Assessing Ozone-Related Health Impacts under a Changing Climate

Climate change may increase the frequency and intensity of ozone episodes in future summers in the United States. However, only recently have models become available that can assess the impact of climate change on O(3) concentrations and health effects at regional and local scales that are relevant to adaptive planning. We developed and applied an integrated modeling framework to assess potential O(3)-related health impacts in future decades under a changing climate. The National Aeronautics and Space Administration–Goddard Institute for Space Studies global climate model at 4° × 5° resolution was linked to the Penn State/National Center for Atmospheric Research Mesoscale Model 5 and the Community Multiscale Air Quality atmospheric chemistry model at 36 km horizontal grid resolution to simulate hourly regional meteorology and O(3) in five summers of the 2050s decade across the 31-county New York metropolitan region. We assessed changes in O(3)-related impacts on summer mortality resulting from climate change alone and with climate change superimposed on changes in O(3) precursor emissions and population growth. Considering climate change alone, there was a median 4.5% increase in O(3)-related acute mortality across the 31 counties. Incorporating O(3) precursor emission increases along with climate change yielded similar results. When population growth was factored into the projections, absolute impacts increased substantially. Counties with the highest percent increases in projected O(3) mortality spread beyond the urban core into less densely populated suburban counties. This modeling framework provides a potentially useful new tool for assessing the health risks of climate change

Intrinsic Thermodynamics of Protein-Ligand Binding by Isothermal Titration Calorimetry as Aid to Drug Design

Isothermal titration calorimetry (ITC) is one of the main techniques to determine specific interactions between molecules dissolved in aqueous solution. This technique is commonly used in drug development programs when low-molecular-weight molecules are sought that bind tightly and specifically to a protein (disease target) molecule. The method allows a complete thermodynamic characterization of an interaction, i.e., ITC enables direct determination of the model-independent observed interaction change in enthalpy (ΔH) and a model-dependent observed interaction affinity (change in Gibbs free energy, ΔG) in a single experiment. The product of temperature and change in entropy (TΔS) can be obtained by the subtraction of ΔG from ΔH, and the change in heat capacity (ΔC p ) can be determined as a slope of the temperature dependence of the binding ΔH. Despite the apparent value of ITC in characterization of interactions, it is often forgotten that many protein-ligand binding reactions are linked to protonation-deprotonation reactions or various conformational changes. In such cases, it is important to determine the linked-reaction contributions and obtain the intrinsic values of the changes in Gibbs energy (affinity), enthalpy, and entropy. These energy values can then be used in various SAR-type structure-thermodynamics and combined with structure-kinetics correlations in drug design, when searching for small molecules that would bind the protein target molecule. This manuscript provides a detailed protocol on how to determine the intrinsic values of protein-ligand binding thermodynamics by ITC

Gender Differences in Emergency Department (ED) Patient Mechanical Fall Risk and Openness to Communication with Providers

