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1.  A prospective study of two isothermal amplification assays compared with real-time PCR, CCNA and toxigenic culture for the diagnosis of Clostridium difficile infection 
BMC Microbiology  2016;16:19.
New molecular methods of detecting Clostridium difficile infection (CDI) provide the routine lab with a sensitive random access method to produce results that are available in a shorter time than traditional methods.
In this prospective study a total of 989 stool specimens were tested over a period of 16 months in parallel using two isothermal amplification assays, AmpliVue® (Quidel) and Illumigene® (Meridian) and the results compared to those from toxigenic culture. In addition all specimens were tested using a cytotoxic cell neutralisation assay (CCNA) and three different Real-time PCR targeting a C. difficile-specific 16S rDNA sequence or the toxin genes tcdA, tcdB/tcdB027 or cdtB.
AmpliVue® was positive in 242 (24.5 %) and Illumigene® in 228 (23.1 %) specimens. 167 (16.9 %) specimens were positive in toxigenic culture. Real-time-tcdA and -tcdB PCR was positive in 211 (21.3 %) specimens, Real-time-cdtB PCR was positive in 101 (10.2 %) specimens and C. difficile-PCR (16S rDNA) in 267 (27.0 %) specimens.
The respective sensitivity, specificity, positive predictive value and negative predictive value compared to toxigenic culture were 91, 89, 62 and 98 % for AmpliVue® and 91, 91, 67 and 98 % for Illumigene®.
PMCID: PMC4751656  PMID: 26868647
Clostridium difficile, Molecular diagnosis, Isothermal amplification, Real-time PCR; CDI
2.  Effects of receptor for advanced glycation endproducts on microvessel formation in endometrial cancer 
BMC Cancer  2016;16:93.
The receptor for advanced glycation endproducts (RAGE) and microvascular status both play a critical role in cancer progression. However, the crosstalk between RAGE and microvascular formation in endometrial cancer remains largely unknown.
RAGE expression and microvessel density were examined in 20 cases of normal endometrial tissue, 37 cases of well-differentiated endometrial cancer tissue, and 35 cases of poorly-differentiated endometrial cancer tissue. Regression analysis was used to examine the relationship between RAGE and microvessel density. The knockdown of RAGE was achieved using a small interfering RNA in HEC-1A endometrial cancer cells. A xenografted tumour model was used to evaluate RAGE-mediated microvascular formation and proliferation of endometrial cancer cells.
It was shown that (i) RAGE expression gradually increased in normal endometrium, well-differentiated endometrial cancer, and poorly-differentiated endometrial cancer, respectively; (ii) a positive correlation existed between RAGE and microvessel density in human endometrial cancer samples; (iii) RAGE knockdown was effective in decreasing microvessel formation in xenografted tumour models; and (iv) RAGE knockdown can significantly inhibit the proliferation of endometrial cancer cells in vivo.
These results indicate that RAGE may be a potential trigger in microvascular formation and proliferation in the development of endometrial cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2126-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4751660  PMID: 26873694
RAGE; Microvascular; Proliferation; Endometrial cancer
3.  Inhibition of cancer cell growth by ruthenium complexes 
Previous studies suggest that certain transition metal complexes, such as cisplatin, are efficacious for treating various cancer types, including ovarian, lung, and breast.
In order to further evaluate ruthenium (Ru) complexes as potential anti-cancer agents, we synthesized and evaluated Ru-arene complexes. Two complexes with the general formula [Ru (η6-p-cym) (N–N) Cl]+ were tested for their abilities to inhibit cancer cells.
The complex with o-phenylenediamine as the N–N ligand (o-PDA) significantly inhibited growth of breast (MDA-MB-231, MCF-7, SKBR-3, and SUM149), lymphoma (Raji), melanoma (Bowes), and osteosarcoma (HT1080); however, the complex with o-benzoquinonediimine (o-BQDI) was ineffective except for SUM149. In contrast, o-PDA failed to inhibit growth of human breast epithelial cells, MCF-10A. Treatment of MDA-MBA-231 cells with o-PDA resulted in a significant reduction of productions of PDGF-AA, GM-CSF, and VEGF-A proteins at the transcriptional levels. Finally, we demonstrated that o-PDA synergistically inhibited MDA-MB-231 cell growth with cyclophosphamide but not doxorubicin or paclitaxel.
These results suggest that Ru-arene complexes are promising anti-cancer drugs that inhibit progression and metastasis by blocking multiple processes for breast and other types of cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-016-0797-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4751662  PMID: 26867596
Ruthenium; Breast cancer; Growth; VFGF; GM-CSF; PDGF; Synergy; Anti-cancer reagents
4.  Using a mHealth tutorial application to change knowledge and attitude of frontline health workers to Ebola virus disease in Nigeria: a before-and-after study 
The Ebola epidemic exposed the weak state of health systems in West Africa and their devastating effect on frontline health workers and the health of populations. Fortunately, recent reviews of mobile technology demonstrate that mHealth innovations can help alleviate some health system constraints such as balancing multiple priorities, lack of appropriate tools to provide services and collect data, and limited access to training in health fields such as mother and child health, HIV/AIDS and sexual and reproductive health. However, there is little empirical evidence of mHealth improving health system functions during the Ebola epidemic in West Africa.
We conducted quantitative cross-sectional surveys in 14 health facilities in Ondo State, Nigeria, to assess the effect of using a tablet computer tutorial application for changing the knowledge and attitude of health workers regarding Ebola virus disease.
