Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

Enrichment analysis of Alu elements with different spatial chromatin proximity in the human genome

Transposable elements (TEs) have no longer been totally considered as “junk DNA” for quite a time since the continual discoveries of their multifunctional roles in eukaryote genomes. As one of the most important and abundant TEs that still active in human genome, Alu, a SINE family, has demonstrated its indispensable regulatory functions at sequence level, but its spatial roles are still unclear. Technologies based on 3C(chromosomeconformation capture) have revealed the mysterious three-dimensional structure of chromatin, and make it possible to study the distal chromatin interaction in the genome. To find the role TE playing in distal regulation in human genome, we compiled the new released Hi-C data, TE annotation, histone marker annotations, and the genome-wide methylation data to operate correlation analysis, and found that the density of Alu elements showed a strong positive correlation with the level of chromatin interactions (hESC: r=0.9, P<2.2×1016; IMR90 fibroblasts: r = 0.94, P < 2.2 × 1016) and also have a significant positive correlation withsomeremote functional DNA elements like enhancers and promoters (Enhancer: hESC: r=0.997, P=2.3×10−4; IMR90: r=0.934, P=2×10−2; Promoter: hESC: r = 0.995, P = 3.8 × 10−4; IMR90: r = 0.996, P = 3.2 × 10−4). Further investigation involving GC content and methylation status showed the GC content of Alu covered sequences shared a similar pattern with that of the overall sequence, suggesting that Alu elements also function as the GC nucleotide and CpG site provider. In all, our results suggest that the Alu elements may act as an alternative parameter to evaluate the Hi-C data, which is confirmed by the correlation analysis of Alu elements and histone markers. Moreover, the GC-rich Alu sequence can bring high GC content and methylation flexibility to the regions with more distal chromatin contact, regulating the transcription of tissue-specific genes

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Brain tumor location influences the onset of acute psychiatric adverse events of levetiracetam therapy: an observational study.

To explore possible correlations among brain lesion location, development of psychiatric symptoms and the use of antiepileptic drugs (AEDs) in a population of patients with brain tumor and epilepsy. The medical records of 283 patients with various types of brain tumor (161 M/122 F, mean age 64.9 years) were analysed retrospectively. Patients with grade III and IV glioma, previous history of epileptic seizures and/or psychiatric disorders were excluded. Psychiatric symptoms occurring after initiation of AED therapy were considered as treatment emergent psychiatric adverse events (TE-PAEs) if they fulfilled the following conditions: (1) onset within 4 weeks after the beginning of AED therapy; (2) disappearance on drug discontinuation; (3) absence of any other identified possible concurrent cause. The possible influence of the following variables were analysed: (a) AED drug and dose; (b) location and neuroradiologic features of the tumor, (c) location and type of EEG epileptic abnormalities, (d) tumor excision already or not yet performed; (e) initiation or not of radiotherapy. TE-PAEs occurred in 27 of the 175 AED-treated patients (15.4%). Multivariate analysis showed a significant association of TE-PAEs occurrence with location of the tumor in the frontal lobe (Odds ratio: 5.56; 95% confidence interval 1.95-15.82; p value: 0.005) and treatment with levetiracetam (Odds ratio: 3.61; 95% confidence interval 1.48-8.2; p value: 0.001). Drug-unrelated acute psychiatric symptoms were observed in 4 of the 108 AED-untreated patients (3.7%) and in 7 of the 175 AED-treated patients (4%). The results of the present study suggest that an AED alternative to levetiracetam should be chosen to treat epileptic seizures in patients with a brain tumor located in the frontal lobe to minimize the possible onset of TE-PAEs

A Long Baseline Neutrino Oscillation Experiment Using J-PARC Neutrino Beam and Hyper-Kamiokande

Document submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresDocument submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresDocument submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresHyper-Kamiokande will be a next generation underground water Cherenkov detector with a total (fiducial) mass of 0.99 (0.56) million metric tons, approximately 20 (25) times larger than that of Super-Kamiokande. One of the main goals of Hyper-Kamiokande is the study of $CP$ asymmetry in the lepton sector using accelerator neutrino and anti-neutrino beams. In this document, the physics potential of a long baseline neutrino experiment using the Hyper-Kamiokande detector and a neutrino beam from the J-PARC proton synchrotron is presented. The analysis has been updated from the previous Letter of Intent [K. Abe et al., arXiv:1109.3262 [hep-ex]], based on the experience gained from the ongoing T2K experiment. With a total exposure of 7.5 MW $\times$ 10$^7$ sec integrated proton beam power (corresponding to $1.56\times10^{22}$ protons on target with a 30 GeV proton beam) to a $2.5$-degree off-axis neutrino beam produced by the J-PARC proton synchrotron, it is expected that the $CP$ phase $\delta_{CP}$ can be determined to better than 19 degrees for all possible values of $\delta_{CP}$, and $CP$ violation can be established with a statistical significance of more than $3\,\sigma$ ($5\,\sigma$) for $76$ ($58$) of the $\delta_{CP}$ parameter space

