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1.  Bioerosion of Inorganic Hard Substrates in the Ordovician of Estonia (Baltica) 
PLoS ONE  2015;10(7):e0134279.
The earliest bioeroded inorganic hard substrates in the Ordovician of Estonia appear in the Dapingian. Hardgrounds are also known from the Sandbian and Katian. Most of the bioerosion of inorganic hard substrates occurs as the boring Trypanites Mägdefrau, 1932 along with some possible Gastrochaenolites borings. North American hardground borings are more diverse than those in Baltica. In contrast to a worldwide trend of increasing boring intensity, the Estonian record seems to show no increase in boring intensities during the Middle and Late Ordovician. Hardgrounds seem to be more common during the temperate climate interval of the Ordovician calcite sea in Estonia (seven hardgrounds during 15 my) than in the part with a tropical climate (four hardgrounds during 12 my). Bioerosion is mostly associated with carbonate hardgrounds, but cobbles and pebbles broken from the hardgrounds are also often penetrated by Trypanites borings. The general diversity of boring ichnotaxa in Baltica increased from one ichnospecies in the Cambrian to seven by the end of Ordovician, showing the effect of the GOBE on bioeroding ichnotaxa. The diversity of inorganic hard substrate borers increased by only two times. This difference can be explained by the wider environmental distribution of organic as compared to inorganic substrates in the Ordovician seas of Baltica, and their more continuous temporal availability, which may have caused increased specialization of several borers. The inorganic substrates may have been bioreroded only by the generalists among boring organisms.
PMCID: PMC4517899  PMID: 26218582
2.  Cadmium alters the formation of benzo[a]pyrene DNA adducts in the RPTEC/TERT1 human renal proximal tubule epithelial cell line 
Toxicology reports  2014;1:391-400.
Previously, we demonstrated the sensitivity of RPTEC/TERT1 cells, an immortalized human renal proximal tubule epithelial cell line, to two common environmental carcinogens, cadmium (Cd) and benzo[a]pyrene (B[a]P). Here, we measured BPDE-DNA adducts using a competitive ELISA method after cells were exposed to 0.01, 0.1, and 1 μM B[a]P to determine if these cells, which appear metabolically competent, produce BPDE metabolites that react with DNA. BPDE-DNA adducts were most significantly elevated at 1 μM B[a]P after 18 and 24 hours with 36.34 +/− 9.14 (n = 3) and 59.75 +/− 17.03 (n = 3) adducts/108 nucleotides respectively. For mixture studies, cells were exposed to a non-cytotoxic concentration of Cd, 1 μM, for 24 hours and subsequently exposed to concentrations of B[a]P for 24 hours. Under these conditions, adducts detected at 1 μM B[a]P after 24 hours were significantly reduced, 17.28 +/− 1.30 (n = 3) adducts/108 nucleotides, in comparison to the same concentration at previous time points without Cd pre-treatment. We explored the NRF2 antioxidant pathway and total glutathione levels in cells as possible mechanisms reducing adduct formation under co-exposure. Results showed a significant increase in the expression of NRF2-responsive genes, GCLC, HMOX1, NQO1, after 1 μM Cd × 1 μM B[a]P co-exposure. Additionally, total glutathione levels were significantly increased in cells exposed to 1 μM Cd alone and 1 μM Cd × 1 μM B[a]P. Together, these results suggest that Cd may antagonize the formation of BPDE-DNA adducts in the RPTEC/TERT1 cell line under these conditions. We hypothesize that this occurs through priming of the antioxidant response pathway resulting in an increased capacity to detoxify BPDE prior to BPDE-DNA adduct formation.
PMCID: PMC4142648  PMID: 25170436
Mixtures toxicology; BPDE-DNA adducts; renal cancer; RPTEC/TERT1
3.  Advancing the field of health systems research synthesis 
Systematic Reviews  2015;4:90.
Those planning, managing and working in health systems worldwide routinely need to make decisions regarding strategies to improve health care and promote equity. Systematic reviews of different kinds can be of great help to these decision-makers, providing actionable evidence at every step in the decision-making process. Although there is growing recognition of the importance of systematic reviews to inform both policy decisions and produce guidance for health systems, a number of important methodological and evidence uptake challenges remain and better coordination of existing initiatives is needed. The Alliance for Health Policy and Systems Research, housed within the World Health Organization, convened an Advisory Group on Health Systems Research (HSR) Synthesis to bring together different stakeholders interested in HSR synthesis and its use in decision-making processes. We describe the rationale of the Advisory Group and the six areas of its work and reflects on its role in advancing the field of HSR synthesis. We argue in favour of greater cross-institutional collaborations, as well as capacity strengthening in low- and middle-income countries, to advance the science and practice of health systems research synthesis. We advocate for the integration of quasi-experimental study designs in reviews of effectiveness of health systems intervention and reforms. The Advisory Group also recommends adopting priority-setting approaches for HSR synthesis and increasing the use of findings from systematic reviews in health policy and decision-making.
