Growth and passivation of individual carbon nanoparticles by C2H2 addition at high temperatures: Dependence of growth rate and evolution on material and size.

Absolute kinetics for reactions of C2H2 with a series of ∼60 individual carbon nanoparticles (NPs) from graphite, graphene, graphene oxide, carbon black, diamond, and nano-onion feedstocks were measured for temperatures (TNP) ranging from 1200 to 1700 K. All the NPs were observed to gain mass by carbon addition under conditions that varied with feedstock but with large variations in initial growth rate. Long reaction periods were studied to allow the evolution of growth rates over time to be observed. Diamond NPs were found to passivate against C2H2 addition if heated above ∼1400 K, and the highly variable initial reactivity for carbon nano-onions was found to depend on the presence of non-onion-structure surface carbon. For graphitic and carbon black NPs, three distinct growth modes were observed, correlated with the initial NP mass (Minitial). Smallest graphitic and carbon black NPs, with masses <∼25 MDa, initially grew rapidly but also passivated quickly after adding <4% of Minitial. NPs in the 20-50 MDa range also passivated but only after multiple waves of fast growth separated by periods of low reactivity, with up to ∼11% total mass gain before passivation. The largest carbon black and graphitic NPs, with Minitial >50 MDa, grew rapidly and continuously, adding up to ∼300% of Minitial with no sign of rate slowing as long as C2H2 was present. The efficiencies for C2H2 addition and etching by O2 are strongly correlated, but the correlation changes as the NPs passivate. Growth and passivation mechanisms are discussed.

High-Temperature Oxidation of Single Carbon Nanoparticles: Dependence on the Surface Structure and Probing Real-Time Structural Evolution via Kinetics.

O2 oxidation and sublimation kinetics for >30 individual nanoparticles (NPs) of five different feedstocks (graphite, graphene oxide, carbon black, diamond, and nano-onion) were measured using single-NP mass spectrometry at temperatures (TNP) in the 1100-2900 K range. It was found that oxidation, studied in the 1200-1600 K range, is highly sensitive to the NP surface structure, with etching efficiencies (EEO2) varying by up to 4 orders of magnitude, whereas sublimation rates, significant only for TNP ≥ ∼1700 K, varied by only a factor of ∼3. Its sensitivity to the NP surface structure makes O2 etching a good real-time structure probe, which was used to follow the evolution of the NP surface structures over time as they were either etched or annealed at high TNP. All types of carbon NPs were found to have initial EEO2 values in the range near 10-3 Da/O2 collision, and all eventually evolved to become essentially inert to O2 (EEO2 < 10-6 Da/O2 collision); however, the dependence of EEO2 on time and mass loss was very different for NPs from different feedstocks. For example, diamond NPs evolved rapidly and monotonically toward inertness, and evolution occurred in both oxidizing and inert atmospheres. In contrast, graphite NPs evolved only under oxidizing conditions and were etched with complex time dependence, with multiple waves of fast but non-monotonic etching separated by periods of near-inertness. Possible mechanisms to account for the complex etching behavior are proposed.

Eltrombopag as frontline treatment of aplastic anaemia in routine practice: implications on cost and efficacy.

The thrombopoietin mimetic eltrombopag (EPAG) is efficacious in clinical trials of newly diagnosed moderate (M), severe (S) and very severe (vS) aplastic anaemia (AA). Its use in routine practice and resource-constrained settings is not well described. Twenty-five men and 38 women at a median age of 54 (18-86) years with newly diagnosed AA treated consecutively in a 7-year period with EPAG (N = 6), EPAG/cyclosporine (CsA) (N = 33) and EPAG/CsA/anti-thymocyte globulin (ATG) (N = 24) were analyzed. Because EPAG was not reimbursed, peak doses ranged from 25 to 200 mg/day depending on affordability. EPAG/CsA-treated patients were older (median age: 61 years) with less severe AA (MAA, N = 15; SAA, N = 14; vSAA, N = 4), whereas EPAG/CsA/ATG-treated patients were younger (median age: 44 years) with more severe AA (MAA, N = 2; SAA, N = 12, vSAA, N = 10). The overall/trilineage response rates were 83%/50% for EPAG-treated patients; 79%/42% for EPAG/CsA-treated patients and 75%/63% for EPAG/CsA/ATG-treated patients. Adverse events included grade 1 liver derangement (N = 7) and grade 1 dyspepsia (N = 3). The 5-year overall survivals/failure-free survivals were 62%/80% for the entire cohort; 55%/75% for EPAG/CsA-treated patients and 82%/78% for EPAG/CsA/ATG-treated patients. EPAG showed robust efficacy in AA in routine practice. However, EPAG dosage and combinations remain to be optimized for AA of different severities.

