Catalase-Containing Silica Particles as Ultrasound-Based Hydrogen Peroxide Sensors to Determine Infected From Noninfected Fluid Collections in Humans.

OBJECTIVE. Hydrogen peroxide (H2O2) plays a key role in neutrophil oxidative defense against infection. Catalase-containing silica nanoshells are nanoparticles that generate O2 microbubbles imaged with ultrasound in the presence of elevated H2O2. We aimed to determine whether ultrasound-detectable O2 microbubbles produced by catalase-containing silica nanoshells can determine whether fluid collections drained from patients are infected. SUBJECTS AND METHODS. During this HIPAA-compliant, institutional review board-approved study, 52 human fluid samples were collected from clinically required image-guided percutaneous drainage procedures. Catalase-containing silica nanoshells were added to the fluid samples during imaging in real time using a Sequoia-512 15L8-S linear transducer (Siemens Healthcare). Production of detectable microbubbles was graded subjectively as negative (noninfected) or positive (infected) with low, moderate, or high confidence by a single observer blinded to all clinical data. The truth standard was microbiology laboratory culture results. Performance characteristics including ROC curves were calculated. RESULTS. Microbubble detection to distinguish infected from noninfected fluids was 84% sensitive and 72% specific and offered negative and positive predictive values of 89% and 64%, respectively. The AUC was 0.79. Six of nine false-positive samples were peritoneal fluid collections that were all collected from patients with decompensated cirrhosis. CONCLUSION. The presence of elevated H2O2 indicated by microbubble formation in the presence of catalase-containing silica nanoshells is sensitive in distinguishing infected from noninfected fluids and offers a relatively high negative predictive value. False-positive cases may result from noninfectious oxidative stress. Catalase-containing silica nanoshells may constitute a novel point-of-care test performed at time of percutaneous drainage, potentially obviating placement of drains into otherwise sterile collections and minimizing risk of secondary infection or other complication

Adrenal vein sampling for ACTH-producing pheochromocytomas

Adrenocorticotropic hormone (ACTH)-producing pheochromocytoma can cause a variety of clinical manifestations of excess catecholamine and corticosteroid. Anatomic localization of this source of ectopic ACTH is critical to facilitate unilateral adrenalectomy and prevent adrenal insufficiency due to bilateral adrenalectomy. Although nuclear scintigraphy remains the diagnostic gold standard, recent radiotracer supply shortages have necessitated alternative diagnostic paradigms to localize adrenal pheochromocytomas. We present a case where adrenal vein sampling (AVS) was utilized to lateralize an adrenal pheochromocytoma and discuss the approach and nuance as it differs from routine AVS for hyperaldosteronism or hypercortisolism

Migraine: treatments, comorbidities, and quality of life, in the USA

This study sought to characterize the experience of stress, treatment patterns, and medical and disability profile in the migraineur population to better understand how the experience of migraines impacts the social and psychological functioning of this group. A 30-minute self-report survey was presented via a migraine-specific website with data collection occurring between May 15 and June 15, 2012. Recruitment for the study was done through online advertisements. In total, 2,907 individuals began the survey and 2,735 met the inclusion criteria for the study. The sample was predominantly female (92.8%). Migraine-associated stress was correlated with length of time since first onset of symptoms (P \u3c 0.01) and number of symptoms per month (P \u3c 0.01). Disorders related to stress, such as depression (P \u3c 0.01) and anxiety (P \u3c 0.01), were also positively correlated with the measured stress resulting from migraines. Migraine-associated stress must be understood as a multidimensional experience with broader impacts of stress on an individual correlating much more highly with negative mental and physical health profiles. Stress resulting from frequent migraine headaches may contribute to the development of medical and psychological comorbidities and may be a part of a cyclical relationship wherein stress is both a cause and effect of the social and medical impairments brought about by migraine

Data-driven methods for diffusivity prediction in nuclear fuels

The growth rate of structural defects in nuclear fuels under irradiation is intrinsically related to the diffusion rates of the defects in the fuel lattice. The generation and growth of atomistic structural defects can significantly alter the performance characteristics of the fuel. This alteration of functionality must be accurately captured to qualify a nuclear fuel for use in reactors. Predicting the diffusion coefficients of defects and how they impact macroscale properties such as swelling, gas release, and creep is therefore of significant importance in both the design of new nuclear fuels and the assessment of current fuel types. In this article, we apply data-driven methods focusing on machine learning (ML) to determine various diffusion properties of two nuclear fuels, uranium oxide and uranium nitride. We show that using ML can increase, often significantly, the accuracy of predicting diffusivity in nuclear fuels in comparison to current analytical models. We also illustrate how ML can be used to quickly develop fuel models with parameter dependencies that are more complex and robust than what is currently available in the literature. These results suggest there is potential for ML to accelerate the design, qualification, and implementation of nuclear fuels