PMCID: PMC4498528  PMID: 26159806
Evidence synthesis; Health systems research; Health policy; Systematic reviews; Decision-making
4.  IFNγ and IL-12 Restrict Th2 Responses during Helminth/Plasmodium Co-Infection and Promote IFNγ from Th2 Cells 
PLoS Pathogens  2015;11(7):e1004994.
Parasitic helminths establish chronic infections in mammalian hosts. Helminth/Plasmodium co-infections occur frequently in endemic areas. However, it is unclear whether Plasmodium infections compromise anti-helminth immunity, contributing to the chronicity of infection. Immunity to Plasmodium or helminths requires divergent CD4+ T cell-driven responses, dominated by IFNγ or IL-4, respectively. Recent literature has indicated that Th cells, including Th2 cells, have phenotypic plasticity with the ability to produce non-lineage associated cytokines. Whether such plasticity occurs during co-infection is unclear. In this study, we observed reduced anti-helminth Th2 cell responses and compromised anti-helminth immunity during Heligmosomoides polygyrus and Plasmodium chabaudi co-infection. Using newly established triple cytokine reporter mice (Il4gfpIfngyfpIl17aFP635), we demonstrated that Il4gfp+ Th2 cells purified from in vitro cultures or isolated ex vivo from helminth-infected mice up-regulated IFNγ following adoptive transfer into Rag1–/– mice infected with P. chabaudi. Functionally, Th2 cells that up-regulated IFNγ were transcriptionally re-wired and protected recipient mice from high parasitemia. Mechanistically, TCR stimulation and responsiveness to IL-12 and IFNγ, but not type I IFN, was required for optimal IFNγ production by Th2 cells. Finally, blockade of IL-12 and IFNγ during co-infection partially preserved anti-helminth Th2 responses. In summary, this study demonstrates that Th2 cells retain substantial plasticity with the ability to produce IFNγ during Plasmodium infection. Consequently, co-infection with Plasmodium spp. may contribute to the chronicity of helminth infection by reducing anti-helminth Th2 cells and converting them into IFNγ-secreting cells.
Author Summary
Approximately a third of the world’s population is burdened with chronic intestinal parasitic helminth infections, causing significant morbidities. Identifying the factors that contribute to the chronicity of infection is therefore essential. Co-infection with other pathogens, which is extremely common in helminth endemic areas, may contribute to the chronicity of helminth infections. In this study, we used a mouse model to test whether the immune responses to an intestinal helminth were impaired following malaria co-infection. These two pathogens induce very different immune responses, which, until recently, were thought to be opposing and non-interchangeable. This study identified that the immune cells required for anti-helminth responses are capable of changing their phenotype and providing protection against malaria. By identifying and blocking the factors that drive this change in phenotype, we can preserve anti-helminth immune responses during co-infection. Our studies provide fresh insight into how immune responses are altered during helminth and malaria co-infection.
PMCID: PMC4493106  PMID: 26147567
5.  Integrated Assessment of Artisanal and Small-Scale Gold Mining in Ghana — Part 3: Social Sciences and Economics 
This article is one of three synthesis reports resulting from an integrated assessment (IA) of artisanal and small-scale gold mining (ASGM) in Ghana. Given the complexities that involve multiple drivers and diverse disciplines influencing ASGM, an IA framework was used to analyze economic, social, health, and environmental data and to co-develop evidence-based responses in collaboration with pertinent stakeholders. We look at both micro- and macro-economic processes surrounding ASGM, including causes, challenges, and consequences. At the micro-level, social and economic evidence suggests that the principal reasons whereby most people engage in ASGM involve “push” factors aimed at meeting livelihood goals. ASGM provides an important source of income for both proximate and distant communities, representing a means of survival for impoverished farmers as well as an engine for small business growth. However, miners and their families often end up in a “poverty trap” of low productivity and indebtedness, which reduce even further their economic options. At a macro level, Ghana’s ASGM activities contribute significantly to the national economy even though they are sometimes operating illegally and at a disadvantage compared to large-scale industrial mining companies. Nevertheless, complex issues of land tenure, social stability, mining regulation and taxation, and environmental degradation undermine the viability and sustainability of ASGM as a livelihood strategy. Although more research is needed to understand these complex relationships, we point to key findings and insights from social science and economics research that can guide policies and actions aimed to address the unique challenges of ASGM in Ghana and elsewhere.
PMCID: PMC4515713  PMID: 26184277
artisanal small-scale gold mining (ASGM); subsistence agriculture; alternative livelihoods; “poverty trap”; ASGM policy; miner registration; West Africa; economic development
6.  Alpha-2-Macroglobulin Is Acutely Sensitive to Freezing and Lyophilization: Implications for Structural and Functional Studies 
PLoS ONE  2015;10(6):e0130036.
