Rejected

Intravenous immunoglobulin (IVIG) was reported to be the third most used monotherapy in livedoid vasculopathy (LV). There is currently a lack of randomized controlled clinical trials and no standardized therapeutic regimen for IVIG therapy in LV.

Due to the chronic nature of knee osteoarthritis (KOA) self-management is considered an essential part of therapy to improve physical function, activity, pain and quality of life (QoL). Web-based rehabilitation may be a potential innovative mode of patient' training to guide management compared to usual care, especially with the current restrictions pandemic imposed. Moreover, in order to alter KOA patients' behavior towards physical activity (PA), it may be more attractive and motivating to combine within their rehabilitation program, outdoor real life local activity that could feasible to be sustained in the future. Aim of the current study is to evaluate the effects of a blended web-based rehabilitation compared with structured PA alone in patients with KOA. This is a randomized multi-center study with two prospective arms. Fifty-six eligible participants with KOA will be recruited from the West Attica region (considered as structurally weak areas). After a comprehensive face-to face training session, participants will follow a 6-week web-based rehabilitation program, consisting of exercise, advice material enhanced outdoor structured PA. The control group will be encouraged to follow the outdoor structured PA alone. Baseline, 6-week and 12-week follow up assessments will be performed. The primary outcome is self-reported physical function as measured by the Knee Injury Osteoarthritis Outcome Score (KOOS). Secondary measures include pain, function (Timed Up and Go Test, Sit to Stand test), PA levels (Lower Extremity Activity Scale, Baecke Scale and pedometer), psychological perspective (Tampa Scale of Kinesiophobia) and health-related QoL (Short-Form 12). Baseline-adjusted Analysis of Variance will be used to test for group differences in the primary and secondary outcomes. The study will evaluate the blended web-based exercise and advice material, enhanced with outdoor PA in many respects compared to the outdoor PA alone so as to promote self-management care programs for KOA patients. Trial registration: Prospectively registered ISRCTN12950684 (27-09-2020).

Acupoint is the key area for needling treatment, but its physiology is not yet understood. Nociceptors, one of the responders in acupoints, are responsible for acupuncture manipulation and delivering acupuncture signals to the spinal or supraspinal level. Recent evidence has shown that various diseases led to sensory hypersensitivity and functional plasticity in sensitized acupoints, namely, acupoint sensitization. Neurogenic inflammation is the predominant pathological characteristic for sensitized acupoints; however, the underlying mechanism in acupoint sensitization remains unclear. Recent studies have reported that silent C-nociceptors (SNs), a subtype of C nociceptors, can be "awakened" by inflammatory substances released by sensory terminals and immune cells under tissue injury or visceral dysfunction. SNs can transform from mechano-insensitive nociceptors in a healthy state to mechanosensitive nociceptors. Activated SNs play a vital role in sensory and pain modulation and can amplify sensory inputs from the injured tissue and then mediate sensory hyperalgesia. Whether activated SNs is involved in the mechanism of acupoint sensitization and contributes to the delivery of mechanical signals from needling manipulation remains unclear? In this review, we discuss the known functions of cutaneous C nociceptors and SNs and focus on recent studies highlighting the role of activated SNs in acupoint functional plasticity.

Low-dose radiotherapy (LD-RT) is a local treatment option for patients with chronic degenerative and inflammatory diseases, in particular musculoskeletal diseases. Despite reported analgesic and anti-inflammatory effects, cellular and molecular mechanisms related to osteoimmunological effects are still elusive. Here we test the hypothesis that X-irradiation inhibits the differentiation of precursor osteoclasts into mature osteoclasts (mOC) and their bone resorbing activity. Circulating monocytes from healthy donors were isolated and irradiated after attachment with single or fractionated X-ray doses, comparable to an LD-RT treatment scheme. Then monocytes underwent differentiation into OC during cultivation up to 21 days, under conditions mimicking the physiological microenvironment of OC on bone. After irradiation, apoptotic frequencies were low, but the total number of OC precursors and mOC decreased up to the end of the cultivation period. On top, we observed an impairment of terminal differentiation, i.e. a smaller fraction of mOC, reduced resorbing activity on bone, and release of collagen fragments. We further analyzed the effect of X-irradiation on multinucleation, resulting from the fusion of precursor OC, which occurs late during OC differentiation. At 21 days after exposure, the observation of smaller cellular areas and a reduced number of nuclei per mOC suggest an impaired fusion of OC precursors to form mOC. Before, at 14 days, the nuclear translocation of Nuclear Factor Of Activated T Cells 1 (NFATc1), a master regulator of osteoclast differentiation and fusion, was decreased. In first results, obtained in the frame of a longitudinal LD-RT study, we previously reported a pain-relieving effect in patients. However, in a subgroup of patients suffering from Calcaneodynia or Achillodynia, we did not observe a consistent decrease of established blood markers for resorption and formation of bone, or modified T cell subtypes involved in regulating these processes. To assess the relevance of changes in bone metabolism for other diseases treated with LD-RT will be subject of further studies. Taken together, we observed that X-irradiation of monocytes results in an inhibition of the differentiation into bone-resorbing OC and a concomitant reduction of resorbing activity. The detected reduced NFATc1 signaling could be one underlying mechanism.