Of 203 participants who completed pre- and post-intervention surveys, 185 people (or 91%) were female, 94 participants (or 46.3%) were community health officers, 26 people (13 %) were nurses/midwives, 8 people (or 4%) were laboratory scientists and 75 people (37%) belonged to a group called others. Regarding knowledge of Ebola: 178 participants (or 87.7%) had foreknowledge of Ebola before the study. Further analysis showed an 11% improvement in average knowledge levels between pre- and post-intervention scores with statistically significant differences (P < 0.05) recorded for questions concerning the transmission of the Ebola virus among humans, common symptoms of Ebola fever and whether Ebola fever was preventable. Additionally, there was reinforcement of positive attitudes of avoiding the following: contact with Ebola patients, eating bush meat and risky burial practices as indicated by increases between pre- and post-intervention scores from 83 to 92%, 57 to 64% and 67 to 79%, respectively. Moreover, more participants (from 95 to 97%) reported a willingness to practice frequent hand washing and disinfecting surfaces and equipment following the intervention, and more health workers were willing (from 94 to 97%) to use personal protective equipment to prevent the transmission of Ebola.
The modest improvements in knowledge and reported attitudinal change toward Ebola virus disease suggests mHealth tutorial applications could hold promise for training health workers and building resilient health systems to respond to epidemics in West Africa.
PMCID: PMC4751664  PMID: 26872824
Ebola virus disease; Improving knowledge and attitude; mHealth; Frontline health workers; Nigeria
5.  Burden of stroke attributable to selected lifestyle risk factors in rural South Africa 
BMC Public Health  2016;16:143.
Rural South Africa (SA) is undergoing a rapid health transition characterized by increases in non-communicable diseases; stroke in particular. Knowledge of the relative contribution of modifiable risk factors on disease occurrence is needed for public health prevention efforts and community-oriented health promotion. Our aim was to estimate the burden of stroke in rural SA that is attributable to high blood pressure, excess weight and high blood glucose using World Health Organization’s comparative risk assessment (CRA) framework.
We estimated current exposure distributions of the risk factors in rural SA using 2010 data from the Agincourt health and demographic surveillance system (HDSS). Relative risks of stroke per unit of exposure were obtained from the Global Burden of Disease Study 2010. We used data from the Agincourt HDSS to estimate age-, sex-, and stroke specific deaths and disability adjusted life years (DALYs). We estimated the proportion of the years of life lost (YLL) and DALY loss attributable to the risk factors and incorporate uncertainty intervals into these estimates.
Overall, 38 % of the documented stroke burden was due to high blood pressure (12 % males; 26 % females). This translated to 520 YLL per year (95 % CI: 325-678) and 540 DALYs (CI: 343-717). Excess Body Mass Index (BMI) was calculated as responsible for 20 % of the stroke burden (3.5 % males; 16 % females). This translated to 260 YLLs (CI: 199-330) and 277 DALYs (CI: 211-350). Burden was disproportionately higher in young females when BMI was assessed.
High blood pressure and excess weight, which both have effective interventions, are responsible for a significant proportion of the stroke burden in rural SA; the burden varies across age and sex sub-groups. The most effective way forward to reduce the stroke burden requires both population wide policies that have an impact across the age spectra and targeted (health promotion/disease prevention) interventions on women and young people.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-016-2805-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4751665  PMID: 26869067
Comparative risk assessment; Stroke; Rural; Body-mass index; Systolic blood pressure; South Africa
6.  Clinical utility of transthoracic echocardiography for screening abdominal aortic aneurysm: a prospective study in a Japanese population 
The aim of the present study was to evaluate the clinical utility of transthoracic echocardiography (TTE) for screening abdominal aortic aneurysm (AAA) and to identify important TTE indices associated with AAA in a Japanese population.
We prospectively studied 1912 patients who were referred for TTE. AAA was defined as ≥ 30 mm in size.
The abdominal aorta was visualized in 95.1 % (1818/1912) by TTE. AAA was identified in 2.6 % (47/1818). The aortic root size was significantly larger in patients with AAA than those without (36.0 ± 4.1 vs. 31.7 ± 4.2 mm, p < 0.001). The aortic root size had a fair correlation with abdominal aortic size (r = 0.31, p < 0.001). The aortic root size of ≥ 34 mm was predictive of AAA by receiver operating characteristic curve analysis (area under the curve = 0.78, p < 0.001). Multiple logistic regression analysis revealed that aortic root size (Hazard ratio 1.23, p < 0.001) and age (Hazard ratio 1.05, p = 0.013) were the independent predictors of AAA.
The feasibility of the abdominal aortic visualization during TTE was excellent. The aortic root size measured by TTE was the independent predictor of AAA. Screening for AAA during TTE appeared to be useful especially in the older patients with a large (≥34 mm) aortic root.
PMCID: PMC4751668  PMID: 26868661
Abdominal aortic aneurysm; Aortic root; Echocardiography; Screening
7.  Receipt of evidence-based brief cessation interventions by health professionals and use of cessation assisted treatments among current adult cigarette-only smokers: National Adult Tobacco Survey, 2009–2010 
BMC Public Health  2016;16:141.
Helping tobacco smokers to quit during a medical visit is a clinical and public health priority. Research suggests that most health professionals engage their patients in at least some of the ‘5 A’s’ of the brief cessation intervention recommended in the U.S. Public Health Service Clinical Practice Guideline, but information on the extent to which patients act on this intervention is uncertain. We assessed current cigarette-only smokers’ self-reported receipt of the 5 A’s to determine the odds of using optimal cessation assisted treatments (a combination of counseling and medication).