Alpha-2-macroglobulin is an abundant secreted protein that is of particular interest because of its diverse ligand binding profile and multifunctional nature, which includes roles as a protease inhibitor and as a molecular chaperone. The activities of alpha-2-macroglobulin are typically dependent on whether its conformation is native or transformed (i.e. adopts a more compact conformation after interactions with proteases or small nucleophiles), and are also influenced by dissociation of the native alpha-2-macroglobulin tetramer into stable dimers. Alpha-2-macroglobulin is predominately present as the native tetramer in vivo; once purified from human blood plasma, however, alpha-2-macroglobulin can undergo a number of conformational changes during storage, including transformation, aggregation or dissociation. We demonstrate that, particularly in the presence of sodium chloride or amine containing compounds, freezing and/or lyophilization of alpha-2-macroglobulin induces conformational changes with functional consequences. These conformational changes in alpha-2-macroglobulin are not always detected by standard native polyacrylamide gel electrophoresis, but can be measured using bisANS fluorescence assays. Increased surface hydrophobicity of alpha-2-macroglobulin, as assessed by bisANS fluorescence measurements, is accompanied by (i) reduced trypsin binding activity, (ii) increased chaperone activity, and (iii) increased binding to the surfaces of SH-SY5Y neurons, in part, via lipoprotein receptors. We show that sucrose (but not glycine) effectively protects native alpha-2-macroglobulin from denaturation during freezing and/or lyophilization, thereby providing a reproducible method for the handling and long-term storage of this protein.
PMCID: PMC4477937  PMID: 26103636
7.  SerpinB2 (PAI-2) Modulates Proteostasis via Binding Misfolded Proteins and Promotion of Cytoprotective Inclusion Formation 
PLoS ONE  2015;10(6):e0130136.
SerpinB2 (PAI-2), a member of the clade B family of serine protease inhibitors, is one of the most upregulated proteins following cellular stress. Originally described as an inhibitor of urokinase plasminogen activator, its predominant cytoplasmic localisation suggests an intracellular function. SerpinB2 has been reported to display cytoprotective properties in neurons and to interact with intracellular proteins including components of the ubiquitin-proteasome system (UPS). In the current study we explored the potential role of SerpinB2 as a modulator of proteotoxic stress. Initially, we transiently transfected wild-type SerpinB2 and SerpinB2-/- murine embryonic fibroblasts (MEFs) with Huntingtin exon1-polyglutamine (fused C-terminally to mCherry). Inclusion body formation as result of Huntingtin aggregation was evident in the SerpinB2 expressing cells but significantly impaired in the SerpinB2-/- cells, the latter concomitant with loss in cell viability. Importantly, recovery of the wild-type phenotype and cell viability was rescued by retroviral transduction of SerpinB2 expression. SerpinB2 modestly attenuated Huntingtin and amyloid beta fibril formation in vitro and was able to bind preferentially to misfolded proteins. Given the modest chaperone-like activity of SerpinB2 we tested the ability of SerpinB2 to modulate UPS and autophagy activity using a GFP reporter system and autophagy reporter, respectively. Activity of the UPS was reduced and autophagy was dysregulated in SerpinB2-/- compared to wild-type MEFs. Moreover, we observed a non-covalent interaction between ubiquitin and SerpinB2 in cells using GFP-pulldown assays and bimolecular fluorescence complementation. We conclude that SerpinB2 plays an important role in proteostasis as its loss leads to a proteotoxic phenotype associated with an inability to compartmentalize aggregating proteins and a reduced capacity of the UPS.
PMCID: PMC4470917  PMID: 26083412
8.  Crystal cryocooling distorts conformational heterogeneity in a model Michaelis complex of DHFR 
Most macromolecular X-ray structures are determined from cryocooled crystals, but it is unclear whether cryocooling distorts functionally relevant flexibility. Here we compare independently acquired pairs of high-resolution datasets of a model Michaelis complex of dihydrofolate reductase (DHFR), collected by separate groups at both room and cryogenic temperatures. These datasets allow us to isolate the differences between experimental procedures and between temperatures. Our analyses of multiconformer models and time-averaged ensembles suggest that cryocooling suppresses and otherwise modifies sidechain and mainchain conformational heterogeneity, quenching dynamic contact networks. Despite some idiosyncratic differences, most changes from room temperature to cryogenic temperature are conserved, and likely reflect temperature-dependent solvent remodeling. Both cryogenic datasets point to additional conformations not evident in the corresponding room-temperature datasets, suggesting that cryocooling does not merely trap pre-existing conformational heterogeneity. Our results demonstrate that crystal cryocooling consistently distorts the energy landscape of DHFR, a paragon for understanding functional protein dynamics.
PMCID: PMC4082491  PMID: 24882744
9.  Dietary variety is associated with larger meals in female rhesus monkeys 
Physiology & behavior  2013;119:190-194.
