Stabilization of urinary biogenic amines measured in clinical chemistry laboratories.

Urinary 5-hydroxyindoleacetic acid (5-HIAA), vanillylmandelic (VMA), homovanillic acid (HVA), catecholamines and metanephrines are produced in excess by catecholamine-producing tumors. These biogenic amines are unstable at low or high pH and require hydrochloric acid (HCl) to prevent their degradation. However, HCl addition may result in very low pH causing degradation or deconjugation of several metabolites. This study evaluated the buffering properties of sodium citrate to stabilize all biogenic amines. The metabolite concentrations were measured by LC-MS/MS or by a coulometric assay in 22 urine samples collected native and with HCl or sodium citrate. We studied the effect of pH, time (48 h, four weeks) and storage temperature at 22 °C, 4 °C, and -20 °C. We found that catecholamines degradation was prevented by HCl and citrate and that 5-HIAA was degraded in 5 out of 22 samples collected with HCl. All biogenic amines were efficiently stabilized by citrate for four weeks at 22 °C, except epinephrine (48 h at 4 °C, or four weeks at -20 °C). Sodium citrate did not cause quantification or analytical artefacts concerns. In conclusion, sodium citrate is a non-hazardous alternative to HCl for patients to send unfrozen urine samples to the laboratory which may safely store the sample for four weeks

Disability, Gender and Race: Does Educational Attainment Reduce Earning Disparity for All or Just Some?

Although interest in research on persons with disabilities has grown steadily, these individuals continue to encounter workplace discrimination and remain marginalized and understudied. We draw on human capital and discrimination theories to propose and test hypotheses on the effects of educational attainment on earnings (in)equality for persons with disabilities and the moderating influence of gender and race using 885,950 records, including 40,438 persons with disabilities from the American Community Survey 2015 (United States Census Bureau, 2015). Consistent with human capital theory, we find that persons with disabilities benefit from greater educational attainment, yet consistent with disability discrimination theories, we find evidence that they are less likely to convert educational gains for master’s and higher degrees into earning gains, and consistent with theories on multiple sources of discrimination, we find that women with disabilities may be doubly disadvantaged. These results, however, are mixed and complex. Considering the importance of harnessing diverse talent in organizations, we outline implications for research and practice toward reducing workplace discrimination

Kinetics of neuropeptide Y, catecholamines, and physiological responses during moderate and heavy intensity exercises.

Neuropeptide Y 1-36 (NPY1-36) is a vasoconstrictor peptide co-secreted with norepinephrine (NE) by nerve endings during sympathetic activation. NPY1-36 potentiates NE action post-synaptically through the stimulation of the Y1 receptor, whereas its metabolite NPY3-36 resulting from DPP4 action activates Y2 presynaptic receptors, inhibiting NE and acetylcholine secretion. The secretions of NPY1-36 and NPY3-36 in response to sympathetic nervous system activation have not been studied due to the lack of analytical techniques available to distinguish them. We determined in healthy volunteers NPY1-36, NPY3-36 and catecholamine kinetics and how these neurotransmitters modulate the physiological stress response during and after moderate- and heavy-intensity exercises. Six healthy males participated in this randomized, double-blind, saxagliptin vs placebo crossover study. The volunteers performed an orthostatic test, a 30-min exercise at moderate intensity and a 15-min exercise at heavy intensity each followed by 50 min of recovery in two separate sessions with saxagliptin or placebo. Oxygen consumption (V̇O <sub>2</sub> ), ventilation and heart rate were continuously recorded. NE, epinephrine, NPY1-36 and NPY3-36 were quantified by tandem mass spectrometry. We found that exercise triggers NPY1-36 and NE secretion in an intensity-dependent manner and that NE returns faster to the baseline concentration than NPY1-36 after exercise. NPY3-36 rises during recovery parallel to the decline of NPY1-36. Saxagliptin reverses the NPY1-36/NPY3-36 ratio but does not affect hemodynamics, nor NPY1-36 and catecholamine concentrations. We found that NPY1-36 half-life is considerably shorter than previously established with immunoassays. NPY1-36 and NE secretions are finely regulated to prevent an excessive physiological Y1 stimulating response to submaximal exercise

SafeWeb: A Middleware for Securing Ruby-Based Web Applications

Web applications in many domains such as healthcare and finance must process sensitive data, while complying with legal policies regarding the release of different classes of data to different parties. Currently, software bugs may lead to irreversible disclosure of confidential data in multi-tier web applications. An open challenge is how developers can guarantee these web applications only ever release sensitive data to authorised users without costly, recurring security audits. Our solution is to provide a trusted middleware that acts as a “safety net” to event-based enterprise web applications by preventing harmful data disclosure before it happens. We describe the design and implementation of SafeWeb, a Ruby-based middleware that associates data with security labels and transparently tracks their propagation at different granularities across a multi-tier web architecture with storage and complex event processing. For efficiency, maintainability and ease-of-use, SafeWeb exploits the dynamic features of the Ruby programming language to achieve label propagation and data flow enforcement. We evaluate SafeWeb by reporting our experience of implementing a web-based cancer treatment application and deploying it as part of the UK National Health Service (NHS)

Knowledge-based patient screening for rare and emerging infectious/parasitic diseases: a case study of brucellosis and murine typhus.