Data came from the 2009–2010 National Adult Tobacco Survey (NATS), a nationally representative landline and mobile phone survey of adults aged ≥18 years. Among current cigarette-only smokers who visited a health professional in the past 12 months, we assessed patients’ self-reported receipt of the 5 A’s, use of the combination of counseling and medication for smoking cessation, and use of other cessation treatments. We used logistic regression to examine whether receipt of the 5 A’s during a recent clinic visit was associated with use of cessation treatments (counseling, medication, or a combination of counseling and medication) among current cigarette-only smokers.
In this large sample (N = 10,801) of current cigarette-only smokers who visited a health professional in the past 12 months, 6.3 % reported use of both counseling and medication for smoking cessation within the past year. Other assisted cessation treatments used to quit were: medication (19.6 %); class or program (3.8 %); one-on-one counseling (3.7 %); and telephone quitline (2.6 %). Current cigarette-only smokers who reported receiving all 5 A’s during a recent clinic visit were more likely to use counseling (odds ratio [OR]: 11.2, 95 % confidence interval [CI]: 7.1–17.5), medication (OR: 6.2, 95 % CI: 4.3–9.0), or a combination of counseling and medication (OR: 14.6, 95 % CI: 9.3–23.0), compared to smokers who received one or none of the 5 A’s components.
Receipt of the ‘5 A’s’ intervention was associated with a significant increase in patients’ use of recommended counseling and medication for cessation. It is important for health professionals to deliver all 5 A’s when conducting brief cessation interventions with patients who smoke.
PMCID: PMC4751655  PMID: 26868930
Smoking cessation; USPHS clinical guideline; Tobacco; Health professionals; Clinicians
8.  The expression of embryonic globin mRNA in a severely anemic mouse model induced by treatment with nitrogen-containing bisphosphonate 
BMC Hematology  2016;16:4.
Mammalian erythropoiesis can be divided into two distinct types, primitive and definitive, in which new cells are derived from the yolk sac and hematopoietic stem cells, respectively. Primitive erythropoiesis occurs within a restricted period during embryogenesis. Primitive erythrocytes remain nucleated, and their hemoglobins are different from those in definitive erythrocytes. Embryonic type hemoglobin is expressed in adult animals under genetically abnormal condition, but its later expression has not been reported in genetically normal adult animals, even under anemic conditions. We previously reported that injecting animals with nitrogen-containing bisphosphonate (NBP) decreased erythropoiesis in bone marrow (BM). Here, we induced severe anemia in a mouse model by injecting NBP injection in combination with phenylhydrazine (PHZ), and then we analyzed erythropoiesis and the levels of different types of hemoglobin.
Splenectomized mice were treated with NBP to inhibit erythropoiesis in BM, and with PHZ to induce hemolytic anemia. We analyzed hematopoietic sites and peripheral blood using morphological and molecular biological methods.
Combined treatment of splenectomized mice with NBP and PHZ induced critical anemia compared to treatment with PHZ alone, and numerous nucleated erythrocytes appeared in the peripheral blood. In the BM, immature CD71-positive erythroblasts were increased, and extramedullary erythropoiesis occurred in the liver. Furthermore, embryonic type globin mRNA was detected in both the BM and the liver. In peripheral blood, spots that did not correspond to control hemoglobin were observed in 2D electrophoresis. ChIP analyses showed that KLF1 and KLF2 bind to the promoter regions of β-like globin. Wine-colored capsuled structures were unexpectedly observed in the abdominal cavity, and active erythropoiesis was also observed in these structures.
These results indicate that primitive erythropoiesis occurs in adult mice to rescue critical anemia because primitive erythropoiesis does not require macrophages as stroma whereas macrophages play a pivotal role in definitive erythropoiesis even outside the medulla. The cells expressing embryonic hemoglobin in this study were similar to primitive erythrocytes, indicating the possibility that yolk sac-derived primitive erythroid cells may persist into adulthood in mice.
Electronic supplementary material
The online version of this article (doi:10.1186/s12878-016-0041-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4751657  PMID: 26877876
Embryonic hemoglobin; Nitrogen-containing bisphosphonate (NBP); Extramedullary erythropoiesis; KLF1; Nucleated erythrocyte
9.  Genomic prediction of unordered categorical traits: an application to subpopulation assignment in German Warmblood horses 
Categorical traits without ordinal representation of classes do not qualify for threshold models. Alternatively, the multinomial problem can be assessed by a sequence of independent binary contrasts using schemes such as one-vs-all or one-vs-one. Class probabilities can be arrived at by normalization or pair-wise coupling strategies. We assessed the predictive ability of whole-genome regression models and support vector machines for the classification of horses into four German Warmblood breeds.
Prediction accuracies of leave-one-out cross-validation were high and ranged from 0.75 to 0.97 depending on the binary classifier and breeds incorporated in the training. An analysis of the population structure using eigenvectors of the genomic relationship matrix revealed clustering of individuals beyond the given breed labels. Admixture between two breeds became apparent which had substantial impact on the prediction accuracies between those two breeds and also influenced the contrasts between other breeds.
Genomic prediction of unordered categorical traits was successfully applied to subpopulation assignment of German Warmblood horses. The applied methodology is a straightforward extension of existing binary threshold models for genomic prediction.
PMCID: PMC4751658  PMID: 26867647
10.  A survey of mindset theories of intelligence and medical error self-reporting among pediatric housestaff and faculty 
BMC Medical Education  2016;16:58.
Intelligence theory research has illustrated that people hold either “fixed” (intelligence is immutable) or “growth” (intelligence can be improved) mindsets and that these views may affect how people learn throughout their lifetime. Little is known about the mindsets of physicians, and how mindset may affect their lifetime learning and integration of feedback. Our objective was to determine if pediatric physicians are of the "fixed" or "growth" mindset and whether individual mindset affects perception of medical error reporting. 