The complex, interacting influences on eating behavior and energy expenditure prevent elucidation of the causal role of any single factor in the current obesity epidemic. However, greater variety in the food supply, particularly in the form of highly palatable, energy-dense foods, has likely made a contribution. This study was undertaken to test the hypothesis that greater dietary variety is associated with greater caloric intake within individual meals consumed by free-feeding, socially-housed female rhesus monkeys. Meal patterns were assessed during two, two-week dietary phases. One phase consisted of a choice between a standard chow diet and a highly palatable diet (HPD). The other phase consisted of access to the chow only. Food intake for each subject was recorded continuously using previously validated, automated feeders, and a meal was defined based on a minimum kilocalorie requirement and a minimum inter-meal interval. During the choice condition, animals electively consumed mixed meals that incorporated both diets as well as other meals that consisted exclusively of a single diet – chow-only or HPD-only. Animals consumed the most calories per meal when the meal was comprised of both the chow and HPD, which differed in caloric density, flavor, and texture. Interestingly, however, there was no significant difference in the amount of calories consumed as HPD-only meals in the choice condition compared to meals in the chow-only, no choice condition, suggesting consumption of a single food during a meal, regardless of palatability, provides a constant sensory experience that may lead to more rapid habituation and subsequent meal cessation. Additionally, during the dietary choice condition, animals consumed fewer calories in the form of chow-only meals. Thus, the present results suggest that limiting dietary variety, regardless of palatability, may be a useful strategy for weight loss in overweight and obese individuals by reducing caloric intake within individual meals.
PMCID: PMC4454609  PMID: 23810992
10.  Phylogenomics of Xanthomonas field strains infecting pepper and tomato reveals diversity in effector repertoires and identifies determinants of host specificity 
Bacterial spot disease of pepper and tomato is caused by four distinct Xanthomonas species and is a severely limiting factor on fruit yield in these crops. The genetic diversity and the type III effector repertoires of a large sampling of field strains for this disease have yet to be explored on a genomic scale, limiting our understanding of pathogen evolution in an agricultural setting. Genomes of 67 Xanthomonas euvesicatoria (Xe), Xanthomonas perforans (Xp), and Xanthomonas gardneri (Xg) strains isolated from diseased pepper and tomato fields in the southeastern and midwestern United States were sequenced in order to determine the genetic diversity in field strains. Type III effector repertoires were computationally predicted for each strain, and multiple methods of constructing phylogenies were employed to understand better the genetic relationship of strains in the collection. A division in the Xp population was detected based on core genome phylogeny, supporting a model whereby the host-range expansion of Xp field strains on pepper is due, in part, to a loss of the effector AvrBsT. Xp-host compatibility was further studied with the observation that a double deletion of AvrBsT and XopQ allows a host range expansion for Nicotiana benthamiana. Extensive sampling of field strains and an improved understanding of effector content will aid in efforts to design disease resistance strategies targeted against highly conserved core effectors.
PMCID: PMC4452888  PMID: 26089818
Xanthomonas; type III effector repertoire; phylogenomics; host specificity; bacterial spot disease; AvrBsT; XopQ
11.  Understanding the Control of Ingestive Behavior in Primates 
Hormones and behavior  2014;66(1):86-94.
Ingestive behavior in free-ranging populations of nonhuman primates is influenced by resource availability and social group organization and provides valuable insight on the evolution of ecologically adaptive behaviors and physiological systems. As captive populations were established, questions regarding proximate mechanisms that regulate food intake in these animals could be more easily be addressed. The availability of these captive populations has lead to the use of selected species to understand appetite control or metabolic physiology in humans. Recognizing the difficulty of quantitating food intake in free ranging groups, the use of captive, singly-housed animals provided a distinct advantage though, at the same time, produced a different social ecology from the animals’ natural habitat. However, with the recent application of novel technologies to quantitate caloric intake and energy expenditure in free feeding, socially-housed monkeys permits prospective studies that can accurately define how food intake changes in response to any number of interventions in the context of a social environment. This review provides an overview of studies examining food intake using captive nonhuman primates organized into three areas: a) neurochemical regulation of food intake in nonhuman primates; b) whether exposure to specific diets during key developmental periods program differences in diet preferences or changes the expression of feeding related neuropeptides; and c) how psychosocial factors influence appetite regulation. Because feeding patterns are driven by more than just satiety and orexigenic signals, appreciating how the social context influences pattern of feeding in nonhuman primates may be quite informative for understanding the biological complexity of feeding in humans.
PMCID: PMC4051844  PMID: 24727080
nonhuman primates; macaques; neuropeptides; estradiol; appetite; programming
12.  Preliminary joint X-ray and neutron protein crystallographic studies of ecDHFR complexed with folate and NADP+  
A 2.0 Å resolution neutron data set and a 1.6 Å resolution X-ray data set were collected for joint X-ray/neutron refinement of the ecDHFR–folate–NADP+ complex in order to study the reaction mechanism of dihydrofolate reductase.
