Hepatic acute phase response protects the brain from focal inflammation during postnatal window of susceptibility

Perinatal inflammation is known to contribute to neurodevelopmental diseases. Animal models of perinatal inflammation have revealed that the inflammatory response within the brain is age dependent, but the regulators of this variation remain unclear. In the adult, the peripheral acute phase response (APR) is known to be pivotal in the downstream recruitment of leukocytes to the injured brain. The relationship between perinatal brain injury and the APR has not been established. Here, we generated focal inflammation in the brain using interleukin (IL)-1β at postnatal day (P)7, P14, P21 and P56 and studied both the central nervous system (CNS) and hepatic inflammatory responses at 4 h. We found that there is a significant window of susceptibility in mice at P14, when compared to mice at P7, P21 and P56. This was reflected in increased neutrophil recruitment to the CNS, as well as an increase in blood–brain barrier permeability. To investigate phenomena underlying this window of susceptibility, we performed a dose response of IL-1β. Whilst induction of endogenous IL-1β or intercellular adhesion molecule (ICAM)-1 in the brain and induction of a hepatic APR were dose dependent, the recruitment of neutrophils and associated blood–brain barrier breakdown was inversely proportional. Furthermore, in contrast to adult animals, an additional peripheral challenge (intravenous IL-1β) reduced the degree of CNS inflammation, rather than exacerbating it. Together these results suggest a unique window of susceptibility to CNS injury, meaning that suppressing systemic inflammation after brain injury may exacerbate the damage caused, in an age-dependent manner

Obstetric opinions regarding the method of delivery in women that have had surgery for retinal detachment

OBJECTIVES: We sought to determine international obstetric opinions regarding the influence of a history of rhegmatogenous retinal detachment on the management of labour and to review the evidence base. DESIGN: A questionnaire containing closed questions, with pre-coded response opinions, was designed to obtain a cross-section of the obstetric opinions. SETTING: Questionnaires were distributed at the 20th European Congress of Obstetrics and Gynaecology in Lisbon, Portugal. PARTICIPANTS: One hundred questionnaires were distributed among obstetricians attending the congress and 74 agreed to participate. MAIN OUTCOME MEASURES: Participants were asked to state their preferred method of delivery in such patients and the reasons for their recommendation. Furthermore, we questioned whether there was any difference in opinions depending on generation. RESULTS: The majority of respondents (76%) would recommend assisted delivery (either Caesarean section or instrumental delivery), whereas the remaining 24% would advise normal delivery. Generation is not a factor influencing this decision. The majority (58%) based their decision to alter the management of labour on their personal opinion of standard of care. CONCLUSION: The literature shows that there is little evidence to support the belief that previous retinal surgery increases the risk of re-detachment of the retina during spontaneous vaginal delivery. This short survey shows that the majority of an international sample of obstetricians questioned does not share this viewpoint. Therefore, unnecessary interventions may be occurring in otherwise fit women with a history of retinal detachment

Heritability Enrichment Implicates Microglia in Parkinson's Disease Pathogenesis

Objective Understanding how different parts of the immune system contribute to pathogenesis in Parkinson's disease is a burning challenge with important therapeutic implications. We studied enrichment of common variant heritability for Parkinson's disease stratified by immune and brain cell types. Methods We used summary statistics from the most recent meta-analysis of genomewide association studies in Parkinson's disease and partitioned heritability using linkage disequilibrium score regression, stratified for specific cell types, as defined by open chromatin regions. We also validated enrichment results using a polygenic risk score approach and intersected disease-associated variants with epigenetic data and expression quantitative loci to nominate and explore a putative microglial locus. Results We found significant enrichment of Parkinson's disease risk heritability in open chromatin regions of microglia and monocytes. Genomic annotations overlapped substantially between these 2 cell types, and only the enrichment signal for microglia remained significant in a joint model. We present evidence suggesting P2RY12, a key microglial gene and target for the antithrombotic agent clopidogrel, as the likely driver of a significant Parkinson's disease association signal on chromosome 3. Interpretation Our results provide further support for the importance of immune mechanisms in Parkinson's disease pathogenesis, highlight microglial dysregulation as a contributing etiological factor, and nominate a targetable microglial gene candidate as a pathogenic player. Immune processes can be modulated by therapy, with potentially important clinical implications for future treatment in Parkinson's disease. ANN NEUROL 202

