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1.  Chronic Antagonism of the Mineralocorticoid Receptor Ameliorates Hypertension and End Organ Damage in a Rodent Model of Salt-Sensitive Hypertension 
We investigated the effects of chronic mineralocorticoid receptor blockade with eplerenone on the development and progression of hypertension and end organ damage in Dahl salt-sensitive rats. Eplerenone significantly attenuated the progressive rise in systolic blood pressure (SBP) (204 ± 3 vs. 179±3 mmHg, p < 0.05), reduced proteinuria (605.5 ± 29.6 vs. 479.7 ± 26.1 mg/24h, p < 0.05), improved injury scores of glomeruli, tubules, renal interstitium, and vasculature in Dahl salt-sensitive rats fed a high-salt diet. These results demonstrate that mineralocorticoid receptor antagonism provides target organ protection and attenuates the development of elevated blood pressure (BP) in a model of salt-sensitive hypertension.
PMCID: PMC3231850  PMID: 21950654
mineralocorticoid receptor antagonist; hypertension; end organ protection; eplerenone; Dahl salt-sensitive rats
2.  Causes of obvious jaundice in South West Wales 
Gut  2002;51(4):613-614.
PMCID: PMC1773414  PMID: 12235095
jaundice; bilirubin; sepsis; hepatitis; gall stones
3.  The monstrous regiment. 
BMJ : British Medical Journal  1988;297(6655):1041.
PMCID: PMC1834789  PMID: 3142605
5.  Heterogeneity in Intratumor Correlations of 18F-FDG, 18F-FLT, and 61Cu-ATSM PET in Canine Sinonasal Tumors 
Intratumor heterogeneity in biologic properties and in relationships between various phenotypes may present a challenge for biologically targeted therapies. Understanding the relationships between different phenotypes in individual tumor types could help inform treatment selection. The goal of this study was to characterize spatial correlations of glucose metabolism, proliferation, and hypoxia in 2 histologic types of tumors.
Twenty canine veterinary patients with spontaneously occurring sinonasal tumors (13 carcinomas and 7 sarcomas) were imaged with 18F-FDG, 18F-labeled 39-deoxy-39-fluorothymidine (18F-FLT), and 61Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone) (61Cu-ATSM) PET/CT on 3 consecutive days. Precise positioning and immobilization techniques coupled with anesthesia enabled motionless scans with repeatable positioning. Standardized uptake values (SUVs) of gross sarcoma and carcinoma volumes were compared by use of Mann– Whitney U tests. Patient images were rigidly registered together, and intratumor tracer uptake distributions were compared. Voxel-based Spearman correlation coefficients were used to quantify intertracer correlations, and the correlation coefficients of sarcomas and carcinomas were compared. The relative overlap of the highest uptake volumes of the 3 tracers was quantified, and the values were compared for sarcomas and carcinomas.
Large degrees of heterogeneity in SUV measures and phenotype correlations were observed. Carcinoma and sarcoma tumors differed significantly in SUV measures, with carcinoma tumors having significantly higher 18F-FDG maximum SUVs than sarcoma tumors (11.1 vs. 5.0; P = 0.01) as well as higher 61Cu-ATSM mean SUVs (2.6 vs. 1.2; P = 0.02). Carcinomas had significantly higher population-averaged Spearman correlation coefficients than sarcomas in comparisons of 18F-FDG and 18F-FLT (0.80 vs. 0.61; P = 0.02), 18F-FLT and 61Cu-ATSM (0.83 vs. 0.38; P < 0.0001), and 18F-FDG and 61Cu-ATSM (0.82 vs. 0.69; P = 0.04). Additionally, the highest uptake volumes of the 3 tracers had significantly greater overlap in carcinomas than in sarcomas.
The relationships of glucose metabolism, proliferation, and hypoxia were heterogeneous across different tumors, with carcinomas tending to have high correlations and sarcomas having low correlations. Consequently, canine carcinoma tumors are robust targets for therapies that target a single biologic property, whereas sarcoma tumors may not be well suited for such therapies. Histology-specific PET correlations have far-reaching implications for the robustness of biologic target definition.