Many infectious and parasitic diseases, especially those newly emerging or reemerging, present a difficult diagnostic challenge because of their obscurity and low incidence. Important clues that could lead to an initial diagnosis are often overlooked, misinterpreted, not linked to a disease, or disregarded. We constructed a computer-based decision support system containing 223 infectious and parasitic diseases and used it to conduct a historical intervention study based on field investigation records of 200 cases of human brucellosis and 96 cases of murine typhus that occurred in Texas from 1980 through 1989. Knowledge-based screening showed that the average number of days from the initial patient visit to the time of correct diagnosis was significantly reduced (brucellosis-from 17.9 to 4.5 days, p = 0.0001, murine typhus-from 11.5 to 8.6 days, p = 0.001). This study demonstrates the potential value of knowledge-based patient screening for rare infectious and parasitic diseases

Inelastic Coulomb scattering rates due to acoustic and optical plasmon modes in coupled quantum wires

We report a theoretical study on the inelastic Coulomb scattering rate of an injected electron in two coupled quantum wires in quasi-one-dimensional doped semiconductors. Two peaks appear in the scattering spectrum due to the optical and the acoustic plasmon scattering in the system. We find that the scattering rate due to the optical plasmon mode is similar to that in a single wire but the acoustic plasmon scattering depends crucially on its dispersion relation at small $q$. Furthermore, the effects of tunneling between the two wires are studied on the inelastic Coulomb scattering rate. We show that a weak tunneling can strongly affect the acoustic plasmon scattering.Comment: 6 Postscript figure

Evolutionarily distinct bacteriophage endolysins featuring conserved peptidoglycan cleavage sites protect mice from MRSA infection

Objectives In the light of increasing drug resistance in Staphylococcus aureus, bacteriophage endolysins [peptidoglycan hydrolases (PGHs)] have been suggested as promising antimicrobial agents. The aim of this study was to determine the antimicrobial activity of nine enzymes representing unique homology groups within a diverse class of staphylococcal PGHs. Methods PGHs were recombinantly expressed, purified and tested for staphylolytic activity in multiple in vitro assays (zymogram, turbidity reduction assay and plate lysis) and against a comprehensive set of strains (S. aureus and CoNS). PGH cut sites in the staphylococcal peptidoglycan were determined by biochemical assays (Park-Johnson and Ghuysen procedures) and MS analysis. The enzymes were tested for their ability to eradicate static S. aureus biofilms and compared for their efficacy against systemic MRSA infection in a mouse model. Results Despite similar modular architectures and unexpectedly conserved cleavage sites in the peptidoglycan (conferred by evolutionarily divergent catalytic domains), the enzymes displayed varying degrees of in vitro lytic activity against numerous staphylococcal strains, including cell surface mutants and drug-resistant strains, and proved effective against static biofilms. In a mouse model of systemic MRSA infection, six PGHs provided 100% protection from death, with animals being free of clinical signs at the end of the experiment. Conclusions Our results corroborate the high potential of PGHs for treatment of S. aureus infections and reveal unique antimicrobial and biochemical properties of the different enzymes, suggesting a high diversity of potential applications despite highly conserved peptidoglycan target site

Quantification of serotonin and eight of its metabolites in plasma of healthy volunteers by mass spectrometry.

Serotonin is transformed into melatonin under the control of the light/dark cycle, representing a cornerstone of circadian rhythmicity. Serotonin also undergoes extensive metabolism to produce 5-hydroxyindoleacetic acid (5-HIAA), a biomarker for the diagnosis and monitoring of serotonin secreting neuroendocrine tumors (NETs). While serotonin, melatonin and their metabolites are part of an integrated comprehensive system, human observations about their respective plasma concentrations are still limited. We report here for the first time a multiplex UHPLC-MS/MS assay for the quantification of serotonin, 5-HIAA, 5-hydroxytryptophol (5-HTPL), N-acetyl-serotonin (NAS), Mel, 6-OH-Mel, 5-methoxytryptamine (5-MT), 5-methoxytryptophol (5-MTPL), and 5-methoxyindoleacetic acid (5-MIAA) in human plasma. Analytes were extracted by protein precipitation and solid phase extraction. Plasma concentrations for these analytes were determined in 102 healthy volunteers. The LLOQ of the assay ranges from 2.2 nM for serotonin to 1.0 pM for 6-OH-Mel. This sensitivity enables the quantification of circulating serotonin, 5-HIAA, NAS, Mel, and 5-MIAA, even at their lowest diurnal concentrations. This assay will enable specific, precise and accurate measurement of serotonin, Mel and their metabolites to draw a detailed picture of this complex pineal metabolism, allowing a dynamic understanding of these pathways and providing promising biomarkers and a metabolic signature for serotonin-secreting NETs