Inter-ictal assay of peripheral circulating inflammatory mediators in migraine patients under adjunctive cervical non-invasive vagus nerve stimulation (nVNS): A proof-of-concept study

Objective

To assay peripheral inter-ictal cytokine serum levels and possible relations with non-invasive vagus nerve stimulation (nVNS) responsiveness in migraineurs.

The cGAS-STING pathway connects mitochondrial damage to inflammation in burn-induced acute lung injury in rat

ObjectiveDamage associated molecular patterns (DAMPs) are pathological mediators linking local tissue damage to systemic inflammation in various diseases. Some DAMPs, such as mitochondrial DNA (mtDNA), can be recognized by the cytoplasmic cGAS protein to trigger the activation of the stimulator of interferon genes (STING)-dependent innate immune pathway responsible for infection or sterile inflammation. The objective of our study was to evaluate the association between circulating mtDNA and cGAS-STING pathway activation in mediating inflammation following burn injury.Methods48 adult Sprague-Dawley male rats were divided into eight groups (Sham, 2, 4, 8, 12, 24, 48, 72 h after burn injury). The animals underwent 40% total body surface area scald injury to produce a full-thickness burn. Plasma samples were collected via cardiac puncture under deep anesthesia. Tissues were harvested and placed in formalin, followed by paraffin embedment. Total plasma DNA was isolated followed by measurement of mtDNA using quantitative polymerase chain reaction. Haemotoxylin-Eosin stain and Western blot was used for lung histology and protein assays, respectively. Statistical analyses were performed using ANOVA and student’s t-test and represented as mean ± s.d.ResultsPlasma mtDNA trended upward at early time-points following burn injury with peak levels at 8 h after burn when compared to the control group (345 ± 83.4 copies/μl vs. 239 ± 43.1 copies/μl, p = 0.07) and followed a bell-shaped distribution. Lung slices from burned rats showed acute injury marked by increased inflammatory infiltrate, with the maximum changes seen at 24 h, accompanied with significant upregulation of neutrophil elastase (p = 0.04). Compared with sham animals, cGAS and STING protein levels in lung tissue were up-regulated at 4 and 8 h after burn (p = 0.03 and p < 0.001, respectively).ConclusionActivation of the cGAS-STING pathway by increased plasma mtDNA is an important pathway driving neutrophil infiltration in burn-induced acute lung injury in rats. A further understanding of the STING-mediated immunopathology in lung and other susceptible organs may be important for the development of novel therapies for burn injury.     

Trichothecene mycotoxins activate NLRP3 inflammasome through a P2X7 receptor and Src tyrosine kinase dependent pathway

Inflammasome is an intracellular molecular platform of the innate immunity that is a key mediator of inflammation. The inflammasome complex detects pathogens and different danger signals, and triggers cysteine protease caspase-1-dependent processing of pro-inflammatory cytokines IL-1β, and IL-18 in dendritic cells and macrophages. Previously, we have shown that water-damaged building associated trichothecene mycotoxins, including roridin A, trigger IL-1β and IL-18 secretion in human macrophages. However, the molecular basis as well as mechanism behind this trichothecene-induced cytokine secretion has remained uncharacterized. Here, we show that the trichothecene-induced IL-1β secretion is dependent on NLRP3 inflammasome in human primary macrophages. Pharmacological inhibition and small interfering RNA approach showed that the trichothecene-induced NLRP3 inflammasome activation is mediated through ATP-gated P2X₇ receptor. Moreover, we show that trichothecene-triggered NLRP3 inflammasome activation is dependent on Src tyrosine kinase activity. In addition, gene silencing of c-Cbl, a negative autophagy-related regulator of c-Src, resulted in enhanced secretion of IL-1β and IL-18 in response to trichothecene mycotoxin stimulation in human macrophages. In conclusion, our results suggest that roridin A, a fungal trichothecene mycotoxin, acts as microbial danger signals that trigger activation of NLRP3 inflammasome through P2X₇R and Src tyrosine kinase signaling dependent pathway in human primary macrophages.     

"A school for all kinds of minds"

This cross-sectional study of reading,writing and mathematics skills in a total population of 589 children attending 4th grade in regular public schools showed that neuropsychiatric disorder was a strong predictor of poor performance, girls scored better than boys on language tests and some mathematics test, and immigrant children had similar results as native Swedish children on most tests. Sixty percent of boys with and 7% of boys without DAMP (Deficits in Attention,Motor control and Perception) or ADHD (Attention- Deficit/Hyperactivity Disorder) had substantial school difficulties. The rate of children requiring individualised special education measures was estimated at a minimum of 15%. This constitutes a major challenge to a society claiming to offer equal opportunities and participation for all children.     