Sublimation Kinetics for Individual Graphite and Graphene Nanoparticles (NPs): NP-to-NP Variations and Evolving Structure-Kinetics and Structure-Emissivity Relationships.

A single nanoparticle (NP) mass spectrometry method was used to measure sublimation rates as a function of nanoparticle temperature (TNP) for sets of individual graphite and graphene NPs. Initially, the NP sublimation rates were ∼400 times faster than those for bulk graphite, and there were large NP-to-NP variations. Over time, the rates slowed substantially, though they remained well above the bulk rate. The initial activation energies (Ea values) were correspondingly low and doubled, as a few monolayers worth of material was sublimed from the surfaces. The high initial rates and low Ea values are attributed to large numbers of edge, defect, and other low coordination sites on the NP surfaces, and the changes are attributed to atomic-scale "smoothing" of the surface by preferential sublimation of the less stable sites. The emissivity of the NPs also changed after heating, more frequently increasing. The emissivity and sublimation rates were anticorrelated, leading to the conclusion that high densities of low-coordination sites on the NP surfaces enhance sublimation but suppress emissivity.

A mesoscale connectome of the mouse brain.

Comprehensive knowledge of the brain's wiring diagram is fundamental for understanding how the nervous system processes information at both local and global scales. However, with the singular exception of the C. elegans microscale connectome, there are no complete connectivity data sets in other species. Here we report a brain-wide, cellular-level, mesoscale connectome for the mouse. The Allen Mouse Brain Connectivity Atlas uses enhanced green fluorescent protein (EGFP)-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain. This systematic and standardized approach allows spatial registration of individual experiments into a common three dimensional (3D) reference space, resulting in a whole-brain connectivity matrix. A computational model yields insights into connectional strength distribution, symmetry and other network properties. Virtual tractography illustrates 3D topography among interconnected regions. Cortico-thalamic pathway analysis demonstrates segregation and integration of parallel pathways. The Allen Mouse Brain Connectivity Atlas is a freely available, foundational resource for structural and functional investigations into the neural circuits that support behavioural and cognitive processes in health and disease.

Thermal emission spectroscopy for single nanoparticle temperature measurement: optical system design and calibration.

We discuss the design of an optical system that allows measurement of 600-1650 nm emission spectra for individual nanoparticles (NPs), laser-heated in an electrodynamic trap in controlled atmospheres. An approach to calibration of absolute intensity versus wavelength for very low emission intensities is discussed, and examples of NP graphite and carbon black spectra are used to illustrate the methodology.

Exploration and visualization of connectivity in the adult mouse brain.

The Allen Mouse Brain Connectivity Atlas is a mesoscale whole brain axonal projection atlas of the C57Bl/6J mouse brain. All data were aligned to a common template in 3D space to generate a comprehensive and quantitative database of inter-areal and cell-type-specific projections. A suite of computational tools were developed to search and visualize the projection labeling experiments, available at http://connectivity.brain-map.org. We present three use cases illustrating how these publicly-available tools can be used to perform analyses of long range brain region connectivity. The use cases make extensive use of advanced visualization tools integrated with the atlas including projection density histograms, 3D computed anterograde and retrograde projection paths, and multi-specimen projection composites. These tools offer convenient access to detailed axonal projection information in the adult mouse brain and the ability to perform data analysis and visualization of projection fields and neuroanatomy in an integrated manner.

Neuroinformatics of the Allen Mouse Brain Connectivity Atlas.

The Allen Mouse Brain Connectivity Atlas is a mesoscale whole brain axonal projection atlas of the C57Bl/6J mouse brain. Anatomical trajectories throughout the brain were mapped into a common 3D space using a standardized platform to generate a comprehensive and quantitative database of inter-areal and cell-type-specific projections. This connectivity atlas has several desirable features, including brain-wide coverage, validated and versatile experimental techniques, a single standardized data format, a quantifiable and integrated neuroinformatics resource, and an open-access public online database (http://connectivity.brain-map.org/). Meaningful informatics data quantification and comparison is key to effective use and interpretation of connectome data. This relies on successful definition of a high fidelity atlas template and framework, mapping precision of raw data sets into the 3D reference framework, accurate signal detection and quantitative connection strength algorithms, and effective presentation in an integrated online application. Here we describe key informatics pipeline steps in the creation of the Allen Mouse Brain Connectivity Atlas and include basic application use cases.

Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous system.