Gender Differences in Emergency Department (ED) Patient Mechanical Fall Risk and Openness to Communication with Providers Bryan G Kane, MD, Michael C Nguyen MD, Robert D Barraco, MD MPH, Brian Stello MD, Arnold Goldberg MD, Clare M Lenhart, PhD MPH, Bernadette G Porter BA ,Anita Kurt PhD, RN, Marna Rayl Greenberg DO, MPH Objectives: The CDC reports that among older adults (≥65), falls are the leading cause of injury-related death and rates of fall-related fractures among older women are more than twice those for men. We set out to determine ED patient perceptions (analyzed by gender) about their personal fall risk compared to their actual risk and their comfort level in discussing their fall history or a home safety plan with their healthcare provider. Methods: After IRB approval, a convenience sample of ED patients (50 years or older) was surveyed at a suburban Level 1 Trauma center with an annual ED census of approximately 75,000. The survey included demographics, the Falls Efficacy Scale (FES), and questions about fall risk. The FES is a validated survey measuring concern of falling. Analysis included descriptive statistics and assessment of fall risk and fear of falling by gender using chi-square and t-tests as indicated. Significance was set at 0.05. Results: Of the 150 surveys collected, 149 indicated gender and were included in this analysis. Fifty-five percent of the sample was female (n=82); 45% (n=67) were male. Most (98%) were Caucasian and 22% reported living alone. There was not a difference in the mean age of female participants 69.79 years (SD=12.08) vs. males 68.06 (SD=10.36; p=0.355). See Table 1 for distribution of reported fall risk factors between genders. Collectively, these variables resulted in a mean risk of falling score of 3.37(SD=1.62) out of 9. On average, female participants had a significantly higher objective risk of falling than did male participants (3.65 vs. 3.02 p=0.018). Similarly, females also reported greater fear of falling than did males (FES score 12.33 vs. 9.62; p=0.005). Significantly more females (41.5%) than males (23.9%, p=0.037) reported having fallen in the past year. Of the 50 participants reporting past-year falls, only 19 (12 female and 7 male, p=0.793) sought treatment. The correlation between actual fall risk and fear of falling were greater among females (p The majority of patients (76.4%) were willing to speak to a provider about their fall risk. No significant difference was noted in willingness to discuss this topic with a provider based on gender (p=0.619), objective fall risk (p=0.145) or FES score (p=0.986). Similarly, many respondents indicated a willing to discuss a home safety evaluation with a provider (58.1%) and responses did not vary significantly by gender (p=.140), objective fall risk (p=0.168) or FES score (p=.584). Conclusion: In this study, female ED patients reported a greater fear of falling, had a significantly higher objective risk of falling, and had a higher correlation between their perceived risk and actual risk of falling than did males. The majority of both genders were amenable to discussing their fall risk and a home safety evaluation with their provider

Modified CAGE as a Screening Tool for Mechanical Fall Risk Assessment: A Pilot Survey

Modified CAGE as a Screening Tool for Mechanical Fall Risk Assessment: A Pilot Survey Marna Rayl Greenberg DO, MPH, Michael C Nguyen MD, Bernadette G Porter BA,Robert DBarraco, MD MPH, Brian Stello MD, Arnold Goldberg MD, Clare M Lenhart, PhD MPH,Anita Kurt PhD, RN, Bryan G Kane, MD Background: Falls in the elderly cause serious injury. The literature does not hold answers to patient perceptions about their personal fall risk, their comfort level in discussing their fall history, or a home safety plan with their healthcare provider. Existing risk-assessing tools may be prohibitive in the Emergency Department due to their length and complexity. Objective: We piloted a modified CAGE screen (Fig1) to identify adults at risk for falls. Methods: At a community health event, a convenience sample ofparticipants (50 years or older) was surveyed. The survey included demographics, the Falls Efficacy Scale (FES), the modified CAGEand questions about fall risk.The FES is a validated, but longer, survey metric for comparison. A modified CAGE score greater than or equal to 1 was considered positive. Analysis included descriptive statistics and modified CAGE groups were compared by gender, fall risk and history with chi-square. Results: One hundred sevensubjects (66.4%female, 32.7% male) with a mean age of 66 (SD7.9)participated; 98 (91.6%)were Caucasian. Twenty (18.7%) lived alone,43 (40.2%) had a cat or dog, and 91 (85%) had stairs at home. Six (5.6%) reported using assistive devices, 2 (1.9%) at-risk alcohol use; 9 (8.4%)taking blood thinners, 50 (46.7%) taking blood pressure medications, and 22 (20.6%) one or more medications that could make them drowsy. Thirty-threesubjects(30.8%) reported having fallen in the past year; only13 (39.4% of those fallen)sought treatment. Collectively, these variables resulted in a mean risk of falling score of 2.49 (SD=1.36) out of 9. Eleven (31.4%)femalesand27 (38.0%)malesrecorded ≥1 positive responses on the modified CAGE.A modified CAGE positive responsewas significantly greater among those with past-year falls (51.5%) than those without (29.7%), p=0.031.A positive modified CAGE screen was also associated with a higher mean FES score (10.82 v7.83, p More females than males reported past year falls (36.6% vs. 17.1%, p=0.04) yet no difference in fall risk was noted between genders (4.44 vs. 4.26, p=0.506). The proportion of modified CAGE positive participants did not vary between females and males (38% vs. 31%, p=0.505). Of those whoscreened positive on the modified CAGE, 36 (92.3%) reported comfort in speaking to their healthcare provider about their fall risk and 26 (66.7%) in having a home safety evaluation. Conclusions: In this pilot, a positive modified CAGE is associated with both higher FES scores and a willingness to discuss fall risk with a health care provider. The modifiedCAGE may be a usefulbrief screening tool to detect fall risk in adults. Further studies to determine the extent of its utility in an Emergency Department should be considered