PMCID: PMC3974156  PMID: 24042031
18F-FDG; 61Cu-ATSM; 18F-FLT; dose painting; heterogeneity
6.  GRIFFIN: A versatile methodology for optimization of protein-lipid interfaces for membrane protein simulations 
As new atomic structures of membrane proteins are resolved, they reveal increasingly complex transmembrane topologies, and highly irregular surfaces with crevices and pores. In many cases, specific interactions formed with the lipid membrane are functionally crucial, as is the overall lipid composition. Compounded with increasing protein size, these characteristics pose a challenge for the construction of simulation models of membrane proteins in lipid environments; clearly, that these models are sufficiently realistic bears upon the reliability of simulation-based studies of these systems. Here, we introduce GRIFFIN, which uses a versatile framework to automate and improve a widely-used membrane-embedding protocol. Initially, GRIFFIN carves out lipid and water molecules from a volume equivalent to that of the protein, so as to conserve the system density. In the subsequent optimization phase GRIFFIN adds an implicit grid-based protein force-field to a molecular dynamics simulation of the pre-carved membrane. In this force-field, atoms inside the implicit protein volume experience an outward force that will expel them from that volume, whereas those outside are subject to electrostatic and van-der-Waals interactions with the implicit protein. At each step of the simulation, these forces are updated by GRIFFIN and combined with the intermolecular forces of the explicit lipid-water system. This procedure enables the construction of realistic and reproducible starting configurations of the protein-membrane interface within a reasonable timeframe and with minimal intervention. GRIFFIN is a standalone tool designed to work alongside any existing molecular dynamics package, such as NAMD or GROMACS.
PMCID: PMC3972769
molecular dynamics; multiscale simulation; transmembrane helix; lipid bilayer; nanodisc
7.  Ceruloplasmin Is a Novel Adipokine Which Is Overexpressed in Adipose Tissue of Obese Subjects and in Obesity-Associated Cancer Cells 
PLoS ONE  2014;9(3):e80274.
Obesity confers an increased risk of developing specific cancer forms. Although the mechanisms are unclear, increased fat cell secretion of specific proteins (adipokines) may promote/facilitate development of malignant tumors in obesity via cross-talk between adipose tissue(s) and the tissues prone to develop cancer among obese. We searched for novel adipokines that were overexpressed in adipose tissue of obese subjects as well as in tumor cells derived from cancers commonly associated with obesity. For this purpose expression data from human adipose tissue of obese and non-obese as well as from a large panel of human cancer cell lines and corresponding primary cells and tissues were explored. We found expression of ceruloplasmin to be the most enriched in obesity-associated cancer cells. This gene was also significantly up-regulated in adipose tissue of obese subjects. Ceruloplasmin is the body's main copper carrier and is involved in angiogenesis. We demonstrate that ceruloplasmin is a novel adipokine, which is produced and secreted at increased rates in obesity. In the obese state, adipose tissue contributed markedly (up to 22%) to the total circulating protein level. In summary, we have through bioinformatic screening identified ceruloplasmin as a novel adipokine with increased expression in adipose tissue of obese subjects as well as in cells from obesity-associated cancers. Whether there is a causal relationship between adipose overexpression of ceruloplasmin and cancer development in obesity cannot be answered by these cross-sectional comparisons.
PMCID: PMC3968011  PMID: 24676332
8.  Feasibility and repeatability for in vivo measurements of stiffness gradients in the canine gastrocnemius tendon using an acoustoelastic strain gauge 
B-mode ultrasound is an established imaging modality for evaluating canine tendon injury. However, full extent of tendon injury often remains difficult to estimate, as small changes in sonographic appearance are associated with large changes in biomechanical strength. The acoustoelastic strain gauge (ASG) is an ultrasound-based tissue evaluation technique that relates the change in echo intensity observed during relaxation or stretching of tendons to the tissue’s mechanical properties. This technique deduces stiffness gradient (the rate of change of normalized stiffness as a function of tissue strain) by analyzing the ultrasound dynamic images captured from gradually deforming tissue. Acoustoelastic strain gauge has been proven to accurately model strain and stiffness within tendons in vitro. To determine the feasibility and repeatability for in vivo ASG measurements of canine tendon function, stiffness gradients for the gastrocnemius tendons of ten clinically normal dogs were recorded by two non-independent observers at three sites (musculotendinous junction, mid tendon, and insertion). Average stiffness gradient indices (0.0132, 0.0141, 0.0136) and dispersion values (0.0053, 0.0054, 0.0057) for each site, respectively, were consistent with published mechanical properties for normal canine tendon. Mean differences of the average stiffness gradient index and dispersion value between observers and between limbs for each site were less than 16%. Using interclass coefficients (ICC), intraobserver (ICC 0.79–0.98) and interobserver (ICC 0.77–0.95) reproducibility was good to excellent. Right and left limb values were symmetric (ICC 0.74–0.92). Findings from this study indicated that ASG is a feasible and repeatable technique for measuring stiffness gradients in canine tendons.
