Glial TLR2-driven innate immune responses and CD8+ T cell activation against brain tumor.

Growing interest has been focused on the roles of microglia as sentinels and effector cells that guard diverse pathological milieu in the brain. Here, it has been reported that microglial TLR2 is a crucial molecule that confers innate and adaptive immunity against brain tumor. TLR2 is preferentially expressed on microglia, brain-resident immune cells, in the tumor-bearing cerebral hemisphere of mouse and rat intracranial tumor models. Microglial TLR2 rapidly responds to brain tumor and modulates the inflammation-associated immune responses including phagocytosis, which are markedly decreased in TLR2-deficient mice. We further reveal that TLR2, but not TLR4, is essential for the tumor-triggered increase of MHC I in microglia. in vitro co-culture and in vivo experiments show that the glial TLR2-MHC I axis contributes to the proliferation and activation of CD8+ T cells by brain tumor. In addition, brain tumor-bearing ß2m-/- , Tlr2-/- , or Rag2 -/- γc -/- mice exhibit higher tumor volumes compared with WT mice with tumor. Survival analysis of GL26-bearing MHC I-defective mice also support the contribution of glial TLR2-MHC I axis to brain tumor immunity. Moreover, using publicly available data sets of human brain tumor patients, we find that glioblastoma (GBM) tissues with high TLR2 level have similar co-occurrence patterns with MHC I molecules, and the amounts and activity of infiltrating CD8+ T cells are correlated with TLR2 level in tissues from GBM patients. Collectively, our findings provide the importance of glial TLR2-driven innate and adaptive immune responses in the brain tumor microenvironment.

Nontuberculosis mycobacterial infections at a specialized tuberculosis treatment centre in the Republic of Korea.

BACKGROUND: The incidence of nontuberculous mycobacteria (NTM) infections is increasing worldwide, however formal evaluations of the epidemiology of NTM infections are limited. Understanding the trends and true prevalence of NTM is a major priority for optimizing infection control programmes and resources. The purpose of this study was to investigate the epidemiology, clinical manifestations, and radiologic findings in NTM-infected patients at specialized Tuberculosis (Tb) treatment centre in South Korea, which is endemic to Tb, and find solutions to control NTM infections. METHODS: A retrospective descriptive study was conducted among patients who were diagnosed with NTM from November 2011 to January 2016 at Seoul Metropolitan Government Seobuk hospital, Korea, using medical records and chest radiography results. Prevalence of NTM using national health insurance data was compared to the prevalence and incidence of Tb using National statistics data. RESULTS: The age- and sex- adjusted prevalence of NTM infection per 100,000 population increased between 2009 (9.4) and 2016 (36.1). However, the prevalence and incidence of Tb per 100,000 population decreased from 106.5 to 74.4, and 81.2 to 61.8, respectively. In total, 64 patients (37 [57.8%] men) were enrolled in the study. Among 33 (51.6%) patients with slowly growing nontuberculous mycobacteria (SGM) infection, 29 were detected with Mycobacterium avium complex (n = 13, M. avium; n = 16, M. intracellulare), and 4 with M. kansasii. Among 31 (48.4%) patients with rapidly growing nontuberculous mycobacteria (RGM) infection, 27 and 4 patients were detected with M. abscessus complex and M. fortuitum complex, respectively. RGM patients were more likely to have current Tb (P = 0.041), cough (P < 0.05), and sputum (P < 0.01) than SGM patients in the univariate analysis, but not in the multivariate analysis. CONCLUSION: Given the increasing prevalence of NTM infections, precise epidemiological and surveillance data should be obtained by reporting NTM infections to public health authorities. Introducing nucleic acid amplification tests to differentiate between Tb and NTM in smear-positive specimens should be considered.

Photoluminescence profiles and fast/slow annealing effects of Eu(III)/Tb(III)-codoped silica phosphor materials.

A silica (SiO2) nanoparticle matrix was codoped with luminescent Eu(III) and Tb(III) ions using a modified Stöber method. The effects of fast and slow thermal annealing on photoluminescence profile imaging were examined. Slow annealing treatment suppressed more quenching sites than fast thermal annealing to further increase the photoluminescence signals. The photoluminescence signals observed between 450 and 720 nm were assigned to the (5)D(0) → (7)F(J) (J = 0,1,2,3,4) of Eu(III) and the (5)D(4) → (7)F(J) (J = 6,5,4,3) transitions of Tb(III). Photoluminescence was largely sensitized by indirect excitation and was much stronger than that generated by direct excitation. The Eu(III) and Tb(III) ions were doped at lower symmetry sites in the silica matrix.

