Rejected

Several studies suggested that migraine attack onset shows a circadian variation; however, there has not been an overview and synthesis of these findings. A PubMed search with keywords "migraine" AND "circadian" resulted in ten studies directly investigating this topic. Results of these studies mostly show that migraine attacks follow a monophasic 24-hour cyclic pattern with an early morning or late night peak while other studies reported an afternoon peak and also a biphasic 24-hour cycle of attacks. The identified studies showed methodological variation including sample size, inclusion of medication use, comorbidities, and night or shift workers which could have contributed to the contradictory results. Several theories emerged explaining the diurnal distribution of migraine attacks suggesting roles for different phenomena including a morning rise in cortisol levels, a possible hypothalamic dysfunction, a circadian variation of migraine triggers, sleep stages, and a potentially different setting of the circadian pacemaker among migraineurs. At the moment, most studies show an early morning or late night peak of migraine attack onset, but a significant amount of studies reveals contradictory results. Further studies should investigate the arising hypotheses to improve our understanding of the complex mechanism behind the circadian variation of migraine attacks that can shed light on new targets for migraine therapy.

Extracellular RNA in circulation mediates intercellular communication in normal and pathological processes. One mode of circulating miRNA transport in bodily fluids is within 30-150 nm small extracellular vesicles (sEVs) or exosomes. Uptake of sEVs can regulate gene expression in recipient cells enabling circulating miRNAs to exert paracrine and systemic effects. Complex regional pain syndrome (CRPS) is a debilitating pain disorder characterized by chronic inflammation. Our previous investigations identified a significant decrease of hsa-miR-939 in whole blood from CRPS patients compared to control; we also observed that overexpression of miR-939 can negatively regulate several proinflammatory genes . Though downregulated in whole blood, miR-939 was significantly upregulated in sEVs isolated from patient serum. Here we investigated miR-939 packaging into sEVs under inflammation induced by monocyte chemoattractant protein-1 (MCP-1), a chemokine that is upregulated in CRPS patients. Stimulation of THP-1 monocytes by MCP-1 led to elevated levels of miR-939 in sEVs, which was abrogated using inhibitors of exosome secretion. miRNAs loaded into exosomes largely contain short miRNA sequence motifs called EXOmotifs. Mutation analysis of miR-939 showed that EXOmotif is one of the possible cellular mechanisms responsible for packaging miR-939 into sEVs. We confirmed gene expression changes in recipient cells following the uptake of sEVs enriched in miR-939 using RNA sequencing. Additionally, our data from primary immune cell-derived sEVs of CRPS patients and controls demonstrate that while the relative expression of miR-939 is higher in sEVs derived from B cells, T cells and NK cells relative to monocyte-derived sEVs in controls, only the B cell-derived sEVs showed a significantly higher level of miR-939 in CRPS patients. Differential miRNA sorting into exosomes and its functional impact on recipient cells may contribute to the underlying pathophysiology of CRPS.

The Treatment Beliefs Questionnaire has been developed to measure patients' beliefs of necessity of and concerns about rehabilitation. Preliminary evidence suggests that these beliefs may be associated with attendance of rehabilitation. The aim of this study was to translate and adapt the Treatment Beliefs Questionnaire for interdisciplinary pain rehabilitation and to examine the measurement properties of the Dutch translation including the predictive validity for dropout.

To study the informative nature of manual therapy for differential diagnosis of migraine and cervicogenic headache (CH).

Individuals living with traumatic brain injury (TBI) are at an increased risk for developing chronic conditions such as diabetes, heart disease, and hypertension compared to the non-injured population. Furthermore, TBI-specific challenges such as physical limitations, pain, mood, and impaired cognition make it difficult to live a healthy lifestyle. Key health behaviors that contribute to overall health and well-being after TBI include physical activity and healthy eating, sleep, participation, eliminating substance abuse, and managing stress. The objectives of this narrative are to (1) describe the key components of a healthy lifestyle for individuals with a TBI, (2) identify the challenges that individuals with TBI face when attempting to establish these health behaviors, and (3) discuss approaches and supports to achieve these health behaviors after TBI, including the role of self-management.

Cogn. (Melastomataceae) is a tropical plant widely used in traditional Cameroonian medicine to relieve and treat many pathologies. It is widespread in the western region where it is used to treat typhoid fever, gastrointestinal disorders, and inflammatory diseases. The purpose of this study is to scientifically demonstrate the anti-inflammatory and antiarthritic properties of the aqueous and ethanolic extracts of the leaves of . The anti-inflammatory properties were evaluated in vitro by inhibition tests for cyclooxygenase, 5-lipoxygenase, protein denaturation, extracellular ROS production, and cell proliferation; while antiarthritic properties were evaluated in vivo in rats using the zymosan A-induced monoarthritis test and the CFA-induced polyarthritis model. This study shows that aqueous and ethanolic extracts at a concentration of 1000 g/ml inhibit the activity of cyclooxygenase (47.07% and 63.36%) and 5-lipoxygenase (66.79% and 77.7%) and protein denaturation (42.51% and 44.44%). Similarly, both extracts inhibited extracellular ROS production (IC = 5.74 g/ml and 2.96 g/ml for polymorphonuclear leukocytes, 7.47 g/ml and 3.28 g ml for peritoneal macrophages of mouse) and cell proliferation (IC = 16.89 g/ml and 3.29 g/ml). At a dose of 500 mg/kg, aqueous and ethanolic extracts significantly reduce edema induced by zymosan A (69.30% and 81.80%) and CFA (71.85% and 79.03%). At the same dose, both extracts decreased sensitivity to mechanical hyperalgesia with 69.00% and 70.35% inhibition, respectively. Systemic and histological analyzes show that both extracts maintain the studied parameters very close to normal and greatly restored the normal architecture of the joint in animals. would therefore be a very promising source for the treatment of inflammatory diseases.