The Allen Brain Atlas (http://www.brain-map.org) provides a unique online public resource integrating extensive gene expression data, connectivity data and neuroanatomical information with powerful search and viewing tools for the adult and developing brain in mouse, human and non-human primate. Here, we review the resources available at the Allen Brain Atlas, describing each product and data type [such as in situ hybridization (ISH) and supporting histology, microarray, RNA sequencing, reference atlases, projection mapping and magnetic resonance imaging]. In addition, standardized and unique features in the web applications are described that enable users to search and mine the various data sets. Features include both simple and sophisticated methods for gene searches, colorimetric and fluorescent ISH image viewers, graphical displays of ISH, microarray and RNA sequencing data, Brain Explorer software for 3D navigation of anatomy and gene expression, and an interactive reference atlas viewer. In addition, cross data set searches enable users to query multiple Allen Brain Atlas data sets simultaneously. All of the Allen Brain Atlas resources can be accessed through the Allen Brain Atlas data portal.

Surface-based mapping of gene expression and probabilistic expression maps in the mouse cortex.

The Allen Brain Atlas (ABA, www.brain-map.org) is a genome wide, spatially registered collection of cellular resolution in situ hybridization gene expression image data of the C57Bl/6J mouse brain. Derived from the ABA, the Anatomic Gene Expression Atlas (AGEA, http://mouse.brain-map.org/agea) has demonstrated both laminar and areal spatial gene expression correlations in the mouse cortex. While the mouse cortex is lissencephalic, its curvature and substantial bending in boundary areas renders it difficult to visualize and analyze laminar versus areal effects in a rectilinear coordinate framework. In context of human and non-human primate cortex, surface-based representation has proven useful for understanding relative locations of laminar, columnar, and areal features. In this paper, we describe a methodology for constructing surface-based flatmaps of the mouse cortex that enables mapping of gene expression data from individual genes in the ABA, or probabilistic expression maps from the AGEA, to identify and visualize genetic relationships between layers and areas.

Areal and laminar differentiation in the mouse neocortex using large scale gene expression data.

Although cytoarchitectonic organization of the mammalian cortex into different lamina has been well-studied, identifying the architectural differences that distinguish cortical areas from one another is more challenging. Localization of large anatomical structures is possible using magnetic resonance imaging or invasive techniques (such as anterograde or retrograde tracing), but identifying patterns in gene expression architecture is limited as gene products do not necessarily identify an immediate functional consequence of a specialized area. Expression of specific genes in the mouse and human cortex is most often identified across entire lamina, and areal patterning of expression (when it exists) is most easily differentiated on a layer-by-layer basis. Since cortical organization is defined by the expression of large sets of genes, the task of identifying individual (or groups of structures) cannot be done using individual areal markers. In this manuscript we describe a methodology for clustering gene expression correlation profiles in the C57Bl/6J mouse cortex to identify large-scale genetic relationships between layers and areas. By using the Anatomic Gene Expression Atlas (http://mouse.brain-map.org/agea/) derived from in situ hybridization data in the Allen Brain Atlas, we show that a consistent expression based organization of areal patterning in the mouse cortex exists when clustered on a laminar basis. Surface-based mapping and visualization techniques are used as a representation to clarify these relationships.

Laboratory based surveillance of travel-related Shigella sonnei and Shigella flexneri in Alberta from 2002 to 2007.

Between 2002 and 2007, travel related cases of Shigella sonnei and S. flexneri in Alberta, Canada were acquired from Central America, the Indian subcontinent and North America. Of this group, resistance to ciprofloxacin and nalidixic acid was identified in isolates from patients who had travelled to the Indian subcontinent. This study provides a Canadian perspective to a growing body of literature linking ciprofloxacin and nalidixic acid resistance to travel to the Indian subcontinent.Shigella is a common cause of diarrheal illness in North America with a rate of 2.0 per 100,000 in Canada 1 and a rate of 3.2 per 100,000 in the United States 23. Imported cases of Shigella infections have been reported in developed countries following travel to a foreign or developing country 45 and may be impacted by factors including socio-economic factors 6, food distribution networks 5 and microbiologic factors 7. Across multiple geographic regions, high rates of antimicrobial resistance to multiple agents (e.g. sulfonamides, tetracycline, chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole) have limited the choices for empiric antimicrobial therapy required to manage Shigella infections and reduce fecal excretion of the bacteria 8910 with descriptions of shifting species dominance and changes in antimicrobial susceptibility 1011. Generally, Shigella flexneri and Shigella sonnei are the dominant species and are heavily impacted by changes in antimicrobial susceptibility 1213.This study identifies the global regions associated with travel-related cases of S. flexneri and S. sonnei in Alberta, Canada and compares antibiotic resistance patterns of these isolates for 2002 to 2007 inclusive.Specimens collected 2002-2007 (inclusive) from S. flexneri and S. sonnei infections in Alberta, Canada were included for study. Data collected at time of specimen submission included: date of specimen collection, outbreak association if present, travel history and antibiogram (data source-ProvLab Information Systems; Communicable Disease Report at Alberta Health and Wellness). Outbreaks were defined by public health officials as ≥ 2 epidemiologically related cases. Each outbreak was assigned a unique incident number. Repeat isolates received within six months of original case infections were excluded. Only one representative case for each outbreak was included, unless the isolates had different antibiotic susceptibility patterns. Based on travel history the origin of an isolate was grouped into corresponding regions and continents. Regions included in the study represented major travel destinations for individuals living in Canada. Domestic exposures were defined as "travel within North America."