A crystal of Escherichia coli dihydrofolate reductase (ecDHFR) complexed with folate and NADP+ of 4 × 1.3 × 0.7 mm (3.6 mm3) in size was obtained by sequential application of microseeding and macroseeding. A neutron diffraction data set was collected to 2.0 Å resolution using the IMAGINE diffractometer at the High Flux Isotope Reactor within Oak Ridge National Laboratory. A 1.6 Å resolution X-ray data set was also collected from a smaller crystal at room temperature. The neutron and X-ray data were used together for joint refinement of the ecDHFR–folate–NADP+ ternary-complex structure in order to examine the protonation state, protein dynamics and solvent structure of the complex, furthering understanding of the catalytic mechanism.
PMCID: PMC4051544  PMID: 24915100
Escherichia coli; dihydrofolate reductase; protonation state
13.  Animal Models of Cerebral Palsy: Hypoxic Brain Injury in the Newborn 
Hypoxic insults are implicated in the spectrum of fetal disorders, including cerebral palsy (CP). In view of the major contribution of intrapartum risk factors and prematurity to subsequent neurological morbidity and mortality in humans, this study aimed to clarify the pathophysiology of brain injury, especially
periventricular white matter damage (WMD), that occur in utero to the immature and near-term fetal CNS.
Materials & Methods
An evaluation of the resulting neurological and behavioural phenotype in the newborn was performed by utilising a battery of neurobehavioural tests, including the Morris water-maze and the open-field test, followed by cerebral MRI and histopathology.
This study used a murine model to examine the deleterious effects of WMD brought about by cerebral hypoxia-ischemia (HI) and the characteristic features of CP in mice. Murine models have proven themselves valuable in the area of experimental neuroscience.
Hypoxia-treated mice were observed to demonstrate a significant neurofunctional deficit compared with sham mice on two behavioral measures. Indeed, different brain regions, including the sensorimotor cortex, the striatum, and the hippocampus were noticeably damaged after HI insult, as determined by both
MRI and histopathology. These results, albeit qualitative in nature, appear to support the pre-existing finding that the long-term neurofunctional outcome in animal subjects with CP is strongly associated with the anatomical extent and pattern of cerebral damage as determined by both delayed neuroimaging and
PMCID: PMC4515335  PMID: 26221157
Neurodevelopmental disorder; Prenatal hypoxia; Cerebral palsy; Murine model
14.  Traumatic bifrontal extradural haematoma resulting from superior sagittal sinus injury: case report 
JRSM Open  2015;6(4):2054270415579137.
Traumatic bilateral extradural haematoma resulting from injury to the superior sagittal sinus is rare; in such cases, early surgical evacuation of the haematoma and control of bleeding from the sinus can achieve an excellent patient outcome.
PMCID: PMC4429041  PMID: 25973216
bilateral; bifrontal; extradural; epidural; haematoma
15.  Oxidant Trade-Offs in Immunity: An Experimental Test in a Lizard 
PLoS ONE  2015;10(5):e0126155.
Immune system functioning and maintenance entails costs which may limit investment into other processes such as reproduction. Yet, the proximate mechanisms and ‘currencies’ mediating the costs of immune responses remain elusive. In vertebrates, up-regulation of the innate immune system is associated with rapid phagocytic production of pro-oxidant molecules (so-called ‘oxidative burst’ responses). Oxidative burst responses are intended to eliminate pathogens but may also constitute an immunopathological risk as they may induce oxidative damage to self cells. To minimize the risk of infection and, at the same time, damage to self, oxidative burst activity must be carefully balanced. The current levels of pro- and antioxidants (i.e. the individual oxidative state) is likely to be a critical factor affecting this balance, but this has not yet been evaluated. Here, we perform an experiment on wild-caught painted dragon lizards (Ctenophorus pictus) to examine how the strength of immune-stimulated oxidative burst responses of phagocytes in whole blood relates to individual oxidative status under control conditions and during an in vivo immune challenge with Escherichia coli lipopolysaccharide (LPS). Under control conditions, oxidative burst responses were not predicted by the oxidative status of the lizards. LPS-injected individuals showed a strong increase in pro-oxidant levels and a strong decrease in antioxidant levels compared to control individuals demonstrating a shift in the pro-/antioxidant balance. Oxidative burst responses in LPS-injected lizards were positively related to post-challenge extracellular pro-oxidants (reflecting the level of cell activation) and negatively related to pre-challenge levels of mitochondrial superoxide (suggesting an immunoregulatory effect of this pro-oxidant). LPS-challenged males had higher oxidative burst responses than females, and in females oxidative burst responses seemed to depend more strongly on antioxidant status than in males. Our results confirm the idea that oxidative state may constrain the activity of the innate immune system. These constraints may have important consequences for the way selection acts on pro-oxidant generating processes.
