A randomized controlled simulation trial comparing video-assisted with telephone-assisted and unassisted cardiopulmonary resuscitation performed by non-healthcare university students.

Our randomized controlled simulation study aimed to compare the CPR quality, time-related factors, attitude and self-assessment of non-healthcare university students (aged 18-25) compared video-assisted (V-CPR, n = 50) with telephone-assisted (T-CPR, n = 49) and unassisted (U-CPR, n = 48) CPR in a simulation setting. Regarding to chest compression depth, no difference was found between the three groups (p = 0.065): 41.8 mm, SD = 9.9 in the V-CPR; 35.9 mm, SD = 11.6 in the T-CPR; and 39.4 mm, SD = 15.6 in the U-CPR group. The mean chest compression rate was the best in the V-CPR group (100.9 min-1, SD = 17.1) which was superior to the T-CPR (82.4 min-1, SD = 35.4; p = 0.005), and the U-CPR (84.2 min-1, SD = 30.6; p = 0.013) groups. The overall proportion of correct hand position was the highest in the V-CPR group (48, 96%), compared to the T-CPR (28, 57.1%; p = 0.001), and the U-CPR (34, 70.8%; p = 0.001) groups. V-CPR led to a delay in the time to the first chest compression compared with the U-CPR group (77.5 s, SD = 19.2 vs. 31.3 s, SD = 13.3, p < 0.001). Although V-CPR technology holds the potential to improve overall CPR quality, the importance of appropriate chest compression depth should be emphasized in training for laypeople and dispatchers, as well. Our study was registered at ClinicalTrials.gov (NCT05639868, 06/12/2022).

Aldh1l1-Cre/ER T2 is expressed in unintended cell types of the salivary gland, pancreas, and spleen.

The Aldh1l1-Cre/ER T2 mouse is a widely used transgenic mouse model to conditionally express Cre recombinase in astrocytes of the central nervous system. Currently, no reports show whether the Cre recombinase activity, driven by the Aldh1l1 promoter, acts in cells outside of its intended astrocyte population. We crossed the Aldh1l1-Cre/ER T2 mouse with a TdTomato reporter mouse line, ROSA26:CAG-LSL-TdTomato, to generate a fluorescent reporter for Aldh1l1 promoter activity. Gross anatomical observations reveal strong TdTomato expression in the spleen and exocrine glands-the salivary gland and the pancreas. We find TdTomato expression, a reporter of Cre activity, specifically targets serous cells in the parotid, submandibular, sublingual glands, and pancreas along with fibroblast-like cells within the submandibular lymph nodes and spleen. Our data indicate that the Aldh1l1-Cre/ER T2 mouse model has unintended Cre recombinase activity in exocrine glands, which may influence biological and behavioral data.

Serum fetuin-A is decreased in cirrhotic patients with Wilson's disease.

INTRODUCTION: Wilson's disease may lead to cirrhosis, but timely medical treatment could slow down its progression. Clinical markers helping early diagnosis are essential. Decreased fetuin-A concentration has been reported in cirrhosis of different etiologies. The aim of this study was to investigate whether decreased serum fetuin-A concentration could identify patients with Wilson's disease who developed cirrhosis. MATERIALS AND METHODS: In this cross-sectional study we determined the serum fetuin-A concentration of 50 patients with Wilson's disease. We analyzed the data of patients with liver involvement, comparing cirrhotic and non-cirrhotic patients. RESULTS: Among patients with liver involvement those with cirrhosis had significantly lower fetuin-A and albumin level, white blood cell and platelet count. Fetuin-A negatively correlated with disease duration, bilirubin level, positively with total protein and albumin concentration, but not with copper and ceruloplasmin concentrations or markers of systemic inflammation. In multivariate analysis with fetuin-A and the Nazer score or its parameters only fetuin-A was a significant determinant of having cirrhosis. In receiver operator curve analysis among patients with liver involvement the fetuin-A level of 523 µg/ml was associated with cirrhosis with 82% sensitivity and 87% specificity. The presence of the H1069Q mutation was not associated with alteration in fetuin-A concentration. CONCLUSIONS: The serum concentration of fetuin-A is a sensitive marker of liver cirrhosis in Wilson's disease, independently of the H1069Q mutation, ceruloplasmin concentration or systemic inflammation.