Importance of performing transesophageal echocardiography in acute stroke patients older than fifty.

BACKGROUND: The purpose of this study was to determine the value of transesophageal echocardiography (TEE) in determining the presence of cardiac manifestations that required anticoagulation in patients presenting with acute stroke. METHODS: Of 626 consecutive stroke patients who underwent TEE, 188 patients with no obvious etiology for stroke were subcategorized according to age. TEE results were analyzed for cardiac findings suggestive of a cause for embolic stroke, including complex atheromas in the arch/ascending aorta, patent foramen ovale (PFO), atrial septal aneurysm (ASA), and intracavitary thrombi. Data were analyzed using Fisher's exact test. RESULTS: Of 188 patients, 66% (125/188) were older than 50 years and 34% (63/188) were younger than 50 years. The incidence of complex atheroma was 12.8% (16/125) in patients older than 50 years as compared to 0% (0/63) in patients who were younger than 50 years (P = 0.002). In patients older than 50 years, findings that indicated a need for anticoagulation based on TEE results were found in 22.4% (28/125) (atheroma = 16, PFO = 12, ASA = 5, thrombus = 3, PFO + ASA = 1) compared to 14.3% (9/63) (atheroma = 0, PFO = 5, ASA = 2, thrombus = 2, PFO + ASA = 1) in patients younger than 50 years. CONCLUSIONS: TEE plays an important role in suspected embolic stroke patients of all age groups. Due to the higher incidence of complex atheromas in patients older than 50 years of age, TEE might be of added importance in identifying the candidates who may benefit from anticoagulation.

A large-scale standardized physiological survey reveals functional organization of the mouse visual cortex.

To understand how the brain processes sensory information to guide behavior, we must know how stimulus representations are transformed throughout the visual cortex. Here we report an open, large-scale physiological survey of activity in the awake mouse visual cortex: the Allen Brain Observatory Visual Coding dataset. This publicly available dataset includes the cortical activity of nearly 60,000 neurons from six visual areas, four layers, and 12 transgenic mouse lines in a total of 243 adult mice, in response to a systematic set of visual stimuli. We classify neurons on the basis of joint reliabilities to multiple stimuli and validate this functional classification with models of visual responses. While most classes are characterized by responses to specific subsets of the stimuli, the largest class is not reliably responsive to any of the stimuli and becomes progressively larger in higher visual areas. These classes reveal a functional organization wherein putative dorsal areas show specialization for visual motion signals.

An anatomic transcriptional atlas of human glioblastoma.

Glioblastoma is an aggressive brain tumor that carries a poor prognosis. The tumor's molecular and cellular landscapes are complex, and their relationships to histologic features routinely used for diagnosis are unclear. We present the Ivy Glioblastoma Atlas, an anatomically based transcriptional atlas of human glioblastoma that aligns individual histologic features with genomic alterations and gene expression patterns, thus assigning molecular information to the most important morphologic hallmarks of the tumor. The atlas and its clinical and genomic database are freely accessible online data resources that will serve as a valuable platform for future investigations of glioblastoma pathogenesis, diagnosis, and treatment.

Neuroinformatics for genome-wide 3D gene expression mapping in the mouse brain.