PMCID: PMC4418811  PMID: 25938441
16.  Integrated Assessment of Artisanal and Small-Scale Gold Mining in Ghana—Part 1: Human Health Review 
This report is one of three synthesis documents produced via an integrated assessment (IA) that aims to increase understanding of artisanal and small-scale gold mining (ASGM) in Ghana. Given the complexities surrounding ASGM, an IA framework was utilized to analyze economic, social, health, and environmental data, and co-develop evidence-based responses with pertinent stakeholders. The current analysis focuses on the health of ASGM miners and community members, and synthesizes extant data from the literature as well as co-authors’ recent findings regarding the causes, status, trends, and consequences of ASGM in Ghana. The results provide evidence from across multiple Ghanaian ASGM sites that document relatively high exposures to mercury and other heavy metals, occupational injuries and noise exposure. The work also reviews limited data on psychosocial health, nutrition, cardiovascular and respiratory health, sexual health, and water and sanitation. Taken together, the findings provide a thorough overview of human health issues in Ghanaian ASGM communities. Though more research is needed to further elucidate the relationships between ASGM and health outcomes, the existing research on plausible health consequences of ASGM should guide policies and actions to better address the unique challenges of ASGM in Ghana and potentially elsewhere.
PMCID: PMC4454960  PMID: 25985314
Ghana; gold; mercury; heavy metals; occupational injuries; mining; noise; research; water; Minamata Convention
17.  Chronic Disease Self-Management Program in the Workplace: Opportunities for Health Improvement 
Disease management is becoming increasingly important in workplace health promotion given the aging workforce, rising chronic disease prevalence, and needs to maintain a productive and competitive American workforce. Despite the widespread availability of the Chronic Disease Self-Management Program (CDSMP), and its known health-related benefits, program adoption remains low in workplace settings. The primary purpose of this study is to compare personal and delivery characteristics of adults who attended CDSMP in the workplace relative to other settings (e.g., senior centers, healthcare organizations, residential facilities). This study also contrasts characteristics of CDSMP workplace participants to those of the greater United States workforce and provides recommendations for translating CDSMP for use in workplace settings. Data were analyzed from 25,664 adults collected during a national dissemination of CDSMP. Only states and territories that conducted workshops in workplace settings were included in analyses (n = 13 states and Puerto Rico). Chi-squared tests and t-tests were used to compare CDSMP participant characteristics by delivery site type. CDSMP workplace participant characteristics were then compared to reports from the United States Bureau of Labor Statistics. Of the 25,664 CDSMP participants in this study, 1.7% (n = 435) participated in workshops hosted in worksite settings. Compared to CDSMP participants in non-workplace settings, workplace setting participants were significantly younger and had fewer chronic conditions. Differences were also observed based on chronic disease types. On average, CDSMP workshops in workplace settings had smaller class sizes and workplace setting participants attended more workshop sessions. CDSMP participants in workplace settings were substantially older and a larger proportion were female than the general United States workforce. Findings indicate opportunities to translate CDSMP for use in the workplace to reach new target audiences.
PMCID: PMC4410423  PMID: 25964909
chronic disease self-management; evidence-based program; workplace wellness; evaluation; translational research
18.  Age-related alterations of plasma glutathione and oxidation of redox potentials in chimpanzee (Pan troglodytes) and rhesus monkey (Macaca mulatta) 
Age  2014;36(2):719-732.
Chimpanzee (Pan troglodytes) and rhesus macaque (Macaca mulatta) and humans (Homo sapiens) share physiological and genetic characteristics, but have remarkably different life spans, with chimpanzees living 50–60 % and the rhesus living 35–40 % of maximum human survival. Since oxidative processes are associated with aging and longevity, we might expect to see species differences in age-related oxidative processes. Blood and extracellular fluid contain two major thiol redox nodes, glutathione (GSH)/glutathione-disulfide (GSSG) and cysteine (Cys)/cystine (CySS), which are subject to reversible oxidation–reduction reactions and are maintained in a dynamic non-equilibrium state. Disruption of these thiol redox nodes leads to oxidation of their redox potentials (EhGSSG and EhCySS) which affects cellular physiology and is associated with aging and the development of chronic diseases in humans. The purpose of this study was to measure age-related changes in these redox thiols and their corresponding redox potentials (Eh) in chimpanzees and rhesus monkeys. Our results show similar age-related decreases in the concentration of plasma GSH and Total GSH as well as oxidation of the EhGSSG in male and female chimpanzees. Female chimpanzees and female rhesus monkeys also were similar in several outcome measures. For example, similar age-related decreases in the concentration of plasma GSH and Total GSH, as well as age-related oxidation of the EhGSSG were observed. The data collected from chimpanzees and rhesus monkeys corroborates previous reports on oxidative changes in humans and confirms their value as a comparative reference for primate aging.
Graphical abstractGSH declined while the GSH/GSSG redox potential (EhGSSG) increased with age indicating age-related increased oxidative stress.