IL-1 Receptor-1 on Vglut2 + neurons in the hippocampus is critical for neuronal and behavioral sensitization after repeated social stress.

Myriad findings connect stress and inflammation to mood disorders. Social defeat in mice promotes the convergence of neuronal, central inflammatory (microglia), and peripheral immune (monocytes) pathways causing anxiety, social avoidance, and "stress-sensitization." Stress-sensitization results in augmented inflammation and the recurrence of anxiety after re-exposure to social stress. Different cell compartments, including neurons, may be uniquely sensitized by social defeat-induced interleukin-1 (IL-1) signaling. Therefore, the aim of this study was to determine if glutamatergic neuronal IL-1 receptor signaling was essential in promoting stress-sensitization after social defeat. Here, wild-type (IL-1R1+/+) mice and mice with IL-1 receptor-1 deleted selectively in glutamatergic neurons (Vglut2-IL-1R1-/-) were stress-sensitized by social defeat (6-cycles) and then exposed to acute defeat (1-cycle) at day 30. Acute defeat-induced neuronal activation (ΔFosB and phospo-CREB) in the hippocampus of stress-sensitized mice was dependent on neuronal IL-1R1. Moreover, acute defeat-induced social withdrawal and working memory impairment in stress-sensitized mice were also dependent on neuronal IL-1R1. To address region and time dependency, an AAV2-IL-1 receptor antagonist construct was administered into the hippocampus after sensitization, but prior to acute defeat at day 30. Although stress-sensitized mice had increased hippocampal pCREB and decreased working memory after stress re-exposure, these events were not influenced by AAV2-IL-1 receptor antagonist. Hippocampal ΔFosB induction and corresponding social withdrawal in stress-sensitized mice after stress re-exposure were prevented by the AAV2-IL-1 receptor antagonist. Collectively, IL-1 signaling in glutamatergic neurons of the hippocampus was essential in neuronal-sensitization after social defeat and the recall of social withdrawal.

How effective are chest compressions when wearing mask? A randomised simulation study among first-year health care students during the COVID-19 pandemic.

BACKGROUND: The resuscitation guidelines provided for the COVID-19 pandemic strongly recommended wearing personal protective equipment. The current study aimed to evaluate and compare the effectiveness of chest compressions and the level of fatigue while wearing two different types of mask (surgical vs. cloth). METHODS: A randomized, non-inferiority, simulation study was conducted. Participants were randomised into two groups: surgical mask group (n = 108) and cloth mask group (n = 108). The effectiveness (depth and rate) of chest compressions was measured within a 2-min continuous chest-compression-only CPR session. Data were collected through an AMBU CPR Software, a questionnaire, recording vital parameters, and using Borg-scale related to fatigue (before and after the simulation). For further analysis the 2-min session was segmented into 30-s intervals. RESULTS: Two hundred sixteen first-year health care students participated in our study. No significant difference was measured between the surgical mask and cloth mask groups in chest compression depth (44.49 ± 10.03 mm vs. 45.77 ± 10.77 mm), rate (113.34 ± 17.76/min vs. 111.23 ± 17.51/min), and the level of fatigue (5.72 ± 1.69 vs. 5.56 ± 1.67) (p > 0.05 in every cases). Significant decrease was found in chest compression depth between the first 30-s interval and the second, third, and fourth intervals (p < 0.01). CONCLUSION: The effectiveness of chest compressions (depth and rate) was non-inferior when wearing cloth mask compared to wearing surgical mask. However, the effectiveness of chest compressions decreased significantly in both groups during the 2-min chest-compression-only CPR session and did not reach the appropriate chest compression depth range recommended by the ERC.