Distinctive responses of brain tumor cells to TLR2 ligands.

Malignant brain tumor mass contains significant numbers of infiltrating glial cells that may intimately interact with tumor cells and influence cancer treatments. Understanding of characteristic discrepancies between normal GLIA and tumor cells would, therefore, be valuable for improving anticancer therapeutics. Here, we report distinct differences in toll-like receptors (TLR)-2-mediated responses between normal glia and primary brain tumor cell lines. We found that tyrosine phosphorylation of STAT1 by TLR2 ligands and its downstream events did not occur in mouse, rat, or human brain tumor cell lines, but were markedly induced in normal primary microglia and astrocytes. Using TLR2-deficient, interferon (IFN)-γ-deficient, and IFNγ-receptor-1-deficient mice, we revealed that the impaired phosphorylation of STAT1 might be linked with defective TLR2 system in tumor cells, and that a TLR2-dependent pathway, not IFNγ-receptor machinery, might be critical for tyrosine STAT1 phosphorylation by TLR2 ligands. We also found that TLR2 and its heterodimeric partners, TLR1 and 6, on brain tumor cells failed to properly respond to TLR2 ligands, and representative TLR2-dependent cellular events, such as inflammatory responses and cell death, were not detected in brain tumor cells. Similar results were obtained in in vitro and in vivo experiments using orthotopic mouse and rat brain tumor models. Collectively, these results suggest that primary brain tumor cells may exhibit a distinctive dysfunction of TLR2-associated responses, resulting in abnormal signaling and cellular events. Careful targeting of this distinctive property could serve as the basis for effective therapeutic approaches against primary brain tumors.

Increased levels of plasma glial-derived neurotrophic factor in children with attention deficit hyperactivity disorder.

BACKGROUND: Recent evidence suggests that neurotrophic growth factor systems, including brain-derived neurotrophic factor, might be involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Glial cell line-derived neurotrophic factor (GDNF) is from the transforming growth factor-ß family and is abundantly expressed in the central nervous system, where it plays a role in the development and function of hippocampal cells. To date, no association studies have been done between ADHD and GDNF. Thus, here we investigate the hypothesis that there are differences in plasma GDNF levels between children with ADHD and healthy controls. METHODS: Plasma GDNF levels were measured in 86 drug-naïve children with ADHD and 128 healthy children. The severity of ADHD symptoms was determined by scores on the Korean ADHD Rating Scale (K-ARS) in patients and healthy controls. RESULTS: The median plasma GDNF levels in ADHD patients was 74.0 (IQR: 23.4-280.1) pg/ml versus 24.6 (IQR: 14.5-87.3) pg/ml in healthy controls; thus the median plasma GDNF levels in ADHD patients were significantly higher than in healthy controls (Mann-Whitney U-test, P < 0.01). Plasma GDNF levels were correlated positively with K-ARS subscale scores (inattention, hyperactivity-impulsivity and total), determined by Spearman's correlation test in ADHD patients and healthy controls (r = 0.371, P < 0.01; r = 0.331, P < 0.01; and r = 0.379, P < 0.01, respectively). CONCLUSIONS: These findings suggest increased plasma GDNF levels in untreated ADHD patients. In addition, plasma GDNF levels had a significant positive correlation with inattention, hyperactivity-impulsivity and K-ARS total scores in ADHD patients and healthy controls. Further studies are required to determine the source and role of circulating GDNF in ADHD.

Protection against experimental aspergillosis by heat-killed yeast is not antibody dependent.