Non-cell autonomous influence of the astrocyte system xc− on hypoglycaemic neuronal cell death

Despite longstanding evidence that hypoglycaemic neuronal injury is mediated by glutamate excitotoxicity, the cellular and molecular mechanisms involved remain incompletely defined. Here, we demonstrate that the excitotoxic neuronal death that follows GD (glucose deprivation) is initiated by glutamate extruded from astrocytes via system xc− – an amino acid transporter that imports l-cystine and exports l-glutamate. Specifically, we find that depriving mixed cortical cell cultures of glucose for up to 8 h injures neurons, but not astrocytes. Neuronal death is prevented by ionotropic glutamate receptor antagonism and is partially sensitive to tetanus toxin. Removal of amino acids during the deprivation period prevents – whereas addition of l-cystine restores – GD-induced neuronal death, implicating the cystine/glutamate antiporter, system xc−. Indeed, drugs known to inhibit system xc− ameliorate GD-induced neuronal death. Further, a dramatic reduction in neuronal death is observed in chimaeric cultures consisting of neurons derived from WT (wild-type) mice plated on top of astrocytes derived from sut mice, which harbour a naturally occurring null mutation in the gene (Slc7a11) that encodes the substrate-specific light chain of system xc− (xCT). Finally, enhancement of astrocytic system xc− expression and function via IL-1β (interleukin-1β) exposure potentiates hypoglycaemic neuronal death, the process of which is prevented by removal of l-cystine and/or addition of system xc− inhibitors. Thus, under the conditions of GD, our studies demonstrate that astrocytes, via system xc−, have a direct, non-cell autonomous effect on cortical neuron survival

Bioavailability in soils

The consumption of locally-produced vegetables by humans may be an important exposure pathway for soil contaminants in many urban settings and for agricultural land use. Hence, prediction of metal and metalloid uptake by vegetables from contaminated soils is an important part of the Human Health Risk Assessment procedure. The behaviour of metals (cadmium, chromium, cobalt, copper, mercury, molybdenum, nickel, lead and zinc) and metalloids (arsenic, boron and selenium) in contaminated soils depends to a large extent on the intrinsic charge, valence and speciation of the contaminant ion, and soil properties such as pH, redox status and contents of clay and/or organic matter. However, chemistry and behaviour of the contaminant in soil alone cannot predict soil-to-plant transfer. Root uptake, root selectivity, ion interactions, rhizosphere processes, leaf uptake from the atmosphere, and plant partitioning are important processes that ultimately govern the accumulation ofmetals and metalloids in edible vegetable tissues. Mechanistic models to accurately describe all these processes have not yet been developed, let alone validated under field conditions. Hence, to estimate risks by vegetable consumption, empirical models have been used to correlate concentrations of metals and metalloids in contaminated soils, soil physico-chemical characteristics, and concentrations of elements in vegetable tissues. These models should only be used within the bounds of their calibration, and often need to be re-calibrated or validated using local soil and environmental conditions on a regional or site-specific basis.Mike J. McLaughlin, Erik Smolders, Fien Degryse, and Rene Rietr

Bringing metabolic networks to life: convenience rate law and thermodynamic constraints