Dynamic Interleukin-1 Receptor Type 1 Signaling Mediates Microglia-Vasculature Interactions Following Repeated Systemic LPS.

Introduction: Lipopolysaccharide (LPS) preconditioning involves repeated, systemic, and sub-threshold doses of LPS, which induces a neuroprotective state within the CNS, thus preventing neuronal death and functional losses. Recently, proinflammatory cytokine, Interleukin-1 (IL-1), and its primary signaling partner, interleukin-1 receptor type 1 (IL-1R1), have been associated with neuroprotection in the CNS. However, it is still unknown how IL-1/IL-1R1 signaling impacts the processes associated with neuroprotection. Methods: Using our IL-1R1 restore genetic mouse model, mouse lines were generated to restrict IL-1R1 expression either to endothelia (Tie2-Cre-Il1r1r/r) or microglia (Cx3Cr1-Cre-Il1r1 r/r), in addition to either global ablation (Il1r1 r/r) or global restoration of IL-1R1 (Il1r1 GR/GR). The LPS preconditioning paradigm consisted of four daily i.p. injections of LPS at 1 mg/kg (4d LPS). 24 hrs following the final i.p. LPS injection, tissue was collected for qPCR analysis, immunohistochemistry, or FAC sorting. Results: Following 4d LPS, we found multiple phenotypes that are dependent on IL-1R1 signaling such as microglia morphology alterations, increased microglial M2-like gene expression, and clustering of microglia onto the brain vasculature. We determined that 4d LPS induces microglial morphological changes, clustering at the vasculature, and gene expression changes are dependent on endothelial IL-1R1, but not microglial IL-1R1. A novel observation was the induction of microglial IL-1R1 (mIL-1R1) following 4d LPS. The induced mIL-1R1 permits a unique response to central IL-1ß: the mIL-1R1 dependent induction of IL-1R1 antagonist (IL-1RA) and IL-1ß gene expression. Analysis of RNA sequencing datasets revealed that mIL-1R1 is also induced in neurodegenerative diseases. Discussion: Here, we have identified cell type-specific IL-1R1 mediated mechanisms, which may contribute to the neuroprotection observed in LPS preconditioning. These findings identify key cellular and molecular contributors in LPS-induced neuroprotection.

Modulation of Neural Networks by Interleukin-1.

Interleukin-1 (IL-1) is an inflammatory cytokine that has been shown to modulate neuronal signaling in homeostasis and diseases. In homeostasis, IL-1 regulates sleep and memory formation, whereas in diseases, IL-1 impairs memory and alters affect. Interestingly, IL-1 can cause long-lasting changes in behavior, suggesting IL-1 can alter neuroplasticity. The neuroplastic effects of IL-1 are mediated via its cognate receptor, Interleukin-1 Type 1 Receptor (IL-1R1), and are dependent on the distribution and cell type(s) of IL-1R1 expression. Recent reports found that IL-1R1 expression is restricted to discrete subpopulations of neurons, astrocytes, and endothelial cells and suggest IL-1 can influence neural circuits directly through neuronal IL-1R1 or indirectly via non-neuronal IL-1R1. In this review, we analyzed multiple mechanisms by which IL-1/IL-1R1 signaling might impact neuroplasticity based upon the most up-to-date literature and provided potential explanations to clarify discrepant and confusing findings reported in the past.

Interleukin-1 receptor on hippocampal neurons drives social withdrawal and cognitive deficits after chronic social stress.