Previously we showed heat-killed yeast (HKY) of Saccharomyces cerevisiae administered as a vaccine are protective against systemic murine aspergillosis (and other mycoses) and that HKY induces antibody and cellular responses. To determine the role of antibodies in this protection, male antibody knockout mice (KO; strain B6.129S2-Igh-6 (tm1Cgn)/J) and C57BL/6 wild-type (WT) mice were vaccinated subcutaneously with 6 × 10(7) HKY or phosphate buffered saline (PBS) given three or four times. Mice were infected intravenously with 6 × 10(6) viable conidia of Aspergillus fumigatus 10AF and mortality tallied through 12 days post infection. HKY vaccination given four times proved protective in the prolongation of survival of WT and KO mice vs. the respective PBS-treated controls. In one study, survival was prolonged in vaccinated WT or KO mice (P < 0.0001). A second study confirmed these results (P < 0.0001). Additionally, a three-dose regimen of HKY was also effective, prolonging survival of WT or KO mice vs. controls (P = 0.0002); no difference was found when the effectiveness of three- or four-dose regimens was compared. No significant differences in survival were found between HKY-vaccinated WT and KO mice, nor were PBS-treated KO mice more susceptible to infection than PBS-treated WT mice. Similar results were noted in another study in which a higher infectious inoculum and a three-dose regimen were used. Overall, antibodies do not appear to play a significant role in HKY-induced prolongation of survival in systemic aspergillosis, nor do antibodies appear to play a role in the innate resistance of the mice to aspergillosis.

Factors Associated With Achieving Complete Skin Clearance Compared to Almost Complete Skin Clearance in Patients With Moderate to Severe Psoriasis Treated With Biologics: A Retrospective Chart Review.

BACKGROUND: Biologics have demonstrated high efficacy in achieving 'almost complete' skin clearance in patients with moderate to severe psoriasis. Nonetheless, achieving 'complete' skin clearance remains a treatment goal for some highly biologics-resistant patients, as residual lesions impact their quality of life. OBJECTIVE: The risk factors for failure to achieve a Psoriasis Area and Severity Index (PASI) 100 response in patients with good response to biologics remain unknown. METHODS: This retrospective study evaluated the risk factors by comparing patients who achieved complete skin clearance (PASI100) with those who achieved almost complete skin clearance (PASI90). A database of 131 psoriasis patients treated with biologics, who achieved a PASI90 or PASI100 response, was reviewed from a tertiary referral hospital in South Korea. The patients were classified into PASI90 and PASI100 groups according to their PASI response. RESULTS: The PASI100 group had a lower prevalence of smoking history (adjusted odds ratio [OR], 0.34; 95% confidence interval [CI], 0.14-0.85; p=0.021) and psoriasis on the anterior lower legs at baseline (adjusted OR, 0.18; 95% CI, 0.03-0.99; p=0.049) than patients in the PASI90 group. CONCLUSION: This study suggested that smoking history and psoriatic skin lesions on the anterior lower legs are considered as the risk factors for the failure to achieve a PASI100 response in psoriasis patients treated with biologics.

Immune Checkpoint-Blocking Nanocages Cross the Blood-Brain Barrier and Impede Brain Tumor Growth.

Glioblastoma (GBM) is the deadliest tumor of the central nervous system, with a median survival of less than 15 months. Despite many trials, immune checkpoint-blocking (ICB) therapies using monoclonal antibodies against the PD-1/PD-L1 axis have demonstrated only limited benefits for GBM patients. Currently, the main hurdles in brain tumor therapy include limited drug delivery across the blood-brain barrier (BBB) and the profoundly immune-suppressive microenvironment of GBM. Thus, there is an urgent need for new therapeutics that can cross the BBB and target brain tumors to modulate the immune microenvironment. To this end, we developed an ICB strategy based on the BBB-permeable, 24-subunit human ferritin heavy chain, modifying the ferritin surface with 24 copies of PD-L1-blocking peptides to create ferritin-based ICB nanocages. The PD-L1pep ferritin nanocages first demonstrated their tumor-targeting and antitumor activities in an allograft colon cancer model. Next, we found that these PD-L1pep ferritin nanocages efficiently penetrated the BBB and targeted brain tumors through specific interactions with PD-L1, significantly inhibiting tumor growth in an orthotopic intracranial tumor model. The addition of PD-L1pep ferritin nanocages to triple in vitro cocultures of T cells, GBM cells, and glial cells significantly inhibited PD-1/PD-L1 interactions and restored T-cell activity. Collectively, these findings indicate that ferritin nanocages displaying PD-L1-blocking peptides can overcome the primary hurdle of brain tumor therapy and are, therefore, promising candidates for treating GBM.

A Case of Generalized Xerotic Eczema in a Patient with Congenital Insensitivity to Pain with Anhidrosis.

Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare disease characterized by insensitivity to pain, anhidrosis, and intellectual disability. CIPA is caused by a genetic mutation in the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene on chromosome 1. The anhidrosis leads to cutaneous changes such as skin dryness, lichenification, and impetiginization. Moreover, patients with CIPA may experience repeated trauma and recalcitrant eczema due to excessive scratching of wounds on their skin, because they do not feel any pain. Severe whole-body eczema in a patient with CIPA may be overlooked, leading these patients to be frequently diagnosed with atopic dermatitis and common eczema. Indeed, in patients with treatment-resistant or atypically distributed eczema and underlying anhidrosis, CIPA should be considered as a potential causative disease. Increased awareness of CIPA among dermatologists is necessary to ensure that patients receive an appropriate diagnosis. Herein, we report a rare case of generalized xerotic eczema in a patient with CIPA.

Dual functionality of myeloperoxidase in rotenone-exposed brain-resident immune cells.

Rotenone exposure has emerged as an environmental risk factor for inflammation-associated neurodegenerative diseases. However, the underlying mechanisms responsible for the harmful effects of rotenone in the brain remain poorly understood. Herein, we report that myeloperoxidase (MPO) may have a potential regulatory role in rotenone-exposed brain-resident immune cells. We show that microglia, unlike neurons, do not undergo death; instead, they exhibit distinctive activated properties under rotenone-exposed conditions. Once activated by rotenone, microglia show increased production of reactive oxygen species, particularly HOCl. Notably, MPO, an HOCl-producing enzyme that is undetectable under normal conditions, is significantly increased after exposure to rotenone. MPO-exposed glial cells also display characteristics of activated cells, producing proinflammatory cytokines and increasing their phagocytic activity. Interestingly, our studies with MPO inhibitors and MPO-knockout mice reveal that MPO deficiency potentiates, rather than inhibits, the rotenone-induced activated state of glia and promotes glial cell death. Furthermore, rotenone-triggered neuronal injury was more apparent in co-cultures with glial cells from Mpo(-/-) mice than in those from wild-type mice. Collectively, our data provide evidence that MPO has dual functionality under rotenone-exposed conditions, playing a critical regulatory role in modulating pathological and protective events in the brain.

Galectin-3 exerts cytokine-like regulatory actions through the JAK-STAT pathway.

Galectin-3, a ß-galactoside-binding lectin, has been proposed to have multifaceted functions in various pathophysiological conditions. However, the characteristics of galectin-3 and its molecular mechanisms of action are still largely unknown. In this study, we show that galectin-3 exerts cytokine-like regulatory actions in rat and mouse brain-resident immune cells. Both the expression of galectin-3 and its secretion into the extracellular compartment were significantly enhanced in glia under IFN-γ-stimulated, inflamed conditions. After exposure to galectin-3, glial cells produced high levels of proinflammatory mediators and exhibited activated properties. Notably, within minutes after exposure to galectin-3, JAK2 and STAT1, STAT3, and STAT5 showed considerable enhancement of tyrosine phosphorylation; thereafter, downstream events of STAT signaling were also significantly enhanced. Treatment of the cells with pharmacological inhibitors of JAK2 reduced the galectin-3-stimulated increases of inflammatory mediators. Using IFN-γ receptor 1-deficient mice, we further found that IFN-γR 1 might be required for galectin-3-dependent activation of the JAK-STAT cascade. However, galectin-3 significantly induced phosphorylation of STATs in glial cells from IFN-γ-deficient mice, suggesting that IFN-γ does not mediate activation of STATs. Collectively, our findings suggest that galectin-3 acts as an endogenous danger signaling molecule under pathological conditions in the brain, providing a potential explanation for the molecular basis of galectin-3-associated pathological events.

Enhanced protein aggregation suppressor activity of N-acetyl-l-arginine for agitation-induced aggregation with silicone oil and its impact on innate immune responses.

Previously, N-acetyl-l-arginine (NALA) suppressed the aggregation of intravenous immunoglobulins (IVIG) more effectively and with a minimum decrease in transition temperature (Tm) than arginine monohydrochloride. In this study, we performed a comparative study with etanercept (commercial product: Enbrel®), where 25 mM arginine monohydrochloride (arginine) was added to the prefilled syringe. The biophysical properties were investigated using differential scanning calorimetry (DSC), dynamic light scattering (DLS), size-exclusion chromatography (SEC), and flow-imaging microscopy (FI). NALA retained the transition temperature of etanercept better than arginine, where arginine significantly reduced the Tm by increasing its concentration. End-over-end rotation was applied to each formulation for 5 days to accelerate protein aggregation and subvisible particle formation. Higher monomeric content was retained with NALA with a decrease in particle level. Higher aggregation onset temperature (Tagg) was detected for etanercept with NALA than arginine. The results of this comparative study were consistent with previous study, suggesting that NALA could be a better excipient for liquid protein formulations. Agitated IVIG and etanercept were injected into C57BL/6J female mice to observe immunogenic response after 24 h. In the presence of silicone oil, NALA dramatically reduced IL-1 expression, implying that decreased aggregation was related to reduced immunogenicity of both etanercept and IVIG.