Knowledge and practices regarding child development among primary healthcare professionals

OBJECTIVE: To evaluate the knowledge and practices regarding child development among physicians working in primary healthcare units. METHOD: Cross-sectional descriptive study carried out at primary healthcare units in Embu, São Paulo, Brazil. Study procedures: 1) Evaluation of knowledge: test consisting of 20 multiple-choice questions on child development applied to all 31 physicians who were providing pediatric care at the primary healthcare units; 2) Evaluation of practices: semi-structured interview applied to a sample of 154 mothers/caregivers of children aged up to 36 months during follow-up visits at primary healthcare units in the municipality. For the comparisons of categorical variables (evaluation/advices about development in visits of children at different ages), the chi-square test was employed. RESULTS: The mean number of correct responses among physicians was 14.8. The error rate for seven questions was greater than 30% (sensory development, language acquisition, physiology of the nervous system, clinical and laboratory diagnosis of congenital infections and innate errors of metabolism) and the rate of correct responses was greater than 85% for four questions (motor and personal-social development markers, risk factors and genetic syndromes). Regarding practices, in 69 (45%) visits, the doctor asked the mother/caregiver's opinion about the child's development; in 80 (52%), the mother/caregiver said that the doctor assessed the development; and in 64 (42%), the mother/caregiver said that the doctor advised them on practices for child's stimulation. CONCLUSIONS: Faulty knowledge and practices regarding child development were identified among primary care professionals, indicating the need for continued education.OBJETIVO: Avaliar o conhecimento e as práticas sobre desenvolvimento infantil de médicos que atuam em Unidades Básicas de Saúde (UBS). MÉTODO: Estudo transversal, descritivo, realizado nas UBS de Embu (SP). Procedimentos do estudo: 1) avaliação do conhecimento por teste contendo 20 questões de múltipla escolha sobre desenvolvimento da criança aplicado a 31 médicos (universo) que prestam assistência pediátrica em UBS; 2) avaliação das práticas - entrevista semiestruturada aplicada para uma amostra de 154 mães/cuidadores que acompanhavam crianças com idade menor ou igual a 36 meses em consulta médica agendada em UBS do município. Para comparação de variáveis categóricas (avaliação/orientações sobre desenvolvimento em consultas de crianças de diferentes faixas etárias), utizou-se o qui-quadrado. RESULTADOS: A média de acertos dos médicos foi de 14,8 questões; sete questões apresentaram índices de erros superiores a 30% (desenvolvimento sensorial, aquisição de linguagem, fisiologia do sistema nervoso, diagnóstico clínico e laboratorial de infecções congênitas, erros inatos do metabolismo) e quatro questões apresentaram acertos acima de 85% (marcos do desenvolvimento motor, pessoal-social, fatores de risco e síndrome genética). Quanto às práticas, em 69 (45%) consultas o médico perguntou a opinião da mãe/cuidador sobre o desenvolvimento da criança, em 80 (52%) a mãe/cuidador referiu que o médico fez alguma pergunta e/ou avaliou o desenvolvimento e em 64 (42%) orientou sobre como estimular a criança. CONCLUSÕES: Identificaram-se falhas de conhecimento e nas práticas dos profissionais referentes ao desenvolvimento da criança, o que indica a necessidade de implementar educação permanente.UNIFESP Curso de MedicinaUNIFESP Projeto DesenvolverSecretaria Municipal de Saúde do EmbuUNIFESP Departamento de Pediatria Disciplina de Pediatria Geral e ComunitáriaUNIFESP, Curso de MedicinaUNIFESP, Projeto DesenvolverUNIFESP, Depto. de Pediatria Disciplina de Pediatria Geral e ComunitáriaSciEL

BPIFB1 (LPLUNC1) is upregulated in cystic fibrosis lung disease

Although the biology the PLUNC (recently renamed BPI fold, BPIF) family of secreted proteins is poorly understood, multiple array based studies have suggested that some are differentially expressed in lung diseases. We have examined the expression of BPIFB1 (LPLUNC1), the prototypic two-domain containing family member, in lungs from CF patients and in mouse models of CF lung disease. BPIFB1 was localized in CF lung samples along with BPIFA1, MUC5AC, CD68 and NE and directly compared to histologically normal lung tissues and that of bacterial pneumonia. We generated novel antibodies to mouse BPIF proteins to conduct similar studies on ENaC transgenic (ENaC-Tg) mice, a model for CF-like lung disease. Small airways in CF demonstrated marked epithelial staining of BPIFB1 in goblet cells but staining was absent from alveolar regions. BPIFA1 and BPIFB1 were not co-localised in the diseased lungs. In ENaC-Tg mice there was strong staining of both proteins in the airways and luminal contents. This was most marked for BPIFB1 and was noted within 2 weeks of birth. The two proteins were present in distinct cells within epithelium. BPIFB1 was readily detected in BAL from ENaC-Tg mice but was absent from wild-type mice. Alterations in the expression of BPIF proteins is associated with CF lung disease in humans and mice. It is unclear if this elevation of protein production, which results from phenotypic alteration of the cells within the diseased epithelium, plays a role in the pathogenesis of the disease