Chronic pain associated with fibromyalgia (FM) affects a large portion of the population but the underlying mechanisms leading to this altered pain are still poorly understood. Evidence suggests that FM involves altered neural processes in the central nervous system and neuroimaging methods such as functional magnetic resonance imaging (fMRI) are used to reveal these underlying alterations. While many fMRI studies of FM have been conducted in the brain, recent evidence shows that the changes in pain processing in FM may be linked to autonomic and homeostatic dysregulation, thus requiring further investigation in the brainstem and spinal cord. Functional magnetic resonance imaging data from 15 women with FM and 15 healthy controls were obtained in the cervical spinal cord and brainstem at 3 tesla using previously established methods. In order to investigate differences in pain processing in these groups, participants underwent trials in which they anticipated and received a predictable painful stimulus, randomly interleaved with trials with no stimulus. Differences in functional connectivity between the groups were investigated by means of structural equation modeling. The results demonstrate significant differences in brainstem/spinal cord network connectivity between the FM and control groups which also correlated with individual differences in pain responses. The regions involved in these differences in connectivity included the LC, hypothalamus, PAG, and PBN, which are known to be associated with autonomic homeostatic regulation, including fight or flight responses. This study extends our understanding of altered neural processes associated with FM and the important link between sensory and autonomic regulation systems in this disorder.

Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is now widely used in procedural sedation and analgesia. This study was designed to observe and compare the efficacy and safety of DEX administered in two different modes.

Evidence shows that chronic prostatitis/chronic pelvic pain syndrome hugely impacts the body and mind. The central mechanisms in patients with CP/CPPS resulted in increased attention as neuroimaging techniques developed. This review investigated the study design and major neuroimaging findings in CP/CPPS patients to provide comprehensive evidence. Seven databases were searched and screened: PubMed, EMBASE/SCOPUS, Cochrane Library Database, China National Knowledge Infrastructure, VIP, Wanfang, and China Biology Medicine disc. Nine studies were eventually included in the analysis. The results demonstrate that the insula, anterior cingulate gyrus, postcentral gyrus, and precuneus are significantly associated with CP/CPPS patients' pain feelings and cause dysregulation of painful emotions, lowering patients' tolerance to stimulus.

Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder characterized by spontaneous and elicited paroxysms of electric-shock-like or stabbing pain in a region of the face. The epigenetic regulation of TN is still obscure. In current study, a rat TN model subject to carbamazepine (CBZ) treatment was established, and transcriptome- and genome-scale profiling of H3K9ac and HDAC3 was performed by RNA-seq and ChIP-seq. We observed that H3K9ac levels in the trigeminal ganglion were lower in the TN rats compared with those in the control, and CBZ treatment led to recovery of H3K9ac levels. Further, we found that HDAC3 was overactivated, which interfered with H3K9 acetylation due to higher phosphorylation in TN compared with that in the control. Finally, the phosphokinase leucine-rich repeat kinase 2 (LRRK2) was demonstrated to contribute to HDAC3 activity via the MAPK signaling pathway. Taken together, we identified a regulatory mechanism in which the phosphate groups transferred from activated ERK and LRRK2 to HDAC3 caused genome-scale deacetylation at H3K9 and resulted in the silencing of a large number of genes in TN. The kinases or important enzymes within this regulatory axis may represent important targets for TN therapy and prevention.

[This corrects the article DOI: 10.3389/fncel.2022.837650.].

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death in the USA. Primary signet ring cell carcinoma (SRCC) of the colon and rectum is extremely rare with a reported incidence of less than 1%. Here we present the case of a 41-year-old man who presented with abdominal pain, severe microcytic anaemia and a negative faecal occult blood test (FOBT). A CT scan of the abdomen revealed thickening of the terminal ileum and proximal right colon with extensive lymphadenopathy and a fistula tract extending from the terminal ileum to the right buttock. Endoscopic features like cobblestoning of the ileocolic junction along with elevated blood and stool inflammatory markers raised suspicion of Crohn's disease (CD). However, histopathological study surprisingly revealed primary colorectal signet cell carcinoma (PCRSCC) with no evidence of CD. Cases of simultaneous PCRSCC and CD have been reported, but no clear association has been established. Our case is unique in that it presented with classic clinical features of CD, but PCRSCC without any histological evidence of underlying CD was found on histology.