PMCID: PMC4039255  PMID: 24532367
Chimpanzee; Rhesus monkey; Glutathione; Cysteine; Redox potential; Oxidative stress; Aging
19.  Conventional NK cells can produce IL-22 and promote host defense in K. pneumoniae pneumonia1 
It has been reported that host defense against pulmonary K. pneumoniae infection requires IL-22, which has been proposed to be of T cell origin. Supporting a role for IL-22, we found that Il22−/− mice had decreased survival as compared with wild type mice after intratracheal infection with K. pneumoniae. Surprisingly, however, Rag2−/− mice did not differ from wild type mice in survival or levels of IL-22 in the lungs after infection with K. pneumoniae. By contrast, K. pneumoniae-infected Rag2−/−Il2rg−/− mice failed to produce IL-22. These data suggested a possible role for NK cells or other innate lymphoid cells (ILC) in host defense and production of IL-22. Unlike NK cell-like ILCs that produce IL-22 and display a surface phenotype of NK1.1−NKp46+CCR6+, lung NK cells showed the conventional phenotype, NK1.1+NKp46+CCR6−. Mice depleted of NK cells using anti-asialo GM1 showed decreased survival and higher lung bacterial counts as well as increased dissemination of K. pneumoniae to blood and liver as compared with control-treated mice. NK cell depletion also led to decreased production of IL-22 in the lung. Within one day after infection, although there was no increase in the number of lung NK cells, a subset of lung NK cells became competent to produce IL-22, and such cells were found in both wild type and Rag2−/− mice. Our data suggest that during pulmonary infection of mice with K. pneumoniae, conventional NK cells are required for optimal host defense, which includes the production of IL-22.
PMCID: PMC3995347  PMID: 24442439
20.  Determinants and Coverage of Vaccination in Children in Western Kenya from a 2003 Cross-Sectional Survey 
This study assesses full and timely vaccination coverage and factors associated with full vaccination in children ages 12–23 months in Gem, Nyanza Province, Kenya in 2003. A simple random sample of 1,769 households was selected, and guardians were invited to bring children under 5 years of age to participate in a survey. Full vaccination coverage was 31.1% among 244 children. Only 2.2% received all vaccinations in the target month for each vaccination. In multivariate logistic regression, children of mothers of higher parity (odds ratio [OR] = 0.27, 95% confidence interval [95% CI] = 0.13–0.65, P ≤ 0.01), children of mothers with lower maternal education (OR = 0.35, 95% CI = 0.13–0.97, P ≤ 0.05), or children in households with the spouse absent versus present (OR = 0.40, 95% CI = 0.17–0.91, P ≤ 0.05) were less likely to be fully vaccinated. These data serve as a baseline from which changes in vaccination coverage will be measured as interventions to improve vaccination timeliness are introduced.
PMCID: PMC3919223  PMID: 24343886
21.  Forceps Delivery Volumes in Teaching and Nonteaching Hospitals: Are Volumes Sufficient for Physicians to Acquire and Maintain Competence? 
The decline in the use of forceps in operative deliveries over the last two decades raises questions about teaching hospitals' ability to provide trainees with adequate experience in the use of forceps. The authors examined: (1) the number of operative deliveries performed in teaching and nonteaching hospitals, and (2) whether teaching hospitals performed a sufficient number of forceps deliveries for physicians to acquire and maintain competence.
The authors used State Inpatient Data from nine states to identify all women hospitalized for childbirth in 2008. They divided hospitals into three categories: major teaching, minor teaching, and nonteaching. They calculated delivery volumes (total operative, cesarean, vacuum, forceps, two or more methods) for each hospital and compared data across hospital categories.
The sample included 1,344,305 childbirths in 835 hospitals. The mean cesarean volumes for major teaching, minor teaching, and nonteaching hospitals were 969.8, 757.8, and 406.9. The mean vacuum volumes were 301.0, 304.2, and 190.4, and the mean forceps volumes were 25.2, 15.3, and 8.9. In 2008, 31 hospitals (3.7% of all hospitals) performed no vacuum extractions, and 320 (38.3%) performed no forceps deliveries. In 2008, 13 (23%) major teaching and 44 (44%) minor teaching hospitals performed five or fewer forceps deliveries.
Low forceps delivery volumes may preclude many trainees from acquiring adequate experience and proficiency. These findings highlighted broader challenges, faced by many specialties, in ensuring that trainees and practicing physicians acquire and maintain competence in infrequently performed, highly technical procedures.
PMCID: PMC4317267  PMID: 24280847
22.  Global low-frequency motions in protein allostery: CAP as a model system 
Biophysical Reviews  2015;7(2):175-182.
Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distant site. There is considerable evidence that allosteric cooperativity can be communicated by the modulation of protein dynamics without conformational change. The Catabolite Activator Protein (CAP) of Escherichia coli is an important experimental exemplar for entropically driven allostery. Here we discuss recent experimentally supported theoretical analysis that highlights the role of global low-frequency dynamics in allostery in CAP and identify how allostery arises as a natural consequence of changes in global low-frequency protein fluctuations on ligand binding.
PMCID: PMC4432019  PMID: 26000062
Protein; Allostery; Dynamics; Catabolite activator protein; Normal modes; Elastic network model
23.  Oestradiol alters central 5HT1A receptor binding potential differences related to psychosocial stress but not differences related to 5HTTLPR genotype in female rhesus monkeys 
Journal of neuroendocrinology  2014;26(2):80-88.