Predatory Bacteria: A Potential Ally against Multidrug-Resistant Gram-Negative Pathogens

Multidrug-resistant (MDR) Gram-negative bacteria have emerged as a serious threat to human and animal health. Bdellovibrio spp. and Micavibrio spp. are Gram-negative bacteria that prey on other Gram-negative bacteria. In this study, the ability of Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus to prey on MDR Gram-negative clinical strains was examined. Although the potential use of predatory bacteria to attack MDR pathogens has been suggested, the data supporting these claims is lacking. By conducting predation experiments we have established that predatory bacteria have the capacity to attack clinical strains of a variety of ß-lactamase-producing, MDR Gram-negative bacteria. Our observations indicate that predatory bacteria maintained their ability to prey on MDR bacteria regardless of their antimicrobial resistance, hence, might be used as therapeutic agents where other antimicrobial drugs fail. © 2013 Kadouri et al

Evaluation of quitnow men: An online, men-centered smoking cessation intervention

Background: Men continue to smoke cigarettes in greater numbers than women. There is growing evidence for the value of developing targeted, men-centered health promotion programs. However, few smoking cessation interventions have been designed for men. A gender-specific website, QuitNow Men, was developed based on focus group interview findings, stakeholder feedback, and evidence-based cessation strategies. The website was designed to incorporate a masculine look and feel through the use of images, direct language, and interactive content. Usability experts and end-users provided feedback on navigation and functionality of the website prior to pilot testing. Objectives: The objectives of the pilot study were to describe (1) men’s use and evaluations of the interactive resources and information on the QuitNow Men website, and (2) the potential of QuitNow Men to engage men in reducing and quitting smoking. Methods: A one-group, pretest-posttest study design was used. Men who were interested in quitting were recruited and invited to use the website over a 6-month period. Data were collected via online questionnaires at baseline, 3-month, and 6-month follow-up. A total of 117 men completed the baseline survey. Over half of those (67/117, 57.3%) completed both follow-up surveys. Results: At baseline, participants (N=117) had been smoking for an average of 24 years (SD 12.1) and smoked on average 15 cigarettes a day (SD 7.4). The majority had not previously used a quit smoking website (103/117, 88.0%) or websites focused on men’s health (105/117, 89.7%). At the 6-month follow-up, the majority of men used the QuitNow Men website at least once (64/67, 96%). Among the 64 users, 29 (43%) reported using the website more than 6 times. The men using QuitNow Men agreed or strongly agreed that the website was easy to use (51/64, 80%), the design and images were appealing (42/64, 66%), they intended to continue to use the website (42/64, 66%), and that they would recommend QuitNow Men to others who wanted to quit (46/64, 72%). Participants reported using an average of 8.76 (SD 4.08) of the 15 resources available on the website. At 6-month follow-up, 16 of the 67 participants (24%) had quit, 27 (40%) had reduced their smoking and 24 (36%) had not changed their smoking habits. Repeated measures general linear model showed a significant decrease in the number of cigarettes smoked between the 3-month and 6-month follow-up (F1,63=6.41, P=.01, eta squared=0.09). Number of resources used on the website, quit confidence, nicotine dependence and age significantly predicted number of quit attempts by those still smoking at 6 months (F4,45=2.73, P=.04), with number of resources used being the strongest predictor (P=.02). Conclusions: The results of this research support efforts to integrate gender-sensitive approaches in smoking cessation interventions and indicate that this novel Web-based resource has potential in supporting men’s smoking cessation efforts