PMCID: PMC3962655  PMID: 23663072
9.  Pilgrimage to Wellness: An Exploratory Report of Rural African American Clergy Perceptions of Church Health Promotion Capacity 
Churches serve a vital role in African American communities and may be effective vehicles for health promotion in rural areas where disease burden is disproportionately greater and healthcare access is more limited than other communities. Endorsement by church leadership is often necessary for the approval of programs and activities within churches; however, little is known about how church leaders perceive their respective churches as health promotion organizations. The purpose of this exploratory pilot was to report perceptions of church capacity to promote health among African American clergy leaders of predominantly African American rural churches. The analysis sample included 27 pastors of churches in Eastern NC who completed a survey on church health promotion capacity and perceived impact on their own health. Capacities assessed included perceived need and impact of health promotion activities, church preparedness to promote health, health promotion actions to take, and the existence and importance of health ministry attributes. The results from this pilot study indicated a perceived need to increase the capacity of their churches to promote health. Conducting health programs, displaying health information, collaborations within the church (i.e., kitchen committee working with the health ministry), partnerships outside of the church, and funding were most commonly reported needed capacities. Findings from this exploratory work lay the foundation for the development of future, larger observational studies that can specify some of the key factors associated with organizational change and ultimately health promotion in these rural church settings.
PMCID: PMC3947504  PMID: 22694157
clergy; African American; health promotion; churches; capacity
10.  Qualitative Development of the PROMIS® Pediatric Stress Response Item Banks 
Journal of Pediatric Psychology  2012;38(2):173-191.
Objective To describe the qualitative development of the Patient-Reported Outcome Measurement Information System (PROMIS®) Pediatric Stress Response item banks. Methods Stress response concepts were specified through a literature review and interviews with content experts, children, and parents. A library comprising 2,677 items derived from 71 instruments was developed. Items were classified into conceptual categories; new items were written and redundant items were removed. Items were then revised based on cognitive interviews (n = 39 children), readability analyses, and translatability reviews. Results 2 pediatric Stress Response sub-domains were identified: somatic experiences (43 items) and psychological experiences (64 items). Final item pools cover the full range of children’s stress experiences. Items are comprehensible among children aged ≥8 years and ready for translation. Conclusions Child- and parent-report versions of the item banks assess children’s somatic and psychological states when demands tax their adaptive capabilities.
PMCID: PMC3579165  PMID: 23124904
child; cognitive interviews; patient-reported outcomes; perceived stress; PROMIS; self-report; stress experiences
11.  Using electronic referral with digital imaging between primary and secondary ophthalmic services: a long term prospective analysis of regional service redesign 
Eye  2012;27(3):392-397.
Demands on publicly funded ophthalmic services worldwide continue to increase with new treatments, waiting time targets, working time limits, and restricted budgets. These highlight the necessity to develop innovative ways of utilising existing capacity more effectively.
A new regional, fully electronic ophthalmic-referral service with digital imaging was trialled using existing information-technology (IT) infrastructure. Following successful pilot study, the service was rolled out regionally. Service delivery data was prospectively collated for all the attendances in the year prior to (2006) and the year following (2008) introduction.
Comparing 2006 against 2008, median waiting times reduced (14 vs 4 weeks), and fewer new patients were observed (8714 vs 7462 P<0.0001), with 1359 referrals receiving electronic diagnosis (e-diagnosis). New patient did not arrive (635 vs 503 P<0.0001) and emergencies also reduced (2671 v 1984 P<0.0001).