We sent an anonymous electronic survey to pediatric residents and attending pediatricians at a tertiary care pediatric hospital. Respondents completed the “Theories of Intelligence Inventory” which classifies individuals on a 6-point scale ranging from 1 (Fixed Mindset) to 6 (Growth Mindset). Subsequent questions collected data on respondents’ recall of medical errors by self or others.
We received 176/349 responses (50 %). Participants were equally distributed between mindsets with 84 (49 %) classified as “fixed” and 86 (51 %) as “growth”. Residents, fellows and attendings did not differ in terms of mindset. Mindset did not correlate with the small number of reported medical errors.
There is no dominant theory of intelligence (mindset) amongst pediatric physicians. The distribution is similar to that seen in the general population. Mindset did not correlate with error reports.
PMCID: PMC4751661  PMID: 26868925
Medical error; Psychology; Psychological theory; Intelligence; Mindset; Graduate medical education; Medical education; Pediatrics; Cohort studies
11.  The Role of Synaptopodin in Membrane Protein Diffusion in the Dendritic Spine Neck 
PLoS ONE  2016;11(2):e0148310.
The dynamic exchange of neurotransmitter receptors at synapses relies on their lateral diffusion in the plasma membrane. At synapses located on dendritic spines this process is limited by the geometry of the spine neck that restricts the passage of membrane proteins. Biochemical compartmentalisation of the spine is believed to underlie the input-specificity of excitatory synapses and to set the scale on which functional changes can occur. Synaptopodin is located predominantly in the neck of dendritic spines, and is thus ideally placed to regulate the exchange of synaptic membrane proteins. The central aim of our study was to assess whether the presence of synaptopodin influences the mobility of membrane proteins in the spine neck and to characterise whether this was due to direct molecular interactions or to spatial constraints that are related to the structural organisation of the neck. Using single particle tracking we have identified a specific effect of synaptopodin on the diffusion of metabotropic mGluR5 receptors in the spine neck. However, super-resolution STORM/PALM imaging showed that this was not due to direct interactions between the two proteins, but that the presence of synaptopodin is associated with an altered local organisation of the F-actin cytoskeleton, that in turn could restrict the diffusion of membrane proteins with large intracellular domains through the spine neck. This study contributes new data on the way in which the spine neck compartmentalises excitatory synapses. Our data complement models that consider the impact of the spine neck as a function of its shape, by showing that the internal organisation of the neck imposes additional physical barriers to membrane protein diffusion.
PMCID: PMC4739495  PMID: 26840625
12.  Projected Impact of Salt Restriction on Prevention of Cardiovascular Disease in China: A Modeling Study 
PLoS ONE  2016;11(2):e0146820.
To estimate the effects of achieving China’s national goals for dietary salt (NaCl) reduction or implementing culturally-tailored dietary salt restriction strategies on cardiovascular disease (CVD) prevention.
The CVD Policy Model was used to project blood pressure lowering and subsequent downstream prevented CVD that could be achieved by population-wide salt restriction in China. Outcomes were annual CVD events prevented, relative reductions in rates of CVD incidence and mortality, quality-adjusted life-years (QALYs) gained, and CVD treatment costs saved.
Reducing mean dietary salt intake to 9.0 g/day gradually over 10 years could prevent approximately 197 000 incident annual CVD events [95% uncertainty interval (UI): 173 000–219 000], reduce annual CVD mortality by approximately 2.5% (2.2–2.8%), gain 303 000 annual QALYs (278 000–329 000), and save approximately 1.4 billion international dollars (Int$) in annual CVD costs (Int$; 1.2–1.6 billion). Reducing mean salt intake to 6.0 g/day could approximately double these benefits. Implementing cooking salt-restriction spoons could prevent 183 000 fewer incident CVD cases (153 000–215 000) and avoid Int$1.4 billion in CVD treatment costs annually (1.2–1.7 billion). Implementing a cooking salt substitute strategy could lead to approximately three times the health benefits of the salt-restriction spoon program. More than three-quarters of benefits from any dietary salt reduction strategy would be realized in hypertensive adults.
China could derive substantial health gains from implementation of population-wide dietary salt reduction policies. Most health benefits from any dietary salt reduction program would be realized in adults with hypertension.
PMCID: PMC4739496  PMID: 26840409
13.  Association of RAC1 Gene Polymorphisms with Primary End-Stage Renal Disease in Chinese Renal Recipients 
PLoS ONE  2016;11(2):e0148270.
RAC1 gene could influence susceptibility to renal failure by altering the activity and expression of Rac1, which is a member of the Rho family of small GTP-binding proteins. In clinical practice, renal transplantation provides the optimal treatment for people with end-stage renal disease (ESRD). The objective of this present study was to determine whether the RAC1 gene polymorphisms were associated with primary ESRD susceptibility in Chinese renal recipients.
Six single nucleotide polymorphisms (SNPs) of RAC1 gene, including rs836488 T>C, rs702482 A>T, rs10951982 G>A, rs702483 A>G, rs6954996 G>A, and rs9374 G>A, were genotyped in 300 renal transplant recipients (cases) and 998 healthy Chinese subjects (controls) by using TaqMan SNP genotyping assay. Allele, genotype, and haplotype frequencies of the six SNPs were compared between cases and controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated in logistic regression models to evaluate the associations of the six SNPs with ESRD risk.