Primary Decompressive Craniectomy: Effects on Neurocritical Care Management, Long-Term Neurologic Status and Mortality

Objectives: Decompressive craniectomy (DC) is a surgical therapy used to treat patients foreseen to be at risk for high intracranial pressure (ICP). In this retrospective case control study, mortality, ICP values, neurocritical care (NCC) management necessity, and long-term neurologic status were examined in patients treated with DC and in a matched control group. Methods: The primary end-points were all-cause mortality and functional status of NCC patients both at discharge and at a 6 month follow-up. Secondary end-points were ICP values at established time points and the use of advanced NCC therapies. Patients who underwent primary DC were matched with individuals with similar demographic and pre-intervention ICP values who had been treated with standard NCC management alone. Results Neurologic status outcome at discharge and the 6 month follow-up was significantly better in patients treated with DC compared to those in the control group: Glasgow Outcome Scale (GOS) 4-5 in 15 versus 5 patients; p = 0.033, and 16 versus 6 patients, p = 0.033. Mortality at 6 months was similar in the study groups (10 versus 16 patients; p = 0.212). ICP values were similar at NCC admission but were better controlled 24 hours after DC than in the control group. Fewer patients treated with DC needed advanced NCC medical therapies. Conclusions: DC is an effective way to normalize ICP levels while reducing the need for aggressive medical therapies. Survival rate and neurological outcome in patients treated with DC were found to be better than in those receiving only medical treatment

Modulation of the endocannabinoids N-Arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) on Executive Functions in Humans

Animal studies point to an implication of the endocannabinoid system on executive functions. In humans, several studies have suggested an association between acute or chronic use of exogenous cannabinoids (Δ9-tetrahydrocannabinol) and executive impairments. However, to date, no published reports establish the relationship between endocannabinoids, as biomarkers of the cannabinoid neurotransmission system, and executive functioning in humans. The aim of the present study was to explore the association between circulating levels of plasma endocannabinoids N-arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) and executive functions (decision making, response inhibition and cognitive flexibility) in healthy subjects. One hundred and fifty seven subjects were included and assessed with the Wisconsin Card Sorting Test; Stroop Color and Word Test; and Iowa Gambling Task. All participants were female, aged between 18 and 60 years and spoke Spanish as their first language. Results showed a negative correlation between 2-AG and cognitive flexibility performance (r = −.37; p<.05). A positive correlation was found between AEA concentrations and both cognitive flexibility (r = .59; p<.05) and decision making performance (r = .23; P<.05). There was no significant correlation between either 2-AG (r = −.17) or AEA (r = −.08) concentrations and inhibition response. These results show, in humans, a relevant modulation of the endocannabinoid system on prefrontal-dependent cognitive functioning. The present study might have significant implications for the underlying executive alterations described in some psychiatric disorders currently associated with endocannabinoids deregulation (namely drug abuse/dependence, depression, obesity and eating disorders). Understanding the neurobiology of their dysexecutive profile might certainly contribute to the development of new treatments and pharmacological approaches

Continuous Positive Airway Pressure effect on visual acuity in patients with type 2 diabetes and Obstructive Sleep Apnoea: a multicentre randomised controlled trial

Objective: We sought to establish whether CPAP for OSA in people with type 2 diabetes and diabetic macular oedema (DME) improved visual acuity. Methods: We randomly assigned 131 eligible patients aged 30–85 years from 23 UK centres with significant DME causing visual impairment (LogMAR letters identified, ≥ 39–≤ 78, score 0.92–0.14) plus severe OSA on screening to either: usual ophthalmology care (n=67) or usual ophthalmology care plus CPAP (n=64) for 12 months. Results: Mean age of participants was 64 years, 73% male, mean BMI 35.0 kg·m−2. Mean 4% oxygen desaturation index was 36/hour. There was no significant difference in the visual acuity at twelve months between the CPAP group and the control group, mean LogMAR (95%CI) 0.33 (0.29, 0.37) versus 0.31 (0.27, 0.35), p=0.39, and no significant correlation between change in LogMAR and average CPAP use. The median daily CPAP use (sd, range) was 3.33 (2.25, 0–7.93) hours at three months, 3.19 (2.54, 0–8.07) hours at six months and 3.21 (2.7, 0–7.98) hours at twelve months. Conclusion: CPAP therapy for OSA did not improve visual acuity in people with type 2 iabetes and diabetic macular oedema compared to usual care alone over 12 months