Chronic stress contributes to the development of psychiatric disorders including anxiety and depression. Several inflammatory-related effects of stress are associated with increased interleukin-1 (IL-1) signaling within the central nervous system and are mediated by IL-1 receptor 1 (IL-1R1) on several distinct cell types. Neuronal IL-1R1 is prominently expressed on the neurons of the dentate gyrus, but its role in mediating behavioral responses to stress is unknown. We hypothesize that IL-1 acts on this subset of hippocampal neurons to influence cognitive and mood alterations with stress. Here, mice subjected to psychosocial stress showed reduced social interaction and impaired working memory, and these deficits were prevented by global IL-1R1 knockout. Stress-induced monocyte trafficking to the brain was also blocked by IL-1R1 knockout. Selective deletion of IL-1R1 in glutamatergic neurons (nIL-1R1-/-) abrogated the stress-induced deficits in social interaction and working memory. In addition, viral-mediated selective IL-1R1 deletion in hippocampal neurons confirmed that IL-1 receptor in the hippocampus was critical for stress-induced behavioral deficits. Furthermore, selective restoration of IL-1R1 on glutamatergic neurons was sufficient to reestablish the impairments of social interaction and working memory after stress. RNA-sequencing of the hippocampus revealed that stress increased several canonical pathways (TREM1, NF-κB, complement, IL-6 signaling) and upstream regulators (INFγ, IL-1ß, NF-κB, MYD88) associated with inflammation. The inductions of TREM1 signaling, complement, and leukocyte extravasation with stress were reversed by nIL-1R1-/-. Collectively, stress-dependent IL-1R1 signaling in hippocampal neurons represents a novel mechanism by which inflammation is perpetuated and social interactivity and working memory are modulated.

Serial Systemic Injections of Endotoxin (LPS) Elicit Neuroprotective Spinal Cord Microglia through IL-1-Dependent Cross Talk with Endothelial Cells.

Microglia are dynamic immunosurveillance cells in the CNS. Whether microglia are protective or pathologic is context dependent; the outcome varies as a function of time relative to the stimulus, activation state of neighboring cells in the microenvironment or within progression of a particular disease. Although brain microglia can be "primed" using bacterial lipopolysaccharide (LPS)/endotoxin, it is unknown whether LPS delivered systemically can also induce neuroprotective microglia in the spinal cord. Here, we show that serial systemic injections of LPS (1 mg/kg, i.p., daily) for 4 consecutive days (LPSx4) consistently elicit a reactive spinal cord microglia response marked by dramatic morphologic changes, increased production of IL-1, and enhanced proliferation without triggering leukocyte recruitment or overt neuropathology. Following LPSx4, reactive microglia frequently contact spinal cord endothelial cells. Targeted ablation or selective expression of IL-1 and IL-1 receptor (IL-1R) in either microglia or endothelia reveal that IL-1-dependent signaling between these cells mediates microglia activation. Using a mouse model of ischemic spinal cord injury in male and female mice, we show that preoperative LPSx4 provides complete protection from ischemia-induced neuron loss and hindlimb paralysis. Neuroprotection is partly reversed by either pharmacological elimination of microglia or selective removal of IL-1R in microglia or endothelia. These data indicate that spinal cord microglia are amenable to therapeutic reprogramming via systemic manipulation and that this potential can be harnessed to protect the spinal cord from injury.SIGNIFICANCE STATEMENT Data in this report indicate that a neuroprotective spinal cord microglia response can be triggered by daily systemic injections of LPS over a period of 4 d (LPSx4). The LPSx4 regimen induces morphologic transformation and enhances proliferation of spinal cord microglia without causing neuropathology. Using advanced transgenic mouse technology, we show that IL-1-dependent microglia-endothelia cross talk is necessary for eliciting this spinal cord microglia phenotype and also for conferring optimal protection to spinal motor neurons from ischemic spinal cord injury (ISCI). Collectively, these novel data show that it is possible to consistently elicit spinal cord microglia via systemic delivery of inflammogens to achieve a therapeutically effective neuroprotective response against ISCI.

[Liver transplantation in Wilson's disease patients, 1996-2017]. / Májátültetés Wilson-kóros betegekben, 1996­2017.