Social subordination in female macaques represents a well-described model of chronic psychosocial stress. Additionally, a length polymorphism (5HTTLPR) in the regulatory region of the serotonin (5HT) transporter (5HTT) gene (SLC6A4) is present in rhesus macaques, which has been linked to adverse outcomes similar to what has been described in humans with an analogous 5HTTLPR polymorphism. The present study determined the effects of social status and the 5HTTLPR genotype on 5HT1A receptor binding potential (5HT1A BPND) in brain regions implicated in emotional regulation and stress reactivity in ovariectomised female monkeys, and then assessed how these effects were altered by 17β-oestradiol (E2) treatment. Areas analyzed included the prefrontal cortex [anterior cingulate (ACC); medial prefrontal cortex (mPFC); dorsolateral prefrontal cortex; orbitofrontal prefrontal cortex], amygdala, hippocampus, hypothalamus and raphe nucleui. Positron emission tomography (PET) using p-[18F]MPPF was performed to determine the levels of 5HT1A BPND under a non-E2 and a 3-wk E2 treatment condition. The short variant (s-variant) 5HTTLPR genotype produced a significant reduction in 5HT1A BPND in the mPFC regardless of social status, and subordinate s-variant females showed a reduction in 5HT1A BPND within the ACC. Both these effects of 5HTTLPR were unaffected by E2. Additionally, E2 reduced 5HT1A BPND in the dorsal raphe of all females irrespective of psychosocial stress or 5HTTLPR genotype. Hippocampal 5HT1A BPND was attenuated in subordinate females regardless of 5HTTLPR genotype during the non-E2 condition, an effect that was normalised with E2. Similarly, 5HT1A BPND in the hypothalamus was significantly lower in subordinate females regardless of 5HTTLPR genotype, an effect reversed with E2. Together, the data indicate that the effect of E2 on modulation of central 5HT1A BPND may only occur in brain regions that show no 5HTTLPR genotype-linked control of 5HT1A binding.
PMCID: PMC3962807  PMID: 24382202
oestradiol; social subordination; psychosocial stress; 5HT1A receptor; 5HTTLPR; monkeys
24.  A Targeted Health Risk Assessment Following the Deepwater Horizon Oil Spill: Polycyclic Aromatic Hydrocarbon Exposure in Vietnamese-American Shrimp Consumers 
Environmental Health Perspectives  2014;123(2):152-159.
Background: The Deepwater Horizon oil spill of 2010 prompted concern about health risks among seafood consumers exposed to polycyclic aromatic hydrocarbons (PAHs) via consumption of contaminated seafood.
Objective: The objective of this study was to conduct population-specific probabilistic health risk assessments based on consumption of locally harvested white shrimp (Litopenaeus setiferus) among Vietnamese Americans in southeast Louisiana.
Methods: We conducted a survey of Vietnamese Americans in southeast Louisiana to evaluate shrimp consumption, preparation methods, and body weight among shrimp consumers in the disaster-impacted region. We also collected and chemically analyzed locally harvested white shrimp for 81 individual PAHs. We combined the PAH levels (with accepted reference doses) found in the shrimp with the survey data to conduct Monte Carlo simulations for probabilistic noncancer health risk assessments. We also conducted probabilistic cancer risk assessments using relative potency factors (RPFs) to estimate cancer risks from the intake of PAHs from white shrimp.
Results: Monte Carlo simulations were used to generate hazard quotient distributions for noncancer health risks, reported as mean ± SD, for naphthalene (1.8 × 10–4 ± 3.3 × 10–4), fluorene (2.4 × 10–5 ± 3.3 × 10–5), anthracene (3.9 × 10–6 ± 5.4 × 10–6), pyrene (3.2 × 10–5 ± 4.3 × 10–5), and fluoranthene (1.8 × 10–4 ± 3.3 × 10–4). A cancer risk distribution, based on RPF-adjusted PAH intake, was also generated (2.4 × 10–7 ± 3.9 × 10–7).
Conclusions: The risk assessment results show no acute health risks or excess cancer risk associated with consumption of shrimp containing the levels of PAHs detected in our study, even among frequent shrimp consumers.
Citation: Wilson MJ, Frickel S, Nguyen D, Bui T, Echsner S, Simon BR, Howard JL, Miller K, Wickliffe JK. 2015. A targeted health risk assessment following the Deepwater Horizon Oil Spill: polycyclic aromatic hydrocarbon exposure in Vietnamese-American shrimp consumers. Environ Health Perspect 123:152–159;
PMCID: PMC4314254  PMID: 25333566
25.  Raised intracranial pressure following abdominal closure in a polytrauma patient 
JRSM Open  2015;6(1):2054270414565958.
We report a polytrauma case requiring simultaneous neurosurgery and laparotomy. Upon abdominal closure, raised intracranial pressure occurred. This illustrates the important physiological interplay between body compartments in critical care patients.
PMCID: PMC4304890  PMID: 25852954
Traumatic brain injury; intracranial hypertension; decompressive laparotomy; multiple compartment syndrome

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