Diesel Exhaust Activates & Primes Microglia: Air Pollution, Neuroinflammation, & Regulation of Dopaminergic Neurotoxicity

BACKGROUND: Air pollution is linked to central nervous system disease, but the mechanisms responsible are poorly understood. OBJECTIVES: Here, we sought to address the brain-region-specific effects of diesel exhaust (DE) and key cellular mechanisms underlying DE-induced microglia activation, neuroinflammation, and dopaminergic (DA) neurotoxicity. METHODS: Rats were exposed to DE (2.0, 0.5, and 0 mg/m3) by inhalation over 4 weeks or as a single intratracheal administration of DE particles (DEP; 20 mg/kg). Primary neuron-glia cultures and the HAPI (highly aggressively proliferating immortalized) microglial cell line were used to explore cellular mechanisms. RESULTS: Rats exposed to DE by inhalation demonstrated elevated levels of whole-brain IL-6 (interleukin-6) protein, nitrated proteins, and IBA-1 (ionized calcium-binding adaptor molecule 1) protein (microglial marker), indicating generalized neuroinflammation. Analysis by brain region revealed that DE increased TNFα (tumor necrosis factor-α), IL-1β, IL-6, MIP-1α (macrophage inflammatory protein-1α) RAGE (receptor for advanced glycation end products), fractalkine, and the IBA-1 microglial marker in most regions tested, with the midbrain showing the greatest DE response. Intratracheal administration of DEP increased microglial IBA-1 staining in the substantia nigra and elevated both serum and whole-brain TNFα at 6 hr posttreatment. Although DEP alone failed to cause the production of cytokines and chemokines, DEP (5 μg/mL) pretreatment followed by lipopolysaccharide (2.5 ng/mL) in vitro synergistically amplified nitric oxide production, TNFα release, and DA neurotoxicity. Pretreatment with fractalkine (50 pg/mL) in vitro ameliorated DEP (50 μg/mL)-induced microglial hydrogen peroxide production and DA neurotoxicity. CONCLUSIONS: Together, these findings reveal complex, interacting mechanisms responsible for how air pollution may cause neuroinflammation and DA neurotoxicity

Multiscale Modeling of a Nanoelectromechanical Shuttle

In this article, we report a theoretical analysis of a nanoelectromechanical shuttle based on a multiscale model that combines microscopic electronic structure data with macroscopic dynamics. The microscopic part utilizes a (static) density functional description to obtain the energy levels and orbitals of the shuttling particle together with the forces acting on the particle. The macroscopic part combines stochastic charge dynamics that incorporates the microscopically evaluated tunneling rates with a Newtonian dynamics. We have applied the multiscale model to describe the shuttling of a single copper atom between two gold-like jellium electrodes. We find that energy spectrum and particle surface interaction greatly influence shuttling dynamics; in the specific example that we studied the shuttling is found to involve only charge states Q=0 and Q=+e. The system is found to exhibit two quasi-stable shuttling modes, a fundamental one and an excited one with a larger amplitude of mechanical motion, with random transitions between them.Comment: 9 pages, 9 figure

Diesel Exhaust Activates and Primes Microglia: Air Pollution, Neuroinflammation, and Regulation of Dopaminergic Neurotoxicity

Background: Air pollution is linked to central nervous system disease, but the mechanisms responsible are poorly understood

‘Putting our heads together’: insights into genomic conservation between human and canine intracranial tumors

Numerous attributes render the domestic dog a highly pertinent model for cancer-associated gene discovery. We performed microarray-based comparative genomic hybridization analysis of 60 spontaneous canine intracranial tumors to examine the degree to which dog and human patients exhibit aberrations of ancestrally related chromosome regions, consistent with a shared pathogenesis. Canine gliomas and meningiomas both demonstrated chromosome copy number aberrations (CNAs) that share evolutionarily conserved synteny with those previously reported in their human counterpart. Interestingly, however, genomic imbalances orthologous to some of the hallmark aberrations of human intracranial tumors, including chromosome 22/NF2 deletions in meningiomas and chromosome 1p/19q deletions in oligodendrogliomas, were not major events in the dog. Furthermore, and perhaps most significantly, we identified highly recurrent CNAs in canine intracranial tumors for which the human orthologue has been reported previously at low frequency but which have not, thus far, been associated intimately with the pathogenesis of the tumor. The presence of orthologous CNAs in canine and human intracranial cancers is strongly suggestive of their biological significance in tumor development and/or progression. Moreover, the limited genetic heterogenity within purebred dog populations, coupled with the contrasting organization of the dog and human karyotypes, offers tremendous opportunities for refining evolutionarily conserved regions of tumor-associated genomic imbalance that may harbor novel candidate genes involved in their pathogenesis. A comparative approach to the study of canine and human intracranial tumors may therefore provide new insights into their genetic etiology, towards development of more sophisticated molecular subclassification and tailored therapies in both species

Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences

We report a high-quality draft of the genome sequence of the grey, short-tailed opossum (Monodelphis domestica). As the first metatherian (\u27marsupial\u27) species to be sequenced, the opossum provides a unique perspective on the organization and evolution of mammalian genomes. Distinctive features of the opossum chromosomes provide support for recent theories about genome evolution and function, including a strong influence of biased gene conversion on nucleotide sequence composition, and a relationship between chromosomal characteristics and X chromosome inactivation. Comparison of opossum and eutherian genomes also reveals a sharp difference in evolutionary innovation between protein-coding and non-coding functional elements. True innovation in protein-coding genes seems to be relatively rare, with lineage-specific differences being largely due to diversification and rapid turnover in gene families involved in environmental interactions. In contrast, about 20% of eutherian conserved non-coding elements (CNEs) are recent inventions that postdate the divergence of Eutheria and Metatheria. A substantial proportion of these eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation. ©2007 Nature Publishing Group

