Rejected

Electroacupuncture (EA) is reported effective in alleviating pain-related emotion; however, the underlying mechanism of its effects still needs to be elucidated. The NPS-NPSR system has been validated for the involvement in the modulation of analgesia and emotional behavior. Here, we aimed to investigate the role of the NPS-NPSR system in the anterior cingulate cortex (ACC), hypothalamus, and central amygdala (CeA) in the use of EA to relieve affective pain modeled by complete Freund's adjuvant- (CFA-) evoked conditioned place aversion (C-CPA). . CFA injection combined with a CPA paradigm was introduced to establish the C-CPA model, and the elevated O-maze (EOM) was used to test the behavioral changes after model establishment. We further explored the expression of NPS and NPSR at the protein and gene levels in the brain regions of interest by immunofluorescence staining and quantitative real-time PCR.

AutoInflammatory Diseases (AIDs) are a group of innate immune system disorders characterized by sterile inflammation without evidence of pathogenic autoantibodies or auto-reactive T lymphocytes. An expanding spectrum of genes and molecular pathways are associated with AIDs. Inflammasomopathies are secondary to dysregulation of multi-protein complexes, called inflammasomes, leading to an excessive maturation and secretion of IL1β and IL18. Patients present with persistent or recurrent systemic inflammation, abdominal and chest pain, skin rashes and are sensible to IL1 inhibitors. Unfolded proteins response causes a small number of AIDs that we propose to call immuno-proteinopathies, characterized by recurrent fevers and deep tissues inflammation. Other inflammatory conditions can occur in case of abnormalities of actin polymerization and the term of immuno-actinopathies is proposed. Generalized pustular psoriasis is a marker of autoinflammation mainly affecting the keratinocytes. Specific treatment targeting the p40 subunit of IL12 and IL23 or IL-17 are usually effective. Granulomatous inflammation characterizes AIDs related to NOD2 signaling defects. Defects in the ubiquitin-proteasome system cause a group of relopathies and some interferonopathies related to defect of the proteasome function (CANDLE syndrome). Gain of function of proteins regulating the production of type I interferons lead to severe inflammatory conditions, called interferonopathies. The JAK/STAT inhibitors are usually effective in these latter conditions. In conclusions, the identification of the main intracellular pathways involved in rare monogenic AIDs allows not only the proper classification of different conditions, but also highlight a pivotal role of possible novel therapeutic targets for the future.

An estimated 1.6 to 3.8 million concussions occur in sport and recreational activities annually. A sport related concussion (SRC) is contemporarily defined as a traumatic brain injury induced by biomechanical forces. Symptoms of concussion are caused by the metabolic cascade that includes excitatory neurotransmitter release, abnormal ion fluxes, increased glucose metabolism, lactic acid accumulation, elevated cerebral blood flow, energy deficit, and inflammation. These changes in the brain are responsible for the hallmark symptoms of a concussion such as headache, nausea, loss of consciousness, and pressure in the head. Most concussions resolve within 2-4 weeks, but approximately 10-33% of individuals have persistent symptoms for months after the initial injury. An associated comorbidity following concussion is post-concussion syndrome (PCS). Clinical diagnostic criteria for PCS requires a history of brain injury and the presence of at least two symptoms for a minimum of four weeks. Having three of eight symptoms (headache, dizziness, fatigue, irritability, insomnia, concentration problems, memory difficulty, or intolerance of stress emotion or alcohol) for at least four weeks has also been identified as grounds for PCS classification. The mainstay of treatment for a SRC traditionally is rest followed by a stepwise return to learn, then physical activity, and finally return to sport. Time lost due to concussion is at least five days following symptom resolution when following best practices for full return to contact sports. Currently, prescribed rest in which patients avoid physical and cognitive activity is the most widely used intervention. Recent research indicates that strict rest longer than one to two days following a concussion does not improve outcomes and may potentially cause an increase in symptom reporting. The increase in symptom reporting especially in athletes after prescribed rest may be due to physical deconditioning and the development of secondary symptoms such as fatigue and reactive depression. Exercise in general has benefits for body composition, skeletal health, cardiorespiratory fitness, depression, anxiety, and academic achievement, and it also improves cognition through increased cerebral blood flow, oxygen extraction, brain metabolism, and neuroplasticity. Aerobic exercise conducted at subsymptom and submaximal intensities has been proposed as a potential intervention for the negative effects of inactivity following a concussion. Subsymptom aerobic exercise has been defined as aerobic exercise performed at an intensity and duration that does not exacerbate post-concussion symptoms. The American College of Sports Medicine defines submaximal exercise as aerobic activity occurring at 85% of the age adjusted maximum heart rate. These terms used by different authors often refer to similar exercise intensities, but they cannot be used interchangeably. Therefore, the purpose of this critically appraised topic is to examine the safety of varying aerobic exercise intensities in patients with a concussion. In appraising the safety of controlled aerobic activity in comparison to complete rest clinicians will be able to determine if physical activity can be implemented in the plan of care for patients with a concussion.

Host sensing in the gut microbiota has been crucial in the regulation of intestinal homeostasis. Although inflammatory bowel diseases (IBDs), multifactorial chronic inflammatory conditions of the gastrointestinal tract, have been associated with intestinal dysbiosis, the detailed interactions between host and gut microbiota are still not completely understood. Enteroendocrine cells (EECs) represent 1% of the intestinal epithelium. Accumulating evidence indicates that EECs are key sensors of gut microbiota and/or microbial metabolites. They can secrete cytokines and peptide hormones in response to microbiota, either in traditional endocrine regulation or by paracrine impact on proximal tissues and/or cells or via afferent nerve fibers. Enteroendocrine cells also play crucial roles in mucosal immunity, gut barrier function, visceral hyperalgesia, and gastrointestinal (GI) motility, thereby regulating several GI diseases, including IBD. In this review, we will focus on EECs in sensing microbiota, correlating enteroendocrine perturbations with IBD, and the underlying mechanisms.