Comparison between Atomoxetine and OROS Methylphenidate as an Adjunctive to SSRIs in Attention-deficit/Hyperactivity Disorder Adults with Comorbid Partially Responsive Major Depressive Disorder: A Head-to-head, 12-week, Randomized, Rater-blinded Clinical Trial.

OBJECTIVE: This study aimed to compare the efficacy and safety of atomoxetine (ATX) and OROS methylphenidate (MPH) as adjunctive to selective serotonin reuptake inhibitors (SSRIs) in adults with attention-deficit hyperactivity disorder (ADHD) with comorbid partially responsive major depressive disorder (MDD). METHODS: Sixty Korean adults with ADHD and comorbid partially responsive MDD were recruited in a 12-week, randomized, rater-blinded, active-controlled trial and were evenly randomized to ATX or OROS MPH treatment. RESULTS: Depressive symptoms measured using the Hamilton Depression Rating Scale and Clinically Useful Depression Outcome Scale, and ADHD symptoms measured using the Adult ADHD Self-Report Scale, as well as the Clinical Global Impression-Severity, Clinical Global Impression-Improvement, and the Sheehan Disability Scale scores were significantly improved in both groups during the 12 weeks of treatment. The changes in all outcome measures during the 12-week treatment were not significantly different between the two groups (all p > 0.05). No serious adverse events were reported and there were no significant differences in systolic and diastolic blood pressure, pulse rate, weight, or body mass index between the ATX and MPH groups. CONCLUSION: Our findings suggest that ATX and MPH can be used as adjunctive treatments in adults with ADHD and comorbid partially responsive MDD. The efficacy and tolerability of ATX and MPH in adults with ADHD did not differ significantly. Further studies should be conducted to draw a definitive conclusion.

Electrophysiological Changes Related to Childhood Trauma in Patients with Major Depressive Disorder: An Event-related Potential Study.

OBJECTIVE: Childhood trauma is the most important environmental factor for several psychiatric disorders. Depressed patients with childhood trauma appear to have severe symptoms that frequently recur. This study investigated whether depressed patients with childhood trauma showed attenuated Nogo event-related potentials (ERPs) and source activity during response-inhibition tasks. METHODS: Forty-four patients patients with major depressive disorder (MDD) were instructed to perform a Go/Nogo task during electroencephalography. Sensors and source activities of N2 and P3 of the Nogo ERPs were analyzed. The participants' clinical symptoms were assessed using the Childhood Trauma Questionnaire (CTQ), Beck Depression Inventory, State-Trait Anxiety Inventory, Barratt Impulsivity Scale, and Affective Lability Scale. The participants were divided into two groups (low and high), based on their total CTQ scores. RESULTS: MDD subjects with high CTQ scores showed significantly decreased Nogo P3 amplitudes at the frontal, frontocentral, central, and parietal electrodes than those with low CTQ scores (all p < 0.01). In Nogo P3, the source activities of the right cuneus, right posterior cingulate cortex, right precuneus, left supramarginal gyrus, and left lingual gyrus were significantly lower in the high CTQ group than in the low one (all p < 0.01). There were significant negative correlations between the total CTQ scores and the Nogo P3 amplitudes in the frontocentral (p = 0.03) and parietal regions (p = 0.02), which showed lower source activity in the Nogo P3 condition. CONCLUSION: Depressed patients with severe childhood trauma showed different Nogo-ERP characteristics, which might reflect inhibitory failure and dysfunction in related brain regions.

Activation of T-cell-factor-dependent transcription by Kaposi's sarcoma-associated herpesvirus replication transactivation activator.