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

A hybrid super hydrophilic ceramic membrane and carbon nanotube adsorption process for clean water production and heavy metal removal and recovery in remote locations

A novel hybrid membrane-adsorption process has been developed for the production of clean water supplies. A 0.2 μm ceramic membrane has been functionalised to produce a super-hydrophilic surface on the microfiltration membrane capable of maintaining flux with little or no fouling under normal operating conditions. The adsorbent used is a supported epoxidised carbon nanotube material capable of removing heavy metals from solution. Both the membrane and the adsorbent can be easily cleaned when necessary using only a solution of readily available vinegar. The intended aim for this new water production system is for the production of clean water in remote locations, in disaster relief zones and for humanitarian purposes. Laboratory studies have shown that the membrane is capable of maintaining flux over a significant period of time and even when tested with an extreme foulant (used motor oil) performed admirably. The rejection properties of the membrane are as expected for small pore microfiltration, i.e. microbial contamination is easily removed. The adsorbent was shown to remove heavy metals (Cd, Hg, Ni, Co and Pb) to a very high degree (>99.3% in all cases) and was easily regenerated to almost complete adsorptive capacity. The hybrid-process was briefly deployed to the Rio Las Vacas (Guatemala) as part of a basic feasibility study and the unit performed as expected. No microbial contamination was detected in the permeate and the flux was maintained consistently at one third of the clean water flux. This demonstrates the system is capable of microbial removal and has good antifouling properties

An exploration of the implementation of open disclosure of adverse events in the UK : a scoping review and qualitative exploration

Background: In 2009 the UK National Patient Safety Agency relaunched its Being Open framework to facilitate the open disclosure of adverse events to patients in the NHS. The implementation of the framework has been, and remains, challenging in practice. Aim: The aim of this work was to both critically evaluate and extend the current evidence base relating to open disclosure, with a view to supporting the implementation of a policy of open disclosure of adverse events in the NHS. Methods: This work was conducted in three phases. The first phase comprised two focused systematic literature reviews, one summarising empirical research on the effectiveness of interventions to enhance open disclosure, and a second, broader scoping review, looking at reports of current opinion and practice and wider knowledge. The second phase involved primary qualitative research with the objective of generating new knowledge about UK-based stakeholders' views on their role in and experiences of open disclosure. Stakeholder interviews were analysed using the framework approach. The third phase synthesised the findings from the first two phases to inform and develop a set of short pragmatic suggestions for NHS trust management, to facilitate the implementation and evaluation of open disclosure. Results: A total of 610 papers met the inclusion criteria for the broad review. A large body of literature discussed open disclosure from a number of related, but sometimes conflicted, perspectives. Evidential gaps persist and current practice is based largely on expert consensus rather than evidence. There appears to be a tension between the existing pragmatic guidance and the more in-depth critiques of what being consistent and transparent in health care really means. Eleven papers met the inclusion criteria for the more focused review. There was little evidence for the effectiveness of disclosure alone on organisational or individual outcomes or of interventions to promote and support open disclosure. Interviews with stakeholders identified strong support for the basic principle of being honest with patients or relatives when someone was seriously harmed by health care. In practice however, the issues are complex and there is confusion about a number of issues relating to disclosure policies in the UK. The interviews generated insights into the difficulties perceived within health care at individual and institutional levels, in relation to fully implementing the Being Open guidance. Conclusions: There are several clear strategies that the NHS could learn from to implement and sustain a policy of openness. Literature reviews and stakeholder accounts both identified the potential benefits of a culture that was generally more open (not just retrospectively open about serious harm). Future work could usefully evaluate the impact of disclosure on legal challenges within the NHS, best practice in models of support and training for open disclosure, embedding disclosure conversations in critical incident analysis and disclosure of less serious events

The Prevalence of Sexually Transmitted Infections in Papua New Guinea: A Systematic Review and Meta-Analysis

Patellofemoral osteoarthritis (PF OA) is more prevalent than previously thought and contributes to patient's suffering from knee OA. Synthesis of prevalence data can provide estimates of the burden of PF OA

Pathogenicity and Impact of HLA Class I Alleles in Aplastic Anemia Patients of Different Ethnicities

Acquired aplastic anemia (AA) is caused by autoreactive T cell-mediated destruction of early hematopoietic cells. Somatic loss of human leukocyte antigen (HLA) class I alleles was identified as a mechanism of immune escape in surviving hematopoietic cells of some patients with AA. However, pathogenicity, structural characteristics, and clinical impact of specific HLA alleles in AA remain poorly understood. Here, we evaluated somatic HLA loss in 505 patients with AA from 2 multi-institutional cohorts. Using a combination of HLA mutation frequencies, peptide-binding structures, and association with AA in an independent cohort of 6,323 patients from the National Marrow Donor Program, we identified 19 AA risk alleles and 12 non-risk alleles and established a potentially novel AA HLA pathogenicity stratification. Our results define pathogenicity for the majority of common HLA-A/B alleles across diverse populations. Our study demonstrates that HLA alleles confer different risks of developing AA, but once AA develops, specific alleles are not associated with response to immunosuppression or transplant outcomes. However, higher pathogenicity alleles, particularly HLA-B*14:02, are associated with higher rates of clonal evolution in adult patients with AA. Our study provides insights into the immune pathogenesis of AA, opening the door to future autoantigen identification and improved understanding of clonal evolution in AA