Reduced ventricular proliferation in the foetal cortex following maternal inflammation in the mouse

It has been well established that maternal inflammation during pregnancy alters neurological function in the offspring, but its impact on cortical development and long-term consequences on the cytoarchitecture is largely unstudied. Here we report that lipopolysaccharide-induced systemic maternal inflammation in C57Bl/6 mice at embryonic Day 13.5 of pregnancy, as early as 8 h after challenge, caused a significant reduction in cell proliferation in the ventricular zone of the developing cerebral cortex, as revealed by quantification of anti-phospho-Histone H3 immunoreactivity and bromodeoxyuridine pulse labelling. The angle of mitotic cleavage, determined from analysis of haematoxylin and eosin staining, cyclin E1 gene expression and the pattern of β-catenin immunoreactivity were also altered by the challenge, which suggests a change from symmetric to asymmetric division in the radial progenitor cells. Modifications of cortical lamination and gene expression patterns were detected at post-natal Day 8 suggesting prolonged consequences of these alterations during embryonic development. Cellular uptake of proteins from the cerebrospinal fluid was observed in brains from lipopolysaccharide-treated animals in radial progenitor cells. However, the foetal blood–brain barrier to plasma proteins remained intact. Together, these results indicate that maternal inflammation can disrupt the ventricular surface and lead to decreased cellular proliferation. Changes in cell density in Layers IV and V at post-natal Day 8 show that these initial changes have prolonged effects on cortical organization. The possible shift in the fate of progeny and the resulting alterations in the relative cell numbers in the cerebral cortex following a maternal inflammatory response shown here will require further investigation to determine the long-term consequences of inflammation on the development of neuronal circuitry and behaviour

TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex

•TNF deficiency alters the spatial organization of neurogenic zones.•TNF deficiency decreases WNT signaling-related proteins.•TNF deficiency alters neuronal and microglial numbers.•Long-term use of non-selective TNF inhibitors impairs learning and memory.•Long-term use of the soluble TNF selective inhibitor XPro1595 does not affect neurogenesis, learning and memory. Although tumor necrosis factor (TNF) inhibitors are used to treat chronic inflammatory diseases, there is little information about how long-term inhibition of TNF affects the homeostatic functions that TNF maintains in the intact CNS. To assess whether developmental TNF deficiency causes alterations in the naïve CNS, we estimated the number of proliferating cells, microglia, and neurons in the developing neocortex of E13.5, P7 and adult TNF knock out (TNF−/−) mice and wildtype (WT) littermates. We also measured changes in gene and protein expression and monoamine levels in adult WT and TNF−/− mice. To evaluate long-term effects of TNF inhibitors, we treated healthy adult C57BL/6 mice with either saline, the selective soluble TNF inhibitor XPro1595, or the nonselective TNF inhibitor etanercept. We estimated changes in cell number and protein expression after two months of treatment. We assessed the effects of TNF deficiency on cognition by testing adult WT and TNF−/− mice and mice treated with saline, XPro1595, or etanercept with specific behavioral tasks. TNF deficiency decreased the number of proliferating cells and microglia and increased the number of neurons. At the same time, TNF deficiency decreased the expression of WNT signaling-related proteins, specifically Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Frizzled receptor 6 (FZD6). In contrast to XPro1595, long-term inhibition of TNF with etanercept in adult C57BL/6 mice decreased the number of BrdU+ cells in the granule cell layer of the dentate gyrus. Etanercept, but not XPro1595, also impaired spatial learning and memory in the Barnes maze memory test. TNF deficiency impacts the organization of neurogenic zones and alters the cell composition in brain. Long-term inhibition of TNF with the nonselective TNF inhibitor etanercept, but not the soluble TNF inhibitor XPro1595, decreases neurogenesis in the adult mouse hippocampus and impairs learning and memory after two months of treatment