The genotype distributions for the six SNPs in controls were consistent with Hardy-Weinberg equilibrium (P > 0.05). Association analysis revealed that three SNPs were significantly associated with ESRD risk. Positive associations with ESRD risk were found for the rs836488, rs702482, and rs702483 in the co-dominant model (minor allele homozygotes versus major allele homozygotes); specifically, the frequencies of the minor allele homozygotes and the minor allele for the three SNPs were higher in the cases than in the controls. In addition, these three SNPs also had associations with increased ESRD risk under the additive model (P < 0.05), and positive associations were also found for the rs836488 in the dominant model (P < 0.05) and for the rs702483 in the recessive model (P < 0.05). All these associations were independent of confounding factors. The other three SNPs (rs10951982, rs6954996, and rs9374), in all comparison models, were not associated with ESRD risk (P > 0.05). In haplotype analysis, carriers with "C-T-G-G-G-G" haplotype had a significantly higher risk of ESRD compared with the most common haplotype "T-A-G-A-G-G" (P = 0.011, OR = 1.46, 95% CI = 1.09–1.94).
This study suggested that polymorphisms of RAC1 gene might influence the susceptibility to ESRD in Chinese Han population. Further studies are necessary to confirm our findings.
PMCID: PMC4739498  PMID: 26841219
14.  Contributions of a Child’s Built, Natural, and Social Environments to Their General Cognitive Ability: A Systematic Scoping Review 
PLoS ONE  2016;11(2):e0147741.
The etiology of a child’s cognitive ability is complex, with research suggesting that it is not attributed to a single determinant or even a defined period of exposure. Rather, cognitive development is the product of cumulative interactions with the environment, both negative and positive, over the life course. The aim of this systematic scoping review was to collate evidence associated with children’s cognitive health, including inherent factors as well as chemical and non-chemical stressors from the built, natural, and social environments. Three databases were used to identify recent epidemiological studies (2003–2013) that examined exposure factors associated with general cognitive ability in children. Over 100 factors were evaluated from 258 eligible studies. We found that recent literature mainly assessed the hypothesized negative effects of either inherent factors or chemical exposures present in the physical environment. Prenatal growth, sleep health, lead and water pollutants showed consistent negative effects. Of the few studies that examined social stressors, results consistently showed cognitive development to be influenced by both positive and negative social interactions at home, in school or the community. Among behavioral factors related to diet and lifestyle choices of the mother, breastfeeding was the most studied, showing consistent positive associations with cognitive ability. There were mostly inconsistent results for both chemical and non-chemical stressors. The majority of studies utilized traditional exposure assessments, evaluating chemical and non-chemical stressors separately. Collective evidence from a limited number of studies revealed that cumulative exposure assessment that incorporates multiple chemical and non-chemical stressors over the life course may unravel the variability in effect on cognitive development and help explain the inconsistencies across studies. Future research examining the interactions of multiple stressors within a child’s total environment, depicting a more real-world exposure, will aid in understanding the cumulative effects associated with a child’s ability to learn.
PMCID: PMC4739499  PMID: 26840411
15.  Phase-Specific Vocalizations of Male Mice at the Initial Encounter during the Courtship Sequence 
PLoS ONE  2016;11(2):e0147102.
Mice produce ultrasonic vocalizations featuring a variety of syllables. Vocalizations are observed during social interactions. In particular, males produce numerous syllables during courtship. Previous studies have shown that vocalizations change according to sexual behavior, suggesting that males vary their vocalizations depending on the phase of the courtship sequence. To examine this process, we recorded large sets of mouse vocalizations during male–female interactions and acoustically categorized these sounds into 12 vocal types. We found that males emitted predominantly short syllables during the first minute of interaction, more long syllables in the later phases, and mainly harmonic sounds during mounting. These context- and time-dependent changes in vocalization indicate that vocal communication during courtship in mice consists of at least three stages and imply that each vocalization type has a specific role in a phase of the courtship sequence. Our findings suggest that recording for a sufficiently long time and taking the phase of courtship into consideration could provide more insights into the role of vocalization in mouse courtship behavior in future study.
PMCID: PMC4739514  PMID: 26841117
16.  Human-Induced Landscape Changes Homogenize Atlantic Forest Bird Assemblages through Nested Species Loss 
PLoS ONE  2016;11(2):e0147058.
The increasing number of quantitative assessments of homogenization using citizen science data is particularly important in the Neotropics, given its high biodiversity and ecological peculiarity, and whose communities may react differently to landscape changes. We looked for evidence of taxonomic homogenization in terrestrial birds by investigating patterns of beta diversity along a gradient of human-altered landscapes (HAL), trying to identify species associated with this process. We analyzed bird data from 87 sites sampled in a citizen science program in the south Brazilian Atlantic Forest. Regional-scale taxonomic homogenization was assessed by comparing beta diversity among sites in different HALs (natural, rural or urban landscapes) accounting for variation derived from geographical distance and zoogeographical affinities by georeferencing sites and determining their position in a phytogeographical domain. Beta diversity was calculated by multivariate dispersion and by testing compositional changes due to turnover and nestedness among HALs and phytogeographical domains. Finally, we assessed which species were typical for each group using indicator species analysis. Bird homogenization was indicated by decreases in beta diversity following landscape changes. Beta diversity of rural sites was roughly half that of natural habitats, while urban sites held less than 10% of the natural areas’ beta diversity. Species composition analysis revealed that the turnover component was important in differentiating sites depending on HAL and phytogeography; the nestedness component was important among HALs, where directional species loss is maintained even considering effects of sampling effort. A similar result was obtained among phytogeographical domains, indicating nested-pattern dissimilarity among compositions of overlapping communities. As expected, a few native generalists and non-native urban specialists were characteristic of rural and urban sites. We generated strong evidence that taxonomic homogenization occurs in the south Brazilian Atlantic Forest as a result of a directional and nested species loss, with the resultant assemblages composed of few disturbance-tolerant birds.