Novel use of existing IT infrastructure improves communication between primary and secondary care. This promotes more effective use of limited outpatient capacity by retaining patients with non-progressive, asymptomatic pathology in the community, whilst fast-tracking patients with sight-threatening disease. Resultant significant, sustained improvements in regional service delivery point to a simple model that could easily be adopted by other providers of universal healthcare globally.
PMCID: PMC3597880  PMID: 23258310
telemedicine; imaging; diagnostic tests/investigation
12.  Relationship between Ceftolozane-Tazobactam Exposure and Drug Resistance Amplification in a Hollow-Fiber Infection Model 
In an era of rapidly emerging antimicrobial-resistant bacteria, it is critical to understand the importance of the relationships among drug exposure, duration of therapy, and selection of drug resistance. Herein we describe the results of studies designed to determine the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. The challenge isolate was a CTX-M-15-producing Escherichia coli isolate genetically engineered to transcribe a moderate level of blaCTX-M-15. This organism's blaCTX-M-15 transcription level was confirmed by relative quantitative reverse transcription-PCR (qRT-PCR), β-lactamase hydrolytic assays, and a ceftolozane MIC value of 16 mg/liter. In these studies, the experimental duration (10 days), ceftolozane-tazobactam dose ratio (2:1), and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The ceftolozane-tazobactam doses studied ranged from 125-62.5 to 1,500-750 mg. Negative- and positive-control arms included no treatment and piperacillin-tazobactam at 4.5 g every 6 h, respectively. An inverted-U-shaped function best described the relationship between bacterial drug resistance amplification and drug exposure. The least- and most-intensive ceftolozane-tazobactam dosing regimens, i.e., 125-62.5, 750-375, 1,000-500, and 1,500-750 mg, did not amplify drug resistance, while drug resistance amplification was observed with intermediate-intensity dosing regimens (250-125 and 500-250 mg). For the intermediate-intensity ceftolozane-tazobactam dosing regimens, the drug-resistant subpopulation became the dominant population by days 4 to 6. The more-intensive ceftolozane-tazobactam dosing regimens (750-375, 1,000-500, and 1,500-750 mg) not only prevented drug resistance amplification but also virtually sterilized the model system. These data support the selection of ceftolozane-tazobactam dosing regimens that minimize the potential for on-therapy drug resistance amplification.
PMCID: PMC3754319  PMID: 23774429
13.  A Gammaherpesvirus Bcl-2 Ortholog Blocks B Cell Receptor-Mediated Apoptosis and Promotes the Survival of Developing B Cells In Vivo 
PLoS Pathogens  2014;10(2):e1003916.
Gammaherpesviruses such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV, HHV-8) establish lifelong latency in their hosts and are associated with the development of several types of malignancies, including a subset of B cell lymphomas. These viruses are thought to co-opt the process of B cell differentiation to latently infect a fraction of circulating memory B cells, resulting in the establishment of a stable latency setpoint. However, little is known about how this infected memory B cell compartment is maintained throughout the life of the host. We have previously demonstrated that immature and transitional B cells are long-term latency reservoirs for murine gammaherpesvirus 68 (MHV68), suggesting that infection of developing B cells contributes to the maintenance of lifelong latency. During hematopoiesis, immature and transitional B cells are subject to B cell receptor (BCR)-mediated negative selection, which results in the clonal deletion of autoreactive B cells. Interestingly, numerous gammaherpesviruses encode homologs of the anti-apoptotic protein Bcl-2, suggesting that virus inhibition of apoptosis could subvert clonal deletion. To test this, we quantified latency establishment in mice inoculated with MHV68 vBcl-2 mutants. vBcl-2 mutant viruses displayed a marked decrease in the frequency of immature and transitional B cells harboring viral genome, but this attenuation could be rescued by increased host Bcl-2 expression. Conversely, vBcl-2 mutant virus latency in early B cells and mature B cells, which are not targets of negative selection, was remarkably similar to wild-type virus. Finally, in vivo depletion of developing B cells during chronic infection resulted in decreased mature B cell latency, demonstrating a key role for developing B cells in the maintenance of lifelong latency. Collectively, these findings support a model in which gammaherpesvirus latency in circulating mature B cells is sustained in part through the recurrent infection and vBcl-2-mediated survival of developing B cells.