Opioid long-term therapy can produce tolerance, opioid-induced hyperalgesia (OIH), and it induces dysfunction in pain descending pain inhibitory system (DPIS). This integrative review with meta-analysis aimed: (i) To discuss the potential mechanisms involved in analgesic tolerance and opioid-induced hyperalgesia (OIH). (ii) To examine how the opioid can affect the function of DPIS. (ii) To show evidence about the tDCS as an approach to treat acute and chronic pain. (iii) To discuss the effect of tDCS on DPIS and how it can counter-regulate the OIH. (iv) To draw perspectives for the future about the tDCS effects as an approach to improve the dysfunction in the DPIS in chronic non-cancer pain. Relevant published randomized clinical trials (RCT) comparing active (irrespective of the stimulation protocol) to sham tDCS for treating chronic non-cancer pain were identified, and risk of bias was assessed. We searched trials in PubMed, EMBASE and Cochrane trials databases. tDCS protocols accepted were application in areas of the primary motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), or occipital area. Fifty-nine studies were fully reviewed, and 24 with moderate to the high-quality methodology were included. tDCS improved chronic pain with a moderate effect size [pooled standardized mean difference; -0.66; 95% confidence interval (CI) -0.91 to -0.41]. On average, active protocols led to 27.26% less pain at the end of treatment compared to sham [95% CI; 15.89-32.90%]. Protocol varied in terms of anodal or cathodal stimulation, areas of stimulation (M1 and DLPFC the most common), number of sessions (from 5 to 20) and current intensity (from 1 to 2 mA). The time of application was 20 min in 92% of protocols. In comparison with sham stimulation, tDCS demonstrated a superior effect in reducing chronic pain conditions. They give perspectives that the top-down neuromodulator effects of tDCS are a promising approach to improve management in refractory chronic not-cancer related pain and to enhance dysfunctional neuronal circuitries involved in the DPIS and other pain dimensions and improve pain control with a therapeutic opioid-free. However, further studies are needed to determine individualized protocols according to a biopsychosocial perspective.

Schwannomas represent only 5% of all soft tissue tumors. As a variant of this tumor, the plexiform schwannoma is rare accounting for less than 5% of all schwannomas. Herein, we report a rare case of a 49-year-old athlete who suffered from a pain in the posterior aspect of the right leg one year before his presentation. Initially, a radiograph of his right leg showed no abnormality, and so, the emergency physician discharged him on analgesics and anti-inflammatory medications, and rest was advised. The persistent pain obliged the patient to consult our orthopedic department. On examination, we found a firm mass in the proximal medial aspect of his right leg. The neurovascular exam was normal. Sonography of the leg was not conclusive. Therefore, magnetic resonance imaging was performed, and a hemangioma or schwannoma was suspected. The patient underwent surgery in which the entire tumor mass was shelled out in one piece with no damage. The histopathological finding was concomitant with a plexiform schwannoma. Follow-up evaluation, sixteen months later, showed no evidence of recurrence, and the patient has regained his previous level of sportive activities. So, given the case described here, despite the rarity of the schwannoma, it should be taken into consideration as a possible diagnosis in such situation to promote early diagnosis and appropriate treatment.

Hereditary angioedema with normal C1 inhibitor (HAE-nC1 INH) is a rare, underappreciated condition characterized by recurrent subcutaneous angioedema. The underlying pathophysiology and diagnostic criteria continues to evolve. There is a significant overlap between HAE-nC1 INH and idiopathic nonhistaminergic angioedema, ultimately this may be found to be the same condition. Characterization of cohorts suspected to have either of these conditions is warranted to help refine diagnosis, pathophysiology, and treatment response.

Chronic pain is a frequent condition that affects an estimated 20% of people worldwide, accounting for 15%-20% of doctors' appointments (Treede et al., 2015). It lacks the acute warning function of physiologic nociception, and instead involves the activation of multiple neurophysiologic mechanisms in the somatosensory system, a complex neuronal network under the control of powerful autoregulatory loops and able to undergo rapid neuroplastic alteration (Verdu et al., 2008). There is a growing body of research suggesting that some such pathways are shared by major psychologic disorders such as depression and anxiety, opening new avenues in co-treatment strategies. In particular, besides anticonvulsants, which are today used as analgesics, other psychopharmaceuticals, such as the tricyclic antidepressants, are displaying efficacy in the treatment of neuropathic and nociceptive chronic pain. The state of the art regarding the mechanisms of nociception and the pharmacology of both the neurotransmitters involved and the wide range of psychoactive compounds that may be useful in the treatment of chronic pain are discussed.