PMCID: PMC4739515  PMID: 26840957
17.  De Novo Assembled Wheat Transcriptomes Delineate Differentially Expressed Host Genes in Response to Leaf Rust Infection 
PLoS ONE  2016;11(2):e0148453.
Pathogens like Puccinia triticina, the causal organism for leaf rust, extensively damages wheat production. The interaction at molecular level between wheat and the pathogen is complex and less explored. The pathogen induced response was characterized using mock- or pathogen inoculated near-isogenic wheat lines (with or without seedling leaf rust resistance gene Lr28). Four Serial Analysis of Gene Expression libraries were prepared from mock- and pathogen inoculated plants and were subjected to Sequencing by Oligonucleotide Ligation and Detection, which generated a total of 165,767,777 reads, each 35 bases long. The reads were processed and multiple k-mers were attempted for de novo transcript assembly; 22 k-mers showed the best results. Altogether 21,345 contigs were generated and functionally characterized by gene ontology annotation, mining for transcription factors and resistance genes. Expression analysis among the four libraries showed extensive alterations in the transcriptome in response to pathogen infection, reflecting reorganizations in major biological processes and metabolic pathways. Role of auxin in determining pathogenesis in susceptible and resistant lines were imperative. The qPCR expression study of four LRR-RLK (Leucine-rich repeat receptor-like protein kinases) genes showed higher expression at 24 hrs after inoculation with pathogen. In summary, the conceptual model of induced resistance in wheat contributes insights on defense responses and imparts knowledge of Puccinia triticina-induced defense transcripts in wheat plants.
PMCID: PMC4739524  PMID: 26840746
18.  Host-Parasite Interactions and Purifying Selection in a Microsporidian Parasite of Honey Bees 
PLoS ONE  2016;11(2):e0147549.
To clarify the mechanisms of Nosema ceranae parasitism, we deep-sequenced both honey bee host and parasite mRNAs throughout a complete 6-day infection cycle. By time-series analysis, 1122 parasite genes were significantly differently expressed during the reproduction cycle, clustering into 4 expression patterns. We found reactive mitochondrial oxygen species modulator 1 of the host to be significantly down regulated during the entire infection period. Our data support the hypothesis that apoptosis of honey bee cells was suppressed during infection. We further analyzed genome-wide genetic diversity of this parasite by comparing samples collected from the same site in 2007 and 2013. The number of SNP positions per gene and the proportion of non-synonymous substitutions per gene were significantly reduced over this time period, suggesting purifying selection on the parasite genome and supporting the hypothesis that a subset of N. ceranae strains might be dominating infection.
PMCID: PMC4739525  PMID: 26840596
19.  Field Measurements Indicate Unexpected, Serious Underestimation of Mussel Heart Rates and Thermal Tolerance by Laboratory Studies 
PLoS ONE  2016;11(2):e0146341.
Attempts to predict the response of species to long-term environmental change are generally based on extrapolations from laboratory experiments that inevitably simplify the complex interacting effects that occur in the field. We recorded heart rates of two genetic lineages of the brown mussel Perna perna over a full tidal cycle in-situ at two different sites in order to evaluate the cardiac responses of the two genetic lineages present on the South African coast to temperature and the immersion/emersion cycle. “Robomussel” temperature loggers were used to monitor thermal conditions at the two sites over one year. Comparison with live animals showed that robomussels provided a good estimate of mussel body temperatures. A significant difference in estimated body temperatures was observed between the sites and the results showed that, under natural conditions, temperatures regularly approach or exceed the thermal limits of P. perna identified in the laboratory. The two P. perna lineages showed similar tidal and diel patterns of heart rate, with higher cardiac activity during daytime immersion and minimal values during daytime emersion. Comparison of the heart rates measured in the field with data previously measured in the laboratory indicates that laboratory results seriously underestimate heart rate activity, by as much as 75%, especially during immersion. Unexpectedly, field estimates of body temperatures indicated an ability to tolerate temperatures considered lethal on the basis of laboratory measurements. This suggests that the interaction of abiotic conditions in the field does not necessarily raise vulnerability to high temperatures.
PMCID: PMC4739526  PMID: 26840775
20.  Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis 
Eye disease due to herpes simplex virus (HSV) commonly presents as epithelial keratitis.
To compare the relative effectiveness of antiviral agents, interferon, and corneal débridement in the treatment of acute HSV epithelial keratitis.
Search methods
We searched CENTRAL (The Cochrane Library 2010, Issue 4), MEDLINE (January 1950 to October 2010), EMBASE (January 1980 to October 2010), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to October 2010), Zetoc (British Library’s Electronic Table of Contents), System for Information on Grey Literature in Europe (openSIGLE), Biosciences Information Service (BIOSIS), the metaRegister of Controlled Trials (mRCT) (, (, Japan Information Center of Science and Technology (JICST-EPlus), and China Academic Journals database (CAJ) via China National Knowledge Infrastructure (CNKI) with citations confirmed using China/Asia On Demand (COAD). There were no language or date restrictions in the search for trials. All databases except CNKI and COAD were last searched on 27 October 2010, CNKI and COAD were searched on 1 April 2010. We also searched literature digests, conference proceedings and reference lists.
Selection criteria
Of 152 eligible studies,106 comparative treatment trials involving 5872 eyes with dendritic or geographic epithelial keratitis were analysed for corneal healing over two weeks.