BACKGROUND: Translating a known metabolic network into a dynamic model requires rate laws for all chemical reactions. The mathematical expressions depend on the underlying enzymatic mechanism; they can become quite involved and may contain a large number of parameters. Rate laws and enzyme parameters are still unknown for most enzymes. RESULTS: We introduce a simple and general rate law called "convenience kinetics". It can be derived from a simple random-order enzyme mechanism. Thermodynamic laws can impose dependencies on the kinetic parameters. Hence, to facilitate model fitting and parameter optimisation for large networks, we introduce thermodynamically independent system parameters: their values can be varied independently, without violating thermodynamical constraints. We achieve this by expressing the equilibrium constants either by Gibbs free energies of formation or by a set of independent equilibrium constants. The remaining system parameters are mean turnover rates, generalised Michaelis-Menten constants, and constants for inhibition and activation. All parameters correspond to molecular energies, for instance, binding energies between reactants and enzyme. CONCLUSION: Convenience kinetics can be used to translate a biochemical network – manually or automatically - into a dynamical model with plausible biological properties. It implements enzyme saturation and regulation by activators and inhibitors, covers all possible reaction stoichiometries, and can be specified by a small number of parameters. Its mathematical form makes it especially suitable for parameter estimation and optimisation. Parameter estimates can be easily computed from a least-squares fit to Michaelis-Menten values, turnover rates, equilibrium constants, and other quantities that are routinely measured in enzyme assays and stored in kinetic databases

Decoupling property of the supersymmetric Higgs sector with four doublets

In supersymmetric standard models with multi Higgs doublet fields, selfcoupling constants in the Higgs potential come only from the D-terms at the tree level. We investigate the decoupling property of additional two heavier Higgs doublet fields in the supersymmetric standard model with four Higgs doublets. In particular, we study how they can modify the predictions on the quantities well predicted in the minimal supersymmetric standard model (MSSM), when the extra doublet fields are rather heavy to be measured at collider experiments. The B-term mixing between these extra heavy Higgs bosons and the relatively light MSSM-like Higgs bosons can significantly change the predictions in the MSSM such as on the masses of MSSM-like Higgs bosons as well as the mixing angle for the two light CP-even scalar states. We first give formulae for deviations in the observables of the MSSM in the decoupling region for the extra two doublet fields. We then examine possible deviations in the Higgs sector numerically, and discuss their phenomenological implications.Comment: 26 pages, 24 figures, text sligtly modified,version to appear in Journal of High Energy Physic

Testing Yukawa-unified SUSY during year 1 of LHC: the role of multiple b-jets, dileptons and missing E_T

We examine the prospects for testing SO(10) Yukawa-unified supersymmetric models during the first year of LHC running at \sqrt{s}= 7 TeV, assuming integrated luminosity values of 0.1 to 1 fb^-1. We consider two cases: the Higgs splitting (HS) and the D-term splitting (DR3) models. Each generically predicts light gluinos and heavy squarks, with an inverted scalar mass hierarchy. We hence expect large rates for gluino pair production followed by decays to final states with large b-jet multiplicity. For 0.2 fb^-1 of integrated luminosity, we find a 5 sigma discovery reach of m(gluino) ~ 400 GeV even if missing transverse energy, E_T^miss, is not a viable cut variable, by examining the multi-b-jet final state. A corroborating signal should stand out in the opposite-sign (OS) dimuon channel in the case of the HS model; the DR3 model will require higher integrated luminosity to yield a signal in the OS dimuon channel. This region may also be probed by the Tevatron with 5-10 fb^-1 of data, if a corresponding search in the multi-b+ E_T^miss channel is performed. With higher integrated luminosities of ~1 fb^-1, using E_T^miss plus a large multiplicity of b-jets, LHC should be able to discover Yukawa-unified SUSY with m(gluino) up to about 630 GeV. Thus, the year 1 LHC reach for Yukawa-unified SUSY should be enough to either claim a discovery of the gluino, or to very nearly rule out this class of models, since higher values of m(gluino) lead to rather poor Yukawa unification.Comment: 32 pages including 31 EPS figure