Author Summary
Gammaherpesviruses such as Epstein-Barr virus and Kaposi's sarcoma herpesvirus are widespread pathogens that establish lifelong infections in a dormant state termed latency. Although most gammaherpesvirus infections are asymptomatic, infection of some individuals leads to the development of B cell lymphoma or other cancers. It is well known that during latency these viruses reside in mature B cells of the immune system; however, little is known about how this reservoir is maintained for life. Using murine gammaherpesvirus 68 infection of mice as a model to study gammaherpesvirus infections inside a living host, we have previously demonstrated that gammaherpesviruses can infect early precursors of B cells. In normal situations, the differentiation of such precursors into mature B cells is a tightly regulated process that leads to the death of cells that react inappropriately to host tissues. Here though, we demonstrate that a gammaherpesvirus protein called vBcl-2 can block the death of infected precursor B cells, and that vBcl-2 is critical for infection of these cells. Finally, we show that depleting precursor B cells reduces mature B cell latency. Together, these data suggest that vBcl-2 proteins play a key role in lifelong gammaherpesvirus latency and may be a potent target for future drug development.
PMCID: PMC3916410  PMID: 24516386
14.  Health and School Outcomes During Children’s Transition into Adolescence 
Normative biopsychosocial stressors that occur during entry into adolescence can affect school performance. As a set of resources for adapting to life’s challenges, health may buffer a child from these potentially harmful stressors. This study examined the associations between health (measured as well-being, functioning, symptoms, and chronic conditions) and school outcomes among children aged 9 to 13 years in 4th to 8th grades.
We conducted a prospective cohort study of 1,479 children from 34 schools followed from 2006 to 2008. Survey data were obtained from children and their parents, and school records were abstracted. Measures of child self-reported health were dichotomized to indicate presence of a health asset. Outcomes included attendance, grade point average, state achievement test scores, and child-reported school engagement and teacher connectedness.
Both the transition into middle school and puberty had independent, negative influences on school outcomes. Chronic health conditions that affected children’s functional status were associated with poorer academic achievement. The number of health assets that a child possessed was positively associated with school outcomes. Low levels of negative stress experiences and high physical comfort had positive effects on teacher connectedness, school engagement, and academic achievement, whereas bullying and bully victimization negatively affected these outcomes. Children with high life satisfaction were more connected with teachers, more engaged in schoolwork, and earned higher grades than those who were less satisfied.
Good health may buffer children from the potentially negative effects of school and pubertal transitions on academic success as children enter adolescence.
PMCID: PMC3552248  PMID: 23332483
health; subjective well-being; children with special health care needs; student engagement; academic achievement; bullying; school performance; middle childhood; adolescence
15.  Genotype Modulates Age-Related Alterations in Sensitivity to the Aversive Effects of Ethanol: An 8 Inbred Strain Analysis of Conditioned Taste Aversion 
Genes, brain, and behavior  2012;12(1):70-77.
Adolescent individuals display altered behavioral sensitivity to ethanol, which may contribute to the increased ethanol consumption seen in this age-group. However, genetics also exert considerable influence on both ethanol intake and sensitivity. Thus far there is little research assessing the combined influence of developmental and genetic alcohol sensitivities. Sensitivity to the aversive effects of ethanol using a conditioned taste aversion (CTA) procedure was measured during both adolescence (P30) and adulthood (P75) in 8 inbred mouse strains (C57BL/6J, DBA/2J, 129S1/SvImJ, A/J, BALB/cByJ, BTBR T+tf/J, C3H/HeJ, and FVB/NJ). Adolescent and adult mice were water deprived, and subsequently provided with access to 0.9% (v/v) NaCl solution for 1h. Immediately following access mice were administered ethanol (0, 1.5, 2.25, 3g/kg, ip). This procedure was repeated in 72h intervals for a total of 5 CTA trials. Sensitivity to the aversive effects of ethanol was highly dependent upon both strain and age. Within an inbred strain, adolescent animals were consistently less sensitive to the aversive effects of ethanol than their adult counterparts. However, the dose of ethanol required to produce an aversion response differed as a function of both age and strain.