The role of molecular chaperonins in warm ischemia and reperfusion injury in the steatotic liver: A proteomic study

BACKGROUND: The molecular basis of the increased susceptibility of steatotic livers to warm ischemia/reperfusion (I/R) injury during transplantation remains undefined. Animal model for warm I/R injury was induced in obese Zucker rats. Lean Zucker rats provided controls. Two dimensional differential gel electrophoresis was performed with liver protein extracts. Protein features with significant abundance ratios (p < 0.01) between the two cohorts were selected and analyzed with HPLC/MS. Proteins were identified by Uniprot database. Interactive protein networks were generated using Ingenuity Pathway Analysis and GRANITE software. RESULTS: The relative abundance of 105 proteins was observed in warm I/R injury. Functional grouping revealed four categories of importance: molecular chaperones/endoplasmic reticulum (ER) stress, oxidative stress, metabolism, and cell structure. Hypoxia up-regulated 1, calcium binding protein 1, calreticulin, heat shock protein (HSP) 60, HSP-90, and protein disulfide isomerase 3 were chaperonins significantly (p < 0.01) down-regulated and only one chaperonin, HSP-1was significantly upregulated in steatotic liver following I/R. CONCLUSION: Down-regulation of the chaperones identified in this analysis may contribute to the increased ER stress and, consequently, apoptosis and necrosis. This study provides an initial platform for future investigation of the role of chaperones and therapeutic targets for increasing the viability of steatotic liver allografts

Implementing health research through academic and clinical partnerships : a realistic evaluation of the Collaborations for Leadership in Applied Health Research and Care (CLAHRC)

Background: The English National Health Service has made a major investment in nine partnerships between higher education institutions and local health services called Collaborations for Leadership in Applied Health Research and Care (CLAHRC). They have been funded to increase capacity and capability to produce and implement research through sustained interactions between academics and health services. CLAHRCs provide a natural ‘test bed’ for exploring questions about research implementation within a partnership model of delivery. This protocol describes an externally funded evaluation that focuses on implementation mechanisms and processes within three CLAHRCs. It seeks to uncover what works, for whom, how, and in what circumstances. Design and methods: This study is a longitudinal three-phase, multi-method realistic evaluation, which deliberately aims to explore the boundaries around knowledge use in context. The evaluation funder wishes to see it conducted for the process of learning, not for judging performance. The study is underpinned by a conceptual framework that combines the Promoting Action on Research Implementation in Health Services and Knowledge to Action frameworks to reflect the complexities of implementation. Three participating CLARHCS will provide indepth comparative case studies of research implementation using multiple data collection methods including interviews, observation, documents, and publicly available data to test and refine hypotheses over four rounds of data collection. We will test the wider applicability of emerging findings with a wider community using an interpretative forum. Discussion: The idea that collaboration between academics and services might lead to more applicable health research that is actually used in practice is theoretically and intuitively appealing; however the evidence for it is limited. Our evaluation is designed to capture the processes and impacts of collaborative approaches for implementing research, and therefore should contribute to the evidence base about an increasingly popular (e.g., Mode two, integrated knowledge transfer, interactive research), but poorly understood approach to knowledge translation. Additionally we hope to develop approaches for evaluating implementation processes and impacts particularly with respect to integrated stakeholder involvement

Collaboration and Co-Production of Knowledge in Healthcare: Opportunities and Challenges

Over time there has been a shift, at least in the rhetoric, from a pipeline conceptualisation of knowledge implementation, to one that recognises the potential of more collaboration, co-productive approaches to knowledge production and use. In this editorial, which is grounded in our research and collective experience, we highlight both the potential and challenge with collaboration and co-production. This includes issues about stakeholder engagement, governance arrangements, and capacity and capability for working in a coproductive way. Finally, we reflect on the fact that this approach is not a panacea, but is accompanied by some philosophical and practical challenges

