Accepted

Painful diabetic neuropathy (PDN) is a common complication in patients with diabetes, and its underlying mechanism remains unclear. Aquaporin-4 (AQP4) plays a crucial role in removing metabolic waste in the glymphatic system. In this study, we aimed to explore the relationship between the spinal glymphatic system and the effect of metformin on PDN. Male Sprague-Dawley rats were randomly allocated into the control group (n = 10), the PDN group (n = 10), and the metformin group (n = 10). A high-fat and high-glucose diet combined with low-dose streptozotocin was used to induce PDN rats. We detected the clearance rate of the contrast agent in the spinal cord of each rat by MRI to reflect the function of the glymphatic system. Immunofluorescence was used to detect the localization of perivascular AQP4 in astrocyte endfeet. Furthermore, we measured the expression of AQP4 in the spinal cord by Western blot. Compared with the rats in the control group, PDN rats exhibited enhanced mechanical allodynia, decreased clearance rate of the contrast agent in the spinal glymphatic system, reversed AQP4 polarization, and increased expression of AQP4. After being treated with metformin, the rats showed opposite changes in the above characteristics. The analgesic effect of metformin on PDN may be related to its ability to restore spinal AQP4 polarization, thus promoting the function of the spinal glymphatic system.

Giant cell arteritis (GCA) is the most common systemic vasculitis in individuals aged ≥50 years. Its course is marked by a high relapse rate requiring long-term glucocorticoid use with its inherent adverse effects. We aimed to identify factors associated with relapses or recurrences in GCA at diagnosis.

Spinal cord injury (SCI) can lead to devastating autonomic dysfunction. One of the most challenging issues for functional repair in SCI is the secondary damage caused by the increased release of glutamate and free Ca from injured cells. Here, an in situ assembled trapping gel (PF-SA-GAD) is developed to sweep glutamate and Ca , promoting SCI repair. The hydrogel solution is a mixture of recombinant glutamate decarboxylase 67 (rGAD67) protein, sodium alginate (SA), and pluronic F-127 (PF-127). After intrathecal administration, temperature-sensitive PF-127 promoted in situ gelation. Glutamate (Glu) is captured and decarboxylated by rGAD67 into γ-aminobutyric acid (GABA). SA reacted with the free Ca to generate gellable calcium alginate. Thereby, this in situ trapping gel retarded secondary neuron injury caused by Glu and free Ca during SCI. In rat models of SCI, PF-SA-GAD reduces the lesion volume and inflammatory response after SCI, restores the motor function of rats with SCI. Together, the in situ assembled trapping gel is a long-term effective and minimally invasive sweeper for the direct elimination of glutamate and Ca from injury lesions and can be a novel strategy for SCI repair by preventing secondary injury.

This cross-sectional study aims to find the prevalence of chronic pain and its correlation with the quality of life and vitamin D levels among hemodialysis patients in Palestine. We used the brief pain inventory, the medical outcomes study 36-item short-form health survey, and Serum 25-hydroxyvitamin D to assess chronic pain, quality of life, and vitamin D levels, respectively. The study included 200 patients, 38.1% (95% confidence interval 31.3-45.4%) of whom had chronic pain, and 77.7% (95% confidence interval 71.0-83.4%) had deficient Vitamin D levels. Quality of life scores were generally low, with the lowest in role emotional and physical functioning. Sex, comorbidities, and vitamin D level significantly correlate with pain severity. Employment, number of comorbidities, pain severity, and albumin level are significantly associated with the Physical component of quality of life. On the other hand, employment and pain severity are significantly related to the mental component of quality of life. In conclusion, low vitamin D levels, chronic pain, and low quality of life scores are common among hemodialysis patients. In addition, vitamin D is negatively correlated with pain severity. Therefore, healthcare workers should assess and manage hemodialysis patients' chronic pain to improve their quality of life and reduce suffering.

Rheumatoid arthritis (RA) is a chronic degenerative disease characterized by persistent systemic synovitis, with a high risk of stiffness, pain, and swelling. It may affect the other extra-articular tissues. There is no ideal treatment for this disease at present, and it can only be controlled by medication to alleviate the prognosis. Exosomes are small vesicles secreted by various cells in the organism under normal or pathological conditions, and play a role in immune response, antigen presentation, cell migration, cell differentiation, tumor invasion and so on. Due to the adverse effects of conventional drugs and treatments in the treatment of RA, exosomes, as a nanocarrier with many advantages, can have a great impact on the loading of drugs for the treatment of RA. This article reviews the role of exosomes in the pathogenesis of RA and the progress of exosome-based therapy for RA.

Chronic pain and opioid use disorder (OUD) individually represent a risk to health and well-being. Concerningly, there is evidence that they are frequently co-morbid. While few treatments exist that simultaneously target both conditions, preliminary work has supported the feasibility of an integrated behavioral treatment targeting pain interference and opioid misuse. This treatment combined Acceptance and Commitment Therapy (ACT) and Mindfulness-Based Relapse Prevention (ACT+MBRP). This paper describes the protocol for the adequately powered efficacy study of this integrated treatment.

Intervertebral disc degeneration (IDD) has been reported to be a major cause of low back pain. Interleukin (IL)-37 is an anti-inflammatory cytokine of the interleukin-1 family, which exerts salutary physiological effects. In this study, we assessed the protective effect of IL-37 on IDD progression and its underlying mechanisms.

This preclinical systematic review aimed to determine the effectiveness of different types and doses of exercise on pain behaviour and biomarkers in preclinical models of focal neuropathic pain. We searched MEDLINE, EMBASE, Web of Science, PubMed, SCOPUS, CINAHL and Cochrane library from inception to November 2022 for preclinical studies evaluating the effect of exercise compared to control interventions on neuropathic pain behaviour after experimental sciatic nerve injury. If possible, data were meta-analysed using random effect models with inverse-variance weighting. Thirty-seven studies were included and 26 meta-analysed. Risk of bias (SYRCLE tool) remained unclear in most studies and reporting quality (CAMARADES) was variable. Exercise reduced mechanical (SMD 0.53 (95% CI 0.31, 0.74), p= 0.0001, I=0%, n=364), heat (0.32 (0.07,0.57), p=0.01, I=0%, n=266) and cold hypersensitivity (0.51 (0.03, 1.0), p=0.04, I=0%, n=90) compared to control interventions. No relationship was apparent between exercise duration or intensity and antinociception. Exercise modulated biomarkers related to different systems (e.g., immune system, neurotrophins). Whereas firm conclusions are prevented by the use of male animals only, variable reporting quality and unclear risk of bias in many studies, our results suggest that aerobic exercise is a promising tool in the management of focal neuropathic pain. Registration PROSPERO CRD42021231286. Perspective: This systematic review and meta-analysis demonstrates that aerobic exercise reduces neuropathic pain-related behavior in preclinical models of sciatic nerve injury. This effect is accompanied by changes in biomarkers associated with inflammation and neurotrophins among others. These results could help to develop exercise interventions for patients with neuropathic pain.

Histamine has been postulated to play a role in atopic dermatitis via histamine receptor 4, mediating pruritic and inflammatory effects. The H4R antagonist adriforant (PF-3893787 or ZPL389) indicated clinical efficacy in a Ph2a study in atopic dermatitis. Preclinical investigations of adriforant had been scarce as experiments in transfectants with H4R from several species suggested partial agonism, not seen in human cells.