PMCID: PMC3553292  PMID: 23171343
16.  Synergistic Activity of Colistin and Rifampin Combination against Multidrug-Resistant Acinetobacter baumannii in an In Vitro Pharmacokinetic/Pharmacodynamic Model 
Combination therapy may be required for multidrug-resistant (MDR) Acinetobacter baumannii. This study systematically investigated bacterial killing and emergence of colistin resistance with colistin and rifampin combinations against MDR A. baumannii. Studies were conducted over 72 h in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model at inocula of ∼106 and ∼108 CFU/ml using two MDR clinical isolates of A. baumannii, FADDI-AB030 (colistin susceptible) and FADDI-AB156 (colistin resistant). Three combination regimens achieving clinically relevant concentrations (constant colistin concentration of 0.5, 2, or 5 mg/liter and a rifampin maximum concentration [Cmax] of 5 mg/liter every 24 hours; half-life, 3 h) were investigated. Microbiological response was measured by serial bacterial counts. Population analysis profiles assessed emergence of colistin resistance. Against both isolates, combinations resulted in substantially greater killing at the low inoculum; combinations containing 2 and 5 mg/liter colistin increased killing at the high inoculum. Combinations were additive or synergistic at 6, 24, 48, and 72 h with all colistin concentrations against FADDI-AB030 and FADDI-AB156 in, respectively, 8 and 11 of 12 cases (i.e., all 3 combinations) at the 106-CFU/ml inoculum and 8 and 7 of 8 cases with the 2- and 5-mg/liter colistin regimens at the 108-CFU/ml inoculum. For FADDI-AB156, killing by the combination was ∼2.5 to 7.5 and ∼2.5 to 5 log10 CFU/ml greater at the low inoculum (all colistin concentrations) and high inoculum (2 and 5 mg/liter colistin), respectively. Emergence of colistin-resistant subpopulations was completely suppressed in the colistin-susceptible isolate with all combinations at both inocula. Our study provides important information for optimizing colistin-rifampin combinations against colistin-susceptible and -resistant MDR A. baumannii.
PMCID: PMC3719722  PMID: 23716052
17.  Population Pharmacokinetics of Oseltamivir: Pediatrics through Geriatrics 
Oseltamivir is a potent inhibitor of influenza virus neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on pharmacokinetic (PK) variability of oseltamivir and its active metabolite form, oseltamivir carboxylate (OC). Dosing history, plasma drug concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1 to 78 years and given oseltamivir doses of 20 to 1,000 mg. Candidate population PK models simultaneously characterizing the time course of oseltamivir and OC in plasma were evaluated by using the NONMEM software program, and subject covariates were assessed using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). A two-compartment model with first-order absorption of oseltamivir and first-order conversion of oseltamivir to OC and a one-compartment model with first-order elimination of OC were utilized. Body weight when evaluated using a power function was a significant predictor of the apparent oseltamivir clearance and both apparent OC clearance (CLm/F) and central volume of distribution (Vcm/F). Creatinine clearance was a significant predictor of CLm/F, while Vcm/F also decreased linearly with age. A visual predictive check indicated that the final model described oseltamivir and OC concentrations in plasma adequately across dose regimens and subject covariate ranges. Concordance of population mean and individual post hoc predictions of maximum concentration of drug at steady state (Cmax) and area under the plasma drug concentration-time curve from 0 to 24 h at steady state (AUC0–24) was high (r2 = 0.81 and 0.71, respectively). In conclusion, a comprehensive population PK model was constructed to bridge the adult to pediatric oseltamivir PK data, allowing for reasonable estimation of the PK of OC using subject demographic data alone.
PMCID: PMC3719735  PMID: 23669384
18.  Pharmacokinetic-Pharmacodynamic Determinants of Oseltamivir Efficacy Using Data from Phase 2 Inoculation Studies 
Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC50] = 0.18 nM) or B/Yamagata (IC50 = 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC0–24), minimum concentration of OC in plasma (Cmin), and maximum concentration of OC in plasma (Cmax). Exposure-response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC0–24 evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC0–24 threshold (∼14,000 ng · h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation.