Introduction: Wilson's disease is a lethal-without-treatment inherited disorder of copper metabolism. Despite the increased focus on the diagnosis and treatment, liver transplantation is needed in a number of cases even nowadays. Aim: To collect and analyze the data of the Hungarian Wilson's disease patients who underwent liver transplantation. Method: Data of 24 Wilson's disease patients who underwent liver transplantation at the Semmelweis University have been analyzed retrospectively. The diagnosis of Wilson's disease was based on the international score system. The diagnosis of acute liver failure corresponded to the King's College criteria. All liver transplantations had been performed at the Department of Transplantation and Surgery of Semmelweis University, in 1996 for the first time. Results: The mean age was 26 years, F/M = 13/11. Twelve patients needed urgent liver transplantation for acute liver failure, and 12 underwent transplantation for decompensated liver cirrhosis. One patient had been retransplanted because of chronic rejection. Three patients with acute on chronic liver failure were transplanted via the Eurotransplant program. The mean time on the waiting list was 3 vs 320 days in acute liver failure and chronic liver disease groups, respectively. The overall 5-year survival was 66%, but it was 80% after 2002 indicating both the learning curve effect and the improvement of vigilance in Hungary. Despite difficulties of the diagnostic process, Wilson's disease was identified in 21/24 patients prior to the transplantation. Conclusion: Liver transplantation is needed in a number of cases of Wilson's disease. The ideal indication and timing of transplantation may improve the survival of the patients. Orv Hetil. 2019; 160(51): 2021-2025.

Interleukin-1 causes CNS inflammatory cytokine expression via endothelia-microglia bi-cellular signaling.

As a major producer of the inflammatory cytokine interleukin-1 (IL-1), peripheral macrophages can augment IL-1 expression via type 1 IL-1 receptor (IL-1R1) mediated autocrine self-amplification. In the CNS, microglial cells are the major producers of inflammatory cytokines, but express negligible levels of IL-1R1. In the present study, we showed CNS IL-1 induced microglial proinflammatory cytokine expression was mediated by endothelial, not microglial, IL-1R1. This paracrine mechanism was further dissected in vitro. IL-1 was unable to stimulate inflammatory cytokine expression directly from the microglial cell line BV-2, but it stimulated the brain endothelial cell line bEnd.3 to produce a factor(s) in the culture supernatant, which was capable of inducing inflammatory cytokine expression in BV-2. We termed this factor IL-1-induced microglial activation factors (IMAF). BV-2 cytokine expression was inducible by extracellular ATP, but IL-1 did not stimulate the release of ATP from bEnd.3 cells. Filtration of IMAF by size-exclusion membranes showed IMAF activity resided in molecules larger than 50 kd and incubation of IMAF at 95 °C for 5 min did not alter its activity. Microglial inhibitor minocycline was unable to block IMAF activity, even though it blocked LPS induced cytokine expression in BV-2 cells. Adding NF-κB inhibitor to the bEnd.3 cells abolished IL-1 induced cytokine expression in this bi-cellular system, but adding NF-κB inhibitor after IMAF is already produced failed to abrogate IMAF induced cytokine expression in BV-2 cells. RNA sequencing of IL-1 stimulated endothelial cells revealed increased expression of genes involved in the production and processing of hyaluronic acid (HA), suggesting HA as a candidate of IMAF. Inhibition of hyaluronidase by ascorbyl palmitate (AP) abolished IMAF-induced cytokine expression in BV-2 cells. AP administration in vivo also inhibited ICV IL-1-induced IL-1 expression in the hippocampus and hypothalamus. In vitro, either TLR2 or TLR4 inhibitors blocked IMAF induced BV-2 cytokine expression. In vivo, however, IL-1 induced cytokine expression persisted in either TLR2 or TLR4 knockouts. These results demonstrate IL-1 induced inflammatory cytokine expression in the CNS requires a bi-cellular system and HA could be a candidate for IMAF.

Cell-Type-Specific Interleukin 1 Receptor 1 Signaling in the Brain Regulates Distinct Neuroimmune Activities.