Toward in vivo detection of hydrogen peroxide with ultrasound molecular imaging

We present a new class of ultrasound molecular imaging agents that extend upon the design of micromotors that are designed to move through fluids by catalyzing hydrogen peroxide (H_2O_2) and propelling forward by escaping oxygen microbubbles. Micromotor converters require 62 mm of H_2O_2 to move – 1000-fold higher than is expected in vivo. Here, we aim to prove that ultrasound can detect the expelled microbubbles, to determine the minimum H_2O_2 concentration needed for microbubble detection, explore alternate designs to detect the H_2O_2 produced by activated neutrophils and perform preliminary in vivo testing. Oxygen microbubbles were detected by ultrasound at 2.5 mm H_2O_2. Best results were achieved with a 400–500 nm spherical design with alternating surface coatings of catalase and PSS over a silica core. The lowest detection limit of 10–100 μm was achieved when assays were done in plasma. Using this design, we detected the H2O2 produced by freshly isolated PMA-activated neutrophils allowing their distinction from naïve neutrophils. Finally, we were also able to show that direct injection of these nanospheres into an abscess in vivo enhanced ultrasound signal only when they contained catalase, and only when injected into an abscess, likely because of the elevated levels of H_2O_2 produced by inflammatory mediators

Adaptive remodeling of the bacterial proteome by specific ribosomal modification regulates Pseudomonas infection and niche colonisation

Post-transcriptional control of protein abundance is a highly important, underexplored regulatory process by which organisms respond to their environments. Here we describe an important and previously unidentified regulatory pathway involving the ribosomal modification protein RimK, its regulator proteins RimA and RimB, and the widespread bacterial second messenger cyclic-di-GMP (cdG). Disruption of rimK affects motility and surface attachment in pathogenic and commensal Pseudomonas species, with rimK deletion significantly compromising rhizosphere colonisation by the commensal soil bacterium P. fluorescens, and plant infection by the pathogens P. syringae and P. aeruginosa. RimK functions as an ATP-dependent glutamyl ligase, adding glutamate residues to the C-terminus of ribosomal protein RpsF and inducing specific effects on both ribosome protein complement and function. Deletion of rimK in P. fluorescens leads to markedly reduced levels of multiple ribosomal proteins, and also of the key translational regulator Hfq. In turn, reduced Hfq levels induce specific downstream proteomic changes, with significant increases in multiple ABC transporters, stress response proteins and non-ribosomal peptide synthetases seen for both ΔrimK and Δhfq mutants. The activity of RimK is itself controlled by interactions with RimA, RimB and cdG. We propose that control of RimK activity represents a novel regulatory mechanism that dynamically influences interactions between bacteria and their hosts; translating environmental pressures into dynamic ribosomal changes, and consequently to an adaptive remodeling of the bacterial proteome

Comparison of dot chromosome sequences from D. melanogaster and D. virilis reveals an enrichment of DNA transposon sequences in heterochromatic domains

BACKGROUND: Chromosome four of Drosophila melanogaster, known as the dot chromosome, is largely heterochromatic, as shown by immunofluorescent staining with antibodies to heterochromatin protein 1 (HP1) and histone H3K9me. In contrast, the absence of HP1 and H3K9me from the dot chromosome in D. virilis suggests that this region is euchromatic. D. virilis diverged from D. melanogaster 40 to 60 million years ago. RESULTS: Here we describe finished sequencing and analysis of 11 fosmids hybridizing to the dot chromosome of D. virilis (372,650 base-pairs) and seven fosmids from major euchromatic chromosome arms (273,110 base-pairs). Most genes from the dot chromosome of D. melanogaster remain on the dot chromosome in D. virilis, but many inversions have occurred. The dot chromosomes of both species are similar to the major chromosome arms in gene density and coding density, but the dot chromosome genes of both species have larger introns. The D. virilis dot chromosome fosmids have a high repeat density (22.8%), similar to homologous regions of D. melanogaster (26.5%). There are, however, major differences in the representation of repetitive elements. Remnants of DNA transposons make up only 6.3% of the D. virilis dot chromosome fosmids, but 18.4% of the homologous regions from D. melanogaster; DINE-1 and 1360 elements are particularly enriched in D. melanogaster. Euchromatic domains on the major chromosomes in both species have very few DNA transposons (less than 0.4 %). CONCLUSION: Combining these results with recent findings about RNAi, we suggest that specific repetitive elements, as well as density, play a role in determining higher-order chromatin packaging