PMCID: PMC3719781  PMID: 23669386
20.  High Rates of Gene Flow by Pollen and Seed in Oak Populations across Europe 
PLoS ONE  2014;9(1):e85130.
Gene flow is a key factor in the evolution of species, influencing effective population size, hybridisation and local adaptation. We analysed local gene flow in eight stands of white oak (mostly Quercus petraea and Q. robur, but also Q. pubescens and Q. faginea) distributed across Europe.
Adult trees within a given area in each stand were exhaustively sampled (range [239, 754], mean 423), mapped, and acorns were collected ([17,147], 51) from several mother trees ([3], [47], 23). Seedlings ([65,387], 178) were harvested and geo-referenced in six of the eight stands. Genetic information was obtained from screening distinct molecular markers spread across the genome, genotyping each tree, acorn or seedling. All samples were thus genotyped at 5–8 nuclear microsatellite loci. Fathers/parents were assigned to acorns and seedlings using likelihood methods. Mating success of male and female parents, pollen and seed dispersal curves, and also hybridisation rates were estimated in each stand and compared on a continental scale.
On average, the percentage of the wind-borne pollen from outside the stand was 60%, with large variation among stands (21–88%). Mean seed immigration into the stand was 40%, a high value for oaks that are generally considered to have limited seed dispersal. However, this estimate varied greatly among stands (20–66%). Gene flow was mostly intraspecific, with large variation, as some trees and stands showed particularly high rates of hybridisation.
Our results show that mating success was unevenly distributed among trees. The high levels of gene flow suggest that geographically remote oak stands are unlikely to be genetically isolated, questioning the static definition of gene reserves and seed stands.
PMCID: PMC3890301  PMID: 24454802
21.  Identifying self-perceived HIV-related stigma in a population accessing antiretroviral therapy 
AIDS care  2012;25(1):10.1080/09540121.2012.687809.
This study identifies factors associated with self-perceived HIV-related stigma (stigma) among a cohort of individuals accessing antiretroviral therapy (ART) in British Columbia, Canada. Data were drawn from the Longitudinal Investigations into Supportive and Ancillary Health Services study, which collects social, clinical, and quality of life (QoL) information through an interviewer-administered survey. Clinical variables (i.e. CD4 count) were obtained through linkages with the British Columbia HIV/AIDS Drug Treatment Program. Multivariable linear regression was performed to determine the independent predictors of stigma. Our results indicate that among participants with high school education or greater the outcome stigma, was associated with a 3.05 stigma unit decrease (95% CI: −5.16, −0.93). Having higher relative standard of living and perceiving greater neighborhood cohesion were also associated with a decrease in stigma (−5.30 95% CI: −8.16, −2.44; −0.80 95% CI: −1.39, −0.21, respectively). Lower levels of stigma were found to be associated with better QoL measures, including perceiving better overall function (−0.90 95% CI: −1.47, −0.34), having fewer health worries (−2.11 95% CI: −2.65, −1.57), having fewer financial worries (−0.67 95% CI: −1.12, −0.23), and having less HIV disclosure concerns (−4.12 95% CI: −4.63, −3.62). The results of this study show that participants with higher education level, better QoL measures, and higher self-reported standards of living are less likely to perceive HIV-related stigma.
PMCID: PMC3879041  PMID: 22672228
stigma; ART; quality of life; HIV
22.  A heartfelt response: new thyroid hormone–sensitive neurons in the hypothalamus 
Thyroid hormone is a well-known regulator of metabolic and cardiovascular functions, and signaling through thyroid receptors has differential effects on cells depending on the receptor isoform that they express. In this issue of the JCI, Mittag et al. provide evidence that thyroid hormone receptors are essential for the formation of a population of parvalbuminergic neurons in the anterior hypothalamus, linking, for the first time, impaired thyroid hormone signaling during development to cellular deficits in the hypothalamus. Since this newly discovered cell group is predicted to play a role in regulating cardiovascular function, these findings suggest that developmental hypothyroidism may be the cause of cardiovascular disorders later in life.