Large scale gene expression studies in the mammalian brain offer the promise of understanding the topology, networks and ultimately the function of its complex anatomy, opening previously unexplored avenues in neuroscience. High-throughput methods permit genome-wide searches to discover genes that are uniquely expressed in brain circuits and regions that control behavior. Previous gene expression mapping studies in model organisms have employed situ hybridization (ISH), a technique that uses labeled nucleic acid probes to bind to specific mRNA transcripts in tissue sections. A key requirement for this effort is the development of fast and robust algorithms for anatomically mapping and quantifying gene expression for ISH. We describe a neuroinformatics pipeline for automatically mapping expression profiles of ISH data and its use to produce the first genomic scale 3-D mapping of gene expression in a mammalian brain. The pipeline is fully automated and adaptable to other organisms and tissues. Our automated study of over 20,000 genes indicates that at least 78.8 percent are expressed at some level in the adult C56BL/6J mouse brain. In addition to providing a platform for genomic scale search, high-resolution images and visualization tools for expression analysis are available at the Allen Brain Atlas web site (http://www.brain-map.org).

Impact of a Post-Discharge Integrated Disease Management Program on COPD Hospital Readmissions.

BACKGROUND: Readmission following a hospitalization for COPD is associated with significant health-care expenditure. METHODS: A multicomponent COPD post-discharge integrated disease management program was implemented at the Cleveland Clinic to improve the care of patients with COPD and reduce readmissions. This retrospective study reports our experience with the program. Groups of subjects who were exposed to different components of the program were compared regarding their readmission rates. Multivariate logistic regression analysis was performed to build predictive models for 30- and 90-d readmission. RESULTS: One hundred sixty subjects completed a 90-d follow-up, of which, 67 attended the exacerbation clinic, 16 subjects received care coordination, 51 subjects completed both, and 26 subjects did not participate in any component despite referral. Thirty- and 90-d readmission rates for the entire group were 18.1 and 46.2%, respectively. Thirty- and 90-d readmission rates for the individual groups were: exacerbation clinic, 11.9 and 35.8%; care coordination, 25.0 and 50.0%; both, 19.6 and 41.2%; and neither, 26.9 and 80.8%, respectively. The model with the best predictive ability for 30-d readmission risk included the number of hospitalizations within the previous year and use of noninvasive ventilation (C statistic of 0.84). The model for 90-d readmission risk included receiving any component of the post-discharge integrated disease management program, the number of hospitalizations, and primary care physician visits within the previous year (C statistic of 0.87). CONCLUSIONS: Receiving any component of a post-discharge integrated disease management program was associated with reduced 90-d readmission rate. Previous health-care utilization and lung function impairment were strong predictors of readmission.

Mitochondria-targeting cyclometalated iridium(III)-PEG complexes with tunable photodynamic activity.

We present a new class of phosphorescent cyclometalated iridium(III) polypyridine poly(ethylene glycol) (PEG) complexes [Ir(N(^)C)2(bpy-CONH-PEG)](PF6) (bpy-CONH-PEG = 4-(N-(2-(ω-methoxypoly-(1-oxapropyl))ethyl)aminocarbonyl)-4'-methyl-2,2'-bipyridine, number average molecular weight (Mn) = 5272.23, weight average molecular weight (Mw) = 5317.38, polydispersity index (PDI) = 1.009; HN(^)C = 2-phenylpyridine, Hppy (1a), 2-((1,1'-biphenyl)-4-yl)pyridine, Hpppy (2a), 2-phenylquinoline, Hpq (3a), 2-phenylbenzothiazole, Hbt (4a), 2-(1-naphthyl)benzothiazole, Hbsn (5a)). The photophysical, photochemical, and biological properties of these complexes have been compared with those of their PEG-free counterparts [Ir(N(^)C)2(bpy-CONH-Et)](PF6) (bpy-CONH-Et = 4-(N-ethylaminocarbonyl)-4'-methyl-2,2'-bipyridine; HN(^)C = Hppy (1b), Hpppy (2b), Hpq (3b), Hbt (4b), Hbsn (5b)). Upon irradiation, all the complexes exhibited intense and long-lived green to orange-red emission under ambient conditions. The emission was phosphorescence in nature and can be quenched by O2 with the generation of singlet oxygen ((1)O2). The quantum yields for (1)O2 production of the complexes in aerated DMSO (0.24-0.83) were found to be dependent on the excited-state lifetimes of the complexes, which can be altered using different cyclometalating ligands (N(^)C). Cell-based assays indicated that the PEG complexes were noncytotoxic in the dark (IC50 > 300 µM); however, most of them became significantly cytotoxic upon irradiation (IC50 = 3.4 - 23.2 µM). Laser-scanning confocal microscopy images revealed localization of complex 3a in the mitochondrial region of HeLa cells and the induction of rapid necrotic cell death upon light activation. Additionally, the lack of dark toxicity and potential application of the PEG complexes as a visualizing reagent have been demonstrated using zebrafish (Danio rerio) as an animal model.