Interleukin-1 (IL-1) signaling is important for multiple potentially pathogenic processes in the central nervous system (CNS), but the cell-type-specific roles of IL-1 signaling are unclear. We used a genetic knockin reporter system in mice to track and reciprocally delete or express IL-1 receptor 1 (IL-1R1) in specific cell types, including endothelial cells, ventricular cells, peripheral myeloid cells, microglia, astrocytes, and neurons. We found that endothelial IL-1R1 was necessary and sufficient for mediating sickness behavior and drove leukocyte recruitment to the CNS and impaired neurogenesis, whereas ventricular IL-1R1 was critical for monocyte recruitment to the CNS. Although microglia did not express IL-1R1, IL-1 stimulation of endothelial cells led to the induction of IL-1 in microglia. Together, these findings describe the structure and functions of the brain's IL-1R1-expressing system and lay a foundation for the dissection and identification of IL-1R1 signaling pathways in the pathogenesis of CNS diseases.

Changes in Differential Expression of Genes in Normal and Metabolically Suppressed Mice in Response to Radiation.

Differential gene expression profiles of mice in active and metabolically suppressed states were evaluated in response to a sublethal dose of gamma radiation to identify the beneficial protective effects of suspended animation. Results demonstrated that nearly 90% suppression of metabolic functions in mice lead to significant changes in gene expression profile of different metabolic pathways responsible for adaptation and maintenance of homeostasis in the new physiological state of suspended animation. This state was found sustainable during 18 hrs of experiment and can be reversed back to the normal active state without any visible effects on physiological and behavioral functions of mice. Gene expression during induced states was gathered via Illumina microarray methods. Further analysis of differential gene expressions yielded a result that a hypometabolic state may be responsible for short term and long-term radioprotection.

Evolution of coeloconic sensilla in the peripheral olfactory system of Drosophila mojavensis.

Populations inhabiting habitats with different environmental conditions, such as climate, resource availability, predation, competition, can undergo selection for traits that are adaptive in one habitat and not the other, leading to divergence between populations. Changes in the olfactory systems of insects that rely on different host plants, for example, can occur in response to differences in sensory stimuli between habitats. In this study, we investigate the evolution of host preference by characterizing the coeloconic sensilla in Drosophila mojavensis, a species that breeds on different necrotic cacti across its geographic range. These cactus species differ in the volatile chemicals they emit, a primary sensory cue for host plant discrimination. Analysis of odor-evoked responses identified four coeloconic sensilla that were qualitatively similar to those of Drosophila melanogaster, but varied in the breadth and strength of their olfactory sensory neuron responses to some acids and amines. Variation in responses to certain odorants among D. mojavensis populations was also observed. Compared to D. melanogaster, there was a lack of sensitivity of antennal coeloconic type 3 (ac3) sensilla to primary ligands of OR35a across all populations. Consistent with this result was a lack of detectable Or35a gene expression. Using a comparative approach, we then examined odor specificity of ac3 sensilla for seven additional Drosophila species, and found that OR35a-like sensitivity may be limited to the melanogaster subgroup. The variation in specificity that was observed among species is not clearly attributable to the degree of ecological specialization, nor to the ecological niche.

Cholangiocarcinoma in Wilson's Disease - a Case Report.

It has been suggested that hepatobiliary carcinomas are less frequent in Wilson's disease (WD) than in liver diseases of other etiology. However, the protective role of copper against malignancies is debated. Only a few cases of cholangiocarcinoma (CCC) in WD have been published. Here we report on a case of a 47-year-old male H1069Q homozygous, Kayser-Fleischer ring positive WD patient with a low ceruloplasmin level who was followed up and treated with chelating agents throughout nine years. The patient presented with neurological symptoms and liver cirrhosis at diagnosis. Clinical symptoms regressed after the treatment initiation. Rapidly developed tumour metastases were found in the bones, lung and liver (without jaundice). Autopsy revealed cholangiocarcinoma as the primary tumour confirmed by strong CK7 positivity and glypican-3 negativity. The curiosity of the presented case is the very rapid development of CCC despite continuous chelating agent therapy.

[Vitamin D metabolism and signaling in human hepatocellular carcinoma and surrounding non-tumorous liver]. / A D-vitamin metabolizmusa humán hepatocellularis carcinomában és az azt körülvevo tumormentes májszövetben.