PMCID: PMC3533311  PMID: 23257363
23.  Gas-Phase Reactivity of Carboxylic Acid Functional Groups with Carbodiimides 
Gas-phase modification of carboxylic acid functionalities is performed via ion/ion reactions with carbodiimide reagents [N-cyclohexyl-N′-(2-morpholinoethyl)carbodiimide (CMC) and [3-(3-Ethylcarbodiimide-1-yl)propyl]trimethylaminium (ECPT). Gas-phase ion/ion covalent chemistry requires the formation of a long-lived complex. In this instance, the complex is stabilized by an electrostatic interaction between the fixed charge quaternary ammonium group of the carbodiimide reagent cation and the analyte dianion. Subsequent activation results in characteristic loss of an isocyanate derivative from one side of the carbodiimide functionality, a signature for this covalent chemistry. The resulting amide bond is formed on the analyte at the site of the original carboxylic acid. Reactions involving analytes that do not contain available carboxylic acid groups (e.g., they have been converted to sodium salts) or reagents that do not have the carbodiimide functionality do not undergo a covalent reaction. This chemistry is demonstrated using PAMAM generation 0.5 dendrimer, ethylenediaminetetraacetic acid (EDTA), and the model peptide DGAILDGAILD. This work demonstrates the selective gas-phase covalent modification of carboxylic acid functionalities.
PMCID: PMC3554847  PMID: 23208744
24.  Drug Take Back in Hawai‘i: Partnership Between the University of Hawai‘i Hilo College of Pharmacy and the Narcotics Enforcement Division 
Unused/unwanted medications in households and patient care facilities expose vulnerable populations, including children, elders, and pets, to potential harm through inadvertent ingestion, as well as the potential for theft and assault. Hawai‘i Administrative Rules prohibit the return of any prescription medications to retail pharmacies after dispensing. The Hawai‘i Narcotics Enforcement Division (NED) partnered with the University of Hawai‘i at Hilo Daniel K. Inouye College of Pharmacy (CoP) in eleven Drug Take Back events throughout the state. Most participants heard of the events via newspaper and television marketing. The most common methods of medication disposal are via trash or down household drains. Over 8,000 lbs of unused/unwanted medications was collected, identified and logged from 2011 through 2012. The majority of returned drugs were non-controlled substances (90%). Commonly returned medications included prescription cardiac medications such as simvastatin and lisinopril, non-prescription analgesics such as aspirin and ibuprofen, and dietary supplements such as vitamins and iron. Commonly returned controlled substance medications included narcotics such as hydrocodone/acetaminophen combinations and oxycodone, and sedative hypnotics such as zolpidem and lorazepam.
PMCID: PMC3901169  PMID: 24470984
25.  Forecasting Distributional Responses of Limber Pine to Climate Change at Management-Relevant Scales in Rocky Mountain National Park 
PLoS ONE  2013;8(12):e83163.
Resource managers at parks and other protected areas are increasingly expected to factor climate change explicitly into their decision making frameworks. However, most protected areas are small relative to the geographic ranges of species being managed, so forecasts need to consider local adaptation and community dynamics that are correlated with climate and affect distributions inside protected area boundaries. Additionally, niche theory suggests that species' physiological capacities to respond to climate change may be underestimated when forecasts fail to consider the full breadth of climates occupied by the species rangewide. Here, using correlative species distribution models that contrast estimates of climatic sensitivity inferred from the two spatial extents, we quantify the response of limber pine (Pinus flexilis) to climate change in Rocky Mountain National Park (Colorado, USA). Models are trained locally within the park where limber pine is the community dominant tree species, a distinct structural-compositional vegetation class of interest to managers, and also rangewide, as suggested by niche theory. Model forecasts through 2100 under two representative concentration pathways (RCP 4.5 and 8.5 W/m2) show that the distribution of limber pine in the park is expected to move upslope in elevation, but changes in total and core patch area remain highly uncertain. Most of this uncertainty is biological, as magnitudes of projected change are considerably more variable between the two spatial extents used in model training than they are between RCPs, and novel future climates only affect local model predictions associated with RCP 8.5 after 2091. Combined, these results illustrate the importance of accounting for unknowns in species' climatic sensitivities when forecasting distributional scenarios that are used to inform management decisions. We discuss how our results for limber pine may be interpreted in the context of climate change vulnerability and used to help guide adaptive management.
PMCID: PMC3877015  PMID: 24391742

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