID-19 is currently unknown. A more recent postulated mechanism is that the effect of famotidine is mediated by histamine-2 receptor antagonism or inverse agonism, inferring that the SARS-CoV-2, resulting in COVID-19 infection at least partially leads to the abnormal release of histamine and perhaps dysfunction of mast cells.

The skin serves as the interface between the body and the environment and plays a fundamental role in innate antimicrobial host immunity. Antiviral proteins are part of the innate host defense system and provide protection against viral pathogens. How breach of the skin barrier influences innate antiviral protein (AVP) production remains largely unknown. Here, we characterize the induction and regulation of AVPs following skin injury and identify a key role of the transient receptor potential cation channel subfamily V member 1 (TRPV1) in this process. Transcriptional and phenotypic profiling of cutaneous wounds revealed that skin injury induces high levels of AVPs in both mice and humans. Remarkably, pharmacological and genetic ablation of TRPV1-mediated nociception abrogated induction of AVPs including Oas2, Oasl2, and Isg15 following skin injury in mice. Conversely, stimulation of TRPV1 nociceptors was sufficient to induce antiviral protein production involving the CD301b cells-interleukin (IL)-27-mediated signaling pathway. Using IL-27 receptor knockout mice, we demonstrate that IL-27 signaling is required in the induction of AVPs following skin injury. Finally, loss of TRPV1 signaling leads to increased viral infectivity of herpes simplex virus. Together, our data indicate that TRPV1 signaling ensures skin antiviral competence upon wounding.

This study aimed to compare the effectiveness of NAC plus low dose contraceptive with low dose contraceptives alone. This was a randomised trial on a sample of women who underwent conservative laparoscopic surgery for ovarian endometrioma. Patients were randomly assigned either to the NAC plus low dose contraceptive group ( = 48) or low dose contraceptive alone ( = 52). To evaluate the recurrence rate transvaginal ultrasound was performed. Pelvic pain was assessed using a visual analogue scale (VAS). All assessments were performed at two points in time: 3 and 6 months post-surgery and compared between the two regimens. The findings indicated that reduction in the recurrence rate of endometrioma and pelvic pain were similar between both groups. The findings showed that adding N-acetylcysteine to low dose contraceptive treatment has a similar effect in reducing the recurrence rate of endometrioma and pelvic pain when compared to low dose contraceptives alone.Impact statement Endometriosis is a frequent benign disease-producing inflammatory response with mild to severe symptoms. Although surgical removal of ectopic lesions is the first-line intervention, the recurrence rate of the disease is high. Thus this study aimed to compare the effectiveness of N-acetylcysteine plus low dose contraceptive with low dose contraceptive alone. The findings showed that adding N-acetylcysteine to low dose contraceptive treatment has a similar effect in reducing the recurrence rate of endometrioma and pelvic pain when compared to low dose contraceptives alone. It is recommended to increase the duration of drug administration in future studies.

GSK3640254 (GSK'254) is a next-generation HIV-1 maturation inhibitor with pharmacokinetics (PK) supporting once-daily therapy.

Multiple representatives of eulipotyphlan mammals such as shrews have oral venom systems. Venom facilitates shrews to hunt and/or hoard preys. However, little is known about their venom composition, and especially the mechanism to hoard prey in comatose states for meeting their extremely high metabolic rates. A toxin (BQTX) was identified from venomous submaxillary glands of the shrew Blarinella quadraticauda. BQTX is specifically distributed and highly concentrated (~ 1% total protein) in the organs. BQTX shares structural and functional similarities to toxins from snakes, wasps and snails, suggesting an evolutional relevancy of venoms from mammalians and non-mammalians. By potentiating thrombin and factor-XIIa and inhibiting plasmin, BQTX induces acute hypertension, blood coagulation and hypokinesia. It also shows strong analgesic function by inhibiting elastase. Notably, the toxin keeps high plasma stability with a 16-h half-life in-vivo, which likely extends intoxication to paralyze or immobilize prey hoarded fresh for later consumption and maximize foraging profit.

The ABCDE bundle is a set of evidence-based practices to systematically reduce the risks of sedation, delirium, and immobility in intensive care patients. Implementing the bundle improves clinical outcome.