OBJECTIVE: To elucidate the cellular function of Kaposi's sarcoma-associated herpesvirus (KSHV) replication transactivation activator (RTA) at the transcriptional level. METHODS: Transcriptional activation of T-cell-factor (TCF)-dependent genes by RTA was determined using the luciferase reporter assay. The specific regions of RTA required for the activation of TCF-dependent transcription and association with ß-catenin were established. RESULTS: RTA specifically activated TCF-dependent transcription in a dose-dependent manner, to an extent comparable to the activation achieved by latency-associated nuclear antigen. In contrast, other KSHV viral proteins investigated, such as basic leucine zipper and viral interferon regulatory factor 1, did not affect TCF-dependent transcription. The C-terminal region of RTA appeared to be necessary for transcription. However, RTA did not affect the ß-catenin level or the subcellular localization thereof. CONCLUSION: Our results collectively demonstrate that KSHV RTA activates TCF-dependent transcription without involving the ß-catenin pathway.

Thermal CO Oxidation and Photocatalytic CO2 Reduction over Bare and M-Al2O3 (M = Co, Ni, Cu, Rh, Pd, Ag, Ir, Pt, and Au) Cotton-Like Nanosheets.

Aluminum oxide (Al2O3) has abundantly been used as a catalyst, and its catalytic activity has been tailored by loading transition metals. Herein, γ-Al2O3 nanosheets were prepared by the solvothermal method, and transition metals (M = Co, Ni, Cu, Rh, Pd, Ag, Ir, Pt, and Au) were loaded onto the nanosheets. Big data sets of thermal CO oxidation and photocatalytic CO2 reduction activities were fully examined for the transition metal-loaded Al2O3 nanosheets. Their physicochemical properties were examined by scanning electron microscopy, high-resolution transmission electron microscopy, X-ray diffraction crystallography, and X-ray photoelectron spectroscopy. It was found that Rh, Pd, Ir, and Pt-loading showed a great enhancement in CO oxidation activity while other metals negated the activity of bare Al2O3 nanosheets. Rh-Al2O3 showed the lowest CO oxidation onset temperature of 172 °C, 201 °C lower than that of bare γ-Al2O3. CO2 reduction experiments were also performed to show that CO, CH3OH, and CH4 were common products. Ag-Al2O3 nanosheets showed the highest performances with yields of 237.3 ppm for CO, 36.3 ppm for CH3OH, and 30.9 ppm for CH4, 2.2×, 1.2×, and 1.6× enhancements, respectively, compared with those for bare Al2O3. Hydrogen production was found to be maximized to 20.7 ppm during CO2 reduction for Rh-loaded Al2O3. The present unique pre-screening test results provided very useful information for the selection of transition metals on Al2O3-based energy and environmental catalysts.

The Relationship between Plasma Erythropoietin Levels and Symptoms of Attention Deficit Hyperactivity Disorder.

OBJECTIVE: There are animal models associating dopamine dysfunction with behavioral impairments that model attention deficit hyperactivity disorder (ADHD). Erythropoietin (EPO) has trophic effects on dopaminergic neurons. The aim of this study was to examine the EPO plasma levels and determine whether there was any correlation between plasma EPO levels and clinical characteristics of ADHD. METHODS: Plasma EPO levels were measured in 78 drug-naïve children with ADHD and in 81 healthy children. The severity of ADHD symptoms was determined by scores on the Korean ADHD Rating Scale (K-ARS) in ADHD children and healthy controls. RESULTS: The difference between median plasma EPO levels in ADHD children and in healthy controls was not statistically significant. Adjusting for age and sex, a linear regression analysis showed that inattention score was significantly higher in the second highest tertile of plasma EPO compared to those in the lowest tertile. Hyperactivity-impulsivity score was significantly higher in the highest tertile of plasma EPO compared to those in the lowest tertile. Moreover, total K-ARS scores were significantly higher in the second highest tertile of plasma EPO compared to those in the lowest tertile. CONCLUSION: These findings suggest that plasma EPO levels were related to some ADHD symptoms, which could be used in the monitoring of the disorder.

Sulfatide, a major lipid component of myelin sheath, activates inflammatory responses as an endogenous stimulator in brain-resident immune cells.