There is a growing body of knowledge characterizing the menopause experience in those with HIV. The primary goal of this study was to assess inflammatory cytokine associations with symptoms and sex-specific differences, and the secondary focus was to assess differences among women by menopause status. One hundred persons living with HIV (PLWH) (25 men and 75 women recruited by menopause stage) completed a blood draw for hormones and cytokines and study questions on demographics, height and weight, reproductive health status, HIV symptoms, PROMIS-29 measures, and most recent viral load; study visits were synchronized to the early follicular phase in women with regular cycles. In both sexes, the most burdensome HIV symptoms were muscle aches/joint pain, difficulty falling asleep, fatigue, and neuropathy. Three of the five symptoms where burden scores differed by menopause stage were related to pain with highest scores in the premenopause group; the postmenopause group also demonstrated a similar burden for muscle aches/joint pain while scores for men and perimenopause women were lowest. Pain intensity scores on the PROMIS-29 also varied significantly by groups. After controlling for sex, menopause stage and body mass index, significant differences were noted in C-reactive protein (CRP), interleukin (IL)-6, and IL-8 for PLWH who reported muscle aches/joint pain. Our findings suggest enhanced burden for HIV-related symptoms in women in the early follicular phase, possibly owing to menstruation. This supports the need for more targeted investigations in younger cycling women with HIV at multiple phases across the menstrual cycle. Muscle aches/pain are strongly associated with decreased CRP and IL-8 levels and increased IL-6 levels suggesting the need for further investigation of the biological pathways contributing to pain in PLWH. Finally, there is evidence to support that in PLWH, systemic inflammation is heightened above recommended clinical guidelines even when viral load is undetectable supporting the need for further study of the effects of persistent elevated inflammation on health outcomes.

Background and Purpose- Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an autosomal dominant small vessel disease caused by C-terminal frameshift mutations in the gene that encodes the major mammalian 3' to 5' DNA exonuclease. RVCL-S is characterized by vasculopathy, especially in densely vascularized organs, progressive retinopathy, cerebral microvascular disease, white matter lesions, and migraine, but the underlying mechanisms are unknown. Methods- Homozygous transgenic RVCL-S knock-in mice expressing a truncated Trex1 (three prime repair exonuclease 1) protein (similar to what is seen in patients) and wild-type littermates, of various age groups, were subjected to (1) a survival analysis, (2) in vivo postocclusive reactive hyperemia and ex vivo Mulvany myograph studies to characterize the microvascular and macrovascular reactivity, and (3) experimental stroke after transient middle cerebral artery occlusion with neurological deficit assessment. Results- The mutant mice show increased mortality starting at midlife (=0.03 with hazard ratio, 3.14 [95% CI: 1.05-9.39]). The mutants also show a vascular phenotype as evidenced by attenuated postocclusive reactive hyperemia responses (across all age groups; F[1, 65]=5.7, =0.02) and lower acetylcholine-induced relaxations in aortae (in 20- to 24-month-old mice; RVCL-S knock-in: E: 37±8% versus WT: E: 65±6%, =0.01). A vascular phenotype is also suggested by the increased infarct volume seen in 12- to 14-month-old mutant mice at 24 hours after infarct onset (RVCL-S knock-in: 75.4±2.7 mm versus WT: 52.9±5.6 mm, =0.01). Conclusions- Homozygous RVCL-S knock-in mice show increased mortality, signs of abnormal vascular function, and increased sensitivity to experimental stroke and can be instrumental to investigate the pathology seen in patients with RVCL-S.

Neuropathic pain (NP) develops because of damage to the peripheral or central nervous system. It results in the hyperalgesia and allodynia. In the recent years, various researchers have studied the involvement of neuro-immune system in causing persistence of pain. The absence of synaptic contacts in the sensory ganglion makes them distinctive in terms of pain related signalling. In sensory ganglia, the neurotransmitters or the other modulators such as inflammatory substances produced by the ganglion cells, because of an injury, are responsible for the cross-excitation between neurons and neuron-glial interaction, thus affecting chemical transmission. This chemical transmission is considered mainly responsible for the chronicity and the persistent nature of neuropathic pain. This review examines the pain signalling due to neurotransmitter or cytokine release within the sensory ganglia. The specific areas focused on include: 1) the role of neurotransmitters released from the somata of sensory neurons in pain, 2) neuron-glia interaction and 3) role of cytokines in neuromodulation and pain.

Phototherapy is an effective treatment modality for many types of pruritus. Although the exact mechanisms by which phototherapy reduces itch vary across pruritic conditions, its effects may result from immune suppression and/or neural modulation. In this article, the authors review the efficacy of different types of phototherapy for common inflammatory and noninflammatory pruritic conditions and discuss common side effects, such as erythema and exacerbation of pruritus. Although phototherapy may be an effective and relatively safe option for skin-directed treatment of chronic itch, barriers may exist for individual patients.

Pruritus is an important, prevalent but often neglected symptom in patients with advanced chronic kidney disease (CKD) or on dialysis. This review addresses the use of activated charcoal and its analogs in the treatment of uremic pruritus, which can be a sign of uremic toxicity.

Lower limb chronic venous disease (CVD), resulting from iliac vein compression syndrome (IVCS), manifests as a series of symptoms ranging from varicose veins to venous ulcerations. Stent implantation has been considered an effective treatment method; however, the management of CVD has rarely been reported. In the present study, we evaluated the treatment and outcomes of patients with CVD.