Deficits in attention, motor control and perception (DAMP): a simplified school entry examination

OBJECTIVE: To suggest an empirically based school entry screening examination for the detection of deficits in attention, motor control and perception (DAMP) in 6-y-old children. MATERIAL AND METHODS: A population-based cohort of 113 children, 6-7 y of age (62 with and 51 without DAMP), compared on measures of attention, motor functions, language and cognition. RESULTS: Attention deficits were convincingly identified by both parents and paediatrician. The motor function tests clearly distinguished between the two groups. Linguistic and meta-linguistic tests demonstrated greater phonological processing difficulties in the DAMP group. The cognitive test revealed an overall lower IQ but no consistent characteristic pattern in the DAMP group. CONCLUSIONS: A simplified paediatric school entry examination test is suggested. Four motor tests (standing on one foot, Fog test, design copying and diadochokinesis) administered by the paediatrician, combined with a brief structured clinical observation and a structured parent interview, identified 80% of children with DAMP-and all those with severe DAMP-as well as a small number of false positives.     

Autophagy in immunity and cell-autonomous defense against intracellular microbes

Autophagy was viewed until very recently primarily as a metabolic and intracellular biomass and organelle quality and quantity control pathway. It has now been recognized that autophagy represents a bona fide immunologic process with a wide array of roles in immunity. The immunologic functions of autophagy, as we understand them now, span both innate and adaptive immunity. They range from unique and sometimes highly specialized immunologic effectors and regulatory functions (referred to here as type I immunophagy) to generic homeostatic influence on immune cells (type II immunophagy), akin to the effects on survival and homeostasis of other cell types in the body. As a concept-building tool for understanding why and how autophagy is intertwined with immunity, it is useful to consider that the presently complex picture has emerged in increments, starting in part from the realization that autophagy acts as an evolutionarily ancient microbial clearance mechanism defending eukaryotic cells against intracellular pathogens. In this review, we build a stepwise model of how the core axis of autophagy as a cell-autonomous immune defense against microbes evolved into a complex but orderly web of intersections with innate and adaptive immunity processes. The connections between autophagy and conventional immunity systems include Toll-like receptors, Nod-like receptors, RIG-I-like receptors, damage-associated molecular patterns such as HMGB1, other known innate and adaptive immunity receptors and cytokines, sequestasome (p62)-like receptors that act as autophagy adapters, immunity-related GTPase IRGM, innate and adaptive functions of macrophages and dendritic cells, and differential effects on development and homeostasis of T- and B-lymphocyte subsets. The disease contexts covered here include tuberculosis, infections with human immunodeficiency virus and other viruses, Salmonella, Listeria, Shigella, Toxoplasma, and inflammatory disorders such as Crohn's disease and multiple sclerosis.     

Stress sounds the alarmin: The role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming

High mobility group box-1 (HMGB1) is an endogenous danger signal or alarmin that mediates activation of the innate immune response including chemotaxis and pro-inflammatory cytokine release. HMGB1 has been implicated in the pathophysiology of several neuroinflammatory conditions including ischemia, traumatic brain injury, seizure and chronic ethanol use. In the present review, the unique structural and functional properties of HMGB1 will be explored including its affinity for multiple pattern recognition receptors (TLR2/TLR4), redox sensitivity and adjuvant-like properties. In light of recent evidence suggesting that HMGB1 may also mediate stress-induced sensitization of neuroinflammatory responses, mechanisms of HMGB1 action in neuroinflammatory priming are explored. A model of neuroinflammatory priming is developed wherein glucocorticoids induce synthesis and release of HMGB1 from microglia, which signals through TLR2/TLR4, thereby priming the NLRP3 inflammasome. We propose that if GCs reach a critical threshold as during a fight/flight response, they may thus function as an alarmin by inducing HMGB1, thereby preparing an organism’s innate immune system (NLRP3 inflammasome priming) for subsequent immune challenges such as injury, trauma or infection, which are more likely to occur during a fight/flight response. In doing so, GCs may confer a significant survival advantage by enhancing the central innate immune and sickness response to immune challenges.     

消癣泡洗方治疗广东地区足癣108例临床疗效观察

[目的]探讨清热除湿杀虫中药外洗对足癣的治疗作用.[方法]将208例确诊为足癣的患者,采用随机对照的方法,分为治疗组(108例)和对照组(100例).治疗组采用消癣泡洗方(由大黄、茵陈、黄柏、苦参、百部、花椒、黄精、藿香等中药组成)泡洗治疗;对照组用达克宁软膏外涂治疗.1周为1个疗程,两组均治疗两个疗程.[结果]1个疗程后,治疗组痊愈65例(痊愈率为60.2%),对照组痊愈45例(痊愈率为45%),两组痊愈率比较,有显著性差异(P<0.05);两个疗程后,治疗组痊愈86例(痊愈率为79.6%),对照组痊愈50例(痊愈率为50%),两组痊愈率比较,有非常显著性差异(P<0.01);对2001年7月至2002年9月期间治愈的患者随访1年,结果治疗组2例复发,对照组9例复发,两组复发率比较有显著性差异(P<0.01).[结论]消癣泡洗方治疗足癣疗效明显,值得临床推广使用.