Data collection and analysis
Interventions were compared at 14 days after trial enrolment by calculating a risk ratio (RR) that was adjusted with indirect RR, assessed by an inconsistency index (I2) and supplemented by a seven-day RR and a hazard ratio (HR).
Main results
Idoxuridine, though uncertainly better in healing outcome than control because of few trials with 14-day follow up, allowed earlier corneal re-epithelialisation. Vidarabine resulted in a significantly better outcome than placebo in one trial (RR 1.96; 95% CI 1.10 to 3.49). Compared to idoxuridine, in combined direct and indirect analyses, vidarabine (RR 1.11; 95% CI 1.03 to 1.19), trifluridine (RR 1.31; 95% CI 1.20 to 1.42), acyclovir (RR 1.23; 95% CI 1.16 to 1.31), brivudine (RR 1.38; 95% CI 1.18 to 1.61), and ganciclovir (RR 1.40; 95% CI 1.25 to 1.57) were significantly more effective. Trifluridine (RR 1.12; 95% CI 1.04 to 1.21) and acyclovir (RR 1.11; 95% CI 1.05 to 1.19) appeared more effective than vidarabine. No significant differences in healing were found in comparisons between acyclovir, trifluridine and brivudine. The comparison of ganciclovir to acyclovir was limited by heterogeneity and possible publication bias. The joint use of two topical antivirals (RR 1.00; 95% CI 0.89 to 1.12) and the use of oral acyclovir alone (RR 0.92; 95% CI 0.79 to 1.07) or combined with a topical antiviral (RR 1.08; 95% CI 0.99 to 1.17) appeared as effective as topical antiviral therapy. Compared to antiviral monotherapy, the combination of an antiviral with interferon (RR 1.03; 95% CI 0.99 to 1.07) or with débridement (RR 1.04; 95% CI 0.95 to 1.14) did not yield significantly better outcomes but may have accelerated healing. The corneal epithelial healing outcome was improved when antiviral therapy followed débridement (RR 1.21; 95% CI 1.04 to 1.42).
Authors’ conclusions
Trifluridine and acyclovir are more effective than idoxuridine or vidarabine and similar in therapeutic effectiveness. Brivudine and ganciclovir are at least as effective as acyclovir. While not improving outcome, the combination of interferon and an antiviral agent may speed healing. The effectiveness of corneal epithelial débridement is improved by an antiviral agent.
PMCID: PMC4739528  PMID: 21154352
Administration, Oral; Administration, Topical; Antiviral Agents [*administration & dosage]; CombinedModality Therapy [methods]; Debridement [*methods]; Interferons [administration & dosage]; Keratitis, Herpetic [*therapy]; Randomized Controlled Trials as Topic; Humans
21.  Complete Mitochondrial Genome of Three Bactrocera Fruit Flies of Subgenus Bactrocera (Diptera: Tephritidae) and Their Phylogenetic Implications 
PLoS ONE  2016;11(2):e0148201.
Bactrocera latifrons is a serious pest of solanaceous fruits and Bactrocera umbrosa is a pest of Artocarpus fruits, while Bactrocera melastomatos infests the fruit of Melastomataceae. They are members of the subgenus Bactrocera. We report here the complete mitochondrial genome of these fruit flies determined by next-generation sequencing and their phylogeny with other taxa of the subgenus Bactrocera. The whole mitogenomes of these three species possessed 37 genes namely, 13 protein-coding genes (PCGs), 2 rRNA and 22 tRNA genes. The mitogenome of B. latifrons (15,977 bp) was longer than those of B. melastomatos (15,954 bp) and B. umbrosa (15,898 bp). This difference can be attributed to the size of the intergenic spacers (283 bp in B. latifrons, 261 bp in B. melastomatos, and 211 bp in B. umbrosa). Most of the PCGs in the three species have an identical start codon, except for atp8 (adenosine triphosphate synthase protein 8), which had an ATG instead of GTG in B. umbrosa, whilst the nad3 (NADH dehydrogenase subunit 3) and nad6 (NADH dehydrogenase subunit 6) genes were characterized by an ATC instead of ATT in B. melastomatos. The three species had identical stop codon for the respective PCGs. In B. latifrons and B. melastomatos, the TΨC (thymidine-pseudouridine-cytidine)-loop was absent in trnF (phenylalanine) and DHU (dihydrouracil)-loop was absent in trnS1 (serine S1). In B. umbrosa, trnN (asparagine), trnC (cysteine) and trnF lacked the TψC-loop, while trnS1 lacked the DHU-stem. Molecular phylogeny based on 13 PCGs was in general concordant with 15 mitochondrial genes (13 PCGs and 2 rRNA genes), with B. latifrons and B. umbrosa forming a sister group basal to the other species of the subgenus Bactrocera which was monophyletic. The whole mitogenomes will serve as a useful dataset for studying the genetics, systematics and phylogenetic relationships of the many species of Bactrocera genus in particular, and tephritid fruit flies in general.
PMCID: PMC4739531  PMID: 26840430
22.  Why Huddle? Ecological Drivers of Chick Aggregations in Gentoo Penguins, Pygoscelis papua, across Latitudes 
PLoS ONE  2016;11(2):e0145676.