Sulfatide, a major lipid component of myelin sheath, participates in diverse cellular events of the CNS, and its cellular level has recently been implicated in many inflammation-associated neuronal diseases. Herein, we report that sulfatide alone can trigger pathological inflammatory responses in glia, brain-resident immune cells. We show that sulfatide changed the morphology of primary microglia to their activated form, and it significantly induced the production of various inflammatory mediators in primary microglia and astrocytes. Moreover, sulfatide rapidly triggered the phosphorylation of p38, ERK, and JNK within 30 min, and it markedly enhanced the NF binding activity to NF-kappaB and AP-1 binding elements. However, nonsulfated galactocerebroside, another major lipid component of myelin, had no effect on activation of glia. We further reveal that CD1d did not contribute to sulfatide-stimulated activation of MAPKs, although its expression was enhanced by sulfatide and sulfatide-treated microglial cells actually stimulated type II NKT cells. Sulfatide significantly stimulated the phosphorylation of MAPKs in glia from CD1d-deficient mice, and the phosphorylation levels were similar to those in wild-type littermates. Sulfatide-triggered inflammatory events appear to occur at least in part through an L-selectin-dependent mechanism. L-selectin was dramatically down-regulated upon exposure to sulfatide, and inhibition of L-selectin resulted in suppression of sulfatide-triggered responses. Collectively, these results show that abnormally released sulfatide at demyelinated regions may act as an endogenous stimulator in the brain immune system, thus causing and further exacerbating pathological conditions in the brain.

The Relationship Between Response-Inhibitory Event-Related Potentials and Symptoms of Attention-Deficit/Hyperactivity Disorder in Adult Patients with Major Depressive Disorder.

OBJECTIVE: Attention-deficit and poor impulse control have frequently been observed in major depressive disorder (MDD) and attention-deficit and hyperactivity disorder (ADHD). Altered event-related potential (ERP) performance, such as GoNogo tasks, has been regarded as a neurocognitive process associated with attention and behavioral inhibition. The aim of this study was to investigate the association between Nogo ERP and adult ADHD in MDD. METHODS: A total of 64 participants with MDD (32 comorbid with ADHD) and 32 healthy controls aged 19-45 years were recruited; they performed GoNogo paradigms during electroencephalogram measurement. Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), and the Adult ADHD Self-Report Scale (ASRS) were evaluated. Clinical measures and GoNogo ERP were compared between three groups: depression with ADHD, depression without ADHD, and healthy controls. RESULTS: MDD subjects with ADHD showed significantly decreased Nogo P3 amplitude at frontal electrode, compared with those without ADHD and healthy controls. MDD subjects with ADHD showed significantly longer Nogo N2 latency at frontal and frontocentral electrodes, compared with those without ADHD and healthy controls. In MDD subjects with ADHD, the Nogo P3 amplitude at the frontal electrode was negatively correlated with the ASRS score and inattention. The Nogo N2 latency at the frontal electrode was positively correlated with false alarm rate. CONCLUSION: The decreased Nogo P3 amplitude in the frontal area might be a potential biological marker for inattention in depressed patients with ADHD.

Glial TIM-3 Modulates Immune Responses in the Brain Tumor Microenvironment.

T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3), a potential immunotherapeutic target for cancer, has been shown to display diverse characteristics in a context-dependent manner. Thus, it would be useful to delineate the precise functional features of TIM-3 in a given situation. Here, we report that glial TIM-3 shows distinctive properties in the brain tumor microenvironment. TIM-3 was expressed on both growing tumor cells and their surrounding cells including glia and T cells in an orthotopic mouse glioma model. The expression pattern of TIM-3 was distinct from those of other immune checkpoint molecules in tumor-exposed and tumor-infiltrating glia. Comparison of cells from tumor-bearing and contralateral hemispheres of a glioma model showed that TIM-3 expression was lower in tumor-infiltrating CD11b+CD45mid glial cells but higher in tumor-infiltrating CD8+ T cells. In TIM-3 mutant mice with intracellular signaling defects and Cre-inducible TIM-3 mice, TIM-3 affected the expression of several immune-associated molecules including iNOS and PD-L1 in primary glia-exposed conditioned media (CM) from brain tumors. Further, TIM-3 was cross-regulated by TLR2, but not by TLR4, in brain tumor CM- or Pam3CSK4-exposed glia. In addition, following exposure to tumor CM, IFNγ production was lower in T cells cocultured with TIM-3-defective glia than with normal glia. Collectively, these findings suggest that glial TIM-3 actively and distinctively responds to brain tumor, and plays specific intracellular and intercellular immunoregulatory roles that might be different from TIM-3 on T cells in the brain tumor microenvironment. SIGNIFICANCE: TIM-3 is typically thought of as a T-cell checkpoint receptor. This study demonstrates a role for TIM-3 in mediating myeloid cell responses in glioblastoma.