INTRODUCTION: 1,25-Dihydroxy vitamin D3 mediates antitumor effects in hepatocellular carcinoma. AIM: We examined mRNA and protein expression differences in 1,25-Dihydroxy vitamin D3-inactivating CYP24A1, mRNA of activating CYP27B1 enzymes, and that of VDR between human hepatocellular carcinoma and surrounding non-tumorous liver. METHODS: Snap-frozen tissues from 13 patients were studied for mRNA and protein expression of CYP24A1. Paraffin-embedded tissues from 36 patients were used to study mRNA of VDR and CYP27B1. mRNA expression was measured by RT-PCR, CYP24A1 protein was detected by immunohistochemistry. RESULTS: Expression of VDR and CYP27B1 was significantly lower in hepatocellular carcinoma compared with non-tumorous liver (p<0.05). The majority of the HCC samples expressed CYP24A1 mRNA, but neither of the non-tumorous liver. The gene activation was followed by CYP24A1 protein synthesis. CONCLUSIONS: The presence of CYP24A1 mRNA and the reduced expression of VDR and CYP27B1 mRNA in human hepatocellular carcinoma samples indicate decreased bioavailability of 1,25-Dihydroxy vitamin D3, providing an escape mechanism from the anti-tumor effect. Orv. Hetil., 2016, 157(48), 1910-1918.

Euflammation attenuates peripheral inflammation-induced neuroinflammation and mitigates immune-to-brain signaling.

Peripheral inflammation can trigger a number of neuroinflammatory events in the CNS, such as activation of microglia and increases of proinflammatory cytokines. We have previously identified an interesting phenomenon, termed "euflammation", which can be induced by repeated subthreshold infectious challenges. Euflammation causes innate immune alterations without overt neuroimmune activation. In the current study, we examined the protective effect of euflammation against peripheral inflammation-induced neuroinflammation and the underlying mechanisms. When Escherichia coli or lipopolysaccharide (LPS) was injected inside or outside the euflammation induction locus (EIL), sickness behavior, global microglial activation, proinflammatory cytokine production in the brain, expression of endothelial cyclooxygenase II and induction of c-fos expression in the paraventricular nucleus of the hypothalamus were all attenuated in the euflammatory mice compared with those in the control unprimed mice. Euflammation also modulated innate immunity outside the EIL by upregulating receptors for pathogen-associated molecular patterns in spleen cells. In addition, euflammation attenuated CNS activation in response to an intra-airpouch (outside the EIL) injection of LPS without suppressing the cytokine expression in the airpouch. Collectively, our study demonstrates that signaling of peripheral inflammation to the CNS is modulated dynamically by peripheral inflammatory kinetics. Specifically, euflammation can offer effective protection against both bacterial infection and endotoxin induced neuroinflammation.

Clinical Use of Next-Generation Sequencing in the Diagnosis of Wilson's Disease.

Objective. Wilson's disease is a disorder of copper metabolism which is fatal without treatment. The great number of disease-causing ATP7B gene mutations and the variable clinical presentation of WD may cause a real diagnostic challenge. The emergence of next-generation sequencing provides a time-saving, cost-effective method for full sequencing of the whole ATP7B gene compared to the traditional Sanger sequencing. This is the first report on the clinical use of NGS to examine ATP7B gene. Materials and Methods. We used Ion Torrent Personal Genome Machine in four heterozygous patients for the identification of the other mutations and also in two patients with no known mutation. One patient with acute on chronic liver failure was a candidate for acute liver transplantation. The results were validated by Sanger sequencing. Results. In each case, the diagnosis of Wilson's disease was confirmed by identifying the mutations in both alleles within 48 hours. One novel mutation (p.Ala1270Ile) was found beyond the eight other known ones. The rapid detection of the mutations made possible the prompt diagnosis of WD in a patient with acute liver failure. Conclusions. According to our results we found next-generation sequencing a very useful, reliable, time-saving, and cost-effective method for diagnosing Wilson's disease in selected cases.