Aggregations of young animals are common in a range of endothermic and ectothermic species, yet the adaptive behavior may depend on social circumstance and local conditions. In penguins, many species form aggregations (aka. crèches) for a variety of purposes, whilst others have never been observed exhibiting this behavior. Those that do form aggregations do so for three known benefits: 1) reduced thermoregulatory requirements, 2) avoidance of unrelated-adult aggression, and 3) lower predation risk. In gentoo penguins, Pygoscelis papua, chick aggregations are known to form during the post-guard period, yet the cause of these aggregations is poorly understood. Here, for the first time, we study aggregation behavior in gentoo penguins, examining four study sites along a latitudinal gradient using time-lapse cameras to examine the adaptive benefit of aggregations to chicks. Our results support the idea that aggregations of gentoo chicks decrease an individual’s energetic expenditure when wet, cold conditions are present. However, we found significant differences in aggregation behavior between the lowest latitude site, Maiviken, South Georgia, and two of the higher latitude sites on the Antarctic Peninsula, suggesting this behavior may be colony specific. We provide strong evidence that more chicks aggregate and a larger number of aggregations occur on South Georgia, while the opposite occurs at Petermann Island in Antarctica. Future studies should evaluate multiple seabird colonies within one species before generalizing behaviors based on one location, and past studies may need to be re-evaluated to determine whether chick aggregation and other behaviors are in fact exhibited species-wide.
PMCID: PMC4739533  PMID: 26840252
23.  A Vulnerability Assessment of Fish and Invertebrates to Climate Change on the Northeast U.S. Continental Shelf 
PLoS ONE  2016;11(2):e0146756.
Climate change and decadal variability are impacting marine fish and invertebrate species worldwide and these impacts will continue for the foreseeable future. Quantitative approaches have been developed to examine climate impacts on productivity, abundance, and distribution of various marine fish and invertebrate species. However, it is difficult to apply these approaches to large numbers of species owing to the lack of mechanistic understanding sufficient for quantitative analyses, as well as the lack of scientific infrastructure to support these more detailed studies. Vulnerability assessments provide a framework for evaluating climate impacts over a broad range of species with existing information. These methods combine the exposure of a species to a stressor (climate change and decadal variability) and the sensitivity of species to the stressor. These two components are then combined to estimate an overall vulnerability. Quantitative data are used when available, but qualitative information and expert opinion are used when quantitative data is lacking. Here we conduct a climate vulnerability assessment on 82 fish and invertebrate species in the Northeast U.S. Shelf including exploited, forage, and protected species. We define climate vulnerability as the extent to which abundance or productivity of a species in the region could be impacted by climate change and decadal variability. We find that the overall climate vulnerability is high to very high for approximately half the species assessed; diadromous and benthic invertebrate species exhibit the greatest vulnerability. In addition, the majority of species included in the assessment have a high potential for a change in distribution in response to projected changes in climate. Negative effects of climate change are expected for approximately half of the species assessed, but some species are expected to be positively affected (e.g., increase in productivity or move into the region). These results will inform research and management activities related to understanding and adapting marine fisheries management and conservation to climate change and decadal variability.
PMCID: PMC4739546  PMID: 26839967
24.  A Site-Specific Integrative Plasmid Found in Pseudomonas aeruginosa Clinical Isolate HS87 along with A Plasmid Carrying an Aminoglycoside-Resistant Gene 
PLoS ONE  2016;11(2):e0148367.
Plasmids play critical roles in bacterial fitness and evolution of Pseudomonas aeruginosa. Here two plasmids found in a drug-resistant P. aeruginosa clinical isolate HS87 were completely sequenced. The pHS87b plasmid (11.2 kb) carries phage-related genes and function-unknown genes. Notably, pHS87b encodes an integrase and has an adjacent tRNAThr-associated attachment site. A corresponding integrated form of pHS87b at the tRNAThr locus was identified on the chromosome of P. aeruginosa, showing that pHS87b is able to site-specifically integrate into the 3’-end of the tRNAThr gene. The pHS87a plasmid (26.8 kb) displays a plastic structure containing a putative replication module, stability factors and a variable region. The RepA of pHS87a shows significant similarity to the replication proteins of pPT23A-family plasmids. pHS87a carries a transposon Tn6049, a truncated insertion sequence ΔIS1071 and a Tn402-like class 1 integron which contains an aacA4 cassette that may confer aminoglycoside resistance. Thus, pHS87b is a site-specific integrative plasmid whereas pHS87a is a plastic antibiotic resistance plasmid. The two native plasmids may promote the fitness and evolution of P. aeruginosa.
PMCID: PMC4739549  PMID: 26841043
25.  Circulating Level of Neutrophil Extracellular Traps Is Not a Useful Biomarker for Assessing Disease Activity in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis 
PLoS ONE  2016;11(2):e0148197.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of life-threatening disorders, and frequently affects the kidneys. This study investigated whether the circulating neutrophil extracellular traps (NETs) levels were associated with disease activity of AAV. We collected serum samples from 34 patients with AAV in active stage and 62 patients with AAV in remission. Cell free DNA in serum was quantified using the Quant-iT PicoGreen assay. NETs associated MPO-DNA complexes, citrullinated-histone H3-DNA (cit-H3-DNA) complexes and the concentration of deoxyribonuclease I (DNase I) were quantified using ELISA. The activity of DNase I was quantified using radial enzyme-diffusion method. Associations between circulating levels of NETs with clinico-pathological parameters were analyzed. Serum levels of NETs in active AAV patients were significantly higher than those in healthy controls, and the level of cell free DNA correlated with C-reactive protein (CRP). However, no correlation was found between MPO-DNA complexes or cit-H3-DNA complexes level and CRP. Also there was no significant correlation between NETs level and initial serum creatinine, estimated glomerular filtration rate (eGFR), crescents formation or Birmingham Vasculitis Activity Score (BVAS). Furthermore, there was no significant difference of serum levels of cell free DNA or MPO-DNA complexes between active stage and remission of AAV. In conclusion, circulating levels of NETs cannot be used as a biomarker to assess disease activity in AAV patients.
PMCID: PMC4739550  PMID: 26840412

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